1. The Evidence for Current Cardiovascular Disease Prevention Guidelines:
Antiplatelet and Anticoagulation Therapy Evidence and Guidelines
American College of Cardiology
Best Practice Quality Initiative Subcommittee
and Prevention Committee 1 1

2. Classification of Recommendations and Levels of Evidence
*Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as gender, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Even though randomized trials are not available, there may be a very clear clinical consensus that a particular test or therapy is useful or effective.
†In 2003, the ACC/AHA Task Force on Practice Guidelines developed a list of suggested phrases to use when writing recommendations. All guideline recommendations have been written in full sentences that express a complete thought, such that a recommendation, even if separated and presented apart from the rest of the document (including headings above sets of recommendations), would still convey the full intent of the recommendation. It is hoped that this will increase readers’ comprehension of the guidelines and will allow queries at the individual recommendation level.

3. Icons Representing the Classification and Evidence Levels for Recommendations
IIa
IIb
III A I
IIa
IIb
III B I
IIa
IIb
III C I
IIa
IIb
III A I
IIa
IIb
III B I
IIa
IIb
III C I
IIa
IIb
III A I
IIa
IIb
III B I
IIa
IIb
III C I
IIa
IIb
III A I
IIa
IIb
III B I
IIa
IIb
III C

4. Antiplatelet Therapy Evidence and Guidelines
Evidence for Current Cardiovascular Disease
Prevention Guidelines
Antiplatelet Therapy Evidence and Guidelines

5. Antiplatelet Therapy: Targets
Clopidogrel bisulfate
Dipyridamole
Ticlopidine hydrochloride
Prasugrel hydrochloride
Phosphodiesterase
Ticagrelor
ADP
ADP
Gp 2b/3a Inhibitors
Collagen Thrombin TXA2
Activation
COX
Platelet activation leads to platelet aggregation. As illustrated above, various classes of antiplatelet agents act by different mechanisms to reduce platelet activation and clot formation.
Aspirin inhibits platelet aggregation by inhibiting the production of thromboxane A2.
The P2Y12 receptor antagonists (clopidogrel, prasugrel and ticlopidine) bind and inhibit adenosine diphosphate (ADP) receptors on platelets, thereby, inhibiting glycoprotein IIb/IIIa-receptor activation and subsequent platelet aggregation.
Dipyridamole interferes with platelet stimulating factors like collagen through various mechanisms including the inhibition of phosphodiesterase and inhibition of cellular uptake of adenosine.
Glycoprotein IIb/IIa inhibitors directly interfere with platelet binding of fibrinogen, the final step in platelet aggregation.
TXA2
Aspirin
ADP=Adenosine diphosphate, COX=Cyclooxygenase, TXA2=Thromboxane A2
Source: Schafer AI. Antiplatelet Therapy. Am J Med 1996;101:199–209 5

6. Antiplatelet Therapy: Common Oral Agents
Acetylsalicylic acid (ASA)
Ticlopidine hydrochloride
Clopidogrel bisulfate
Prasugrel
hydrochloride
Ticagrelor
Trade Name
Aspirin1-3
Ticlid®4
Plavix®5
Effient®6
Brilinta®7
Class
Salicylate
P2Y12 Receptor Antagonist
Formulation
Active Drug
Pro-Drug
Maintenance Dose
mg daily*
250 mg BID
75 mg daily
10 mg daily
90 mg BID
Reversible No
Yes
Numerous oral antiplatelet agents are approved for use in the prevention and/or treatment of CV disease.
Among the P2Y12 receptor antagonists, clopidogrel has generally been given preference over ticlopidine because of a superior safety profile (unless an allergy is present). The newest FDA approved agent is prasugrel. The standard dose is 10 mg a day. It is approved for use in the setting of moderate to high risk ACS patients undergoing PCI as an adjunct to aspirin therapy. It should not be used in patients with a history of stroke or TIA, age >75 years (unless prior CHD or DM), or weight less than 60 kg.
*81 mg is the low dose aspirin option in the United States
Sources:
1Pearson TA, et al. Circulation, 2002;106:
2Mosca L, et al. Circulation, 2007;115:
3 Smith SC Jr. et al. JACC 2011;58:
4http://
5http://
6http://
7http:// 6

7. Aspirin: Mechanism of Action Membrane Phospholipids Arachadonic Acid
COX-1
Aspirin
Prostaglandin H2
Aspirin inhibits the production of thromboxane A2, thereby inhibiting platelet aggregation. Thromboxane promotes platelet aggregation and vasoconstriction. During platelet activation, the hydrolysis of membrane phospholipids yields arachadonic acid, which is converted to prostaglandin H2 by the catalytic activity of the cyclooxygenase enzyme prostaglandin G/H synthase.
By the selective and irreversible acetylation of a single serine residue within prostaglandin G/H synthase, aspirin causes the inactivation of cyclooxygenase activity. Aspirin also inhibits the production of endothelial-produced prostacyclin, a vasodilator and inhibitor of platelet aggregation. Unlike platelets, endothelial cells recover their ability to synthesize prostacyclin within a couple of hours.
References:
1. Husain S, Andrews NP, Mulcahy D, Et al. Aspirin improves endothelial dysfunction in atherosclerosis. Circulation. 1998;97:
2. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature. 1971;231:235-5.
3. Patrono C. Aspirin as an antiplatelet drug. NEJM 1994;330:
Thromboxane A2
 Platelet Aggregation
Vasoconstriction
Prostacyclin
 Platelet Aggregation
Vasodilation 7

8. Aspirin Evidence: Primary Prevention Physician’s Health Study (PHS)
22,071 male participants randomized to aspirin (325 mg every other day) followed for an average of 5 years
Aspirin reduces the risk of myocardial Infarction among men
The Physicians' Health Study was a randomized, double-blind, placebo-controlled primary prevention trial designed to determine whether aspirin (325 mg every other day) was associated with a reduction in cardiovascular disease mortality. The trial included 22,071 participants, with an average follow-up of 60 months.
Aspirin use was associated with a 44% reduction in the risk of MI; however, this effect was mainly present in men >50 years of age and no reduction in total cardiovascular mortality (RR 0.96; 95% CI 0.60 to 1.54) was observed. A slightly increased risk of stroke was observed among those taking aspirin (p=NS). This trend was noted primarily in the subgroup with hemorrhagic stroke (RR 2.14; 95% CI [0.96 to 4.77]; p=0.06). There was a non-significant increased risk of gastrointestinal ulcers in the aspirin group (RR 1.22, CI [0.98 to 1.53]; p=0.08).
Overall: In men (especially >50 years of age), aspirin is associated with a reduced risk of a first MI.
CI=Confidence interval, CV=Cardiovascular
Source: Steering Committee of the Physicians’ Health Study Research Group. NEJM 1989;321: 8

9. Aspirin Evidence: Primary Prevention Womens’ Health Study (WHS)
39,876 women randomized to aspirin (100 mg every other day) or placebo for an average of 10 years
Aspirin does not reduce cardiovascular events among women
The Women's Health Study was a double-blind, placebo-controlled trial that randomized 39,876 healthy women >45 years of age to low dose aspirin (100 mg every other day) versus placebo for a mean follow up of 10 years. There was no reduction in the primary composite endpoint of nonfatal MI, nonfatal stroke, or death from a cardiovascular cause. Aspirin use was associated with a 17% reduction in the risk of stroke (RR 0.83; ; P=0.04), a 24% reduction in the risk of ischemic stroke (RR 0.76; ; P=0.009), and a non-significant increase in the risk of hemorrhagic stroke (RR 1.24; ; P=0.31). Aspirin had no effect on the risk of fatal or nonfatal myocardial infarction (RR 1.02; ; P=0.83).
Among women >65 years of age, aspirin use was associated with a reduction of major cardiovascular events (RR 0.74; ; P=0.008) and risk of ischemic stroke (RR 0.70; ; P=0.05). GI bleeding requiring transfusion was more frequent in the aspirin group (RR 1.40; ; P=0.02).
Overall: The routine use of aspirin in low risk women (<10% 10 year risk of a CHD event) is not recommended. Aspirin use in women >65 can reduce the risk of cardiovascular events.
Source: Ridker P et al. NEJM 2005;352: 9

