Post on 28-Oct-2021
01/11/2017
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DOACS: What’s New and Important and What’s Old and Still Important!
WelcomeWe will begin shortly.
Wm. Semchuk, MSc,Pharm.D,FCSHP
Manager, Pharmacy Practice
Regina Qu’Appelle Health Region
Assistant Clinical Professor,
College of Pharmacy and Nutrition
College of Medicine
University of Saskatchewan
Member – Thrombosis Canada
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DOACS: What’s New and Important and What’s Old and
Still Important!
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Session Objectives
• After participating in this session, participants will be better able to:
• Describe current and emerging indications for DOACs
• Discuss evidence pertaining to DOAC use in AF and VTE
• Describe current challenges in DOAC use
• Discuss opportunities for pharmacist involvement to ensure best outcomes with DOAC use
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Conflict of interest/disclosure:
Company Involvement
Bayer Advisory Board, Honoraria
Sanofi Aventis Advisory Board, Honoraria and Research Grants
BMS Advisory Board, Honoraria and Research Grant
Pfizer Advisory Board, Honoraria and Research Grant
Servier Advisory Board, Honoraria
Astra Zeneca Advisory Board, Honoraria
Boehringer Ingelheim Advisory Board, Honoraria and Research Grants
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Parenteral
Oral
1910 201019601950194019301920 1970 1980 1990 2000
Heparin
Warfarin
LMWH’s
Direct Thrombin
Inhibitors
Indirect FXaInhibitors
Direct Thrombin Inhibitors Direct FXaInhibitors
Adapted from: Weitz J, Hirsh J. Chest. 2001;119:95S; Alban. Eur J Clin Invest 2005; Link. Circulation 1959; Maraganore et al. Biochemistry 1990
Timeline of Anticoagulation Options
2008 201120102009 20132012
2014
Health Canada Approvals of DOACs
DabigatranVTE prophylaxis following THR/TKRCDR Approved
RivaroxabanVTE prophylaxis following THR/TKRCDR Approved
ApixabanVTE prophylaxis following THR/TKRCDR Approved
DabigatranStroke prevention in AFCDR Approved
bApixabanStroke prevention in AFCDR Approved
RivaroxabanTreatment of DVTCDR Approved
RivaroxabanStroke prevention in AFCDR Approved
ApixabanTreatment of DVTCDR Approved
DabigatranTreatment of DVT
8VTE, venous thromboembolism; THR, total hip replacement; TKR, total knee replacement; CDR, common drug review; AF, atrial fibrillation, DVT, deep vein thrombosis
20152016 2017 REDUAL
COMPASSIdarucizamab
REVERSE‐AD
EINSTEINChoice
PIONEER
b
pp
EdoxabanStroke prevention in AF Treatment of DVT
CDR Approved
Health Canada Drug Product Database http://www.hc-sc.gc.ca/dhp-mps/prodpharma/databasdon/index-eng.php
2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028
Maybe not so new? Patent Expirations ‐ Canada
Pradaxa
Pradaxa
Pradaxa
Xarelto
Xarelto
Eliquis
Eliquis
Lixiana Lixian
a
Xarelto
x2
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Trends in Oral Anticoagulant Utilization – Coverage is Important in Uptake
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Share of O
ral Anticoagulants Total
Prescription
apixabanrivaroxabandabigatran etexilatewarfarin
Weitz J, Semchuk W, Turpie G. Clin Ther 2015;37(11):2506‐2514.
Major Indications for Oral Anticoagulation
• Atrial Fibrillation
• Treatment of VTE and prevention of recurrent events
• Prevention of thrombosis in patients with valvular heart disease
• Prevention of thrombosis post orthopedic procedures
Atrial Fibrillation (AF) and Stroke
1. Heart and Stroke Foundation of Canada web site2. AFib Invest Group Arch Intern Med 1994 3. Singer DE et al. Chest 2008
4. Sanna T et al NEJM 2014;370:24785. Sally Lee et al. BMJ Open 2011;1:e0002696. 2014 CCS AF Guidelines. Can J Cardiol. 2014; 30: 113‐1130.
