- 1 Clinical Question
- 2 Bottom Line
- 3 Major Points
- 4 Guidelines
- 5 Design
- 6 Population
- 7 Interventions
- 8 Outcomes
- 9 Criticisms
- 10 Funding
- 11 Further Reading
In patients with recent ischemic CVA or TIA, does clopidogrel plus aspirin reduce recurrent events when compared to clopidogrel alone?
Addition of aspirin to clopidogrel therapy in patients with prior ischemic CVA or TIA did not reduce rates of recurrent ischemic CVA or TIA or related complications. Combination therapy conferred a great risk of major bleeding, including life-threatening hemorrhage.
The evidence-based use of aspirin in cerebrovascular disease was initially based upon early trials such as IST (1997) and Chinese Acute Stroke Trial (1997), which demonstrated a clear benefit of the antiplatelet agent in secondary prevention of ischemic CVA and TIA. This was confirmed in the 2002 Antithrombotic Trialists' Collaboration meta-analysis. The use of clopidogrel was initially based upon extrapolation from studies of CAD, and then from direct study in the CAPRIE trial (1996). CURE (2001) and CREDO (2002) demonstrated a clear benefit of combination therapy with aspirin plus clopidogrel compared to aspirin alone in CAD, but combination therapy had not yet been studied in cerebrovascular disease. MATCH sought to compare combination therapy with aspirin plus clopidogrel to clopidogrel alone in secondary prevention of ischemic stroke/TIA.
Published in 2004, the Management of Atherothrombosis with Clopidogrel in High-risk patients (MATCH) study randomized 7,599 patients with recent ischemic stroke/TIA and at least one additional CV risk factor to either combination therapy with aspirin plus clopidogrel or single-agent clopidogrel. At a mean follow-up of 18 months, MATCH failed to demonstrate a statistically significant difference in efficacy between the two groups. However, there were more major bleeding events with combination therapy, including life-threatening bleeding.
MATCH was criticized for including patients who would not likely have benefited from antiplatelet therapy as the majority of patients had lacunar infarcts rather than atherothrombotic events. The subsequent CHANCE trial (2013) demonstrated a benefit from dual antiplatelet therapy in Chinese patients with high-risk TIAs and minor ischemic strokes in the acute (rather than recent) care setting. The NIH-sponsored Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial is currently enrolling, and will investigate a similar approach to dual antiplatelet therapy in US patients.
2014 AHA/ASA Secondary Stroke Prevention Guidelines 
- For patients with noncardioembolic ischemic stroke or TIA, the use of antiplatelet agents rather than oral anticoagulation is recommended to reduce the risk of recurrent stroke and other cardiovascular events (Class I; Level of Evidence 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 of Evidence B) is indicated as initial therapy after TIA or ischemic stroke for prevention of future stroke. (Revised recommendation)
- Clopidogrel (75 mg) monotherapy is a reasonable option for secondary prevention of stroke in place of aspirin or combination aspirin/dipyridamole (Class IIa; Level of Evidence B). This recommendation also applies to patients who are allergic to aspirin.
- The selection of an antiplatelet agent should be individualized on the basis of patient risk factor profiles, cost, tolerance, relative known efficacy of the agents,and other clinical characteristics (Class I; Level of Evidence C).
- 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 of Evidence B). (New recommendation in 2014 Update)
- 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 of Evidence A).
- For patients who have an ischemic stroke or TIA while taking aspirin, there is no evidence that increasing the dose of aspirin provides additional benefit. Although alternative antiplatelet agents are often considered, no single agent or combination has been adequately studied in patients who have had an event while receiving aspirin (Class IIb; Level of Evidence C).
- For patients with a history of ischemic stroke or TIA, AF, and CAD, the usefulness of adding antiplatelet therapy to VKA therapy is uncertain for purposes of reducing the risk of ischemic cardiovascular and cerebrovascular events (Class IIb; Level of Evidence C).
