“Oral Anticoagulant and Antiplatelet combinations:

Benefits and Risks ”

John Fanikos, BS Pharm, MBA

Brigham and Women’s Hospital

February 2015

Disclosures

► Speaker’s Bureau● None

► Consultant● Boehringer Ingelheim, Marathon, Portola

► Board of Directors● North American Thrombosis Forum

(NATF)● Hospital Quality Foundation (HQF)

► Family● Dad (James) CVS ● Brother (Paul) Boehringer Ingelheim

Daily Snowfall in Boston

2015 = 3 meters

Storm

Storm

Storm

Storm

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.

Outline

• Magnitude of the problem• Background and history• Studies offering alternative

options• Novel anticoagulants and

antiplatelet agents• Conclusions

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

Cardiac Catheterization

N=1,221,00

PCIN=500,000

Indication for ACN=50,000

< 65 years > 65 years

Mozzafarian D. Circulation. 2015;131:e29-e322.

US Heart and Stroke Statistics 2015

Outline

• Background and history

17.1

6.5*

Placebo ASA0

5

10

15

20

Patie

nts

(%)

Unstable Angina

25.0

11.0*

ASA0

10

20

303.3

1.9*

ASA0

1

2

3

4

11.8

9.4*

ASA0

5

10

15

Acute MI*P<.0001

Death or MI*P=.001

Reocclusion*P=.012

MI*P<.001

Vascular Death

N= 397 399 513 419 8,587 8,600 8,587 8,600

MI=myocardial infarctionASA=acetylsalicylic acidRISC=Research on Instability in Coronary Artery Disease

Placebo Placebo Placebo

RISC Group. Lancet. 1990; 336:827-830.Roux S. J Am Coll Cardiol. 1992;19:671:-677.

ISIS-2. Lancet. 1988;2:349-360.

Aspirin in Acute Coronary Syndromes (ACS)

Antiplatelet Trialists’ Collaboration: Meta-analysis

Aspirin Dose # Trials OR* (%) Odds Ratio

500-1500 mg

34 19

160-325 mg

19 26

75-150 mg 12 32

<75 mg 3 13

Any Aspirin

65 230 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.

Secondary Prevention After MI: WARIS II

Hurelen M. WARIS II NEJM 2002;347:969-974.

Randomized, multicenter trialN=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

Meta-analysis: Oral Anticoagulation and Aspirin vs DAPT after Coronary Stenting

Outcome

Death, MI, Revascularization

Stent thrombosis

Major Bleeding0 0.5 1.0 1.5 2.0

Antiplatelet therapy better OAC plus Aspirin better

2,436 patients, 30-day follow-up

Rubboli A. Cardiology 2005;104:101–106.

(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)

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).

Olesen JB et al. N Engl J Med. 2012; 367:625-635.

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 (0.57-0.62) < 0.001

Aspirin 1.11 (1.07-1.15) < 0.001

Warfarin and aspirin 0.70 (0.65-0.75) < 0.001

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 (1.23-1.33) < 0.001

Aspirin 1.21 (1.16-1.26) < 0.001

Warfarin and aspirin

2.15 (2.04-2.26) < 0.001

Olesen JB et al. N Engl J Med. 2012; 367:625-635.

Connolly SJ et al. Circulation 2008;118:2029-2037.

OAC

OAC

C+A

C+A

Years Years

Even

t R

ate

(%

)

Even

t R

ate

(%

)

TTR < 65% TTR ≥ 65%

RR=0.93 (0.70-1.24)p=0.61

RR=2.14 (1.61-2.85)P=0.0001

0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5

12

10

8

6

4

2

0

12

10

8

6

4

2

0

ACTIVE-W: Risk of Stroke / SEE / MI / Vascular Death by cTTR

ACTIVE - Major Bleeding

The ACTIVE Writing Group. Lancet 2006;367:1903-1912

0.0

0.0

10.0

20.0

30.0

4

0.0 0.5 1.0 1.5

OAC

Clopidogrel+ASACum

ula

tive H

aza

rd R

ate

s

Years

# at RiskC+A 3335 3172 2403 914OAC 3371 3212 2423 901

2.4 %/year

2.2 %/year

RR = 1.06

P = 0.67

OAC

Clopidogrel+ASA

ORBIT-AF Registry (N=7,347): 6-month major bleeding

Steinberg B et al. Circulation 2013;128:721-728

Lamberts M et al. Circulation. 2012; 126:1185-1193.