AFAGE
STROKE
• AF affects 1‐2% of Canadians and prevalence increases with age1
• About 6% of Canadians over age 65 years live with AF
• AF is an independent predictor of stroke (RR = 5)2
• AF accounts for 15% ‐ 20% of all strokes3
• Individuals with paroxysmal, persistent or permanent AF are all at increased risk of stroke
• AF is the leading preventable cause of stroke• AF is not diagnosed un l a er CVA in ⅓ of AF
strokes4
• Subclinical (asymptomatic) AF accounts for about 10% of cryptogenic strokes
• AF related embolic strokes are often severe: 25% mortality, 60% disabled5
• AF patients with an absolute risk of embolic stroke of > 1.5% per year require long‐term anticoagulation –represents over 95% of Canadians with AF6
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Warfarin (N=2900)
Relative RR vs. placebo 64% (CI 49–74%)Absolute RR primary 2.7%/yrAbsolute RR secondary 8.4%/yrNNT primary prevention 37NNT secondary prevention 12
100% 50% 0 -50% -100%Favours Warfarin Favours Placebo
or Control
Adjusted-dose warfarin compared with placebo or control
AFASAK I, 1989; 1990
SPAF I, 1991
BAATAF, 1990
CAFA, 1991
SPINAF, 1992
EAFT, 1993
All trials (n=6)
A Study, Year Relative Risk Reduction(95% CI)
Antiplatelet (ASA) (N=4876)
Relative RR vs. placebo 19% (CI -1–35%)Absolute RR primary 0.8%/yrAbsolute RR secondary 2.5%/yrNNT primary prevention 125NNT secondary prevention 40
100% 50% 0 -50% -100%Favours Antiplatelet Favours Placebo
or Control
Antiplatelet agents compared with placebo or control
B Study, Year Relative Risk Reduction(95% CI)
AFASAK I, 1989; 1990SPAF I, 1991EAFT, 1993ESPS II, 1997LASAF, 1997
DailyAlternate day
UK-TIA, 1999300 mg daily1200 mg daily
JAST, 2006
Aspirin trials (n=7)
SAFT, 2003ESPS II, 1997
DipyridamoleCombination
All antiplatelet trials (n=8)
Hart et al. Ann Intern Med 2007
Warfarin vs Antiplatelet (N=12,963)
Relative RR 37% (CI 23–48%)Absolute RR primary 0.9%/yrNNT primary prevention 111
Heterogeneity for secondary prevention trials precluded meta-analytic estimates.
100% 50% 0 -50% -100%Favours Warfarin Favours Antiplatelet
Adjusted-dose warfarin compared with antiplatelet agents
AFASAK I, 1989; 1990
C Study, Year Relative Risk Reduction(95% CI)
AFASAK II, 1998Chinese ATAFS, 2006EAFT, 1993PATAF, 1999SPAF II, 1994
Age ≤75 yAge >75 y
SIFA, 1997
Aspirin trials (n=8)*
ACTIVE-W, 2006NASPEAF, 2004
All antiplatelet trials (n=11)
Relative Effects of Antithrombotic Therapies on All Stroke From Randomised Trials in AF
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Trials supports DOAC Efficacy vs Warfarin
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Ruff CT, et al. The Lancet, Published online Dec 4, 2013 http://dx.doi.org/10.1016/S0140-6736(13)62343-0*dabigatran, rivaroxaban, apixaban, edoxaban (current not available in Canada)
