VTE: A PRACTICAL APPROACH

Samuel Z. Goldhaber, MDSection Head, Vascular Medicine

Director, Thrombosis Research GroupCardiovascular Division

Brigham and Women’s HospitalProfessor of Medicine

Harvard Medical SchoolJune 5, 2017

DISCLOSURESResearch Support:

BiO2 Medical; Boehringer-Ingelheim; BMS; BTG EKOS; Daiichi; Janssen; NHLBI; Thrombosis Research Institute

Consultant:Agile; Bayer; Boehringer-Ingelheim; BMS; Daiichi; Janssen; Portola; Zafgen

LEARNING OBJECTIVES1) Epidemiology

2) Risk Factors

3) NOAC Efficacy and Safety for VTE

4) Optimal Duration of Anticoagulation

5) Inflammation and aspirin

6) Psychological Impact of VTE

FATAL SADDLE PE: 41 y.o. woman with sudden collapse

Stroke

PE

AHA 2016 STATISTICS: PE IS THE #3 CAUSE OF CV DEATH

(Circulation 2016; 133: e38-e360)

MI

PE

STROKE

Up to180,000 PE deaths/year

VTE INCIDENCE: INCREASING

140

120

100

80

60

40

20

085/86/88/89//199920012003200520072009

First-Time OccurrenceAn

nualEventRate,

per1

00,000

7381

95106 103 105

119

133

4958

6568 68

5460

68

24 2330

37 35

5059 65

VTE

DVTPE

(Huang W. Am J Med 2014; 127: 829-839)

DECLINING PE MORTALITY, HIGH READMISSION RATES

(Minges KE. Am J Cardiol 2015; 116: 1436-1442)

CARDIOVASCULAR RISK FACTORS AND VTE

(N=63,552 meta-analysis)RF RRObesity 2.3Hypertension 1.5Diabetes 1.4Cigarettes 1.2High Cholesterol 1.2

(Ageno W. Circulation 2008; 117: 93-102)

HOSPITALIZATION FOR SYNCOPE (N=560): THINK OF PE (17% !!!)

HOSPITALIZATION with SYNCOPE PE %All patients 17%No alternative explanation 25%Alternative explanation for syncope 13%Wells Score “likely” (> 4 Wells Score Points) or elevated D-dimer 42%PE in main pulmonary artery 42%

(Prandoni P. NEJM 2016; 375: 1524-1531)

VTE-INFLAMMATION LINK:RISK FACTORS

1) Pneumonia

2) Inflammatory bowel disease

3) Psoriasis

4) Systemic lupus erythematosus

5) ESRD/ Dialysis

6) Blood transfusion (preservatives)

PSORIASIS: VTE RISK FACTOR

(Chung W-S. Thromb Haemost 2017; 117: in press)

GENETIC RISK FACTORS

1) Factor V Leiden

2) Prothrombin Gene Mutation

3) Deficiency of protein C, S, or

antithrombin

ACQUIRED RISK FACTORAntiphospholipid Antibody Syndrome

• Predisposes to MI, Stroke, PE• Predicts high risk of a recurrent

event if anticoagulation is discontinued

―Lupus Anticoagulant―Anticardiolipin Antibodies―Beta-2-Glycoprotein―Antiprothrombin

ANTICOAGULATION:

THE FOUNDATION OF PE TREATMENT

ACUTE VTE TREATMENT: NOAC EFFICACY

(van Es N, et al. Blood 2014; 124: 1968-1975)

(van Es N, et al. Blood 2014; 124: 1968-1975)

NOACs: noninferior to warfarin

NOACs: 39% lower major bleeding 64% lower fatal bleeding, 63% less ICH than warfarin

ACUTE VTE TREATMENT: NOAC SAFETY (N=27,235)

(van Es N, et al. Blood 2014; 124: 1968-1975)

2016 CHEST/ ACCP GUIDELINES FOR VTE

“Based on less bleeding with NOACs and greater convenience for patients and healthcare providers, we now suggest that a NOAC be used in preference to warfarin for the initial and long-term treatment of VTE.”. (CHEST 2016; 149: 315-352)

NOAC DOSE Dabigatran 150 mg twice daily, starting after

5 days of LMWHRivaroxaban 15 mg twice daily for 3 weeks;

then 20 mg daily with dinnerApixaban 10 mg twice daily for 1 week;

then 5 mg twice daily; after 6 months, switch to ExtendedDuration Dose: 2.5 mg BID

Edoxaban 60 mg once daily, except for 30 mg daily with low GFR or weight

DOSING NOACS FOR PE

OBJECTIVE NOACAntidote Dabigatran

Minimize Inflammation (heparin loading)