Antithrombotic Regimen & BleedingThe Dangers of Triple of Therapy

11,480 pts in Denmark with AF & MI or PCI

Observational Studies TT vs DAPT

0 5 10 15 20 250

5

10

15

20

25

Bleeding (%)

MA

CE (

%)

Rossini-DAPTRossini-TT

Rogacka-TT

Karjalainen-TT

Gao-DAPT

Karjalainen-DAPT

Khurram-TTKhurram-DAPT

Sambola-TT

Sambola-AC- single AP

Sambola-DAPT

Gao-TT

Ideal Outcome

Worse Outcome

Sambola A. Heart 2009;95:1483-1488. Khurram Z. J Invas Cardiol 2006;18;(4)Rossini R. Am J Cardiol 2008;103:1618-1623. Rogacka R. JACC-Cardiovasc Interven 2008;1:56-61. Karjalainen PP. Eu H J 2007;28:726-732.Gao F. Circ Journal 2010;74:701-708.

Should we recommend OAC in Patients with AF Undergoing and Coronary Stenting ?

Ruiz-Nodar, JM, et al. Circ Cardiovasc Interven 2012; 5:459-466.

AF undergoing PCICHADS-VASC >1

(n=590)

Efficacy and Safety endpoints

HAS-BLED 0-2 (170, 29%)

HAS-BLED > 3 (n=420, 71%)

HAS-BLED>3

HAS-BLED >3 and AC

p value

Anticoagulation at discharge

Mortality 20.1% 9.3% <0.01

MACE 26.4% 13.0 <0.01

Major Bleeding

4.0% 11.8% <0.01

Multi-variate analysisPredictors of MACE:

• AGE, • CHF.

Predictor of Bleeding:• Chronic renal failure• Use of drug eluting

stents

VKA +aspirin+

clopidogrel

Drug Combinations and Duration

VKA+ASA+

Clop

VKA+ASA

VKA+Clo

p

ASA+Clo

p02468

10121416

1.9

15.2

0

5.9

Regimen

Perc

en

t

Karjalainen PP. Eu H J 2007;28:726-732.

D 1-7 D 8-28 D 28-90

D 91-360

0

2

4

6

8

10

Maj BleedStent Thrombosis

Pati

en

ts

Stent Thrombosis Timing of Events

Inappropriate Aspirin Use

Hira RS. J Am Coll Cardiol 2015;65:111-121.

• 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)

Outline

• Studies offering alternative options

What is the Optimal antiplatElet and anticoagulant therapy in Pts w/ OAC and coronary StenTing

(WOEST)

Dewilde W, et al. Lancet 2013; 381:1107-1115.

• Open-label, randomized, multicenter trial

• N=573 patients

• Belgium & Netherlands

• Target INR: 2-3.

• Duration: 1 mos-1 year

Adults receiving OAC

PCI

Randomization

Any bleeding episodes with 1 year

Double TherapyOAC+Clopidogrel

Triple TherapyOAC+Clopidogrel+ASA 80-100 mg

What is the Optimal antiplatElet and anticoagulant therapy in Pts w/ OAC and coronary StenTing (WOEST)

N = 563

Days

Bleeding Events

(OAC + clopidogrel)

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)

Dewilde W, et al. Lancet 2013; 381:1107-1115.

P = 0.027 0.38 0.88 0.13 0.17

Duration of triple therapy in patients requiring OAC after DES implantation (ISAR-TRIPLE Trial)

Herzzentrum D, et al. Presented at TCT Fall 2014.