Meta‐analyses – Stroke or Systemic Embolic Events
Stroke or systemic embolic events 19% 0.81 [0.73‐0.91, p<0.0001]
. . . DOAC Benefits on Mortality and ICH
15Ruff CT, et al. The Lancet, Published online Dec 4, 2013 http://dx.doi.org/10.1016/S0140-6736(13)62343-0*dabigatran, rivaroxaban, apixaban, edoxaban (current not available in Canada)
Meta‐analyses – Secondary Efficacy and Safety Outcomes
All‐cause Mortality 10% 0.90[0.85‐0.95, p=0.0003]
Intracranial Hemorrhage (ICH) 52% 0.48 [0.39‐0.50, p<0.0001]
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. . . Lack of difference in Major Bleeding
16Ruff CT, et al. The Lancet, Published online Dec 4, 2013 http://dx.doi.org/10.1016/S0140-6736(13)62343-0*dabigatran, rivaroxaban, apixaban, edoxaban (current not available in Canada)
Meta‐analyses – Major Bleeding
Major bleeding 0.86[0.73‐1.00, p=0.0]
Risks and Benefits of NOACs Compared with Warfarin (NNT/NNH)
Clinical Outcome Apixaban (5mg bid), HR, NNT per 2 years
Dabigatran (150 mg bid), RR, NNT or NNH per 2 years
Edoxaban (60 mg daily) HR,NNT or NNH per 3 years
Rivaroxaban (20mg daily), HR or RR, NNT or NNH per 3 years
Stroke or SE Superiority vs WHR = 0.79 (0.66‐0.95)
NNT=168
Superiority vs WRR = 0.66 (0.53‐ 0.82)
NNT=91
Non‐inferiority vs WHR =0.79 (0.63‐0.99),
NNT=141*
Non‐inferiority vs W
HR = 0.79 (0.65 – 0.95), NNT = 134*
Intracranial bleed Superiority vs WHR = 0.51 (0.35 to 0.75)
NNT=238
Superiority vs WRR=0.26 (0.14‐0.49),
NNT=182
Superiority vs WHR=0.54 (0.38 – 0.77),
NNT = 172
Superiority vs WHR = 0.67 (0.47 – 0.93),
NNT=247
Major bleed Superiority vs WHR 0.69 (0.60‐0.80)
NNT = 79
RR = 0.93 (0.81 – 1.07),
NSSuperiority vs WHR = 0.80 (0.71 – 0.91),
NNT 66
HR = 1.04 (0.90 – 1.20),
NS
GI bleed HR =0.89 (0.70‐1.15),
NSInferior vs WRR = 1.50 (1.19 – 1.89),
NNH = 100
Inferior vs WHR = 1.23 (1.02 – 1.50),
NNH 167
Inferior vs WRR = 1.45,
NNH 101
Any cause of death Superiority vs WHR =0.89 (0.80‐0.99),
NNT=132
RR = 0.88 (0.77 – 1.00),
NSHR = 0.92 (0.83 – 1.01),
NSHR = 0.85 (0.70‐1.02),
NS
1. Hijazi Z, et.al. Circulation 2014;129(9):961‐70.2. Fox KA, et.al. Eur Heart J 2011;32:2387‐94.3. Hohnloser SH, et al. Eur Heart J 2012; 22:2821‐30. 4. Bohula EA, et.al. Circulation 2016;134:24‐36.
* Indicates on treatment analysis used to calculate NNT as superiority was not demonstrated in ITT analysis
1. Hijazi Z, et.al. Circulation 2014;129(9):961‐70.
2. Fox KA, et.al. Eur Heart J 2011;32:2387‐94.
3. Hohnloser SH, et al. Eur Heart J 2012; 22:2821‐30.
4. Bohula EA, et.al. Circulation 2016;134:24‐36.
Age and Ageing 2015: 0:1-7 doi: 10.1093/ageing/afv156
Apixaban vs ASA: Stroke prevention above and below 75 years of age in AVERROES
P-value for interaction = 0.04Cumulative hazard rates of stroke in ASA and apixaban treatment groups, in patients <75 years or ≥ 75 years old.