10. Aspirin Evidence: Primary Prevention RR of MI in Men RR of CVA in Men
BDT, 1988
RR of MI in Men
RR of CVA in Men
PHS, 1989
TPT, 1998
HOT, 1998
PPP, 2001
RR = 0.68 ( ) P=0.001
RR = 1.13 ( ) P=0.15
Combined
0.2
0.5
1.0
2.0
5.0
0.2
0.5
1.0
2.0
5.0
RR of MI in Women
HOT, 1998
RR of CVA in Women
PPP, 2001
WHS, 2005
This slide demonstrates a reduction in the incidence of MI among men but not women and a reduction of CVA in women but not men in the major aspirin primary prevention trials. These differences may be due to a proportionally higher incidence of CVA versus MI in women as compared to men, as well as, differences in total CVD risk among the men and women in these trials. Ultimately, however, the reasons for these sex-based differences in the efficacy of aspirin for primary prevention of CVD are unclear and require further exploration.
Combined
RR = 0.99 ( ) P=0.95
RR = 0.81 ( ) P=0.01
0.2
0.5
1.0
2.0
5.0
0.2
0.5
1.0
2.0
5.0
Aspirin Better
Placebo Better
Aspirin Better
Placebo Better
CVA=Cerebrovascular accident, MI=Myocardial infarction, RR=Relative risk
Source: Ridker P et al. NEJM 2005;352: 10

11. Aspirin reduces the risk of stroke in women and MI in men
Aspirin Evidence:
Primary Prevention
Sex-specific meta-analysis of 51,342 women and 44,114 men randomized to aspirin (doses ranging between 100 mg every other day to 500 mg daily) vs. placebo for years
Aspirin reduces the risk of stroke in women and MI in men *
Odds ratio
* p<0.05
Data from six studies were included in this meta-analysis: The Physicians' Health Study (1989), the Women's Health Study (2005), the Primary Prevention Project (2001), the Thrombosis Prevention Trial (1998), the Hypertension Optimal Treatment (HOT) trial (1998), and the British Doctor's Trial (1988).
Among 51,342 women, there were 1285 major cardiovascular events: 625 strokes, 469 MIs, and 364 cardiovascular deaths. Aspirin therapy was associated with a significant 12% reduction in cardiovascular events (odds ratio [OR], 0.88; 95% confidence interval [CI], ; P = .03) and a 17% reduction in stroke (OR, 0.83; 95% CI, ; P = .02), predominantly resulting from reduced rates of ischemic stroke (OR, 0.76; 95% CI, ; P = .008). There was no significant effect on MI or cardiovascular mortality.
Among 44,114 men, there were 2047 major cardiovascular events: 597 strokes, 1023 MIs, and 776 cardiovascular deaths. Aspirin therapy was associated with a significant 14% reduction in cardiovascular events (OR, 0.86; 95% CI, ; P = .01) and a 32% reduction in MI (OR, 0.68; 95% CI, ; P = .001). There was no significant effect on stroke or cardiovascular mortality.
Aspirin treatment increased the risk of bleeding in women (OR, 1.68; 95% CI, ; P = .01) and men (OR, 1.72; 95% CI, ; P<.001) alike.
AC=All cause, CV=Cardiovascular, MCE=Major cardiovascular events, MI=Myocardial infarction
Source: Berger JS et al. JAMA. 2006;295: 11

12. Aspirin Evidence: Primary Prevention
Prevention of Progression of Arterial Disease and Diabetes (POPADAD) Study
1,276 asymptomatic patients with DM and an ABI <0.99 randomized in a 2 x 2
design to aspirin (100 mg), antioxidants, aspirin plus antioxidants, or placebo
Aspirin does not reduce the risk of adverse CV events in diabetics 30
P=0.86 15
P=0.36 20
18.2
18.3 10
Composite primary
end point* (%)
Death from CHD or stroke (%)
6.7
5.5 10 5
Aspirin
No Aspirin
Aspirin
No Aspirin
*Includes fatal CHD or stroke, non-fatal MI or stroke, or amputation above the ankle for critical limb ischemia
ABI=Ankle brachial index, CHD=Coronary heart disease, CV=Cardiovascular, DM=Diabetes mellitus, MI=Myocardial infarction
Source: Belch J et al. BMJ. 2008;337:a1840 12

13. Aspirin Evidence: Primary Prevention
Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) Study
2,539 diabetic patients without known coronary artery disease randomized to aspirin ( mg) or placebo for a median of 4.7 years
Aspirin does not reduce the risk of adverse CV events in diabetics 1 2 3 4 5
Years
Non-aspirin Group
Aspirin Group
HR (95% CI): 0.80 (0.58–1.10), P=0.16
Atherosclerotic Event (%) 9 6
The JPAD trial was a multicenter, prospective, randomized, open-label trial which enrolled 2539 patients in Japan with type 2 diabetes and no history of atherosclerotic disease. Patients were assigned to a low-dose aspirin group (81 or 100 mg per day) or a non-aspirin group for a median of 4.37 years. Primary end points were atherosclerotic events, including fatal or nonfatal ischemic heart disease, fatal or nonfatal stroke, and peripheral arterial disease. Secondary end points included each primary end point and combinations of primary end points as well as death from any cause.
A total of 154 atherosclerotic events occurred: 68 in the aspirin group (13.6 per 1000 person-years) and 86 in the non-aspirin group (17.0 per 1000 person-years) (hazard ratio [HR], 0.80; 95% confidence interval [CI], ; p = .16). The combined end point of fatal coronary events and fatal cerebrovascular events occurred in 1 patient (stroke) in the aspirin group and 10 patients (5 fatal myocardial infarctions and 5 fatal strokes) in the non-aspirin group (HR, 0.10; p = .0037). A total of 34 patients in the aspirin group and 38 patients in the non-aspirin group died from any cause (HR, 0.90; 95% CI, ; P = .67). The composite of hemorrhagic stroke and significant gastrointestinal bleeding was not significantly different between the aspirin and non-aspirin groups.
CI=Confidence interval, CV=Cardiovascular, HR=Hazard ratio
Source: Ogawa H et al. JAMA 2008;300: 13

14. Aspirin Evidence: Primary Prevention
Aspirin for Asymptomatic Atherosclerosis Trial
3,350 patients with an ABI <0.95 but no known cardiovascular disease randomized to aspirin (100 mg) or placebo for 8.2 years
Aspirin does not reduce the risk of CV events in those with an ABI <0.95 * *
Events/1000 patient-years *
The Aspirin for Asymptomatic Atherosclerosis trial was an intention-to-treat, double-blind, randomized controlled trial conducted from April 1998 to October 2008, involving 28,980 men and women aged 50 to 75 years living in central Scotland. Eligible individuals were recruited from a community health registry, were free of clinical cardiovascular disease, and had an ABI screening test. A total of 3350 patients with a low ABI (0.95) were entered into the trial. Patients were randomized to once daily 100 mg aspirin (enteric coated) or placebo and were followed for a mean of 8.2 years. Treatment with aspirin was associated with no statistically significant reduction in the rate of fatal or nonfatal coronary events, stroke, or revascularization and no difference in all cause mortality. **
*Not statistically significant
**Composite of initial fatal or nonfatal coronary event or stroke or revascularization
ABI=Ankle brachial index, CV=Cardiovascular
Source: Fowkes FGR et al. JAMA 2010;303:

15. Aspirin Evidence: Primary Prevention
Antithrombotic Trialists’ (ATT) Collaboration
Rate Ratios for Vascular Events
P-value
Non-fatal MI
P<0.0001
Any stroke
P=0.40
Vascular Mortality
P=0.70
Major extracranial bleed
P<0.0001
Serious Vascular Events
P=0.0001
This data was taken from a meta-analysis of 6 randomized trials of antiplatelet therapy for prevention of death, MI, and stroke in low risk patients. In the primary prevention trials the absolute risk of a serious vascular event was an order of magnitude less than in the secondary prevention trials, and the absolute reduction in occlusive events only about twice as large as the absolute increase in bleeding. Moreover, these trials of aspirin were mainly in people who were not taking statin therapy, which would have reduced both MI and stroke rates with little hazard.
Overall: Aspirin is of uncertain net value for the primary prevention of CVD.
0.5
1.0
1.5
2.0
Antiplatelet Better
Antiplatelet Worse
Aspirin reduces the risk of MI and vascular events at the expense of bleeding
Source: Antithrombotic Trialists’ Collaboration. Lancet 2009;373:

16. Aspirin Evidence: Primary Prevention
Antithrombotic Trialists’ (ATT) Collaboration
Meta-analysis of 95,456 low risk patients randomized to aspirin (100 mg every other day to 500 mg daily) vs. placebo for years
Aspirin reduces the risk of ischemic events, but with a higher rate of bleeding
Number of Events (Aspirin vs. Control)
Rate ratio (95% CI) (Aspirin vs. Control)
Major coronary event
934 vs. 1115
0.82 ( )
Non-fatal MI
596 vs. 756
0.77 ( )
CHD mortality
372 vs. 393
0.95 ( )
Stroke
655 vs 682
0.95 ( )
Hemorrhagic
116 vs. 89
1.32 ( )
Ischemic
317 vs. 367
0.86 ( )
Unknown cause
222 vs. 226
0.97 ( )
Vascular death
619 vs. 637
0.97 ( )
Any serious vascular event
1671 vs. 1883
0.88 ( )
Major extracranial bleed
335 vs. 219
1.54 ( )
This data was taken from a meta-analysis of 6 randomized trials of antiplatelet therapy for prevention of death, MI, and stroke in low risk patients. In the primary prevention trials the absolute risk of a serious vascular event was an order of magnitude less than in the secondary prevention trials, and the absolute reduction in occlusive events only about twice as large as the absolute increase in bleeding. Moreover, these trials of aspirin were mainly in people who were not taking statin therapy, which would have reduced both MI and stroke rates with little hazard.
Source: Antithrombotic Trialists’ Collaboration. Lancet 2009;373:

17. Aspirin Evidence: Secondary Prevention
Effect of antiplatelet treatment* on vascular events**
Category % Odds Reduction
Acute MI
Acute CVA
Prior MI
Prior CVA/TIA
Other high risk
CVD (e.g. unstable angina, heart failure)
PAD (e.g. intermittent claudication)
High risk of embolism (e.g. Afib)
Other (e.g. DM)
All trials
This data was taken from a meta-analysis of randomized trials of antiplatelet therapy for prevention of death, MI, and stroke in high risk patients. Absolute reductions in the risk of having a serious vascular event were 36 ± 5 per 1,000 treated for 2 years among patients with previous MI; 38 ± 5 per 1,000 patients treated for 1 month among patients with acute MI; 36 ± 6 per 1000 treated for 2 years among those with previous stroke or TIA; 9 ± 3 per 1000 treated for 3 weeks among those with acute stroke; and 22 ± 3 per 1000 treated for 2 years among other high risk patients (with separately significant results for those with stable angina (P=0.0005), peripheral arterial disease (P=0.004), and atrial fibrillation (P=0.01).
In each of these high risk categories, the absolute benefit substantially outweighed the absolute risk of major extra-cranial bleeding.
Overall: Aspirin is recommended for the secondary prevention of CVD.
0.0
0.5
1.0
1.5
2.0
Antiplatelet better
Control better
Aspirin reduces the risk of adverse cardiovascular events
*Aspirin was the predominant antiplatelet agent studied
**Include MI, stroke, or death
Source: Antithrombotic Trialists’ Collaboration. BMJ 2002;324:71–86 17

18. Aspirin Evidence: Dose and Efficacy
Effect of aspirin doses on vascular events in high-risk patients (excluding those with acute stroke)
% Odds Aspirin Dose No. of Trials Reduction
Odds Ratio for Vascular Events mg mg mg
<75 mg
This slide demonstrates that high doses of aspirin are no more effective than medium or low doses in reducing the odds of a vascular event. Because trials using very low doses (<75 mg) are less conclusive, current data supports daily doses of aspirin in the  mg range.
Several studies have demonstrated in both healthy volunteers and CHD patients that low dose enteric coated may have decreased bioavailability and may not sufficiently inhibit cyclooxygenase in a subset of patients. [Maree AO et al. J Am Coll Cardiol, 2005; 46: and Cox D et al. Stroke. 2006;37: ]
Overall: For secondary prevention of CVD an aspirin dose of  mg/d is recommended. If mg aspirin is used, consideration should be given towards a non-enteric coated preparation.
Any aspirin
P<0.0001
0.5
1.0
1.5
2.0
Antiplatelet Better
Antiplatelet Worse
High dose aspirin does not provide improved efficacy
Source: Antithrombotic Trialists’ Collaboration. BMJ 2002;324:71-86 18

19. Higher dose aspirin does not provide benefit in ACS
Aspirin Evidence:
Dose and Efficacy
Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events (CURRENT)-OASIS 7 Trial
25,087 patients with an ACS randomized in a 2 x 2 factorial trial to double dose clopidogrel (600 mg LD, 150 mg x 7 days, then 75 mg MD) vs. standard dose clopidogrel (300 mg LD and 75 mg MD) and high dose aspirin ( mg) vs. low dose aspirin ( mg)
Days
Death, MI, or Stroke (%)
0.0
0.01
0.02
0.03
0.04 3 6 9 12 15 18 21 24 27 30
Aspirin mg
Aspirin mg
HR=0.97, P=0.61
Higher dose aspirin does not provide benefit in ACS
ACS=Acute coronary syndrome, MI=Myocardial infarction, LD=Loading dose, MD=Maintenance dose
Source: CURRENT-OASIS 7 Investigators. NEJM 2010;363:

20. B B B Aspirin Recommendations Primary Prevention
IIa
IIb
III B
Aspirin (81 mg daily or 100 mg every other day) in at risk women >65 years of age
Aspirin in at risk women <65 years of age for ischemic stroke prevention
Aspirin in optimal risk women <65 years of age I
IIa
IIb
III B I
IIa
IIb
III B
Source: Mosca L et al. Circulation 2007;115: 20

21. A Aspirin Recommendations (Continued) Primary Prevention
IIa
IIb
III A
Aspirin ( mg daily) in [men]* at intermediate risk (10-year risk of CHD >10%)
*Specific guideline recommendations for men do not exist, but these guidelines are based on previous general (not gender specific) primary prevention guidelines
CHD=Coronary heart disease
Source: Pearson TA et al. Circulation 2002;106: 21

22. B ADA/AHA/ACCF Primary Prevention of CV Disease
Antiplatelet Agent Recommendations
Primary Prevention
Low-dose aspirin therapy ( mg/day) is reasonable for adults with DM and no previous history of vascular disease who are at increased CVD risk (10-year risk >10%) and who are not at increased risk for bleeding (based on a history of previous GI bleeding or peptic ulcer disease or concurrent use of other medications that increase bleeding risk such as NSAIDs or warfarin). Those adults with DM at increased CVD risk include most men >50 years of age or women >60 years of age who have at least one additional major risk factor.*† I
IIa
IIb
III B
*ADA Level C
†Includes those with family history of premature CVD, hypertension, smoking, dyslipidemia, or albuminuria
ACCF=American College of Cardiology Foundation, ADA=American Diabetes Association, AHA=American Heart Association, CV=Cardiovascular, CVD=Cardiovascular disease, DM=Diabetes mellitus, GI=Gastrointestinal, NSAIDs=Non-steroidal anti-inflammatory drugs
Source: Pignone M et al. Circulation 2010;121:

23. C C ADA/AHA/ACCF Primary Prevention of CV Disease
Antiplatelet Agent Recommendations (Continued)
Primary Prevention
Aspirin should not be recommended for CV prevention for adults with DM at low CVD risk (men <50 years of age and women <60 years of age with no major additional CVD risk factors* [10-year risk <5%], as the potential adverse effects from bleeding offset the potential benefits.†
Low-dose aspirin ( mg/day) may be considered for those with DM at intermediate CVD risk (younger patients with >1 risk factors* or older patients with no risk factors*, or patients with a 10-year risk of 5-10% until further research is available.‡ I
IIa
IIb
III C I
IIa
IIb
III C
*Includes those with family history of premature CVD,
hypertension, smoking, dyslipidemia, or albuminuria
†ADA Level C, ‡ADA Level E
ACCF=American College of Cardiology Foundation, ADA=American Diabetes Association, AHA=American Heart Association, CV=Cardiovascular, CVD=Cardiovascular disease, DM=Diabetes mellitus
Source: Pignone M et al. Circulation 2010;121:

24. A A B Aspirin Recommendations (Continued) Secondary Prevention
IIa
IIb
III A
Aspirin ( mg daily) if known CAD† or NSTE-ACS‡
Aspirin ( mg daily) following PCI or fibrinolytic therapy for a STEMI*
Aspirin (preferentially at 81 mg daily) following PCI for a NSTE-ACS# or a STEMI* or fibrinolytic therapy for a STEMI* I
IIa
IIb
III A I
IIa
IIb
III B
ASVD=Atherosclerotic vascular disease, CAD=Coronary artery disease, NSTE-ACS=Non-ST segment elevation acute coronary syndrome, PCI=Percutaneous coronary intervention, STEMI=ST-segment elevation myocardial infarction
Sources:
†\Smith SC Jr. et al. JACC 2011;58:
‡Wright RS et al. JACC 2011;57:e
*O’Gara PT et al. JACC 2013;61:e78-e140
#Jneid H et al. JACC 2012;60:

25. B A C Aspirin Recommendations (Continued) Secondary Prevention
Aspirin ( mg daily) for at least 1 month after bare metal stent implantation (Class I, Level B), at least 3 months after sirolimus-eluting stent implantation (Class I, Level B), and at least 6 months after paclitaxel-eluting stent implantation (Class I, Level B) after which aspirin ( mg daily) should be continued indefinitely (Class I, Level A for a bare metal stent and Class I, Level B for a drug eluting stent)
Aspirin ( mg daily) as the initial dose after stent implantation in those at higher bleeding risk I
IIa
IIb
III B I
IIa
IIb
III A I
IIa
IIb
III C
Source: King SB 3rd et al. JACC 2008;51:

26. A Aspirin Recommendations (Continued) Secondary Prevention
IIa
IIb
III A
Aspirin ( mg daily) following CABG surgery*
*To be initiated within 6 hours of surgery
CABG=Coronary artery bypass graft
Source: Hillis LD et al. JACC 2011;58:e

27. P2Y12 Receptor Antagonist: Mechanism of Action
ADP / ATP
P2Y1
P2X1
P2Y12
Gq coupled
Cation influx
Calcium mobilization
Gi2 coupled
Ca2+
Ca2+
cAMP
The P2Y12 receptor antagonists (clopidogrel, ticlopidine, prasugrel, and ticagrelor) selectively bind P2Y12, one of the adenosine diphosphate (ADP) receptors on platelets. This binding inhibits ADP-induced activation of the platelet glycoprotein IIb/IIIa-receptor and prevents platelet aggregation.
No effect on
fibrinogen
receptor
Platelet shape change Transient aggregation
Fibrinogen receptor activation
Thromboxane A2 generation
Sustained Aggregation Response
Sources:
Savi P et al. Biochem Biophys Res Commun 2001; 283:379–383
Ferguson JJ. The Physiology of Normal Platelet Function. In: Ferguson JJ, Chronos N, Harrington RA (Eds). Antiplatelet Therapy in Clinical Practice. London: Martin Dunitz; 2000: pp.15–35 27

28. Clopidogrel provides slightly greater risk reduction than aspirin
Clopidogrel Evidence:
Secondary Prevention
Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) Trial
19,185 patients with ischemic CVA, MI, or PAD randomized to daily aspirin (325 mg) or clopidogrel (75 mg) for 2 years
Clopidogrel provides slightly greater risk reduction than aspirin
Months of follow-up 3 6 9 12 15 18 21 24 27 30 33 36
Cumulative risk* (%)
8.7% RRR, p=0.043
Aspirin
Clopidogrel
CAPRIE was a randomized, double blind trial designed to assess the relative efficacy of clopidogrel (75 mg daily) versus aspirin (325 mg daily) in reducing the risk of ischemic stroke, MI, or vascular death in patients with atherosclerotic vascular disease. An intention-to-treat analysis showed that patients treated with clopidogrel had an annual 5% risk of ischemic stroke, myocardial infarction, or vascular death compared to 6% with aspirin, resulting in a statistically significant relative risk reduction of 9% (95% Cl , P= 0.043).
There were no major differences between the treatments with regard to the incidence of rash, diarrhea, upper gastrointestinal discomfort, intracranial hemorrhage, and gastrointestinal hemorrhage.
Overall: Clopidogrel is slightly more efficacious than aspirin for the prevention of CVD events in patients with recent ischemic stroke, recent MI, or symptomatic peripheral arterial disease but its cost is much higher.
*Composite of myocardial infarction, ischemic stroke, or vascular death
CVA=Cerebrovascular accident, MI=Myocardial infarction, PAD=Peripheral arterial disease
Source: CAPRIE Steering Committee. Lancet 1996;348: 28

29. Clopidogrel Evidence: Secondary Prevention
Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial
12,562 patients with a NSTE-ACS randomized to daily aspirin ( mg) or clopidogrel (300 mg load, 75 mg thereafter) plus aspirin ( mg) for 9 months
Dual antiplatelet therapy is more efficacious in a NSTE-ACS
Aspirin + Placebo
Rate of CV death, myocardial infarction, or stroke
Aspirin + Clopidogrel
The CURE trial evaluated the efficacy and safety of clopidogrel and aspirin in patients with a non-ST-segment elevation acute coronary syndrome. Patients that presented within 24 hours after the onset of symptoms were randomly assigned to receive clopidogrel (300 mg immediately, followed by 75 mg once daily) (6,259 patients) or placebo (6,303 patients), in addition to aspirin for 3 to 12 months.
A composite of death from cardiovascular causes, nonfatal MI, or stroke, occurred in 9.3% of the patients in the clopidogrel + aspirin group and 11.4% in the aspirin alone group, corresponding to a significant 20% RR reduction.
The co- primary outcome (a composite of the first primary outcome along with refractory ischemia) occurred in 16.5% of patients in the clopidogrel + aspirin group vs. 19% of patients in the aspirin alone group, resulting in a significant 14% RR reduction. The percentage of patients with in-hospital refractory or severe ischemia, heart failure, and revascularization procedures was also significantly lower in the clopidogrel + aspirin group.
Patients on clopidogrel + aspirin had a significantly increased risk of major bleeding as compared to patients on aspirin alone (4% vs. 3%; relative risk, 1.38; P=0.001), but no greater incidence of life-threatening bleeding (2% vs. 2%, P=0.13) or hemorrhagic strokes.
Overall: The combination of aspirin + clopidogrel (for 3-12 months) is more efficacious than aspirin alone for the prevention of subsequent CVD events in patients presenting with a non-ST-segment elevation acute coronary syndrome.
P<0.001 3 6 9 12
Months of Follow Up
NSTE-ACS=Non ST-segment elevation acute coronary syndrome
Source: Adapted from Figure 1 in The CURE Trial Investigators. NEJM 2001;345: 29

30. Clopidogrel Evidence: Secondary Prevention
Clopidogrel for the Reduction of Events during Observation (CREDO) Trial
2,116 patients undergoing PCI randomized to 4 weeks of DAP* followed by aspirin ( mg) monotherapy vs. persistent DAP* for 1 year
DAP therapy produces greater benefit when used for 1 year 15
4 weeks of DAP* 10
Risk of MI, stroke, or death (%)
1 year of DAP* 5
27% RRR, P=0.02
In the Clopidogrel for the Reduction of Events during Observation (CREDO) trial, 2,116 patients scheduled to undergo percutaneous coronary intervention (PCI) or thought to be at high likelihood of undergoing PCI were randomized to a 300 mg loading dose of clopidogrel vs. placebo 3-24 hrs prior to PCI. Following PCI, all patients received clopidogrel (75mg daily) through day 28. From day 28 through 1 year, patients in the loading dose group received 75mg of clopidogrel daily.
Clopidogrel reduced the 1-year risk of MI, CVA, or death by 27% (P=.02; absolute reduction 3%). No significant difference was seen in the 28 day combined risk of MI, death, or urgent target vessel revascularization (risk reduction 19%;p=0.23). 3 6 9 12
Months from Randomization
*Dual antiplatelet therapy=Aspirin ( mg daily) plus clopidogrel (300 mg load followed by 75 mg daily)
DAP=Dual antiplatelet, PCI=Percutaneous coronary intervention, RRR=Relative risk reduction
Source: Steinhubl S et al. JAMA 2002;288: 30 30

31. Clopidogrel Evidence: Secondary Prevention
Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT)
45,852 patients presenting within 24 hours of a STEMI treated medically and randomized to clopidogrel (75 mg daily) vs. placebo
DAP therapy produces greater benefit in medically managed STEMI patients
9% relative risk reduction (P=.002)
(10.1%)
(9.2%)
Days Since Randomization (up to 28 days)
Death, MI, or Stroke, % 10 9 8 7 6 5 4 3
In-Hospital Mortality, %
(8.1%)
(7.5%)
7% relative risk reduction (P=.03) 14 21 28 2 1
The COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial)/CCS-2 (Second Chinese Cardiac Study), a collaboration between the UK Oxford Clinical Trials Unit and Chinese investigators, involved 45,852 patients with an MI (either ST-segment change or left bundle-branch block) within 24 hours of symptom onset. Patients undergoing primary percutaneous coronary intervention or at high risk of bleeding were excluded.
The study randomized patients to treatment with clopidogrel (75 mg daily) for the duration of hospital stay (mean 16 days) or placebo. All patients received aspirin 162 mg daily.
The two primary end points were the composite of death, reinfarction, or stroke and death from any cause at hospital discharge, both of which were significantly reduced. As shown in the figure on the left, allocation to clopidogrel produced a 9% reduction (P=.002) in death, reinfarction, or stroke. Predischarge deaths (shown in the figure on the right) were reduced by 7% (P=.03) in the clopidogrel group.
The benefits of clopidogrel treatment were not associated with an increased risk of major bleeding or ICH.
DAP=Dual antiplatelet, MI=Myocardial infarction, STEMI=ST-segment elevation myocardial infarction
Source: COMMIT Collaborative Group. Lancet 2005;366:
Chen ZM, Jiang LX, Chen YP, et al; COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366:

32. DAP therapy benefits STEMI patients treated with fibrinolytic therapy
Clopidogrel Evidence:
Secondary Prevention
Clopidogrel as Adjunctive Reperfusion Therapy in Thrombolysis in Myocardial Infarction (CLARITY) Trial
3,491 patients (<75 years of age) presenting within 12 hours of a STEMI treated with fibrinolytic, aspirin, and heparin and randomized to clopidogrel (300 mg load followed by 75 mg daily) vs. placebo
DAP therapy benefits STEMI patients treated with fibrinolytic therapy
Days
End Point (%)* 5 10 15 20 25 30
20% RRR
Aspirin + Clopidogrel
Aspirin + Placebo
P=0.03
*Composite of cardiovascular death, myocardial infarction, and need for urgent revascularization
STEMI=ST-segment elevation myocardial infarction
Source: Sabatine MS et al. NEJM 2005; 352:

33. Clopidogrel Evidence: Secondary Prevention
Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) Trial
15,603 patients with multiple CV risk factors or known CVD randomized to aspirin ( mg) or aspirin ( mg) & clopidogrel (75 mg) for a mean of 30 months
Routine DAP therapy offers little long-term benefit
Months 8 6 4 2 12 18 24 30
Placebo
Clopidogrel
Incidence of CV death, MI, or CVA (%)
P = 0.22
The CHARISMA trial randomized 15,603 patients with multiple CV risk factors or known CVD to aspirin ( mg) or aspirin ( mg) + clopidogrel (75 mg) for a mean of 30 months. The primary endpoint of stroke, myocardial infarction, or death from cardiovascular causes occurred in 6.8% of the clopidogrel + aspirin group and 7.3% of the placebo + aspirin group (RR 0.93; 95% CI, 0.83 to 1.05; P=0.22). There was a trend towards increased adverse events in the primary prevention group (RR 1.2; 95% CI, 0.91 to 1.59; P=0.20) and a modest trend towards benefit in those with a history of prior atherothrombotic disease (RR 0.88; 95% CI, 0.77 to 0.99; P=0.046).
Overall: The combination of aspirin + clopidogrel provided no benefit over aspirin alone for the prevention of CVD events.
CV=Cardiovascular, CVA=Cerebrovascular accident, CVD=Cardiovascular disease, DAP=Dual antiplatelet, MI=Myocardial infarction
Source: Adapted from Figure 4 in Bhatt DL et al. NEJM 2006;354: 33

34. High dose clopidogrel does not provide benefit in ACS
Clopidogrel Evidence:
Secondary Prevention
Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events (CURRENT)-OASIS 7 Trial
25,087 patients with an ACS randomized in a 2 x 2 factorial trial to double dose clopidogrel (600 mg LD, 150 mg x 7 days, then 75 mg MD) vs. standard dose clopidogrel (300 mg LD and 75 mg MD) and high dose aspirin ( mg) vs. low dose aspirin ( mg)
Type of Bleeding
D (%)
S (%)
TIMI Major
1.7
1.3
CURRENT Major*
2.5
2.0
Fatal
0.13
0.11
ICH
0.03
0.05
CABG-related
1.0
0.9
Days
CV death, MI, or stroke
0.0
0.02
0.04 3 6 9 12 15 18 21 24 27 30
Clopidogrel Standard
Clopidogrel Double
HR 0.95, P=0.370
This trial has not yet been published.
The CURRENT-OASIS-7 trial randomized 25,087 ACS patients in a 2 x 2 factorial design to a high dose clopidogrel load and maintenance (600 mg LD, 150 mg MD x 1 week followed by 75 mg thereafter) versus a standard dose clopiodgrel load and maintenance (300 mg LD, followed by 75 mg thereafter), as well as, high dose aspirin ( mg) versus low dose aspirin ( mg).
The primary endpoint of CV death, MI, or CVA at 30 days was not statistically different with the two clopidogrel regimens. However, in a pre-specified subgroup of patients undergoing PCI (70% of enrollees), the higher clopidogrel loading dose reduced the risk of the primary endpoint by 15% (HR 0.85, 95% CI 0.74 to 0.99). PCI patients in the high dose group had a 42% reduction in the risk of stent thrombosis (P<0.001) compared with patients receiving the standard dose of clopidogrel. Treatment with high dose clopidogrel was also associated with a 25% increase in the CURRENT definition of major bleeding (p=0.01); however, there was no statistically significant increased risk of TIMI major, fatal, intracranial, and CABG-related bleeding.
No difference in outcome was noted with the different doses of aspirin. There was also no increased bleeding with higher dose aspirin.
High dose clopidogrel does not provide benefit in ACS
*p=0.01
ACS=Acute coronary syndrome, CABG=Coronary artery bypass graft, ICH=Intracranial hemorrhage, LD=Loading dose, MD=Maintenance dose
Source: CURRENT-OASIS 7 Investigators. NEJM 2010;363:

35. Prasugrel reduces ischemic events with a higher rate of bleeding
Prasugrel Evidence:
Secondary Prevention
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON-TIMI 38)
13,608 patients with high-risk ACS scheduled for PCI randomized to clopidogrel (300 mg LD and 75 mg MD) or prasugrel (60 mg LD and 10 mg MD) for a median of 12 months
12.1
HR 0.81, P=0.0004 11
Clopidogrel
9.9
Bleeding Events
C (%) P (%) P-value
TIMI major
Life threatening
Nonfatal
Fatal
ICH 9
Prasugrel
CV death, MI, or stroke % 7
In TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel–Thrombolysis In Myocardial Infarction 38), 13,608 patients with moderate-to-high-risk acute coronary syndromes with scheduled percutaneous coronary intervention were randomly assigned to receive prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose) for 6 to 15 months. The primary efficacy end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.
The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel vs clopidogrel, 0.81; 95% CI: ; P<.001).
Major bleeding was observed in 2.4% of patients who received prasugrel and in 1.8% of patients who received clopidogrel (hazard ratio, 1.32; 95% CI: ; P=.03). Also greater in the prasugrel group was the rate of life-threatening bleeding (1.4% vs 0.9%; P=.01), including nonfatal bleeding (1.1% vs 0.9%; hazard ratio, 1.25; P=.23) and fatal bleeding (0.4% vs 0.1%; P=.002). The incidence of intracranial hemorrhage was reported in 19 patients (0.3%) receiving prasugrel and in 17 patients (0.3%) receiving clopidogrel (P=.74).
The TRITON-TIMI 38 trial randomized 13,608 moderate- to high-risk ACS patients scheduled for PCI to receive prasugrel (60-mg loading dose and then 10-mg daily maintenance dose) or clopidogrel (300-mg/75-mg) for 6 to 15 months.
Treatment with prasugrel resulted in a significant reduction in the primary efficacy end point (cardiovascular death/MI/stroke), as well as, MI, urgent target vessel revascularization (TVR), and stent thrombosis. However, this was at the expense of a significant increase in major bleeding (2.4% vs 1.8%, HR 1.32, p=0.03), life-threatening bleeding (1.4% vs 0.9%; P=0.01), and fatal bleeding (0.4% vs 0.1%; P=0.002). Subgroups that appeared to be particularly prone to serious bleeding include the elderly (age > 75) and the underweight (< 60kg). In the small subgroup of patients in this study with a previous stroke or transient ischemic attack, prasugrel resulted in reduced efficacy in reducing the ischemic end point.
In a substudy, among the 3,534 patients with a STEMI (Lancet, Feb 2009), the primary endpoint of CV death, non-fatal MI, or non-fatal CVA was reduced with prasugrel at 30 days (6.5% with prasugrel vs 9.5% with clopidogrel; p=0.0017) and 15 months (10·0% vs 12·4%; p=0·0221). The secondary endpoint of cardiovascular death, myocardial infarction, or urgent target vessel revascularization was also significantly reduced with prasugrel at 30 days (HR 0.75 p=0·0205) and 15 months (HR0.79; p=0·0250), as was stent thrombosis.
As opposed to the initial study, TIMI life-threatening bleeding and TIMI major or minor bleeding were also similar with the two treatments in patients with a STEMI. Only TIMI major bleeding after CABG surgery was significantly increased with prasugrel (p=0·0033).
*Patients in the clopidogrel arm only received a 300mg load (600mg is now standard of care for PCI) 5
HR 0.77 P=.001
HR 0.80 P=.001 30 60 90
180
270
360
450
Days
Prasugrel reduces ischemic events with a higher rate of bleeding
ACS=Acute coronary syndrome, ICH=Intracranial hemorrhage, LD=Loading dose, MD=Maintenance dose
Source: Wiviott SD et al. NEJM 2007;357:
Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357: 35

