Antiplatelet Therapy for Secondary Prevention of Stroke
Author Affiliations: From the Division of Cerebrovascular Diseases, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
Abstract: Stroke is a leading cause of death and disability in the United States and worldwide. It preferentially affects older adults and has high risk of recurrence. Because of the aging population, the burden will increase greatly; thus, the need for secondary prevention strategies is crucial. Antiplatelet therapy remains paramount in prevention of recurrent vascular events following stroke or transient ischemic attack. Aspirin, clopidogrel, and the combination of aspirin plus extended-release dipyridamole are all effective in reducing the risk of recurrent vascular events. The use of either clopidogrel or the combination of aspirin plus extended-release dipyridamole may be more effective than aspirin alone for secondary stroke prevention. Current guidelines endorse any of these antiplatelet agents (including aspirin) as appropriate treatment options. Choosing antiplatelet agents must be tailored according to patient characteristics, cost, and tolerability. (Annals of Long-Term Care: Clinical Care and Aging 2009;17[3]:13-17)
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Introduction
Stroke is a leading cause of death and disability in the United States and worldwide. Each year, about 795,000 people have a stroke in the United States, and close to 25% of them (185,000) are recurrent attacks.1 The economic consequences of stroke are substantial. The estimated direct and indirect cost of stroke in 2009 is $68.9 billion.1
Patients who have experienced a cerebrovascular event are at high risk of a recurrence, as well as an increased risk of myocardial infarction (MI) and sudden cardiac death.2,3 Given the higher risk of stroke in older people, the need for secondary prevention is even greater to decrease the burden of cerebrovascular diseases. Antiplatelet therapy remains a cornerstone to preventing recurrent vascular events in symptomatic cerebrovascular disease.
In this article, we review the evidence from randomized trials for established and emerging antiplatelet therapies for secondary stroke prevention, and provide evidence-based recommendations for their use.
Efficacy of Antiplatelet Therapies
Since the early 1990s, the role of antiplatelet therapy in reducing the risk of recurrent vascular events in patients with a history of stroke or transient ischemic attack (TIA) has become increasingly clear. The Antiplatelet and Antithrombotic Trialists’ collaboration4 analyzed 195 randomized clinical trials (144,051 patients) comparing antiplatelet therapy with placebo in the prevention of stroke, MI, and vascular death among patients with an increased risk of occlusive vascular disease. Patients treated with an antiplatelet agent (primarily aspirin) had a 25% relative risk reduction (RRR) in nonfatal stroke as compared with placebo. The benefit of antiplatelet therapy was independent of sex, age (greater or less than 65 yr), diabetes, or hypertension. In a subset of patients with prior stroke/TIA, the odds reduction was 22%.
On the other hand, stopping antiplatelet therapy in high-risk patients increases the risk of stroke.5,6 Aspirin, the combination of aspirin with extended-release (ER) dipyridamole, clopidogrel, and others have been studied separately and have been shown to provide effective secondary prevention for patients after ischemic stroke; some will be discussed in this review.
Aspirin
Aspirin is the first agent to be used for secondary stroke prevention and remains the most commonly prescribed. Its antiplatelet properties relate to the irreversible inhibition of the enzyme cyclooxygenase, which in turn reduces production of thromboxane A2 (stimulator of platelet aggregation).
In 1991, three European trials demonstrated the effects of aspirin in secondary prevention of stroke.7-9 This was supported by a meta-analysis by the Antithrombotic Trialists’ collaboration, where the majority of patients received aspirin.4 In addition, in Algra and van Gijn’s10 meta-analysis, which included 10 randomized controlled trials, showed that aspirin therapy reduced the risk of all serious vascular events by 13% (ie, stroke, MI, and vascular death) (relative risk [RR], 0.87%; 95% confidence interval [CI], 0.81-0.94) in patients with previous ischemic stroke or TIA. Similar results were demonstrated in the European Stroke Prevention Study 2 (ESPS-2).11 The dose of aspirin used in studies ranged from 20-1300 mg per day. Most data indicate that lower-dose aspirin (50-325 mg/d) could be as effective in secondary stroke prevention as a higher dose and have fewer side effects.4,8,9,12-14 Based on those observations and laboratory data,15 the guidelines recommended dosing from 81-325 mg per day for secondary stroke prevention.
