Long-term antithrombotic therapy for the secondary prevention of ischemic stroke

INTRODUCTION — Antiplatelet therapy is used for both the management of acute ischemic stroke and for the prevention of stroke. Antiplatelet therapy reduces the incidence of stroke in patients at high risk for atherosclerosis and in those with known symptomatic cerebrovascular disease.

Antiplatelet therapy for secondary stroke prevention will be reviewed here. Antiplatelet therapy for acute ischemic stroke and for primary stroke prevention is discussed separately. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack" and "Overview of primary prevention of cardiovascular disease".)

Prevention of recurrent stroke with antithrombotic therapy in patients with atrial fibrillation is reviewed elsewhere. (See "Atrial fibrillation in adults: Use of oral anticoagulants".)

IMMEDIATE TREATMENT — Short-term antithrombotic therapy after acute ischemic stroke or transient ischemic attack (TIA) may differ from long-term therapy. Antithrombotic treatment for patients in the first days to weeks after the onset of acute ischemic stroke or TIA, including the short-term use of dual antiplatelet therapy, is summarized in the algorithms (algorithm 1 and algorithm 2) and discussed in detail separately. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".)

Importantly, despite evidence of benefit with short-term use in acute ischemic stroke, aspirin and clopidogrel should not be used in combination for long-term stroke prevention, given the lack of greater efficacy compared with either agent alone, and given the substantially increased risk of bleeding complications. (See 'Aspirin plus clopidogrel' below.)

LONG-TERM TREATMENT

Choosing therapy — For the long-term secondary prevention of stroke in patients with a history of noncardioembolic ischemic stroke or transient ischemic attack (TIA) of atherothrombotic, lacunar (small vessel occlusive type), or cryptogenic type, we recommend treatment with an antiplatelet agent using either aspirin, clopidogrel, or aspirin-extended-release dipyridamole. (See 'Aspirin' below and 'Clopidogrel' below and 'Aspirin plus dipyridamole' below.)

The choice between aspirin, clopidogrel, and aspirin-extended-release dipyridamole is dependent mainly on patient tolerance, contraindications, availability, and cost. All three are acceptable options for preventing recurrent noncardioembolic ischemic stroke [1,2]. We suggest antiplatelet therapy using either clopidogrel (75 mg daily) as monotherapy or the combination of aspirin-extended-release dipyridamole (25 mg/200 mg twice a day), rather than aspirin alone [1]. Compared with aspirin for the long-term secondary prevention of serious vascular events (ie, nonfatal stroke, nonfatal myocardial infarction, or vascular death), the benefit appears to be modestly greater with clopidogrel alone and with aspirin-extended-release dipyridamole [3]. (See 'Clopidogrel' below and 'Aspirin plus dipyridamole' below.)

Nevertheless, aspirin is often used as the first-line agent [4], given that the apparent modest advantage in benefit of alternative antiplatelet regimens (clopidogrel or aspirin-extended-release dipyridamole) is potentially offset by a disadvantage in cost and access, since aspirin is available without a prescription. In addition, headache and gastrointestinal symptoms have limited the use of aspirin-extended-release dipyridamole [4]. Aspirin use is also associated with a decreased risk of colorectal cancer. (See "NSAIDs (including aspirin): Role in prevention of colorectal cancer" and "Aspirin in the primary prevention of cardiovascular disease and cancer".)

Other antiplatelet agents have a more limited role. Cilostazol is a reasonable option for patients of East Asian ethnicity or for patients with allergies that preclude use of the other recommended antiplatelet medications, but there are no high-quality data regarding the use of cilostazol for secondary stroke prevention in non-East Asian ethnic groups. Also, the twice daily dosing, lower tolerability, and higher cost of cilostazol compared with aspirin may limit its more widespread use for stroke prevention. (See 'Cilostazol' below.)

Aspirin combined with low-dose rivaroxaban (2.5 orally twice a day) is another reasonable treatment option for some patients with non-lacunar, non-cardioembolic ischemic stroke and evidence of systemic atherosclerosis. (See 'Combination antiplatelet and anticoagulant therapy' below.)

Specific clinical situations

Antiplatelet intolerance or allergy — Clopidogrel is an appropriate option for patients unable to tolerate aspirin (including the combination drug aspirin-extended-release dipyridamole) due to allergy or gastrointestinal upset. Cilostazol is a reasonable option if the other agents are not available or tolerated. Ticagrelor is another option for the small subset of patients who cannot take another first-line agent; examples include a patient allergic to aspirin who is also intolerant of clopidogrel or has a clopidogrel CYP2C19 poor metabolizer genotype. (See 'Clopidogrel resistance' below.)

Patients having carotid revascularization — Most patients having carotid endarterectomy are treated with aspirin (81 to 325 mg daily) monotherapy started before surgery and continued indefinitely, barring a long-term indication for anticoagulation such as concomitant atrial fibrillation, while most patients having carotid stenting are treated with aspirin plus clopidogrel for 30 days, followed by long-term single-agent antiplatelet therapy (algorithm 1 and algorithm 2). The use of antiplatelet therapy for patients undergoing carotid endarterectomy or carotid stenting is discussed in greater detail separately. (See "Carotid endarterectomy", section on 'Antiplatelet therapy' and "Overview of carotid artery stenting", section on 'Dual antiplatelet therapy'.)

Patients of East Asian ethnicity — Randomized controlled trial data support the safety and efficacy of cilostazol for secondary stroke prevention in East Asian populations. Therefore, cilostazol is a reasonable antiplatelet treatment option for patients of East Asian ethnicity. Efficacy may be similar in non-East Asian populations, but data are extremely limited. (See 'Cilostazol' below.)