36. Prasugrel Evidence: Secondary Prevention
Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY-ACS)
7243 patients with a medically managed NSTE-ACS randomized to prasugrel (10 mg) or clopidogrel for up to 30 months
Prasugrel does not provide benefit in medically managed NSTE-ACS 20
16.0%
Clopidogrel
13.9%
CV Death, Nonfatal MI, and Nonfatal Stroke (%) 10
Prasugrel
HR=0.91, P=0.21
360
720
Time (Days)
CV=Cardiovascular, MI=Myocardial infarction, NSTE-ACS=Non-ST-segment elevation acute coronary syndrome
Source: Roe, MT et al. NEJM 2012;367:

37. Ticagrelor Evidence: Secondary Prevention
Platelet Inhibition and Patient Outcomes (PLATO) Study
18,624 patients with a moderate to high risk ACS randomized to clopidogrel ( mg LD and 75 mg MD) or ticagrelor (180 mg LD and 90 mg twice daily MD) for 12 months 60
120
180
240
300
360 12 10 8 6 4 2
CV Death, MI, or Stroke (%)
9.8
11.7
HR 0.84, p=0.001
Clopidogrel
Ticagrelor
Bleeding Events*
C (%) T (%)
TIMI major/year
PLATO major/year
Life threatening/year
Fatal/year
Ticagrelor is an oral, reversible, direct inhibitor of the adenosine diphosphate receptor, P2Y12.
PLATO was a multicenter, double-blind, randomized trial of 18,624 ACS patients comparing ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter). At 12 months, the primary end point of death from vascular causes, myocardial infarction, or stroke occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (p< ).
Secondary endpoint analysis showed a decrease in the rate of MI alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P=0.005) and death from vascular causes (4.0% vs. 5.1%, P=0.001) but not stroke alone (1.5% vs. 1.3%, P=0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001).
No significant difference in the rates of overall major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P=0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03).
Days after randomization
Ticagrelor reduces ischemic events with no higher rate of bleeding overall
*No statistically significant differences were observed in bleeding rates overall
ACS=Acute coronary syndrome, CV=Cardiovascular, LD=Loading dose, MD=Maintenance dose
Source: Wallentin L et al. NEJM 2009;361:

38. B C B P2Y12 Receptor Antagonist Recommendations Secondary Prevention
IIa
IIb
III B
Clopidogrel (75 mg daily; Class I, Level B), prasugrel* (10 mg daily; Class I, Level C), or ticagrelor (90 mg twice daily; Class I, Level C) if aspirin intolerance or a true aspirin allergy following a NSTE-ACS
Clopidogrel (75 mg daily) or ticagrelor (90 mg twice daily) in addition to aspirin for up to 1 year following a NSTE-ACS managed conservatively I
IIa
IIb
III C I
IIa
IIb
III B
*In PCI treated patients
NSTE-ACS=Non ST-segment elevation acute coronary syndrome; PCI=Percutaneous coronary intervention, STEMI=ST-segment elevation myocardial infarction
Source: Jneid H et al. JACC 2012;60:

39. B A C P2Y12 Receptor Antagonist Recommendations Secondary Prevention
IIa
IIb
III B
Clopidogrel (75 mg daily), prasugrel (10 mg daily), or ticagrelor (90 mg twice daily) in addition to aspirin for 1 year following PCI for a NSTE-ACS† or a STEMI‡
Clopidogrel (75 mg daily) in addition to aspirin for a minimum of 14 days (Class I, Level A) and up to 1 year (Class I, Level C) following fibrinolytic therapy for a STEMI‡ I
IIa
IIb
III A I
IIa
IIb
III C
NSTE-ACS=Non ST-segment elevation acute coronary syndrome; PCI=Percutaneous coronary intervention, STEMI=ST-segment elevation myocardial infarction
Sources:
†Jneid H et al. JACC 2012;60:
‡O’Gara PT et al. JACC 2013;61:e78-e140

40. C C P2Y12 Receptor Antagonist Recommendations (Continued)
Secondary Prevention I
IIa
IIb
III C
If the risk of morbidity because of bleeding outweighs the anticipated benefit afforded by a P2Y12 receptor antagonist, earlier discontinuation should be considered
Continuation of a P2Y12 receptor antagonist beyond 1 year may be considered in patients undergoing drug eluting stent placement I
IIa
IIb
III C
Sources:
Kushner F et al. JACC 2009;54:
Jneid H et al. JACC 2012;60:
O’Gara PT et al. JACC 2013;61:e78-e140

41. Anticoagulant Therapy Evidence and Guidelines
Evidence for Current Cardiovascular Disease
Prevention Guidelines
Anticoagulant Therapy Evidence and Guidelines

42. Synthesis of Non- Functional Coagulation Factors
Warfarin:
Mechanism of Action
Vitamin K
Antagonism of
Vitamin K
VII
Synthesis of Non- Functional Coagulation Factors IX X II
Vitamin K is required for the carboxylation of clotting proteins II, VII, IX, and X. Without adequate levels of vitamin K, the liver produces partially carboxylated and decarboxylated clotting proteins, which have reduced procoagulant activity. Warfarin interferes with vitamin K dependent production of clotting proteins. Warfarin also decreases protein S levels, which initially creates a prothrombotic state.
Warfarin
Source: Ansell J et al., Council on Clinical Cardiology. American Heart Association, Management of Oral Anticoagulant Therapy, 42

43. Warfarin Evidence: Primary Prevention
Thrombosis Prevention Trial (TPT)
5,499 men at high risk for CHD randomized to aspirin (75 mg), warfarin (mean INR=1.5), warfarin and aspirin, or placebo for 6.4 years WA
N=1277 W
N=1268 A P
N=1272
MI and coronary death (primary end point)
71 (0.87%)
83 (1.03%)
83 (1.02%)
107 (1.33%)
Stroke
29 (0.36%)
22 (0.27%)
18 (0.22%)
26 (0.32%)
All cause mortality
103 (1.24%)
95 (1.14%)
113 (1.36%)
110 (13.1%)
RRR of ischemic heart disease events compared to placebo
34% (p=0.006)
21% (p=0.02)
20% (p=0.04)
N/A
The Thrombosis Prevention Trial evaluated the effect of low dose oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischemic heart disease (IHD).
The primary end point was an IHD composite, defined by the sum of coronary death and fatal and non-fatal myocardial infarction (MI). Warfarin reduced the primary end point by 21% (95% CI 4-35, P=0.02) due to a 39% reduction (95% CI 15-57, P=0.003) in fatal events and reduced all-cause mortality by 17% (95% CI 1-30, P=0.04). The main effect of aspirin was a reduction in the primary end point by 20% (95% CI 1-35, P=0.04), almost entirely due to a 32% reduction (95% CI 12-48, P=0.004) in non-fatal events. Absolute reductions in the primary end point due to warfarin or aspirin were 2.6 and 2.3 per 1,000 person years, respectively. Combination therapy with warfarin and aspirin reduced the primary end point by 34% (95% CI 11-51%, P=0.006) compared with placebo, but increased hemorrhagic and fatal strokes.
Overall: Aspirin and warfarin to INR of 1.5 are equally efficacious in the reduction of first time MI, stoke and mortality. Warfarin + aspirin was more effective at reducing primary IHD events, but with a higher risk of hemorrhagic and ischemic strokes.
Warfarin provides similar efficacy to aspirin
A=Aspirin, CHD=Coronary heart disease, P=Placebo, W=Warfarin, WA=Warfarin and aspirin
Source: The Medical Research Council’s General Practice Research Framework. Lancet 1998;351: 43

