Antiplatelet therapy to prevent recurrent stroke: Three good options
ABSTRACTDrugs that prevent platelets from sticking together—ie, aspirin, dipyridamole, and clopidogrel—are an important part of therapy to prevent recurrence of ischemic stroke of atherosclerotic origin. We discuss current indications for these drugs and review the evidence behind our current use of aspirin, dipyridamole, and clopidogrel.
KEY POINTS
- After a stroke, antiplatelet therapy lowers the rate of recurrent nonfatal stroke by about 25%.
- Aspirin is the most established, best tolerated, and least expensive of the three approved drugs.
- Adding dipyridamole to aspirin increases the efficacy, with a 22% reduction in relative risk, but only a 1% reduction in absolute risk.
- Clopidogrel is similar in efficacy to aspirin and to dipyridamole.
- All three agents are regarded as equal and appropriate for secondary prevention of stroke; the choice is based on individual patient characteristics.
- A small number of strokes result from atherosclerotic disease of the common carotid bifurcation, and patients with symptomatic carotid disease can be treated with the combination of surgery or stenting and drug therapy, or with drug therapy alone.
What is the optimal aspirin dose?
Studies of aspirin have used different daily doses—the earliest studies used large doses of 1,000 to 1,500 mg.6–10
Boysen et al11 in 1988 found a trend toward benefit (not statistically significant) with doses ranging from 50 mg to 100 mg.
In 1991, three separate studies found that higher doses of aspirin were no more effective than lower doses.
The UK-TIA trial12 compared aspirin 300 mg vs 1,200 mg and found a higher risk of gastrointestinal bleeding with the higher dose.
The SALT Collaborative Group13 found 75 mg to be effective.
The Dutch TIA trial16 compared 30 mg vs 283 mg; end point outcomes were similar but the rate of adverse events was higher with 283 mg.
ESPS-2 was able to show efficacy at a dose of only 50 mg.14
Taylor et al17 compared lower doses (81 or 325 mg) vs higher doses (650 or 1,300 mg) for patients undergoing carotid endarterectomy and found that the risk of adverse events was twice as high with the higher doses.
The ATT Collaboration15 found that efficacy was 40% lower with the highest dose of aspirin than with the lowest doses.
Algra and van Gijn18 performed a meta-analysis of all these studies and found no difference in risk reduction between low-dose and high-dose aspirin, with an overall relative risk reduction of 13% at any dose above 30 mg.
Campbell et al,19 in a 2007 review, found that doses greater than 300 mg conferred no benefit, and that rapid and maximum suppression of thromboxane A2 can be achieved by chewing or ingesting dissolved forms of aspirin 162 mg.
Conclusion. Aspirin doses higher than 81 mg (the US standard) confer no greater benefit and may even decrease the efficacy of aspirin. In an emergency, rapid suppression of thromboxane A2 can be achieved by chewing a minimum dose of 162 mg.
DIPYRIDAMOLE CAN BE ADDED TO ASPIRIN
In 1967, Weiss and Aledort5 found that aspirin’s antiplatelet effect could be blocked by adenosine diphosphate, which is released by activated platelet cells and is an essential part of thrombus formation. Adjacent platelets are then activated, leading to up-regulation of thromboxane A2 and glycoprotein IIb/IIIa receptors and resulting in a cascade of platelet activation and clot formation.20 Dipyridamole inhibits aggregation of platelets by inhibiting their ability to take up adenosine diphosphate.
Studies of dipyridamole
AICLA.9 Bousser et al9 randomized patients who suffered one or more cerebral or retinal infarctions to receive placebo, aspirin 1 g, or aspirin 1 g plus dipyridamole 225 mg. Aspirin was significantly better than placebo in preventing a recurrence of stroke. The event rate with aspirin plus dipyridamole was similar to the rate with aspirin alone, although on 2-by-2 analysis, the difference between placebo and aspirin plus dipyridamole did not reach statistical significance. However, the rate of carotid-origin stroke was 17% with aspirin alone and 6% with aspirin plus dipyridamole, a statistically significant difference.
Thus, this study confirmed the benefit of aspirin in preventing ischemic events but did not fully support the addition of dipyridamole, except in preventing stroke of carotid origin. The study had a number of limitations: the sample size was small, TIA was not included as an end point, computed tomography was not required for entry, and many patients were lost to follow-up, decreasing the statistical power of the trial.