Dabigatran/ Edoxa

Minimize Bleeding Apixaban

Submassive PE Edoxaban

Severe CKD Apixaban

Once Daily Dosing Rivaroxaban/ Edoxaban

All Oral Therapy Rivaroxaban/ Apixaban

DIFFERENTIATING NOACS

ANTIDOTES TO NOACSIdarucizumabTarget: DabigatranStructure: Humanized antibody fragment (FAb) to dabigatran; FDA approved in October 2015 (NEJM 2015; 373: 511-520)

Andexanet alpha Target: FXa inhibitorsStructure: FXa lacking catalytic & binding activity;This decoy looks like FXa. Antidote for rivaroxaban, apixaban, edoxaban

(NEJM 2016; 375:1131-1141)

OPTIMAL DURATION:

ANTICOAGULATION

1) VTE is mostly a chronic inflammatory disease, like MI or diabetes mellitus.2) VTE does not disappear after 3 months of anticoagulation. 3) VTE lurks subclinically, waiting

to recur.4) VTE requires lifelong attention to risk factor reduction with heart-healthy lifestyles (exercise, nutrition) and medication.

(Prandoni.Haematolo-gica 2007; 92: 199-205)

(N=1,626 DVT patients)

High VTE RecurrenceRate

LONG-TERM VTE MORTALITY

• Danish cohort: 128,223 VTE vs. 640,760 general population patients

• 30-year follow-up• VTE patients: inc’d death rate X 30 y• Most common cause of death: VTE

(Sogaard KK. Circulation 2014; epub June 26)

PADIS-PE: 6 VERSUS 24 MONTHS OF WARFARIN

• 373 unprovoked PE patients• Goals: 1) prevent recurrent PE after

additional 18 months of warfarin compared with 6 month group, and to 2) compare recurrent PE rates in both groups, 2 years after completing warfarin therapy in all patients

24 MONTHS VS. 6 MONTHS OF WARFARIN: PE

(PADIS-PE. JAMA 2015; 314: 31-40)

PADIS-PE: 6 VERSUS 24 MONTHS OF WARFARIN

• Benefit of 18 additional months of warfarin is not maintained following cessation of warfarin.

• The group in which extended warfarin is completed develops new PE at a rate twice as high as the group that never had extended warfarin, suggesting a rebound effect.

LONG VS SHORT-TERM VKA FOR VTE (N=3,716)—80% Reduction in

Recurrence

(Middeldorp S. JAMA 2015; 314: 72-73)

X 3.4 more major bleeds

NOACS VS. PLACEBO: EXTENDED VTE TREATMENT

RE-SONATE

Dabigatran vs. placebo

↓92%

EINSTEIN-EXT

Rivaroxaban vs. placebo

↓82%

AMPLIFY-EXT

Apixaban vs. placebo

↓81%

CHEST ACCP GUIDELINES 2016: DURATION OF RX

If unprovoked with low to moderate bleeding risk, we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B). If provoked by surgery or a nonsurgical transient risk factor, anticoagulate for 3 months (Grade 1B).

(CHEST 2016; 149: 315-352)

EINSTEIN CHOICE: LONG-TERM PREVENTION OF

RECURRENT VTE

(Weitz JI. Thromb Haemost 2015; 114: 645-650)

Both Rivaroxaban Doses Reduced Recurrent VTE Rates with Similar Risk of Bleeding versus ASA

Efficacy

(Weitz JI. NEJM 2017; 376: 1211-1222)

0

1

2

4

5

3

Days‡

ASA 100 mg od

Rivaroxaban 20 mg odRivaroxaban 10 mg od

1 30 60 90 120 150 180 210 240 270 300 330 360

Cum

ulat

ive

inci

denc

e (%

)

Rivaroxaban 20 mg vs ASA(0.5%) vs (0.3%)HR=2.01 (95% CI 0.50–8.04), p=0.32

Rivaroxaban 10 mg vs ASA(0.4%) vs (0.3%)HR=1.64 (95% CI 0.39–6.84), p=0.50

Major bleeding

ASA 100 mg od

Rivaroxaban 20 mg od

Rivaroxaban 10 mg od

Days

0

1

2

3

4

5

Cum

ulat

ive

inci

denc

e (%

)

