Combination Anti-Platelet Therapy: Does it Have a Role in the Prevention of Stroke?

Abstracts & Commentary

By Dana Leifer, MD, Associate Professor, Neurology, Weill Medical College, Cornell University. Dr. Leifer reports no financial relationship relevant to this field of study.

Synopsis: The ESPRIT trial found that aspirin combined with dipyridamole reduced the long-term risk of recurrent vascular events in stroke and TIA patients, compared with a low dose of aspirin, alone. In contrast, the CHARISMA trial did not find a significant difference between outcomes with combined aspirin/clopidogrel treatment compared to aspirin alone in patients with documented vascular disease or multiple atherothrombotic risk factors.

Sources: Bhatt DL, et al. Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events. N Engl J Med. 2006;354:1706-1717; Halkes PH, et al. Aspirin Plus Dipyridamole versus Aspirin Alone After Cerebral Ischaemia of Arterial Origin (ESPRIT): Randomised Controlled Trial. Lancet. 2006;367:1665-1673.

The role of anti-platelet therapy in stroke prevention is well established. The American Stroke Association guidelines for stroke prevention (Stroke 2006;37:577) recommend that patients with noncardioembolic ischemic stroke or TIA be treated with antiplatelet therapy. However, the optimal anti-platelet regimen or optimal dosage has not been established. The ESPRIT and CHARISMA trials provide new data about the benefits and risks of combining 2 antiplatelet drugs compared to a single agent.

The ESPRIT trial randomized patients within 6 months of TIA or minor stroke to aspirin (30 to 325 mg/day) alone, or combined with dipyridamole 200 mg twice daily. The primary outcome measure was a composite of stroke, myocardial infarction (MI), vascular death, or major bleeding. Thirteen percent of patients on combination therapy reached the primary end point compared to 17% of those on aspirin, alone, with an absolute risk reduction of 1% per year (95% confidence limits 0.1-1.8 on the basis of intention to treat). There was no significant difference in bleeding complications between the 2 treatment groups. The results confirm the ESPS-2 trial, which showed that aspirin plus dipyridamole was more effective in preventing vascular events than aspirin alone, at a dose of 50 mg/d.

A major problem with ESPRIT is that the dose of aspirin was left to the discretion of the treating physician. Forty-eight percent of the patients were treated with 50 mg/day or less of aspirin, and only 5% were treated with at least 300 mg/day. The low dose that many of the patients received may not have been adequate and may explain why there was a significant difference from the aspirin/dipyridamole combination.

The CHARISMA trial compared outcomes with clopidogrel 75 mg combined with aspirin (75 to 162 mg/day) to outcomes with clopidogrel 75 mg alone. The study followed 15,603 patients with documented atherosclerosis or with multiple atherothrombotic risk factors. The primary end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes. During the trial, 6.8% of patients taking both drugs reached the end point, whereas 7.3% of those taking only aspirin reached the end point. The difference was not significant. The main conclusion was that there is no benefit to adding clopidogrel to aspirin in patients who met the entry criteria.

However, there was a small but significant benefit to combined therapy for the secondary end point of MI, stroke, cardiovascular death, or hospitalization for unstable angina, TIA, or a revascularization procedure. The event rate was 16.7% for combination therapy and 17.9% for aspirin (P = 0.04).

The benefits of combined therapy with clopidogrel and aspirin came at the price of increased rates of severe bleeding (1.7% vs 1.3%) and moderate bleeding (2.1% vs 1.3%; P < 0.001) compared to aspirin alone. These results are similar to those of the MATCH trial, which found no benefit to combined aspirin and clopidogrel therapy compared to clopidogrel alone after ischemic stroke or TIA, and found a significant increase in the rate of hemorrhagic complications (Lancet. 2004;364:331).

The CHARISMA investigators also reported differences between patients who qualified for the study on the basis of established cardiovascular disease vs those who qualified because of multiple risk factors. The disease group was defined as patients with MI, TIA, or stroke within 5 years, symptomatic multivessel coronary disease, multiple coronary interventions or bypass surgery, or claudications and an abnormal ankle-brachial index. Seven percent of patients in this group who were treated with combined aspirin and clopidogrel reached the primary end point, whereas 7.9% treated with aspirin alone did not (P = 0.046, relative risk 0.88).

Among the asymptomatic patients with multiple risk factors, the rate of primary events increased from 5.5% with aspirin alone to 6.6% with combined therapy. This was not statistically significant, but the results suggest that there may be a difference between symptomatic and asymptomatic patients.

With regard to stroke prevention, 2.4% of the total group of patients taking aspirin had a nonfatal stroke, whereas only 1.9% of patients taking combined therapy had a stroke, but this difference is not significant.

Commentary

The CHARISMA trial suggests that there is no significant benefit to combining aspirin and clopidogrel for long-term prevention of vascular events. There is a small benefit for symptomatic patients, but the combination may actually be harmful for asymptomatic patients. In contrast, the ESPRIT trial suggests that aspirin and dipyridamole are better for prevention of recurrent ischemic events and death after stroke than aspirin alone, but many of the ESPRIT patients received low doses of aspirin. Additional work is needed to define specific patients who may benefit from combined therapy for long-term prevention, and to assess the role of combined therapy in the first days or weeks after a stroke or TIA when the risk of recurrence is especially high. In addition, more research is needed regarding the differential anti-platelet effects of these medications, singly and in combination. Hopefully, the recently developed assays for platelet resistance will aid us in tailoring our therapy for each patient to achieve maximum benefit.