44. Warfarin Evidence: Secondary Prevention
Meta-analysis of 31 trials comparing the effects of oral anticoagulation with and without aspirin on CV outcomes
Events prevented per 1000 patients treated (95% CI)
Major bleeds per 1000 patients treated (95% CI)
High intensity OA vs. control
98 (73-123)
39 (35-43)
Moderate intensity OA vs. control
24 (22-26)
35 (21-49)
Moderate to high intensity OA and ASA vs. ASA
54 (43-65)
16 (10-22)
Moderate to high intensity OA vs. ASA
13 (11-14)
14 (12-16)
Low intensity OA and ASA vs. ASA
7 (6-8)
5 (4-6)
This meta-analysis was designed to analyze the effects of long-term oral anticoagulation (OA), stratified by the intensity of anticoagulation and aspirin therapy, on outcomes in patients with CAD.
Compared to placebo, high-intensity (INR ) OA produced significant reductions in mortality, MI, and thromboembolic complications (including stroke), but with a 6-fold increased risk of major bleeding (including hemorrhagic stroke). Compared to placebo, moderate (INR 2-3) OA produced significant reductions in MI, stroke, but not death and had an 8-fold increased risk of major bleeding.
Compared to aspirin therapy, moderate or high-intensity OA (INR>2) produced no reduction in death, MI, or stroke, and was associated with a 2.4 fold increased risk of major bleeding. Compared to aspirin therapy, low-intensity OA (INR, <2) + aspirin produced no significant reduction in death, MI, or stroke, nor a significant increased risk of major bleeding. Compared to aspirin therapy alone, moderate or high-intensity OA (INR>2) + aspirin produced a 56% reduction in death, MI, or stroke, and was associated with a 1.6 fold increased risk of major bleeding that did not reach statistical significance.
Overall: High intensity OA (INR ) is an option for reducing CVD risk. In patients with an indication for moderate to high intensity OA (INR>2), the addition of aspirin is associated with fewer CVD events, but greater bleeding risk than OA alone.
Warfarin plus aspirin reduces the rate of adverse events with a higher rate of major bleeding
ASA=Aspirin, CI=Confidence interval, CV=Cardiovascular, OA=Oral anticoagulation
Source: Anand SS et al. JAMA 1999;282: 44

45. Warfarin Evidence: Secondary Prevention
Warfarin, Aspirin, or Both After Myocardial Infarction (WARIS II) Trial
3,630 patients following a myocardial infarction randomized to warfarin (INR ), aspirin (160 mg daily) or warfarin (INR ) plus aspirin (75 mg daily) for a mean of 4 years
Warfarin plus aspirin reduces the rate of adverse events with a higher rate of major bleeding
Type of Bleeding
A (n)
W (n)
W + A (n)
Cerebral 1 5 3 GI 6 18 21
Other 7 4
Total 8 33 28
Rate**
0.62%
0.17% *
The WARIS II trial enrolled 3,630 patients under the age of 75 years hospitalized with an acute myocardial infarction* and randomized them to one of three groups: Warfarin (in a dose intended to achieve an INR of 2.8 to 4.2), aspirin (160 mg daily), or aspirin (75 mg daily) combined with warfarin (in a dose intended to achieve an INR of 2.0 to 2.5). Patients were excluded if they had malignant disease or poor compliance was anticipated.
The primary outcome, a composite of death, nonfatal reinfarction, or thromboembolic cerebral stroke, occurred in 20.0% of patients receiving aspirin alone, 16.7% of patients receiving warfarin alone, and 15% of patients receiving warfarin and aspirin. The difference between the two groups receiving warfarin was not statistically significant. As compared with aspirin alone, the risk reduction in patients receiving warfarin plus aspirin was 29 percent (P=0.001) and in those receiving warfarin alone it was 19 percent (P=0.03). The reduction in the primary endpoint was driven by a decrease in non-fatal reinfarction and thromboembolic stroke.
Episodes of major, nonfatal bleeding were observed in 0.62% of patients per treatment-year in both groups receiving warfarin and in 0.17% of patients receiving aspirin (P<0.001). Major bleeding episodes** were not more frequent among patients receiving aspirin plus warfarin than among those receiving warfarin alone, but the incidence of minor bleeding episodes was higher in the combined-therapy group.
*Acute myocardial infarction was defined by the 1979 WHO recommendation - two or more of the following: a history of typical chest pain, electrocardiographic changes typical of myocardial infarction, and a creatine kinase level greater than 250 U per liter, an aspartate aminotransferase level greater than 50 U per liter, or both, of probable cardiac origin.
**Major bleeding episodes were defined as nonfatal cerebral hemorrhage or bleeding necessitating surgical intervention or blood transfusion.
*Composite of death, reinfarction, and stroke
**p<0.001
A=Aspirin, W=Warfarin
Source: Hurlen M et al. NEJM 2002;347:

46. Warfarin Evidence: Secondary Prevention
Clinical Trial Comparing Combined Warfarin and Aspirin With Aspirin Alone in Survivors of Acute Myocardial Infarction (CHAMP)
5059 patients within 14 days of a myocardial infarction randomized to aspirin (162 mg daily) or warfarin (INR ) plus aspirin (81 mg daily) for 2.7 years
Warfarin plus aspirin provides no greater benefit compared to treatment with aspirin alone
The CHAMP study was a randomized open-label study to compare the efficacy of warfarin (INR 1.5 to 2.5) plus aspirin (81 mg daily) with the efficacy of aspirin monotherapy (162 mg daily) in reducing the total mortality in 5,059 patients enrolled within 14 days of myocardial infarction and followed for a median of 2.7 years. Secondary end points included recurrent myocardial infarction, stroke, and major hemorrhage. Four hundred thirty-eight (17.3%) of 2537 patients assigned to the aspirin group and 444 (17.6%) of 2522 patients assigned to the combination group died (log-rank P=0.76).
Recurrent myocardial infarction occurred in 333 patients (13.1%) taking aspirin and in 336 patients (13.3%) taking combination therapy (log-rank P=0.78). Stroke occurred in 89 patients (3.5%) taking aspirin and in 79 patients (3.1%) taking combination therapy (log-rank P=0.52).
Major bleeding occurred more frequently in the combination therapy group than in the aspirin group (1.28 versus 0.72 events per 100 person years of follow-up, respectively; P<0.001). There were 14 individuals with intracranial bleeds in both the aspirin and combination therapy groups.
This trial failed to show a clinical benefit of adding warfarin to aspirin for secondary prevention. The results of this trial are in contrast to the WARIS II trial. Of note, the INR goal for the WARIS II trial was and patients were followed for 4 years.
W + A A
W + A A
W + A A
W + A A
A=Aspirin, CVD=Cardiovascular disease, INR=International normalized ratio, MI=Myocardial infarction, W=Warfarin
Source: Fiore LD et al. Circulation 2002;105:

47. Routine use of warfarin after MI does not reduce all-cause mortality
Warfarin Evidence:
Secondary Prevention
Meta-analysis of 24,542 patients with recent MI comparing warfarin-containing regimens (OAC) with or without aspirin to non-warfarin-containing regimens with or without aspirin (No OAC)
Routine use of warfarin after MI does not reduce all-cause mortality
In this meta-analysis of 24,542 secondary prevention patients, there was no difference in all cause mortality between patients receiving warfarin containing regimens with or without aspirin compared to non-warfarin containing regimens with or without aspirin.
All-case Mortality
CI=Confidence interval, MI=Myocardial infarction OAC=Oral anticoagulant
Source: Figure 2 in Haq SA et al. Am J Med; 2010;123:

48. Warfarin and Antiplatelet Therapy in Heart Failure (WATCH) Trial
Warfarin Evidence:
Secondary Prevention
Warfarin and Antiplatelet Therapy in Heart Failure (WATCH) Trial
1,587 patients with HF and LVSD (EF <0.35) randomized to aspirin (162 mg), clopidogrel (75 mg), or warfarin (mean INR=2.6) for 23 months
Clopidogrel and warfarin provide no greater benefit than aspirin in LVSD
Outcome
Aspirin (n=523)
Warfarin
(n=540)
Clopidogrel
(n=524)
Death, MI, or stroke (%)
20.5
19.8
21.8
HF hospitalizations (%)
22.2
16.1
18.3
Major bleeding (number of episodes) 19 30
13*
The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial prospectively randomized symptomatic heart failure patients in sinus rhythm with an ejection fraction <35% to treatment with open-label warfarin (target INR ) or double-blind antiplatelet therapy with aspirin (162 mg) or clopidogrel (75 mg).
Although the trial was designed to enter 4,500 patients, it was terminated 18 months prematurely in June 2003 by the VA Cooperative Study Program because of poor enrollment, resulting in a reduction in power to achieve the original objective. Nonetheless, the results demonstrated no significant benefit to warfarin or clopidogrel over aspirin for the specified end points.
Overall: Anti-platelet/anticoagulation recommendations are not impacted by left ventricular systolic dysfunction.
*p=0.012 vs warfarin
EF=Ejection fraction, HF=Heart failure, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction
Source: Massie BM, et al. Circulation 2009;119: 48