1 30 60 90 120 150 180 210 240 270 300 330 367

Riva 20 mg vs ASA (1.5%) vs (4.4%)HR=0.34 (95% CI 0.20–0.59), p<0.001

Riva 10 mg vs ASA (1.2%) vs (4.4%)HR=0.26 , p<0.001

RECURRENT VTE:PROVOKED vs UNPROVOKED

Riva 20 mg

Riva 10 mg ASA 100 mg

Provoked 1.4% 0.9% 3.6%

Unprovoked 1.8% 1.5% 5.6%

(Weitz JI. NEJM 2017; 376: 1211-1222)

SPECIAL CONTRIBUTIONS OF EINSTEIN CHOICE

• Largest Extension Study ever of VTE (N=3,396 randomized patients)

• Largest Extension Study ever of Provoked VTE (N=1,976; 59%)

• Rivaroxaban: equally effective in recurrent VTE risk reduction (70%) in both provoked/ unprovoked VTE

(Weitz JI. NEJM 2017; 376: 1211-1222)

CASE #1• 42 y.o. man suffers symptomatic

bilateral PE, despite enoxaparin prophylaxis, on Hospital Day #3, following gastric bypass surgery.

• No past history or family history of VTE

• Hypercoagulability workup is negative• How long do you anticoagulate?

CASE #2• 23 y.o. woman suffers symptomatic

bilateral PE, 8 months after starting a third-generation estrogen-containing birth control pill.

• No past history or family history of VTE

• Hypercoagulability workup is negative• How long do you anticoagulate?

PATHOPHYSIOLOGY/

INFLAMMATION

PE: FILLED WITH WBCs and PLATELETS—INFLAMMATION

(Savchenko AS.J Thromb Haemostas2014; 12: 860-870)

HEPARIN BLOCKS THE SYSTEMIC INFLAMMATORY

RESPONSE TO THROMBOSIS

(Poterucha T, Libby P, Goldhaber SZ. Thrombosisand Haemostasis 2017; 117: 437-444)

THROMBIN-INDUCED

INFLAMMATION LEADS TO

THROMBOSIS(Croce K, Libby P. Intertwining of thrombosis and inflammation in atherosclerosis. Curr Opin Hematol 2007;14: 55)

Aspirin

Effects of aspirin treatment on recurrent venous thromboembolism and other outcomes after adjustment for baseline characteristics: age (<50 years, 50–65, ≥65), sex (male vs female), qualifying event (deep-vein thrombosis only vs pulmonary embolism with or without deep-

vein thrombosis), body mass index (normal, overweight, obese) and duration of anticoagulation (<6, 6–9, ≥9 months).

Simes J et al. Circulation. 2014;130:1062-1071

Copyright © American Heart Association, Inc. All rights reserved.

LOW-DOSE ASPIRIN: 35% LESS VTE

(Circulation 2014; 130: 1062-1071)

PE AND DVT:

PSYCHOLOGICAL IMPACT AND LACK

OF PUBLIC AWARENESS

RX OF ANTIPSYCHOTIC, ANXIOLYTIC, SEDATIVE, AND ANTIDEPRESSANT DRUGS TO YOUNG VTE PATIENTS

(Hojen AA. Thrombosis Research 2015; 135: 643-647)

THEMES FROM OUR PE SUPPORT GROUP (patients regionally referred) • Anger at delay in diagnosis• Feeling well, looking well, yet

harboring a major illness• Yearning for an answer to “why me?”• Protection of family members• Optimal duration of anticoagulation• NOAC versus VKA

CODE PE: ROOM #1 (ALPHA) IN ED; “MASSIVE PE ON 10

OF LEVOPHED”• 62 y.o. woman awakened and

became dizzy, cold, sweaty, SOB, and faint while sitting on the toilet

• Called RN daughter who called 911• On low-dose aspirin VTE prophylaxis

for nondisplaced fibula fracture 10 days ago after a fall

PRESENTATION TO ED• Markedly SOB; gasping, pale,

diaphoretic; RR=30/min; BP=70/ to 82/56 mm Hg; HR=134/min; O2 sat=89% RA; 98 kg (obese)

• PMH: Hypertension; Hyperlipidemia; no PE/ DVT; quit cigs 9 years ago

• Meds: Atenolol 25 mg/d; HCTZ 25 mg/d; simvastatin 40 mg/d

• FH: PGM had DVT; father d. MI-50s

MANAGEMENT IN ED• TnT=0.06 U; WBC=15.4K;

Gluc=233; Creat=1.0; GFR=55; AST=137; Lactic Acid=4.5

• Levophed titrated up to 10 mcg/min; BP now 117/78 mm Hg

• IV heparin bolus 80 U/kg given• Bedside ECHO: Marked RV

dilatation/ HK; septum bows to LA; positive McConnell’s sign

PE RESPONSE TEAM (PERT)PERTTeamActivationviaPagingSystem

PERTEvaluationbyOn-CallPhysician

Web-BasedVideoConference

DiscussionandConsensus

VascularMedicine

InterventionalCardiology

PulmonaryCriticalCare

Echocardiography

CardiothoracicSurgery

Radiology

OptionsandRecommendationsPresentedtothePatient,Family,andCareTeam

ACTION

(Dudzinski D, Piazza G. Circulation 2016; 133: 98-103)

WHAT IS THE VERY

NEXT THING YOU

RECOMMEND DOING

AT THIS POINT?