0 3 6 9 12 15 18
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Months
Cumulative hazard
ASA
Apixaban
No. at risk
ASA
Apixaban
1799
1901
1766
1869
1643
1745
1384
1455
1009
1037
675
722
402
419
0 3 6 9 12 15 18
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
Months
Cumulative hazard
ASA
Apixaban
No. at risk
ASA
Apixaban
992
906
951
887
885
820730651
536
479
375
327
229
196
0.08
Age <75 yearsHR with apixaban, 0.68
(95% Cl, 0.42–1.08)
Age ≥75 yearsHR with apixaban, 0.33
(95% Cl, 0.19–0.54)
Age and Ageing 2015: 0:1-7 doi: 10.1093/ageing/afv156
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Age and Ageing 2015: 0:1-7 doi: 10.1093/ageing/afv156
Apixaban vs ASA: Bleeding above & below 75 years of age in AVERROES
P-value not availableCumulative hazard rates of major bleeding in ASA and apixaban treatment groups, in patients <75 years or ≥ 75 years old.
0 3 6 9 12 15 18
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Months
Cumulative hazard
Apixaban
ASA
No. at risk
ASA
Apixaban
1799
1901
1776
1872
1654
174813971455
1019
1040
682
724
407
424
0 3 6 9 12 15 18
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
Months
Cumulative hazard
Apixaban
ASA
No. at risk
ASA
Apixaban
992
906
960
885
896
816
740
645
548
474
382
321
233
195
0.08
Age <75 yearsHR with apixaban, 1.14
(95% Cl, 0.58–2.30)
Age ≥75 yearsHR with apixaban, 1.21
(95% Cl, 0.69–2.12)
Age and Ageing 2015: 0:1-7 doi: 10.1093/ageing/afv156
Opportunities and Challenges in AF
• Continue to ensure that patients with AF are identified and treated to minimize stroke risk
• Frail populations:• Elderly
• Renal function : Need to ensure that patients are on the right dose• CCS guidelines suggest reduced dose for patients with CrCl < 50 mL/min – however remember that apixaban requires 2 out 3 criteria based on ABC rule
• Periodic renal function assessment for patients on AF
• Mitigate bleeding risk
• Adherence is important!
• Periprocedural management• Thrombosis Canada Guidelines
• ASRA guidelines
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Epidemiology of VTE: Deep Vein Thrombosis and Pulmonary Embolism
Deep Vein Thrombosis
45,000 Canadians are affected by DVT each year
• 1/3 will suffer from post‐thrombotic syndrome*
• 1/3 will have a recurrent event within 10 years
• 1/3 of untreated DVT will result in potentially fatal pulmonary embolism
Pulmonary Emblism
Although Canadian data is lacking, est. 15,000 Canadians present with PE in the emergency department each year
Mortality rate for undiagnosed and untreated PE est. 5‐30%
PE causes more deaths annually in North America than
• breast cancer
• AIDS
• highway fatalities
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The Risk of Recurrent VTE
• Overall incidence of recurrent VTE at 6 months is 7%, despite anticoagulant therapy
• After an initial DVT, ~80% of the recurrences are DVTs2
• After an initial PE, ~60% of the recurrences are PEs2
1. Line B. Semin Nucl Med. 2001;31:90–101 2. Kearon C. Circulation 2003;107:I22–I30
Events occurring subsequent to an acute episode are termed recurrent VTE, and their prevention is termed secondary
prevention
Chance of recurrent VTE in first 3 months
47%If proximal DVT inadequately treated1
<2%If adequate anticoagulant response is achieved1 (2-4% in
subsequent 3 months)
Therapeutic Options for VTE
“Bridging” (5-10 d) to provide immediate ACLMWH SC or UFH IV or SCor fondaparinux SC
Warfarin INR 2-3, oral
Warfarin
Special cases - UFH
LMWH LMWH monotherapy, SC
UFH, SC - if CrCl <30 mL/min, increased risk for bleeding, if patient might need rapid reversibility, or thrombolytic therapy being considered
DOAC
Apixaban 10 mg BID for 7 days, then 5 mg BID
LMWH for 5-10 days, then dabigatran 150 mg bid or edoxaban 60 mg qd
Rivaroxaban 15 mg BID for 21 days, then 20 mg OD
Summary of Recent Trial Results in Acute VTE Treatment
• 1. Agnelli G et al. N Engl J Med 2013; 369: 799‐808. / 2. The EINSTEIN Investigators. New Engl J Med 2010; 363: 2499‐510 / 3. The EINSTEIN‐PE Investigators. New Engl J Med 2012; 366: 1287‐97. / 4. Schulman S et al. N Engl J Med. 2009;361:2342–2352. / 5. Schulman S et al. Blood (ASH Annual Meeting Abstracts) 2011;118: Abstract 205.