The ESPS study21 was also a randomized controlled trial of aspirin plus dipyridamole vs placebo. But unlike AICLA, ESPS included patients with TIA.
ESPS found a 38.1% relative risk reduction in stroke with aspirin plus dipyridamole compared with placebo, and a 30.6% reduction in death from all causes. Interestingly, patients who had a TIA as the qualifying event had a lower end-point incidence and larger end-point reduction than those who had a stroke as the qualifying event. However, ESPS did not resolve the question of whether adding dipyridamole to aspirin affords any benefit over aspirin alone.
ESPS-214 hoped to answer this question. Patients were randomized to placebo, aspirin, dipyridamole, or aspirin plus dipyridamole. On 2 × 2 analysis, the dipyridamole group had a 16% lower rate of recurrent stroke than the placebo group, and patients on aspirin plus dipyridamole had a 37% lower rate. Aspirin plus dipyridamole yielded a 23.1% reduction compared with aspirin alone, and a 24.7% reduction compared with dipyridamole alone. Similar benefit was reported for the end point of TIA with combination therapy compared with either agent alone.
However, nearly 25% of patients had to withdraw because of side effects, particularly in the dipyridamole-alone and aspirin-dipyridamole groups, and, as mentioned above, verification of compliance in the aspirin group was an issue.14,22 Nevertheless, ESPS-2 clearly showed that aspirin plus dipyridamole was better than either drug alone in preventing recurrent stroke. It also showed the effectiveness of dipyridamole, which AICLA and ESPS could not do, because it had a larger study population, used a lower dose of aspirin, and perhaps because it used an extended-release form of dipyridamole.23
The ATT meta-analysis15 showed a clear benefit of antiplatelet therapy. However, much of this benefit was derived from aspirin therapy, with the addition of dipyridamole resulting in a nonsignificant 6% reduction of vascular events. Most of the patients on dipyridamole were from the ESPS-2 study. In effect, the ATT was a meta-analysis of aspirin, as aspirin studies dominated at that time.
A Cochrane review24 publsihed in 2003 attempted to rectify this by analyzing randomized controlled trials of dipyridamole vs placebo.24 Like the ATT meta-analysis, it did not bear out the benefits of dipyridamole: compared with placebo, there was no effect on the rate of vascular death, and only a minimal benefit in reduction of vascular events—and this latter point is only because of the inclusion of ESPS-2.
Directly comparing aspirin plus dipyridamole vs aspirin alone, the reviewers found no effect on the rate of vascular death, and with the exclusion of ESPS-2, no effect on vascular events.
The Cochrane review had the same limitation as the ATT meta-analysis, ie, dependence on a single trial (ESPS-2) to show benefit, and perhaps the fact that ESPS-2 was the only study that used an extended-release form of dipyridamole.
Leonardi-Bee et al25 performed a meta-analysis that overcame the limitation of ESPS-2 being the only study at the time with positive findings: they used pooled individual patient data from randomized trials and analyzed them en masse. Patients on aspirin plus dipyridamole had a 39% lower risk than with placebo and a 22% lower risk than with aspirin alone. Unlike the ATT and the Cochrane review, excluding ESPS-2 did not alter the statistically significant lower stroke rate with aspirin plus dipyridamole compared with controls. This meta-analysis helped to confirm ESPS-2’s finding of the additive effect of aspirin plus dipyridamole compared with aspirin and placebo control.
ESPRIT.26,27 The European/Australasian Stroke Prevention in Reversible Ischaemia Trial confirmed these findings. This randomized controlled trial compared aspirin plus dipyridamole against aspirin alone in patients with a TIA or minor ischemic stroke of arterial origin within the past 6 months. For the primary end point (death from all vascular causes, nonfatal stroke, nonfatal MI, nonfatal major bleeding complication), the hazard ratio was 0.80 favoring aspirin plus dipyridamole, with a number needed to treat of 104 over a mean of 3.5 years (absolute risk reduction of 1% per year). Importantly, twice as many patients taking aspirin plus dipyridamole discontinued the medication.
Caveats to interpreting this study are that it was not blinded, the aspirin doses varied (although the median aspirin dose—75 mg—was the same between the two groups), and not all patients received the extended-release form of dipyridamole.