“VERY NEXT STEP” OPTIONS THAT WE DISCUSSED)

1) Begin heparin continuous IV infusion at 18 U/kg/h

2) Chest CT scan, with contrast3) EKOS with TPA 24 mg total dose4) TPA 100 mg/ 2h via peripheral IV5) Surgical pulmonary embolectomy6) Something else (none of the above)

LYSIS CHOICES FOR PE1) Systemically administered (via

peripheral IV) thrombolysis:FDA Full Dose (TPA 100 mg)MOPETT Half Dose (TPA 50 mg)

2) Pharmacomechanical therapy with catheter-directed (ultrasound-facilitated) thrombolysis: TPA 24 mg

WHAT WE DID (in collaboration with ED and pt)1) Begin heparin continuous IV

infusion at 10 U/kg/h, not 18 U/kg/h2) Ordered chest CT (in the queue)3) Decided on systemic lysis with

“half-dose TPA”, using MOPETT regimen

4) TPA 10 mg/ 1 min via peripheral IV5) TPA 40 mg/2h

CLINICAL COURSE IN ED1) CCU bed reserved; transferred 2h

later, after CT was done.2) All symptoms of respiratory distress

resolved prior to her CT scan.3) Levophed was weaned.4) She felt “90% back to normal” prior

to discharge from ED.5) No bleeding, not even slight oozing,

at IV or phlebotomy puncture sites

TPA 10mg/1 min followed by 40 mg/2 hNo bleeding complications/ no ICHPA Pressure (ECHO) lower with TPA

(Am J Cardiology 2013; 111: 273-277)

SUBMASSIVE PE: 50 mg TPA versus heparin (MOPETT) (N=121)

TPA PA systolic Controls P valueAdmission 50 51 0.4Within 48h 34 41 < 0.0016 months 31 49 < 0.00128 months 28 43 < 0.001

HEPARIN DOSING: MOPETT• Patients are almost always on

heparin when decision is made to proceed with MOPETT-TPA

• Reduce heparin infusion to 10U/Kg/h• PTT at 6h; target: 60-100 seconds;

increase heparin by increasing infusion rate; do not bolus heparin

• Stop heparin at 24h and start NOAC

Case PresentationThis 29 year old man with compound heterozygous Factor V Leiden and prothrombin gene mutation suffered a large R proximal vein DVT. He was treated with enoxaparin 120 mg twice daily for 5 days, followed by dabigatran 150 mg twice daily thereafter.

NO COMPRESSION COMPRESSION

FA FV FAFV

ACUTE DVT in a 29 y.o. man

DEFENDING A YOUNG LADYHe likes playing “pool” at the local bar and belongs to a competitive “pool league” that meets at the bar.He noted from the corner of his eye that a man in the bar was becoming increasingly rough and was starting to push and shake a female customer.He stepped in between the two of them to protect her.

NO GOOD DEED SHALL GO UNPUNISHED

She escapes harm.However, a few minutes later, he is surrounded by a group of thugs. They stab him repeatedly in the L chest. He bled profusely. They leave him for dead and flee the bar. (They are subsequently arrested and imprisoned.)

LEFT HEMOTHORAX

Labs at the time of Admission

• HCT=27%•aPTT=62 seconds

The Thoracic Surgical Team recommends Emergency Surgery, with evacuation of the hematoma.

QUESTION #1• To control bleeding within thoracic cavity, you recommend:A) “Tincture of Time” to allow

dabigatran to be metabolizedB) Fresh Frozen PlasmaC) Vitamin KD) Dabigatran Antibody: IdarucizumabE) Prothrombin Complex Concentrate

TAKE HOME MESSAGES1. PE: #3 CV killer, with a 15%

Medicare readmission rate w/in 30d2. PE incidence is increasing.3. VTE is a chronic inflammatory

disease with a high recurrence rate after cessation of anticoagulation.

4. NOACs are much safer than warfarin, and NOACs are preferred by ACCP/ CHEST Guidelines.