RECURRENT VTE + VTE DEATH
MAJOR BLEEDINGMAJOR + CRNM BLEEDING
Trial Study Drug Comparator NOAC vs Comparator (%), P‐value
AMPLIFY1Apixa 10 mg BID for 7d, then 5 mg BID
Enoxa/WarfarinNon‐inferiority
2.3 vs 2.7P<0.001 (NI)
SuperiorityRRR 69%
0.6 vs 1.8 P<0.001
SuperiorityRRR 56%
4.3 vs 9.7 P<0.001
EINSTEIN‐ DVT2Riva 15 mg BID for 21d, then 20 mg QD
Enoxa/VKANon‐inferiority
2.1 vs 3.0 P<0.001 (NI)
Not signif.0.8 vs 1.2P=0.21
Not signif.8.1 vs 8.1P=0.77
EINSTEIN‐PE3Riva 15 mg BID for 21d, then 20 mg QD
Enoxa/VKANon‐inferiority
2.1 vs 1.8P=0.003 (NI)
SuperiorityRRR 51%1.1 vs 2.2P=0.003
Not signif.10.3 vs 11.4
P=0.23
RE‐COVER4 LMWH or UFH/Dabi 150 mg BID
LMWH or UFH/Warfarin
Non‐inferiority2.4 vs 2.1
P<0.001 (NI)
Not signif.1.6 vs 1.9P=0.38
SuperiorityRRR 37%5.6 vs 8.8P=0.002
RE‐COVER II5,6LMWH or UFH/Dabi 150 mg BID
LMWH or UFH/Warfarin
Non‐inferiority2.4 vs 2.2
P<0.0001 (NI)
Not signif.1.2 vs 1.7
NR*Not reported
HOKUSAI‐VTE7LMWH or UFH/Edoxa 60 mg QD (30 mg QD in selected pts)
LMWH or UFH/Warfarin
Non‐inferiority3.2 vs 3.5
(1.6 vs 1.9 on‐Tx)P<0.001 (NI)**
Not signif.1.4 vs 1.6 P=0.35
SuperiorityRRR 19%
8.5 vs 10.3 P=0.004
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Treat VTE for Three Months and Reassess
Isolated distal DVT
Reversible provoking factor
Stop at 3 MonthsIndefinite therapy or until cancer
inactiveStop at 3 Months
Unprovoked proximal DVT or PE
High Bleeding RiskOR
Prefers to stop even if D‐dimer was positive1
Stop at 3 Months
Stay off therapy(Stop at 3 Months)
Cancer
Others
Stop and measureD‐dimer after
1 month
Not High Bleeding Risk
AND
Prefers to stay
on even if D‐dimer
was negative2
Indefinite therapy Indefinite therapy
Second VTE
Negative D‐dimerRestart therapy
(Indefinite therapy)
Positive D‐dimer
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How Can We Prevent Recurrent VTE?
