1. John Fanikos, BS Pharm, MBA Brigham and Women’s Hospital February 2015
“Oral Anticoagulant and Antiplatelet combinations: Benefits and Risks ”
John Fanikos, BS Pharm, MBA
Brigham and Women’s Hospital
February 2015

2. Disclosures Speaker’s Bureau Consultant Board of Directors Family None
Boehringer Ingelheim, Marathon, Portola
Board of Directors
North American Thrombosis Forum (NATF)
Hospital Quality Foundation (HQF)
Family
Dad (James) CVS
Brother (Paul) Boehringer Ingelheim

4. Daily Snowfall in Boston
2015 = 3 meters
Storm
Storm
Storm
Storm

5. Discuss clinical data that has shaped practice.
Objectives
Describe benefits and risks associated with combining oral anticoagulants and antiplatelet agents.
Discuss clinical data that has shaped practice.
Review strategies to reduce risks.
Review new agents that may impact practice.

6. Outline Magnitude of the problem Background and history
Studies offering alternative options
Novel anticoagulants and antiplatelet agents
Conclusions

7. Magnitude of the Problem
Atrial fibrillation (AF) with concomitant Coronary artery disease (CAD) requiring percutaneous coronary intervention (PCI) is present in 20-30% of patients with AF.
Dual antiplatelet therapy (DAPT) is required to prevent stent thrombosis
Aspirin + ADP inhibitor
Bare metal stent: 4 weeks
Drug eluting stent: 12 months
ACS: 12 months
10% of PCI have an indication for long term anticoagulation therapy AF
VTE prevention or treatment
Mechanical heart valve
“Triple therapy”
Warfarin + Aspirin + ADP inhibitor
US Heart and Stroke Statistics 2015
Cardiac Catheterization
N=1,221,00
PCI
N=500,000
Indication for AC
N=50,000
< 65 years
> 65 years
Mozzafarian D. Circulation. 2015;131:e29-e322.

8. Outline
Background and history

9. Aspirin in Acute Coronary Syndromes (ACS)
Unstable Angina
Acute MI
*P<.0001
Death or MI
*P=.001
Reocclusion
*P=.012 MI
*P<.001
Vascular Death 20 30 4 15
17.1
25.0
3.3
11.8 15 3
9.4* 20 10
1.9*
Patients (%) 10 2
11.0*
6.5* 10 5 5 1
To determine the effects of antiplatelet therapy among patients at high risk of occlusive vascular events.
DESIGN:
Collaborative meta-analyses (systematic overviews).
INCLUSION CRITERIA:
Randomised trials of an antiplatelet regimen versus control or of one antiplatelet regimen versus another in high risk patients (with acute or previous vascular disease or some other predisposing condition) from which results were available before September Trials had to use a method of randomisation that precluded prior knowledge of the next treatment to be allocated and comparisons had to be unconfounded-that is, have study groups that differed only in terms of antiplatelet regimen.
STUDIES REVIEWED:
287 studies involving patients in comparisons of antiplatelet therapy versus control and in comparisons of different antiplatelet regimens.
MAIN OUTCOME MEASURE:
"Serious vascular event": non-fatal myocardial infarction, non-fatal stroke, or vascular death.
RESULTS:
Overall, among these high risk patients, allocation to antiplatelet therapy reduced the combined outcome of any serious vascular event by about one quarter; non-fatal myocardial infarction was reduced by one third, non-fatal stroke by one quarter, and vascular mortality by one sixth (with no apparent adverse effect on other deaths). In each of these high risk categories, the absolute benefits substantially outweighed the absolute risks of major extracranial bleeding. Aspirin was the most widely studied antiplatelet drug, with doses of mg daily at least as effective as higher daily doses. The effects of doses lower than 75 mg daily were less certain. Clopidogrel reduced serious vascular events by 10% (4%) compared with aspirin, which was similar to the 12% (7%) reduction observed with its analogue ticlopidine. Addition of dipyridamole to aspirin produced no significant further reduction in vascular events compared with aspirin alone.
CONCLUSIONS:
Aspirin (or another oral antiplatelet drug) is protective in most types of patient at increased risk of occlusive vascular events, including those with an acute myocardial infarction or ischaemic stroke, unstable or stable angina, previous myocardial infarction, stroke or cerebral ischaemia, peripheral arterial disease, or atrial fibrillation. Low dose aspirin ( mg daily) is an effective antiplatelet regimen for long term use, but in acute settings an initial loading dose of at least 150 mg aspirin may be required.
Placebo
ASA
Placebo
ASA
Placebo
ASA
Placebo
ASA
N= ,587 8,600 8,587 8,600
MI=myocardial infarction
ASA=acetylsalicylic acid
RISC=Research on Instability in Coronary Artery Disease
RISC Group. Lancet. 1990; 336:
Roux S. J Am Coll Cardiol. 1992;19:671:-677.
ISIS-2. Lancet. 1988;2:

10. Antiplatelet Trialists’ Collaboration: Meta-analysis
Aspirin Dose
# Trials
OR* (%)
Odds Ratio mg 34 19 mg 26 mg 12 32
<75 mg 3 13
Any Aspirin 65 23
0.5
1.0
1.5
2.0
Antiplatelet Better
Antiplatelet Worse
*Odds reduction.
Treatment effect p<0.0001
Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71-86.

11. Secondary Prevention After MI: WARIS II
Randomized, multicenter trial
N=3630 patients:
Warfarin INR 2.8 to 4.2,
Aspirin 160 mg daily,
Aspirin 75 mg daily + Warfarin INR of 2.0-
2.5.
Observation over 4 years.
Bleeding
ASA (%)
Warfarin
(%)
Warfarin + ASA (%)
Major
0.66
2.7
2.3
Minor
3.8
8.5
11.0
Hurelen M. WARIS II NEJM 2002;347:

12. Meta-analysis: Oral Anticoagulation and Aspirin vs DAPT after Coronary Stenting
2,436 patients, 30-day follow-up
Outcome
Death, MI, Revascularization
Stent thrombosis
Major Bleeding
(RR 0.41; 95% CI 0.25–0.69)
(RR 0.26; 95% CI 0.06–1.14)
(RR 0.36; 95% CI 0.14–1.02)
The combination of oral anticoagulation (OAC) and aspirin was the antithrombotic treatment initially adopted after coronary stenting (PCI-S).
Although dual antiplatelet therapy with aspirin and a thienopyridine subsequently roved safer and more effective, OAC and aspirin combination is still used in patients with an indication for long-term OAC undergoing PCI-S. The absolute (AR) and relative (RR) risk of cardiac events and hemorrhagic/vascular complications of OAC and aspirin versus antiplatelet therapy were evaluated in a meta-analysis of four historical clinical trials.
In 2,436 patients, the RR of a 30-day primary composite endpoint of death, myocardial infarction and the need for revascularization was significantly reduced by antiplatelet therapy (RR 0.41; 95% CI 0.25–0.69), whereas the RR of stent thrombosis (RR 0.26; 95% CI 0.06–1.14) and major bleeding (RR 0.36; 95% CI 0.14–1.02) was not statistically different.
The 30-day AR of death, myocardial infarction, need for revascularization, major bleedings and vascular complications with OAC and aspirin were 0.65, 3.8, 4.2, 6.4 and 6.6%, respectively. In conclusion, due to the low AR of adverse events, the combination of OAC and aspirin appears an acceptable treatment after PCI-S in patients in whom long-term OAC is deemed mandatory.
Cardiology 2005;104:101–106  (DOI: / )
Meta-Analysis of Trials Comparing Oral Anticoagulation and Aspirin versus Dual Antiplatelet Therapy after Coronary Stenting
0.5
1.0
1.5
2.0
Antiplatelet therapy better
OAC plus Aspirin better
Rubboli A. Cardiology 2005;104:101–106.

13. Comparison of Aspirin vs Control in AF
Review: Prevention of Stroke in Non-valvular AF patients with no history of stroke or
TIA
Comparison: Aspirin vs Control (placebo)
EndPoint: All ischemic stroke and ICH
Aguilar M, Hart R. Cochrane Database Syst. Rev. 4, CD0019 (2005).