Generally, aspirin is well tolerated, and the major side effects are gastrointestinal (GI)-related, which may be reduced with lower doses. It also increases the RR of any major bleeding, major GI bleeding, and intracranial bleeding by 1.7- to 2.1-fold. However, the absolute annual increase in risk for any major bleeding episode (mostly GI) and for intracranial bleeding was 0.13% and 0.03%, respectively.16
Clopidogrel
Clopidogrel is a thienopyridine that inhibits adenosine diphosphate (ADP)-dependent platelet aggregation. Inhibition of platelet aggregation starts 2 hours after a single oral dose and reaches steady state usually by 1 week. In the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial,17 19,185 patients with ischemic stroke, MI, or claudication were randomly assigned to treatment with aspirin or clopidogrel. The primary endpoint, a composite outcome of stroke, MI, or vascular death, was significantly reduced with clopidogrel treatment (RRR, 8.7%), as compared with aspirin treatment (P = 0.043), with no increase in bleeding. Within the subgroup of participants with previous ischemic stroke, the RR was 7.3%; but this difference was not statistically significant (P = 0.26). However, in the subset of patients with peripheral arterial disease (PAD), the benefit favoring clopidogrel over aspirin was significant (P = 0.0028).17
More recently, the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial showed that clopidogrel monotherapy and aspirin plus dipyridamole ER have similar risks and benefits for secondary stroke prevention.18
The side-effect profile of clopidogrel is favorable compared with aspirin, with lower GI discomfort and bleeding. The yearly rate of symptomatic intracranial hemorrhage was comparable in both groups. Rash and diarrhea were more frequent with clopidogrel.16,17 Thrombotic thrombocytopenic purpura is very rare but has been reported with clopidogrel use.
Aspirin plus Dipyridamole
Dipyridamole inhibits platelet aggregation and acts as an arterial vasodilator by inhibiting the activity of adenosine deaminase and phosphodiesterase deaminase. It is a weak direct platelet inhibitor, but its action is primarily on the vascular endothelium, decreasing platelet adhesion to the endothelium. Although some studies have shown the effectiveness of dipyridamole alone for secondary stroke prevention,11,18 current recommendation for secondary stroke prevention is for combined therapy only.19-21
Data supporting the use of combined therapy came from ESPS-2, where the combination reduced the risk of stroke by 22.1 (95% CI, 9% to 33%) as compared to aspirin alone.11 This was later confirmed by the European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT).22
In ESPRIT, a total of 2739 patients with cerebrovascular events were randomly assigned to aspirin or the aspirin-plus-dipyridamole combination. Over a mean follow-up of 3.5 years, the composite primary outcome (death from all vascular causes, nonfatal stroke, nonfatal MI, or major bleeding complication) was significantly less frequent in the aspirin-plus-dipyridamole group than the aspirin group (13% vs 16%; hazard ratio [HR], 0.80; 95% CI, 0.66-0.98), with an absolute RR of 1.0% per year.22
A meta-analysis of all six trials found that the combination of aspirin plus dipyridamole was associated with significant lower RR of serious vascular events (RR, 0.82; 95% CI, 0.74-0.91) and stroke (RR, 0.77; 95% CI, 0.67-0.89) as compared with aspirin alone.23 In the ESPS-2 and ESPRIT studies, the risk of bleeding was the same in aspirin monotherapy and the combination therapy. Headache was the most frequent adverse event, occurring more in subjects age 55 years and older (up to 40%) and in women.18 Thought to be due to its vasodilatory effects, it is mostly self-limited and resolves within a week. However, it remains the most frequent reason cited for medication discontinuation.
Dual Therapy With Aspirin and Clopidogrel
Although the combination of aspirin and clopidogrel was more effective than monotherapy in patients with acute coronary syndromes,24-27 the Management of AtheroThrombosis with Clopidogrel in High-risk patients with recent transient ischemic attack or ischemic stroke (MATCH) and Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trials, which evaluated the dual therapy against monotherapy with clopidogrel and aspirin, respectively, do not offer significant added benefits for stroke prevention than using monotherapy. Concerningly, the combination nearly doubled the risk of bleeding as compared with monotherapy.28,29 However, in a subgroup analysis of the CHARISMA trial, it was found that in the population with any vascular event (MI, stroke, or symptomatic PAD) the aspirin-clopidogrel combination significantly reduced the risk of recurrent ischemic events without increasing the rate of severe bleeding.30
In a pilot study that evaluated the use of a brief course of dual antiplatelet therapy with aspirin and clopidogrel for treatment of high-risk patients with recent TIA, the risk of stroke (ischemic or hemorrhagic) at 90 days was shown to be 11% in patients treated with aspirin alone and 7% in those treated with clopidogrel and aspirin. This 36% RRR is not statistically significant (P = 0.19)31 and needs be investigated in a larger trial. Therefore, in the absence of cardiac indications, dual therapy with aspirin and clopidogrel is not recommended for long-term stroke prevention because of the lack of greater efficacy when compared with monotherapy and the associated increased risk of bleeding.19,20
The PRoFESS trial compared the effects of aspirin plus dipyridamole ER versus clopidogrel alone for secondary prevention in patients with noncardioembolic ischemic stroke. A total of 20,332 patients were enrolled and randomized to each treatment arm. During a mean follow-up of 2.5 years, there was no difference between treatment with aspirin plus dipyridamole and clopidogrel for the primary outcome of recurrent stroke (9.0 vs 8.8%, HR 1.01; 95% CI, 0.92-1.11). Also, there was no difference in composite secondary outcome of stroke, MI, or vascular death (13.1 vs 13.1%; HR, 0.99; 95% CI, 0.92-1.07). The risk-benefit ratio, expressed as the combination of recurrent stroke plus major hemorrhage, was not significantly different between the two treatment groups (11.7 vs 11.4%; HR 1.03; 95% CI, 0.95-1.11). The discontinuation of the treatment in this study occurred more in the patients taking aspirin plus dipyridamole than those taking clopidogrel, largely because of headaches (5.9% vs 0.9%, respectively).32
Other Antiplatelets
Ticlopidine is an antiplatelet agent shown to reduce the risk of recurrent stroke.33-35 Its pharmacologic effects are similar to clopidogrel. Side effects of ticlopidine include diarrhea, abdominal distress, skin eruptions, and rare yet serious hematological side effects (neutropenia and thrombotic thrombocytopenic purpura). Because of its safety profile and presence of other effective antiplatelet therapies, ticlopidine use is rare.