- Unstable angina and coronary artery stenting represent special circumstances in which management may warrant DAPT/VKA therapy. (New Recommendation in 2014 Update)
- Multicenter, randomized, placebo-controlled trial
- Enrollment: 2000-2002
- Setting: 507 stroke/neurology centers in 28 countries
- Analysis: Intention-to-treat
- Mean follow-up: 18 months
- N=7,599 patients with recent stroke and ≥1 additional CV risk factor
- Aspirin plus clopidogrel (n=3,797)
- Clopidogrel (n=3,802)
- Primary outcome: First occurrence of ischemic stroke, MI, CV death, or hospitalization for acute ischemic event
- Ischemic stroke/TIA in prior 3 months
- ≥1 risk factors in past 3 years:
- Ischemic stroke
- Angina pectoris
- Diabetes mellitus
- Symptomatic PAD
- Age <40 years
- Severe comorbid conditions
- Increased risk of bleeding
- Scheduled for major surgery or vascular surgery
- Contraindications for aspirin or clopidogrel
- Demographics: Age 66 years, female: 37%
- Qualifying event: TIA: 21%, ischemic stroke: 79%
- Mean time from event to randomization:
- <7 days: 19%
- 7-31 days: 49%
- >31 days: 32%
- Modified Rankin Scale:
- 0-2 (none to slight disability): 73%
- 3 (moderate disability): 15%
- 4 (severe disability): 12%
- TOAST classification:
- Small artery (lacunar): 53%
- Large artery: 34%
- Cardioembolic: 2%
- Etiology unknown: 11%
- Risk Factors: Previous ischemic stroke 27%, previous TIA 19%, previous MI 5%, angina pectoris 13%, symptomatic PAD 10%, hypertension 78%, diabetes mellitus 68%, hyperlipidemia 56%, past or current smoker 38%
Randomized to aspirin (75 mg) plus clopidogrel (75 mg) daily or clopidogrel (75 mg) plus matching placebo
Comparisons are aspirin/clopidogrel vs. clopidogrel.
- First occurrence of ischemic stroke, MI, CV death, or hospitalization for acute ischemic event*
- *Unstable angina, worsening PAD needing intervention, or TIA
- 16% vs. 17%. (P=0.244)
- MI: 2% in each group (P=0.660)
- Ischemic stroke: 8% vs. 9% (P=0.353)
- CV death: 3% in each group (P=0.854)
- Any stroke
- 9% in each group (P=0.790)
- 5% in each group (P=0.992)
There were no differences in the primary outcome for ischemic stroke vs. TIA, time from randomization, age, sex, certain PMH (HTN, DM, ischemic CVA, TIA, MI, angina, or PAD), or PSH (cardiac surgery, vascular surgery)
- Life-threatening bleeding: 3% vs. 1% (Difference +1.26%; 95% CI +0.64 to +1.88%; P<0.0001)
- Major bleeding: 2% vs. 1% (Difference +1.36%; 95% CI +0.86 to +1.86%; P<0.0001)
- Minor bleeding: 3% vs. 1% (Difference +2.16%; 95% CI +1.51 to +2.81%; P<0.0001)
- Most patients had lacunar/microangiopathic CVA, which the authors think may not be of "true atherothrombotic origin" and may be at an increased bleeding risk
- Bleeding risks may be outweighed in certain scenarios that were not evaluated in this trial
- No functional platelet assays reported to detect response to the antiplatelet medications
- Since up to 80% of those involved had a qualifying event while on aspirin, the design may have included individuals who were unlikely to benefit from aspirin therapy in the first place
- Was not a comparison of the first line treatment: aspirin monotherapy
- The primary outcome did not balance potential benefits from stroke reduction to the risks of bleeding
Sponsored by the manufacturers of Plavix (the brand name of clopidogrel), Sanofi-Synthelabo Research and Bristol Myers Squibb
- Chen ZM et al. CAST: randomized placebo-controlled trial of early aspirin use in 20,000 patients with acute ischemic stroke Lancet (1997): 349.9,066; 1-641.
- "Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients". BMJ 324 (7329): 71–86. January 2002.
- Steinhubl SR, et al. "Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention." JAMA (2002):288;19:2411-2420.
- Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial homepage. Accessed 2013-07-08.
- 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.
- PDF File - Modified Rankin Scale
- The Lancet letters to the editor