1. Goldhabber SZ. Circulation 2004;110:IV‐20‐IV‐24; 2. Kakkos SK. Eur J Vasc Endo Surgery 2014;48(5):565‐75.
9-12%Approx. 0%
During anticoagulation After anticoagulation is stopped
Rate of recurrence at 3 years1
Extension trials ‐ NOAC vs placebo83% relative risk reduction in recurrent VTE
Similar rates of major bleedingStatistically significant net clinical benefit favoring NOACs226
NOAC Trials for Extended VTE Treatment ≥ 6 months
1. Agnelli G et al. N Engl J Med 2013; 368: 699-708 2. The EINSTEIN Investigators. N Engl J Med. 2010;363:2499-25103. Schulman S et al. N Engl J Med. 2013; 368:709-718
Apixaban1 Dabigatran3 Rivaroxaban2Einstein Extension
RivaroxabanEinstein Choice4
Comparator and size Placebo, 2482 Placebo, 1353 Placebo, 1196 ASA, 3396
Duration of treatment 12 months 6 months 6 or 12 months 12 months
Dosing BID BID QD QD
Dose/s of NOAC studied/approved 2.5mg & 5mg150mg or 110mg*
20mg 10mg and 20mg
Superior efficacy (recurrent or fatal VTE) vs comparator
Yes Yes Yes Yes
Major bleeding vs comparator NS NS NS NS
Major or clinically-relevant non-major bleeding vs comparator
NS NS
Significant increase p<0.05To date there are no head-to-head trials between dabigatran, apixaban and rivaroxaban, therefore comparative efficacy and safety have not been established
NS = no significant difference
*not studied1. Agnelli G et al. N Engl J Med 2013; 368: 699-708 2. The EINSTEIN Investigators. N Engl J Med. 2010;363:2499-25103. Schulman S et al. N Engl J Med. 2013; 368:709-7184. Weitz J et al. N Engl J Med 2017;376(13):1211
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Co‐morbidity considerations in Atrial Fibrillation
Pfizer Canada Inc./BMS Canada. Eliquis (apixaban) Product Monograph, June 16, 2016.Boehringer Ingelheim Canada Ltd. Pradaxa (dagbatran) Product Monograph. August 11, 2016.Bayer Inc. Xarelto (rivaroxaban) Product Monograph. July 20, 2015.
Cairns Which OAC for which AF Patient Can J Cardiol 2013; :1‐8
2
Co‐Morbidity Expert Recommendation
Mechanical (metal) heart valve /Rheumatic mitral stenosis
warfarin absolutely indicated
Chronic kidney disease (CrCl<30mL/min) warfarin (NOACs contraindicated)
Chronic kidney disease (CrCl 30‐49mL/min) apixaban and rivaroxaban 15 mg preferred
Age ≥ 80 apixaban, rivaroxaban or dabigatran110 mg (recommended dose adjustment as per as per monograph)
Stable coronary artery disease ASA (Low Risk – CHADS2= 0 and age < 65 yrs) apixaban or rivaroxaban (if CHADS2 ≥ 1)
Recent ACS ASA + ticagrelor* x 12 mos (if age < 65 and CHADS2= 0)clopidogrel@ + NOAC x 12 mos (age ≥ 65 or CHADS2≥ 1)
Previous gastrointestinal bleeding apixaban preferred (as per results of 3 pivotal trials)
Dyspepsia Consider avoiding dabigatran
* or prasugrel if PCI performed@ and ASA x 3‐6 months if PCI performed
Granger et al., NEJM 2011; 365: 981‐992Connolly et al., NEJM 2009; 361: 1139‐1151Patel et al., NEJM 2011; 365: 883‐891Macle L et al. 2016 Focused Update of the CCS Management of AF. CJC 32;1170
Risk of Bleeding with Combination Antithrombotic Therapy
ASA alone
Clopidogrel Alone
Warfarin Alone
ASA + Clopidogrel
ASA + VKA
Clopidogrel + VKA
ASA + Clopidogrel + VKA
0.1 0.3 2.0 3.0 10.0
Hazard Ratio (95% CI)
1.00 Reference
HR 95% CI
1.33 1.11-1.59
1.23 0.94-1.61
1.47 1.28-1.69
1.84 1.51-2.23
3.52 2.42-5.11
4.05 3.08-5.33
Lancet 2009; 374: 1967-74.
P value not reported
CI = Confidence Interval
New data/new uses:
• A number of areas are actively being explored, data is being presented and as clinicians we may be challenged as these indications do not yet have indications and in some instances the dosage forms are not yet available
• ROUGH timeline is about a year to indication from submission if all goes well and then about another year from indication to CDR and then PCPA….
• PCI in the face of AF (PIONEER Trial, REDUAL Trial)
• Patients with established vascular disease (COMPASS Trial)
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PCI – in the face of AF • PIONEER: Gibson CM et al. N Engl J Med 2016; 375(25):2423.
