Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
Eur Heart J 2014
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
תרשים1
DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243
PE
PE
DVT
DVT
VTE
VTE
DVT
PE
ALL
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
Eur Heart J 2014
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
תרשים1
DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243
PE
PE
DVT
DVT
VTE
VTE
DVT
PE
ALL
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
Eur Heart J 2014
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
תרשים1
DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243
PE
PE
DVT
DVT
VTE
VTE
DVT
PE
ALL
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
Eur Heart J 2014
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
תרשים1
DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243
PE
PE
DVT
DVT
VTE
VTE
DVT
PE
ALL
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
Eur Heart J 2014
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
תרשים1
DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243
PE
PE
DVT
DVT
VTE
VTE
DVT
PE
ALL
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
Eur Heart J 2014
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
תרשים1
DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243
PE
PE
DVT
DVT
VTE
VTE
DVT
PE
ALL
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
Eur Heart J 2014
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
תרשים1
DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243
PE
PE
DVT
DVT
VTE
VTE
DVT
PE
ALL
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
Eur Heart J 2014
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
תרשים1
DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243
PE
PE
DVT
DVT
VTE
VTE
DVT
PE
ALL
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
Eur Heart J 2014
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
תרשים1
DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243
PE
PE
DVT
DVT
VTE
VTE
DVT
PE
ALL
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
Eur Heart J 2014
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
תרשים1
DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243
PE
PE
DVT
DVT
VTE
VTE
DVT
PE
ALL
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
Eur Heart J 2014
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
תרשים1
DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243
PE
PE
DVT
DVT
VTE
VTE
DVT
PE
ALL
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
Eur Heart J 2014
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
תרשים1
DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243
PE
PE
DVT
DVT
VTE
VTE
DVT
PE
ALL
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
Eur Heart J 2014
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
תרשים1
DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243
PE
PE
DVT
DVT
VTE
VTE
DVT
PE
ALL
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
Eur Heart J 2014
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
תרשים1
DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243
PE
PE
DVT
DVT
VTE
VTE
DVT
PE
ALL
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
Eur Heart J 2014
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
תרשים1
DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243
PE
PE
DVT
DVT
VTE
VTE
DVT
PE
ALL
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
Eur Heart J 2014
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
תרשים1
DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243
PE
PE
DVT
DVT
VTE
VTE
DVT
PE
ALL
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
Eur Heart J 2014
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
תרשים1
DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243
PE
PE
DVT
DVT
VTE
VTE
DVT
PE
ALL
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
Eur Heart J 2014
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
תרשים1
DVT
PE
ALL
115
6
175
294623115578
124324324324
418947439902
351226415094
143181818182
494408233276
33190529876
235606820461
567512119221
325077399381
281967213115
607044612496
411063153112
404565117349
815628270462
440065298507
47976054732
919825845828
592418032787
695776475513
12881945083
610827754108
78242865463
1393256408739
1129411764706
1365647592565
2495059357271
1102678571429
1975555555556
3078234126984
1736176239182
3152611319587
4888787558769
1952003874561
3612906834971
5564910709532
2429045193454
6037140768715
8466185962169
2455329448256
7075487012987
9530816461243
PE
PE
DVT
DVT
VTE
VTE
DVT
PE
ALL
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Presenter
Presentation Notes
VTE disease is a healthcare problem that causes significant morbidity and mortality13This table summarizes various risk factors that have been unequivocally linked to an increased rate of VTE disease13In general almost all hospitalized patients have at least one risk factor for VTE disease and approximately 40have three or more risk factors13Most important for the purposes of our discussion is the fact that cancer (whether present or occult) cancer therapy and the presence of central venous catheters which many cancer patients receive are independent risk factors for VTE disease1313Reference131 Geerts WH et al Chest 2008133(Suppl)381S-453S
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurgitation jet or combinations of the above On computed tomographic (CT) angiography (four-chamber13views of the heart) RV dysfunction is defined as an increased end-diastolic RVLV (left ventricular) diameter ratio (with a threshold of 09 or 10)13cMarkers of myocardial injury (eg elevated cardiac troponin I or -T concentrations in plasma) or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic13peptide concentrations in plasma)13dNeither calculation of the PESI (or sPESI) nor laboratory testing are considered necessary in patients with hypotension or shock13ePatients in the PESI Class IndashII or with sPESI of 0 and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests are also to be classified into the intermediate-low-risk13category This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index
Eur Heart J 2014
Presenter
Presentation Notes
PE frac14 pulmonary embolism PESI frac14 Pulmonary embolism severity index RV frac14 right ventricular sPESI frac14 simplified Pulmonary embolism severity index13aPESI Class III to V indicates moderate to very high 30-day mortality risk sPESI ge1 point(s) indicate high 30-day mortality risk13bEchocardiographic criteria of RV dysfunction include RV dilation andor an increased end-diastolic RVndashLV diameter ratio (in most studies the reported threshold value was 09 or1310) hypokinesia of the free RV wall increased velocity of the tricuspid regurg
