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.
Conclusions about dipyridamole
ESPS-2, ESPRIT, and the meta-analysis by Leonardi-Bee et al showed that aspirin plus dipyridamole is more effective than placebo or aspirin alone in secondary prevention of vascular events, including stroke. Also, extended-release dipyridamole appears to be more effective.
Unfortunately, many patients stop taking dipyridamole because of side effects (primarily headache).
Based on the results of ESPRIT, the absolute benefit of dipyridamole used alone may be small.
CLOPIDOGREL: SIMILAR TO ASPIRIN IN EFFICACY?
Like dipyridamole, clopidogrel targets adenosine diphosphate to prevent clot formation, blocking its ability to bind to its receptor on platelets. It is a thienopyridine and, unlike its sister drug ticlopidine, does not seem to be associated with the potentially serious side effects of neutropenia. However, a few cases of thrombotic thrombocytopenic purpura have been reported.28 The other drugs in this class have not been evaluated in clinical trials for secondary stroke prophylaxis.
Trials of clopidogrel
CAPRIE.29 The Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events trial, in 1996, was one of the first to compare the clinical use of clopidogrel against aspirin. It was a randomized controlled noninferiority trial in patients over age 21 (inclusion criteria: ischemic stroke, MI, or peripheral arterial disease) randomized to aspirin 325 mg once daily or clopidogrel 75 mg once daily. Patients were followed for 1 to 3 years.
Patients on clopidogrel had a relative risk reduction of 8.7% in primary events (ischemic stroke, MI, or vascular death); patients on aspirin were at significantly higher risk of gastrointestinal hemorrhage. Patients with peripheral arterial disease as the qualifying event did particularly well on clopidogrel, with a significant relative risk reduction of 23.8%.
Limitations of the CAPRIE trial included its inability to measure the effect of treatment on individual outcomes, particularly stroke, and the fact that the relative risk reduction for patients with stroke as the qualifying event was not significant (P = .66). Another limitation was that it did not use TIA as an entry criterion or as part of the composite outcome. Also, the relative risk reduction had a wide confidence interval, and a large number of patients discontinued therapy for reasons other than the defined outcomes.
Nevertheless, the CAPRIE trial showed clopidogrel to be an effective antiplatelet prophylactic, particularly in patients with peripheral artery disease, but with no discernible difference from aspirin for those patients with MI or stroke as a qualifying event.
MATCH.30 The Management of Atherothrombosis With Clopidogrel in High-risk Patients trial hoped to better assess clopidogrel’s efficacy, particularly in patients with ischemic cerebral events. Cardiac studies leading up to MATCH suggested that adding a thienopyridine to aspirin might offer additive benefit in reducing the rate of vascular outcomes.15,31 MATCH randomized high-risk patients (inclusion criteria were ischemic stroke or TIA and a history of vascular disease) to clopidogrel or to aspirin plus clopidogrel.
There was a nonsignificant 6.4% relative risk reduction in the combined primary outcome of MI, ischemic stroke, vascular death, other vascular death, and re-hospitalization for acute ischemic events in the aspirin-plus-clopidogrel group compared with clopidogrel alone. However, this came at the cost of double the number of bleeding events in the combination group, mitigating most of the benefit of combination therapy.
An important caveat in interpreting the results of MATCH, as compared with the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study, is that aspirin was being added to clopidogrel, not vice versa. CURE, which looked at the addition of clopidogrel to aspirin vs aspirin alone in cardiac patients, found a significant reduction of ischemic events taken as a group (relative risk 0.8), and a trend toward a lower rate of stroke (relative risk 0.86, but 95% confidence interval encompassing 1) for aspirin plus clopidogrel vs aspirin alone.31 However, patients in the CURE trial did not have high-risk vasculopathy per se but rather non-ST-elevation MI, perhaps skewing the benefit of combination therapy and lessening the risk of intracranial bleeding.
CHARISMA.32 The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial, like the CURE trial, compared aspirin plus clopidogrel vs aspirin in patients with established cardiovascular, cerebrovascular, or peripheral arterial disease, or who were at high risk of events. As in the MATCH study, the findings for combination therapy were a nonsignificant relative risk of 0.93 for primary events (MI, stroke, or death from cardiovascular causes), and a significant reduction of secondary end points (primary end point event plus TIA or hospitalization for unstable angina) (relative risk 0.92, P = .04).
Importantly, combination therapy significantly increased the rate of bleeding events. In asymptomatic patients (those without documented vascular disease but with multiple atherothrombotic risk factors), there was actually harm with combined treatment. Conversely, for symptomatic patients (those with documented vascular disease), there was a negligible, but significant reduction in primary end points.
The result was that in patients with documented vascular disease, aspirin plus clopidogrel combination therapy provided little or no benefit over aspirin alone. For patients with elevated risk factors but no documented vascular burden, there may actually be harm from combination therapy.
PRoFESS.33 Logically following is the question of whether aspirin plus dipyridamole offers any benefit over clopidogrel as a stroke prophylactic. The Prevention Regimen for Effectively Avoiding Second Strokes trial hoped to answer this by comparing clopidogrel against aspirin plus dipyridamole, both with and without telmisartan, in patients with recent stroke.
The rate of recurrent stroke was similar in the two groups, but there were 25 fewer ischemic strokes in patients on aspirin plus dipyridamole, offset by an increase in hemorrhagic strokes. Rates of secondary outcomes of stroke, death, or MI were nearly identical between the groups. Early discontinuation of treatment was significantly more frequent in those patients taking aspirin plus dipyridamole, meaning better compliance for those taking clopidogrel.
Initially, patients were to be randomized to either aspirin plus dipyridamole or aspirin plus clopidogrel. However, after MATCH30 demonstrated a significantly higher bleeding risk with aspirin plus clopidogrel, patients were changed to clopidogrel alone. But despite this, the bleeding risk was still higher with aspirin plus dipyridamole.
During the trial, the entry criteria were expanded, allowing for the inclusion of younger patients and those with less recent strokes; but despite this change, the study remained underpowered to demonstrate its goal of noninferiority. Thus, it showed only a trend of noninferiority of clopidogrel vs aspirin plus dipyridamole.
What the clopidogrel trials tell us
Clopidogrel confers a benefit similar to that of aspirin (as shown in the CAPRIE study).29 Although aspirin plus dipyridamole confers greater benefit than aspirin alone (as shown in the ESPS-2,14 Leonardi-Bee,25 and ESPRIT26 studies), aspirin plus dipyridamole is not superior to clopidogrel, and may even be inferior.34
WARFARIN FOR ATRIAL FIBRILLATION ONLY
Warfarin acts by disrupting the coagulation cascade rather than acting at the site of platelet plug formation. In theory, warfarin should be as effective as the antiplatelet drugs in preventing clot formation, and so it was thought to possibly be effective in preventing stroke of arterial origin.
However, in at least three studies, warfarin increased the risk of death, MI, and hemorrhage, with perhaps a slight decrease in the risk of recurrent stroke in patients with suspected stroke or TIA.35–37 This should be differentiated from stroke originating from cardiac dysrhythmias, for which warfarin has clearly been shown to be beneficial.28
THREE GOOD MEDICAL OPTIONS FOR PREVENTING STROKE RECURRENCE
Antiplatelet therapy offers benefit in the primary and secondary prevention of stroke, with a 25% reduction in the rate of nonfatal stroke and a 17% reduction in the rate of death due to vascular causes.15