• Patients with AF who require PCI randomized to: Riva 15 mg daily + Clopidogrel 75mg daily; or Riva 2.5 mg bid + Clopidogrel 75 mg daily + ASA 75‐100 mg daily for 1,6 or 12 months and then Riva 15 mg qd + ASA 75‐100 mg daily; or VKA + Clopidogrel 75 mg qd + ASA 75‐100 mg qd for 1, 6 or 12 months then VKA and ASA
• Result: Safety Riva and DAPT and Riva and P2Y12 had significantly lower bleeding rates than traditional triple therapy (18.0%, 16.8% vs 26.7%) with no difference in efficacy
• REDUAL: Cannon C et al. N Engl J Med 2017;377(16):1513.
• Patients with AF who require PCI randomized to Dabi 150 bid + P2Y12 or Dabi 110 bid + P2Y12 or traditional Tribple therapy with 6 month minimum treatment duration
• Result: both dabi arms significantly less bleeding than triple therapy; efficacy similar though trend to more MI and stent thrombosis in lower dose dabi arms
• Take home:• Data is still emerging (AUGUSTUS to come)
• In the face of AF and PCI – individualized decision making is occurring
Practice Questions Around Oral Anticoagulant Use….
• Indication?
• Dosing regimen and factors that affect it?
• Clot risk/bleed risk?
• Drug interactions?
• Follow Up?
• Reversal?
• Switching?
• Periop interruption?
Indications and Options:Need to know why we are using the drug….• AF:
• warfarin, apixaban, dabigatran, edoxaban, rivaroxaban
• ASA suboptimal choice, especially in the elderly
• PCI in face of AF: • ASA + P2Y12 inhibitor + VKA
• Clopidogrel 75 mg daily + Riva 15 mg daily
• ASA + Clopidogrel + Riva 2.5 mg bid
• P2Y12 + Dabi 150 bid
• P2Y 12 + Dabi 110 bid
• ASA + P2Y12 + VKA
• VTE• Treatment: Injectable and then oral; injectable than dabigatran or edoxaban; or apixaban or rivaroxaban
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DOAC Usual Starting Dose Dosing adjustmentCriteria
Apixaban (Eliquis) 5 mg BID 2.5 mg BID if any 2 of the following criteria: ‐ Age ≥80 years‐ Body weight ≤60 kg‐ Creatinine ≥133 μmol/L
Dabigatran (Pradaxa) 150 mg BID 110 mg BID if ‐ Age >80 or‐ >75 + ≥ one hemorrhagic risk factors* or‐ CrCl 30‐50 ml/min
Edoxaban(Lixiana)
60 mg OD
30 mg once daily if:‐ CrCl 30‐50 ml/min‐ body weight ≤60 kg‐ Concomitant use of P‐gp inhibitors except
amiodarone and verapamil
rivaroxaban (Xarelto)20 mg OD taken with food 15 mg OD taken with food
if CrCl 30‐49 mL/min
Dosing of DOACs is Important (AF):
Antithrombotic Dosing in VTE
Drug Initial Treatment Long Term (additional 3 months)
Extended >6 months if indicated
Apixaban 10 mg bid x 7 days 5 mg bid 2.5 mg bid
ASA Not indicated Not indicated 81-100 mg daily if OAC not possible
Dabigatran LMWH for 5-10 days 150 mg bid * 150 mg bid *
Edoxaban LMWH for 5-10 days 60 mg daily 60 mg daily
Rivaroxaban 15 mg bid x 21 days 20 mg daily 20 mg daily
Warfarin LMWH for 5 days min & INR > 2for 2 days
Variable (INR 2-3) Variable (INR 2-3)
Pfizer Canada Inc./BMS Canada. Eliquis (apixaban) Product Monograph, June 16, 2016. Bayer Inc. Xarelto (rivaroxaban) Product Monograph. July 20, 2015.Boehringer Ingelheim Canada Ltd. Pradaxa (dagbatran) Product Monograph. August 11, 2016.Daiichi Sankyp Inc. Lixiana (edoxaban) Product Monograph. November 2, 2016.Thrombosis Canada Clinical Guide. Deep Vein Thrombosis (DVT): Tretament. www.thrombosiscanada.ca
*(110 mg bid if age≥80, or age≥75 + higher risk of bleeding, including CrCl 30-50 mL/min)
Use determination to minimize Bleeding
Calculator available onlineThrombosisCanada.ca
Co‐prescribe PPI (if recurrent GI bleeding) Anticoagulation
should not be withheld based on bleeding risk, unless bleeding is active
or risk is extreme
Measure and monitor renal function
Ensure blood pressure controlled to target