Cilostazol acts as an antiplatelet agent similarly to dipyridamole by inhibiting phosphodiesterase activity and suppressing breakdown of cyclic adenosine monophosphate; it also has a vasodilatory effect on the endothelium to decrease platelet adherence to the endothelium. In the Cilostazol Stroke Prevention Study (CSPS), over a mean follow-up of about 1.5 years, cilostazol treatment achieved a significant RRR of 41.7% (95% CI, 9.2%-62.5%) in the recurrence of cerebral infarction as compared with the placebo treatment (P = 0.0150).36 Patients reported headache often after first using cilostazol. The medication is not Food and Drug Administration–approved in the United States for cerebrovascular indications but has been used widely for peripheral vascular occlusive disease.
Triflusal, which is also not approved in the United States, is a selective cyclooxygenase-2. It is structurally related to aspirin with similar efficacy at preventing vascular events after stroke.37-39 It has, however, a lower rate of hemorrhagic complications.
The advent of drugs that are antagonists of the glycoprotein (GP) platelet llb/llla complex gives promise of even more effective inhibition of platelet functions. The platelet GP llb/llla complex is the site of binding to adhesive proteins, including fibrinogen. Binding to fibrinogen activates platelet aggregation and adhesion to blood vessels. Abciximab is a humanized monoclonal antibody that binds to the GP llb/llla complex on platelets. Abciximab has been used mostly acutely and intravenously in patients after invasive coronary and cerebral revascularization procedures. This drug produces a profound impairment of the function of platelets similar to a temporary thrombasthenia so that the rate of bleeding is potentially high. GP llb/llla–inhibiting agents that can be used orally and chronically are now being tested but to date have been associated with excess bleeding, and have not been introduced into clinical practice.40-42
Summary
The effectiveness of antiplatelet drugs in reducing the risk of recurrent vascular events in patients with cerebrovascular disease is now well established, and their efficacy is independent of patient age. However, given a higher risk of stroke in older people, the need for secondary prevention is even greater.
Current guidelines from the American Heart Association/American Stroke Association (AHA/ASA) and the American College of Chest Physicians (ACCP) state that aspirin, clopidogrel, and the combination of aspirin plus dipyridamole ER are all acceptable options to be used in patients with noncardioembolic stroke or TIA to reduce the risk of recurrence.
Available data may suggest the use of either clopidogrel or the combination of aspirin plus dipyridamole ER over aspirin monotherapy for secondary prevention of stroke. Nevertheless, aspirin remains the first-line treatment by many experts because of well-established efficacy, availability, and low cost. When prescribing aspirin, a dose of 50-100 mg daily could be as effective as high doses with fewer side effects. In patients allergic to aspirin, clopidogrel is a reasonable alternative.
The combination of aspirin and clopidogrel, which is effective in patients with acute coronary syndrome, has not been shown to be either more effective or safe, compared with either agent alone in patients who have had a stroke.
Choosing one antiplatelet therapy over the other for an individual patient, and choosing antiplatelet treatment over anticoagulants or other treatments such as surgery or endovascular interventions, will depend highly on the specific cause and cardio-cerebrovascular-hematological lesions present in that individual. Treatment must also be tailored in light of patient characteristics, cost, and tolerability.
Dr. Caplan has been on the advisory boards for Boehringer Ingelheim, Genentech, Reneuron, NovoVision Neurologica Corporation, and Avanir; he has been an advisory consultant for AstraZeneca, Bayer, Takeda Pharmaceuticals, CoAxia, Millenium, Jones-Davis, and Novo Nordisk; and he has been on speaker bureaus for Boehringer Ingelheim, Bristol-Myers Squibb, Sanofi-Synthelabo, AstraZeneca, and Otsuka.
The other authors report no relevant financial relationships.
