“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
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