Among patients at high risk for cardiovascular events, does combination aspirin plus clopidogrel therapy provide greater protection against cardiovascular events than aspirin alone?
Among patients at high risk for cardiovascular events, combination aspirin plus clopidogrel did not significantly reduce the rates of MI, stroke, or death from CV causes. There was increased bleeding with combination therapy.
Aspirin prevents some, but certainly not all, cardiovascular (CV) events among high-risk patients. CAPRIE and other trials demonstrated that the P2Y12 receptor inhibitor clopidogrel further reduced rates of CV events. Combination therapy with aspirin plus clopidogrel has been used successfully in ACS in CURE, CREDO, CLARITY-TIMI, and COMMIT. It was not known whether the benefits of dual antiplatelet therapy would extend to the non-ACS setting.
The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study enrolled 15,603 patients with stable CAD or otherwise at high-risk of CV events. Patients were randomized to either combination aspirin plus clopidogrel or aspirin monotherapy and followed prospectively for CV events including MI, stroke, or death due to CV cause. With median follow-up of 2.3 years, rates of composite outcome of MI, stroke, or CV-related death were observed at similar rates between groups (6.8% vs. 7.3%). There was increased bleeding in the combination therapy group.
Post hoc subgroup analyses demonstrated that among symptomatic patients, CV events were less frequent with combination therapy. Also, combination therapy was associated with fewer non-fatal strokes compared to aspirin monotherapy (2.4% vs. 1.9%). There was no difference in outcomes between patients who had previously received antiplatelet therapy and those who had not.
In practice, low-dose daily aspirin should be considered for all adults greater than 50 with risk factors for CV events. Patients who experienced a CV event on aspirin monotherapy, or those with an aspirin allergy, may benefit from clopidogrel monotherapy. However, CHARISMA and other studies have helped establish dual antiplatelet inhibition for few patients other than those after cardiac bypass surgery or coronary stent placement. A substudy of the CHARISMA patients helped support the hypothesis that dual antiplatelet therapy following TIA/stroke may be superior to monotherapy.
ACCF/AHA CV primary prevention (2009, adapted)
- Aspirin 75-162 mg/day recommended for all patients with coronary artery disease unless contraindicated (Class 1, level A)
- Clopidogrel 75mg once daily is recommended for patients if they are intolerant or allergic to aspirin (Class I, Level B)
AHA CVD and stroke primary prevention (2014, adapted) 
- For patients with noncardioembolic ischemic stroke or TIA, use antiplatelet agents rather than oral anticoagulation (Class I; Level A).
- Aspirin (50–325 mg/d) monotherapy (Class I; Level of Evidence A) or the combination of aspirin 25 mg and extended-release dipyridamole 200 mg twice daily (Class I; Level B) is indicated as initial therapy after TIA or ischemic stroke for secondary prevention.
- Clopidogrel (75 mg) monotherapy is a reasonable option for secondary prevention of stroke in place of aspirin or combination aspirin/dipyridamole (Class IIa; Level B). This recommendation also applies to patients who are allergic to aspirin.
- The combination of aspirin and clopidogrel might be considered for initiation within 24 hours of a minor ischemic stroke or TIA and for continuation for 90 days (Class IIb; Level B). (New recommendation in 2014 Update in response to the CHANCE trial results)
- The combination of aspirin and clopidogrel, when initiated days to years after a minor stroke or TIA and continued for 2 to 3 years, increases the risk of hemorrhage relative to either agent alone and is not recommended for routine long-term secondary prevention after ischemic stroke or TIA (Class III; Level A).
USPSTF Aspirin for CVD prevention (2009, adapted)
- Strongly recommends aspirin use in men 45-79 years if risk reduction of having a myocardial infarction outweighs the risk of a gastrointestinal bleed. (Grade A)
- Strongly recommends aspirin use in women 55-79 years if risk reduction of having a myocardial infarction MI outweighs the risk of a gastrointestinal bleed GI harm. (Grade A)
ACCP CVD primary and secondary prevention (2012, adapted)
- For primary prevention of coronary artery disease, low dose aspirin (75-100 mg/day is suggested over no therapy in patients ≥50 without symptomatic cardiovascular disease. (Grade 2B)
- Prospective, multicenter, randomized, double-blind, placebo controlled study
- N=15,603 patients with either clinically evident cardiovascular disease or multiple risk factors
- Clopidogrel plus aspirin (n=7,802)
- Placebo plus aspirin (n=7,801)
- Medium follow up: 28 months
- Analysis: Intention-to-treat
- Age ≥ 45 years of age plus one of the following conditions:
- Multiple atherothrombotic risk factors
- Documented coronary disease
- Documented cerebrovascular disease
- Documented symptomatic peripheral arterial disease
- Taking oral antithrombotic medications or NSAIDs on a long term basis
- Had established indications for clopidogrel therapy (such as recent ACS)
- Were scheduled to undergo revascularization, they could not enroll until after the procedure.