14. Aspirin does not prevent stroke in Chronic Kidney Disease
Stroke Risk and Aspirin
Aspirin does not prevent stroke in Chronic Kidney Disease
Characteristic
Total Population (n = 132,372)
Hazard Ratio (95% CI)
P Value
Antithrombotic Therapy
None
1.00
Warfarin
0.59 ( )
< 0.001
Aspirin
1.11 ( )
Warfarin and aspirin
0.70 ( )
Olesen JB et al. N Engl J Med. 2012; 367:

15. Aspirin and warfarin increase bleeding
Aspirin and Bleeding
Aspirin and warfarin increase bleeding
Characteristic
Total Population (n = 132,372)
Hazard Ratio (95% CI)
P Value
Antithrombotic Therapy
None
1.00
Warfarin
1.28 ( )
< 0.001
Aspirin
1.21 ( )
Warfarin and
aspirin
2.15 ( )
Olesen JB et al. N Engl J Med. 2012; 367:

16. ACTIVE-W: Risk of Stroke / SEE / MI / Vascular Death by cTTR12 10 8 6 4 2 12 10 8 6 4 2
TTR < 65%
TTR ≥ 65%
RR=0.93 ( )
p=0.61
RR=2.14 ( )
P=0.0001
Event Rate (%)
Event Rate (%)
C+A
OAC
C+A
OAC
Years
Years
Connolly SJ et al. Circulation 2008;118:

17. The ACTIVE Writing Group. Lancet 2006;367:1903-1912
ACTIVE - Major Bleeding
2.4 %/year
RR = 1.06
P = 0.67
2.2 %/year
Cumulative Hazard Rates
OAC .
Clopidogrel+ASA
# at Risk
C+A
OAC
Years
The ACTIVE Writing Group. Lancet 2006;367: 17

18. ORBIT-AF Registry (N=7,347): 6-month major bleeding
Unadjusted, 6-month major bleeding rates among high-risk subgroups are shown with absolute numbers of events per group noted above. ASA indicates aspirin; ATRIA, Anticoagulation and Risk Factors in Atrial Fibrillation; GI, gastrointestinal; and OAC, oral anticoagulation.
Steinberg B et al. Circulation 2013;128:

19. Antithrombotic Regimen & Bleeding The Dangers of Triple of Therapy
11,480 pts in Denmark with AF & MI or PCI
Patients with AF and admitted with MI or for PCI between
11,480 subjects in Denmark. Fatal or non-fatal (requiring hospitalization) bleeding was determined according to antithrombotic treatment regimen.
Conclusions - High risk of bleeding is immediately evident with TT after MI/PCI in AF patients.
A continually elevated risk associated with TT indicates no safe therapeutic window and triple therapy should only be prescribed after thorough bleeding risk assessment of patients.
Lamberts M et al. Circulation. 2012; 126:

20. Observational Studies TT vs DAPT
Worse Outcome
Rogacka-TT
Karjalainen-TT
Gao-DAPT
Sambola-AC- single AP
Gao-TT
Karjalainen-DAPT
Sambola-TT
Rossini-TT
Sambola-DAPT
Khurram-TT
Khurram-DAPT
Ideal Outcome
Sambola A. Heart 2009;95: Khurram Z. J Invas Cardiol 2006;18;(4)
Rossini R. Am J Cardiol 2008;103: Rogacka R. JACC-Cardiovasc Interven 2008;1: Karjalainen PP. Eu H J 2007;28:
Gao F. Circ Journal 2010;74:

21. Efficacy and Safety endpoints
Should we recommend OAC in Patients with AF Undergoing and Coronary Stenting ?
HAS-BLED
>3
>3 and AC
p value
Anticoagulation at discharge
Mortality
20.1%
9.3%
<0.01
MACE
26.4%
13.0
Major Bleeding
4.0%
11.8%
AF undergoing PCI
CHADS-VASC >1
(n=590)
VKA +
aspirin+
clopidogrel
Multi-variate analysis
Predictors of MACE:
AGE,
CHF.
Predictor of Bleeding:
Chronic renal failure
Use of drug eluting stents
HAS-BLED
0-2 (170, 29%)
HAS-BLED
> 3 (n=420, 71%)
Efficacy and Safety endpoints
Ruiz-Nodar, JM, et al. Circ Cardiovasc Interven 2012; 5:

22. Drug Combinations and Duration
Stent Thrombosis
Timing of Events
Karjalainen PP. Eu H J 2007;28:

23. Inappropriate Aspirin Use
Pinnacle Registry on cardiovascular disease prevention.
36% of adult US population takes aspirin regularly
Inappropriate use defined aspirin in patients with 10-year cardiovascular risk < 6%
> 9 million patient encounters
11.6% received ASA inappropriately
80% women
Young (< 49 years)
Hira RS. J Am Coll Cardiol 2015;65:

24. Outline
Studies offering alternative options

25. Any bleeding episodes with 1 year
What is the Optimal antiplatElet and anticoagulant therapy in Pts w/ OAC and coronary StenTing (WOEST)
Open-label, randomized, multicenter trial
N=573 patients
Belgium & Netherlands
Target INR: 2-3.
Duration: 1 mos-1 year
Adults receiving OAC
PCI
Randomization
Double Therapy
OAC+Clopidogrel
Triple Therapy
OAC+Clopidogrel
+ASA mg
Any bleeding episodes with 1 year
Dewilde W, et al. Lancet 2013; 381:

26. Dewilde W, et al. Lancet 2013; 381:1107-1115.
What is the Optimal antiplatElet and anticoagulant therapy in Pts w/ OAC and coronary StenTing (WOEST)
(OAC + clopidogrel)
N = 563
Bleeding Events
Days
Dewilde W, et al. Lancet 2013; 381:

27. Dewilde W, et al. Lancet 2013; 381:1107-1115.
What is the Optimal antiplatElet and anticoagulant therapy in Pts w/ OAC and coronary StenTing (WOEST)
P = 0.027
0.38
0.88
0.13
0.17
Dewilde W, et al. Lancet 2013; 381:

28. Duration of triple therapy in patients requiring OAC after DES implantation (ISAR-TRIPLE Trial)
•Optimal duration of triple therapy after DES implantation has not been defined.
1.The risk of stent thrombosis is highest in the early after PCI and declines over time.
2.The risk of bleeding is dependent on length and intensity of OAC therapy
614 patients with DES
Randomization, Open label
Aspirin + VKA
6-week Clopidogrel (n=307)
6-month clopidogrel (n=307)
Follow-up at 9 months (n=606 patient, 99%)
Herzzentrum D, et al. Presented at TCT Fall 2014.

29. Results: Composite
Herzzentrum D, et al. Presented at TCT Fall 2014.

30. Results: Safety Conclusion:
6 week triple therapy is not superior to 6 month triple therapy.
Shortening the duration of triple therapy did not impact ischemic or bleeding events.
Herzzentrum D, et al. Presented at TCT Fall 2014.

31. Optimizing Therapy in Low-Moderate Risk (MUSICA-2 Trial)
Hypothesis: DAPT reduces the risk of bleeding and is not inferior to “triple therapy”.
ASA 300 mg will provide additional efficacy benefit
Tighter INR range will improve safety
Patients with Non-valvular AF
(CHADS2 <2 points)
PCI with Stent
(ACS or stable angina)
Randomization, Open label
DAPT
Aspirin 300 mg + Clopidogrel 75 mg daily
“Triple therapy”
Aspirin 100 mg + Clopidogrel 75 mg + warfarin INR 2-2.5
Follow-up for 12 months
Stroke, systemic embolism, MACE, any bleeding
Sambola A et al. Am Heart J 2013;166:

32. Outline
Novel anticoagulants and antiplatelet agents

33. TIMI 51 Placebo Recent ACS: STEMI, NSTEMI, UA RIVAROXABAN
G w_script.ppt
4/15/2017 3:27:34 PM
ATLAS ACS 2
TIMI 51
Recent ACS: STEMI, NSTEMI, UA
No increased bleeding risk, No warfarin, No ICH, No prior stroke if on ASA + Thienopyridine
Stabilized 1-7 Days Post-Index Event
+ ASA 75 to
100 mg/day
Stratified by Thienopyridine use at MD Discretion
RIVAROXABAN
2.5 mg BID
n=5,174
ASA + Thieno, n=4,825
ASA, n=349
RIVAROXABAN
5.0 mg BID
N=5,176
ASA + Thieno, n=4,827
ASA, n=349
Placebo
N=5,176
ASA + Thieno, n=4,821
ASA, n=355
PRIMARY ENDPOINT:
EFFICACY: CV Death, MI, Stroke* (Ischemic + Hemg.)
SAFETY: TIMI major bleeding not associated with CABG
Event driven trial of 1,002 events in 15,342 patients**
* Stroke includes ischemic stroke, hemorrhagic stroke, and uncertain stroke
** 184 subjects were excluded from the efficacy analyses prior to unblinding
Mega JL. ATLAS TIMI-51. NEJM 2012; 366:9-19 33

34. PRIMARY EFFICACY ENDPOINT: CV Death / MI / Stroke* (Ischemic + Hemg.)
ATLAS ACS 2
PRIMARY EFFICACY ENDPOINT: CV Death / MI / Stroke* (Ischemic + Hemg.)
TIMI 51
2 Yr KM Estimate
Placebo
10.7%
8.9%
HR ( )
ARR 1.7%
mITT p = 0.008
ITT p = 0.002
NNT = 59
Estimated Cumulative Rate (%)
Rivaroxaban
(both doses)
Months After Randomization
No. at Risk
Placebo
5113
4307
3470
2664
1831
1079
421
Rivaroxaban
10229
8502
6753
5137
3554
2084
831
*: First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC across thienopyridine use strata
Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT approach; Stratified log-rank p-values are provided for both mITT and ITT approaches; ARR=Absolute Relative Reduction; NNT=Number needed to treat; Rivaroxaban=Pooled Rivaroxaban 2.5 mg BID and 5 mg BID. 34

35. TREATMENT-EMERGENT FATAL BLEEDS AND ICH
ATLAS ACS 2
TREATMENT-EMERGENT FATAL BLEEDS AND ICH
TIMI 51
p= Riva
Vs Placebo
p=NS for Riva
vs Placebo
p=0.044 for
2.5 mg vs 5.0 mg
p=NS for Riva
vs Placebo *
n=9
n=6
n=15
n=5
n=14
n=18
n=4
n=5
n=8
*Among patients treated with aspirin + thienopyridine, there was an increase in fatal bleeding among patients treated with 5.0 mg of Rivaroxaban (15/5110) vs 2.5 mg of Rivaroxaban (5/5115) (p=0.02)

36. Pharmacology Vorapaxar: First-in-class Oral PAR-1 inhibitor Vorapaxar
Platelet
Vorapaxar:
First-in-class
Oral PAR-1 inhibitor
Metabolism:
Primarily hepatic via CYP 3A4
Terminal half-life: ~126–269 hrs
Prior trials:
No increase in bleeding and fewer MIs
Vorapaxar
Thrombin
PAR-1
PAR-4
Clopidogrel
Prasugrel
Ticagrelor
Cangrelor
Anionic
phospholipid
surfaces
ADP
I have simplified graphic and content.
I don't think we need P2Y 1 receptor. I would also leave out PAR-4.
P2Y12
TBXA2-R
TBX A2
GP IIb/IIIa
ASA
Chackalamannil S, J Med Chem, 2006

37. Vorapaxar Trial
Morrow D. TIMI 50-TRA2P NEJM 2012; 366:

38. Outcomes
Morrow D. TIMI 50-TRA2P NEJM 2012; 366:

39. Outcomes
Morrow D. TIMI 50-TRA2P NEJM 2012; 366:

40. Conclusions
Consider thrombosis risk and bleeding risk for individual patient (risk stratification).
Consider special risks (optimize patient selection):
Mechanical heart valve, prior thrombosis history, type of stent.
Consider medications:
Optimize selection, dose and duration.
Don’t neglect the anticoagulant.
Recognize the potential for “quadruple therapy”. 40 40