•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

Aspirin + VKA

Randomization, Open label

Follow-up at 9 months (n=606 patient, 99%)

6-week Clopidogrel

(n=307)

6-month clopidogrel

(n=307)

Results: Composite

Herzzentrum D, et al. Presented at TCT Fall 2014.

Results: Safety

Herzzentrum D, et al. Presented at TCT Fall 2014.

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.

Optimizing Therapy in Low-Moderate Risk(MUSICA-2 Trial)

Sambola A et al. Am Heart J 2013;166:669-675.

1. Hypothesis: DAPT reduces the risk of bleeding and is not inferior to “triple therapy”.

2. ASA 300 mg will provide additional efficacy benefit

3. Tighter INR range will improve safety

Patients with Non-valvular AF(CHADS2 <2 points)

Follow-up for 12 monthsStroke, systemic embolism, MACE, any

bleeding

DAPTAspirin 300 mg +

Clopidogrel 75 mg daily

PCI with Stent(ACS or stable angina)

“Triple therapy”Aspirin 100 mg +

Clopidogrel 75 mg + warfarin INR 2-2.5

Randomization, Open label

Outline

• Novel anticoagulants and antiplatelet agents

Recent ACS: STEMI, NSTEMI, UANo increased bleeding risk, No warfarin, No ICH, No

prior stroke if on ASA + ThienopyridineStabilized 1-7 Days Post-Index Event

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**

RIVAROXABAN5.0 mg BID

N=5,176ASA + Thieno, n=4,827

ASA, n=349

Stratified by Thienopyridine use at MD Discretion+ ASA 75 to 100 mg/day

TIMI51

PlaceboN=5,176

ASA + Thieno, n=4,821ASA, n=355

RIVAROXABAN2.5 mg BID

n=5,174ASA + Thieno, n=4,825

ASA, n=349

* Stroke includes ischemic stroke, hemorrhagic stroke, and uncertain stroke** 184 subjects were excluded from the efficacy analyses prior to unblinding

ATLAS ACS 2

Mega JL. ATLAS TIMI-51. NEJM 2012; 366:9-19

Months After Randomization

PRIMARY EFFICACY ENDPOINT: CV Death / MI / Stroke* (Ischemic + Hemg.)

Rivaroxaban(both doses)

HR 0.84 (0.74-0.96)ARR 1.7%

mITT p = 0.008ITT p = 0.002

NNT = 59

10.7%

8.9%

Est

imat

ed C

um

ula

tive

Rat

e (

%)

TIMI51

Placebo

*: First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC across thienopyridine use strataTwo 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.

5113 4307 3470 2664 1831 1079 421

10229 8502 6753 5137 3554 2084 831

PlaceboRivaroxaban

2 Yr KM Estimate

No. at Risk

ATLAS ACS 2

TREATMENT-EMERGENT FATAL BLEEDS AND ICH

0.2 0.20.10.1

0.4

0.1

0.4

0.7

0.2

0

0.2

0.4

0.6

0.8

1

1.2

Fatal ICH Fatal ICH

Placebo

2.5 mg Rivaroxaban

5.0 mg Rivaroxaban

TIMI51

n=4 n=5 n=8n=9 n=6 n=15

*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)

*

p=0.009 Riva Vs Placebo

p=NS for Riva vs Placebo

n=5 n=18n=14

p=NS for Rivavs Placebo

p=0.044 for 2.5 mg vs 5.0 mg

ATLAS ACS 2

• 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

Pharmacology

Chackalamannil S, J Med Chem, 2006

Platelet

PAR-4

TBX A2

TBXA2-R

Thrombin

Anionicphospholipidsurfaces

GP IIb/IIIa

ADPP2Y12

PAR-1

Clopidogrel

Prasugrel

Ticagrelor

Cangrelor

ASA

Vorapaxar

Vorapaxar Trial

Morrow D. TIMI 50-TRA2P NEJM 2012; 366:1404-1413.

Outcomes

Morrow D. TIMI 50-TRA2P NEJM 2012; 366:1404-1413.

Outcomes

Morrow D. TIMI 50-TRA2P NEJM 2012; 366:1404-1413.

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”.

Conclusions