Comparisons are aspirin/clopidogrel vs. aspirin alone.
- Median age: 64 vs. 64 years
- Female: 29.7% vs. 29.8%
- Inclusion subgroup
- Documented vascular disease: 77.7% vs. 78.1%
- Multiple risk factors: 21.3% vs. 20.8%
- Neither group: 1.0% vs. 1.1%
- Baseline drug use:
- Diuretic: 48.2% vs. 47.1%
- Nitrate: 23.2% vs. 24.1%
- Beta-blocker: 55% vs. 55.7%
- ACE inhibitor: 64% vs. 64.6%
- ARB: 25.5% vs. 25.9%
- Statin: 76.8% vs. 76.9%
- Antidiabetic medication: 41.8% vs. 41.5%
- All patients received aspirin 75-162 mg per day
- Randomized to receive either clopidogrel 75 mg per day or placebo
- All patients also received standard therapy as appropriate (eg, statins and beta-blockers)
- Follow-up at 1, 3, and 6 months, and then every 6 months until trial end.
Comparisons are intensive therapy vs. standard therapy.
- Primary efficacy end point (first occurrence of myocardial infarction, stroke or death from cardiovascular causes)
- 6.8% vs. 7.3% (RR 0.93; 95% CI 0.83-1.05; P=0.22)
- Myocardial Infarction
- 1.9% vs. 2.0% (RR 0.94; 95% CI 0.75-1.18; P=0.059)
- 1.9% vs. 2.4% (RR 0.79; 95% CI 0.64-0.98; P=0.03) NNT= 200
- Death from cardiovascular causes
- 3.1% vs. 2.9% (RR 1.04; 95% CI (0.87-1.25; P=0.68)
- Severe bleeding (GUSTO definition)
- 1.7% vs. 1.3% (RR 1.25; 95% CI 0.97 -1.61; P=0.09)
- Moderate bleeding
- 2.1% vs. 1.3% (RR 1.62; 95% CI 1.27-2.08; P<0.001) NNH= 125
- Secondary efficacy end point (first occurrence of myocardial infarction, stroke, death from cardiovascular causes, or hospitalization for unstable angina, transient ischemic attack, or a revascularization procedure)
- 16.7% vs. 17.9% (RR 0.92; 95% CI, 0.86-0.995; P=0.04)
- Clinically evident atherothrombosis
- 6.9% vs. 7.9% (RR 0.88; 95%, 0.77-0.998; P=0.046)
The subgroup analysis supporting a benefit of dual anti-platelet therapy in symptomatic patients was not pre-planned. These results should be taken as hypothesis-generating given their implicit biases.
- Sanofi-Aventis and Bristol-Myers Squibb
- Pfeffer M, et al. "The charisma of subgroups and the subgroups of CHARISMA.” NEJM 2006;355:1744-1746.
- Correspondence: Clopidogrel for the Prevention of Atherothrombotic Events. N Engl J Med 2006; 355:418-421.
- Hankey G, et al. "Effect of clopidogrel plus ASA vs. ASA early after TIA and ischaemic stroke: a substudy of the CHARISMA trial." Int J Stroke 2011;6(1):3-9.
- Redberg RF, et al. "ACCF/AHA 2009 performance measures for primary prevention of cardiovascular disease in adults." Journal of the American College of Cardiology. 2009;54(14):1364-1405.
- Kernan WN et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014. 45:2160-236.
- National Guideline Clearing House. "Guideline summary: Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement." Guideline.gov. Published 2009-06-30. Accessed 2014-09-09.
- Vandvik PO, et al. "Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines." Chest. 2012;141(2 sup):e637S-e668S.