Encourage alcohol abstinence
Correct anemia and determine cause
Provide mobility aids Discontinue ASA and NSAIDs if possible
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Drug Interactions
Dabigatran Rivaroxaban/Apixaban/Edoxaban
Contraindicated – clinically significant increased plasma levels
Potent P‐gp Inhibitors:Systemic azole antifungals (except fluconazole), cyclosporine, dronedarone, tacrolimus, simultaneous initiation with verapamil
Potent P‐gp and /or CYP 3A4 inhibitors:Systemic azole antifungals (except fluconazole), HIV‐protease inhibitors
Caution – avoid use or seek advice, dose change may be warranted
Less potent P‐gp inhibitors:Amiodarone, clarithromycin, erythromycin,fluconazole, HIV protease inhibitors, quinidine, ticagrelor
Less potent P‐gp and/or CYP3A4 inhibitors: amiodarone, cyclosporine, clarithromycin, erythromycin, diltiazem, fluconazole, quinidine, tacrolimus, verapamil
Potent P‐gp/CYP3A4 inducers: carbamazepine, phenobarbitone, phyenytoin, rifampin, St. John’s wort
Antiplatelet agents/anticoagulants: e.g.. warfarin, clopidogrel, prasugrel, ticagrelor, heparins
Some antidepressants: SSRI or SNRI
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How to take
• Apixaban – take with or without food; can be crushed, suspended in water and administered by NG
• Rivaroxaban – take with food, alteration of AUC for doses greater than 10mg/day; can be crushed and administered by NG
• Dabigatran may be taken with food, or on an empty stomach. It should be taken with a glass of water to facilitate delivery to the stomach; do not chew, break or open capsules. Swallow capsules whole
• Edoxaban – take with or without food
• VTE missed doses• Rivaroxaban (15mg bid phase): if you miss a dose, take the dose as soon as remembered. If you forget to take a dose
you can take two 15mg tablets at the same time to get to a total dose of 30mg on one day• Apixaban: if you miss a dose, take as soon as remembered, and then continue with the remaining daily dose that day.
Do not take a double dose• Dabigatran: if a dose is missed, take the dose as soon as you remember, but if it is almost time for your next dose (less
than 6 h before next dose) take your next dose when you are supposed to• Edoxaban: if you miss a dose, take as soon as remembered. Do not double the dose for a missed dose
• Apixaban, Dabigatran, Ribaroxaban Edoxaban PM 38
Thrombosis Canada App
Search “Thrombosis” for the free app in the iTunes store, Google Play and BlackBerry App World or visit www.thrombosiscanada.ca
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Bungard et al. Can Pharm J (Ott.) 2015;148:241–245.
Pharmacist Follow Up: Repeat Visit/Refills
Gladstone et al. Ann Int Med 2015;163:382–385.
Patient Education
• Rationale for therapy
• Potential for minor, major or life‐threatening bleeding
• Dosing instructions, adherence, risk of non‐adherence, handling missed doses
• Avoiding OTC ASA and NSAIDs and minimizing EtOH to reduce bleeding risks
• Dosing around upcoming procedure/surgery if applicable
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Summary
• Evolution of management of both arterial and venous thrombosis
• New agents will continue to account for more and more patient management
• Best use of agents will result in optimization of outcomes.
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Questions
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Thank you!
This presentation and any resources will be available online to CPhA members at
http://www.pharmacists.ca/index.cfm/education‐practice‐resources/professional‐
development/pharmacy‐practice‐webinars/