49. A + W provide comparable benefit to A + C but with greater bleeding
Warfarin Evidence:
Secondary Prevention
Meta-analysis of 61,905 patients with CV disease comparing treatment regimens with aspirin plus warfarin, aspirin plus clopidogrel, or aspirin alone
A + W provide comparable benefit to A + C but with greater bleeding * *
Odds Ratio** * * * * * *
This meta-analysis included 10 studies comparing Aspirin (A) + Warfarin at an INR of 2 to 3 versus Aspirin (A) alone and 3 studies comparing Aspirin (A) + Clopidogrel (C) versus Aspirin (A) alone. A+W versus A+C were studied using an adjusted indirect comparison.
Each combined approach yielded a significantly lower risk of major adverse events, with albeit an increased risk of major bleeds, compared with aspirin alone. No significant difference was found for A + W versus A + C for risk of overall major adverse events, death, or acute MI. However, A + W (as compared to A + C) was associated with a significantly lower risk of thromboembolic stroke (OR 0.53, 95% CI 0.31 to 0.88, number needed to treat 60) and all types of stroke (OR 0.58, 95% CI 0.35 to 0.94, p = 0.038), with an increased risk of major bleeds (OR 1.9, 95% CI 1.2 to 2.8, number needed to harm 300).
*p<0.05
**Include all-cause mortality, acute MI, thromboembolic stroke, major bleeds, and other types of stroke
A=Aspirin, C=Clopidogrel, P=Placebo, W=Warfarin
Source: Testa L et al. Am J Cardiol. 2007;99(12): 49

50. Warfarin provides no greater benefit than aspirin in LVSD
Warfarin Evidence:
Secondary Prevention
Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial
2305 patients with LV systolic dysfunction (mean LV EF of 25%) and sinus rhythm randomized to warfarin or aspirin
Warfarin provides no greater benefit than aspirin in LVSD 10
7.93
7.47
Events*/100 Patient-Years 5
Warfarin
Aspirin
P=0.4
*Composite of death, ischemic stroke, or intracerebral hemorrhage
LVSD=Left ventricular systolic dysfunction
Homma S et al. NEJM 2012;366:

51. Triple Antithrombotic Therapy Evidence: Secondary Prevention
Retrospective analysis of 40,812 patients admitted with a first myocardial infarction in a national registry in Denmark
This analysis used a nationwide registry in Denmark that included 40,812 patients aged 30 years or older who had been admitted to hospital with a first-time myocardial infarction between 2000 and Claimed prescriptions starting at hospital discharge were used to determine the regimen prescribed according to the following groups: monotherapy with aspirin, clopidogrel, or vitamin K antagonist; dual therapy with aspirin plus clopidogrel, aspirin plus vitamin K antagonist, or clopidogrel plus vitamin K antagonist; or triple therapy including all three drugs.
During a mean follow-up of days (SD 142.0), 1,891 (4.6%) patients were admitted to the hospital with bleeding. The yearly incidence of bleeding was 2.6% for the aspirin group, 4.6% for clopidogrel, 4.3% for vitamin K antagonist, 3.7% for aspirin plus clopidogrel, 5.1% for aspirin plus vitamin K antagonist, 12.3% for clopidogrel plus vitamin K antagonist, and 12.0% for triple therapy.
With aspirin as a reference, the adjusted hazard ratios for bleeding were 1.33 (95% CI ) for clopidogrel, 1.23 ( ) for vitamin K antagonist, 1.47 ( ) for aspirin plus clopidogrel, 1.84 ( ) for aspirin plus vitamin K antagonist, 3.52 ( ) for clopidogrel plus vitamin K antagonist, and 4.05 ( ) for triple therapy. Numbers needed to harm were 81.2 for aspirin plus clopidogrel, 45.4 for aspirin plus vitamin K antagonist, 15.2 for clopidogrel plus vitamin K antagonist, and 12.5 for triple therapy.
A total of 702 (37.9%) of 1,852 patients with non-fatal bleeding had recurrent myocardial infarction or died during the study period compared with 7,178 (18.4%) of 38,960 patients without non-fatal bleeding (HR 3.00, , p<0.0001).
Treatment with triple therapy or dual therapy with clopidogrel plus vitamin K antagonist should be prescribed only after thorough individual risk assessment.
Triple antithrombotic therapy significantly increases the rate of bleeding
Source: Sorensen R et al. Lancet 2009;374:

52. Dual antithrombotic therapy significantly reduces CV risk and bleeding
Warfarin Evidence:
Secondary Prevention
What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary Stenting (WOEST) Trial
573 patients undergoing PCI with an indication for oral anticoagulation randomized to double versus triple antithrombotic therapy*
Days
TIMI bleeding (%) 30 60 90
120
180
270
365 0%
10%
20%
30%
40%
50%
Triple therapy
44.9%
Days
Cumulative incidence of death, myocardial infarction, target vessel revascularizaton , stroke and stent trhombosis 30 60 90
120
180
270
365 0% 5%
10%
15%
20%
Triple therapy
17.7%
Double therapy
Double therapy
11.3%
19.5%
Dual antithrombotic therapy significantly reduces CV risk and bleeding
*Triple therapy=Aspirin (80 mg/day), clopidogrel, and OAC, Double therapy=Clopidogrel and OAC
OAC=Oral anticoagulant
Source: Presented at the Eurospean Society of Cardiology Congress, August 2012

53. A B Warfarin Recommendations Secondary Prevention
Use of warfarin in conjunction with aspirin and/or a P2Y12 receptor antagonist is associated with an increased risk of bleeding, and patients and clinicians should watch for bleeding, especially GI, and seek medical evaluation for evidence of bleeding
Warfarin either without (INR ) or with low-dose aspirin (81 mg daily, INR ) may be reasonable for patients at high CAD risk and low bleeding risk who do not require or are intolerant of a P2Y12 receptor antagonist I
IIa
IIb
III A I
IIa
IIb
III B
CAD=Coronary artery disease, INR=International normalized ratio
Source: Jneid H et al. JACC 2012;60: 53

54. B C Warfarin Recommendations (Continued) Secondary Prevention
IIa
IIb
III B
The addition of warfarin (INR ) may be reasonable for patients with a NSTE-ACS who have an indication for anticoagulation*
Targeting oral anticoagulant therapy to a lower INR ( ) might be reasonable in patients with a NSTE-ACS or STEMI managed with aspirin and a P2Y12 receptor antagonist I
IIa
IIb
III C
*Indications for anticoagulation include: atrial fibrillation; left ventricular thrombus; or central, venous, or pulmonary emboli
INR=International normalized ratio, NSTE-ACS=Non ST-segment elevation acute coronary syndrome, STEMI=ST-segment elevation myocardial infarction
Sources:
Jneid H et al. JACC 2012;60:
O’Gara PT et al. JACC 2013;61:e78-e140 54

55. C C C Warfarin Recommendations (Continued) Secondary Prevention
Anticoagulation therapy with a Vitamin K antagonist should be provided to patients with STEMI and atrial fibrillation with CHADS2 score >2, mechanical heart valves, venous thromboembolism, or hypercoagulable disorder
Anticoagulant therapy with a Vitamin K antagonist is reasonable for patients with STEMI and asymptomatic LV mural thrombi (Class IIa, Level C) and may be considered for patients with STEMI and anterior-apical akinesis or dyskinesis (Class IIb, Level C) I
IIa
IIb
III C I
IIa
IIb
III C I
IIa
IIb
III C
LV=Left ventricular, STEMI=ST-segment elevation myocardial infarction
Source: O’Gara PT et al. JACC 2013;61:e78-e140 55

56. C Warfarin Recommendations (Continued) Secondary Prevention
The duration of triple antithrombotic therapy with a Vitamin K antagonist, aspirin, and a P2Y12 receptor antagonist should be minimized to the extent possible to limit the risk of bleeding. I
IIa
IIb
III C
Source: O’Gara PT et al. JACC 2013;61:e78-e140 56