Patients with an indication for anticoagulation — In general, patients with a history of ischemic stroke or TIA due to atrial fibrillation or another condition that requires anticoagulation are not treated with antiplatelet therapy due to the increased risk of bleeding.

Note that a history of cryptogenic stroke, including embolic stroke of undetermined source (ESUS), is generally not an indication for anticoagulation, and antiplatelet therapy is preferred in most such cases. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Embolic stroke of undetermined source' and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Lack of benefit with anticoagulation'.)

Patients with coronary artery disease — Some patients with coronary artery disease have indications for up to 12 months of dual antiplatelet therapy (eg, recent coronary artery stent placement, acute coronary syndrome) or combined antiplatelet and anticoagulant therapy, as reviewed elsewhere. (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients" and "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy" and "Acute ST-elevation myocardial infarction: Antiplatelet therapy" and "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy".)

Decisions regarding antithrombotic therapy for these patients should be individualized in consultation with neurology and cardiology, while accounting for patient preferences.

Limited role of long-term dual antiplatelet therapy for stroke prevention — For the vast majority of patients with a noncardioembolic stroke or TIA, we recommend not using aspirin and clopidogrel in combination for long-term stroke prevention, given the lack of greater efficacy for dual therapy compared with either medicine alone and the substantially increased risk of bleeding complications. (See 'Dual antiplatelet therapy' below.)

Treatment with combination antiplatelet therapy has a limited role in other settings. As examples, selected patients with a recent acute myocardial infarction, other acute coronary syndrome, or arterial stent placement, including carotid stenting, are treated with aspirin plus an oral platelet P2Y₁₂ receptor blocker (ie, clopidogrel, ticagrelor, or prasugrel). In these settings, most patients are not treated with dual therapy indefinitely; the exact duration is influenced by the assessment of bleeding and ischemic risks. Importantly, prasugrel is generally avoided due to an increased risk of bleeding in patients with a history of TIA or stroke, and there are essentially no long-term data for the use of ticagrelor in patients with a history of TIA or stroke.

Recommendations for combination antiplatelet therapy in these settings are discussed elsewhere. (See "Acute ST-elevation myocardial infarction: Antiplatelet therapy" and "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy" and "Antithrombotic therapy for elective percutaneous coronary intervention: General use" and "Long-term antiplatelet therapy after coronary artery stenting in stable patients" and "Overview of carotid artery stenting", section on 'Dual antiplatelet therapy'.)

Prevention of gastroduodenal toxicity — For patients at increased risk of gastroduodenal toxicity from antiplatelet agents, particularly those 75 years of age or older, it is reasonable to coadminister a proton pump inhibitor [5]. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)

Risk of stopping antiplatelet treatment — Stopping antiplatelet therapy in high-risk patients may itself increase the risk of stroke. One study found that 13 of 289 patients hospitalized with cerebral infarction had recently stopped antiplatelet therapy; most had been taking aspirin [6]. In all 13, the antiplatelet agent had been discontinued within 6 to 10 days of stroke onset, a time course consistent with the known lifespan (approximately 10 days) of inhibited platelets. Additionally, a case-control study comparing 309 patients with stroke to 309 matched controls found that discontinuation of aspirin was associated with a significantly increased risk of TIA or ischemic stroke (odds ratio 3.4, 95% CI 1.08-10.63) [7].

Antiplatelet treatment failure — Treatment failure is defined by the occurrence of a thrombotic or ischemic event (eg, stroke, TIA, or other cardiovascular occlusive event) despite adherence to antiplatelet therapy at recommended doses. Some experts prefer the term "breakthrough stroke" for a stroke that occurs despite antiplatelet therapy [8].

●Explanations – Possible explanations for antiplatelet treatment failure include antiplatelet nonresponsiveness or resistance, alternative mechanisms of stroke, poor control of modifiable comorbid stroke risk factors (eg, hypertension, diabetes mellitus, dyslipidemia, smoking, inadequate exercise), and presence of nonmodifiable risk factors (eg, increased age).

Nonadherence to antiplatelet treatment is believed to be the most frequent cause of apparent antiplatelet resistance [9]. The issues of nonresponse and resistance to aspirin, and the effect of enteric coating on antiplatelet activity, are reviewed in detail elsewhere. (See "Nonresponse and resistance to aspirin" and "Clopidogrel resistance and clopidogrel treatment failure".)

●Re-evaluation – In cases of antiplatelet treatment failure, it is important to determine the correct mechanism of stroke, including a thorough evaluation for mechanisms that are unlikely to be optimally treated with antiplatelet therapy. These include atrial fibrillation, paradoxical embolism, hemodynamic insufficiency, inflammatory or infectious vasculopathies, hypercoagulable states (eg, due to cancer), and certain genetic disorders [8].

●Role of laboratory testing – There is no proven role for routinely evaluating patients with antiplatelet treatment failure for aspirin or clopidogrel resistance, whether by laboratory assessment or by genetic testing. (See "Nonresponse and resistance to aspirin", section on 'Laboratory testing' and "Clopidogrel resistance and clopidogrel treatment failure", section on 'Screening'.)

●Treatment considerations – The optimal antiplatelet strategy for breakthrough ischemic stroke is unknown [8]. Options include modifying the antiplatelet regimen by switching to another antiplatelet agent or continuing the existing regimen.

When the most likely mechanism is noncardioembolic ischemic stroke, short-term dual antiplatelet therapy with aspirin plus clopidogrel may be indicated in the acute phase, as illustrated by the algorithm (algorithm 2 and algorithm 1), followed by long-term single agent antiplatelet therapy using aspirin, clopidogrel, or aspirin-extended-release dipyridamole. In general, we suggest switching to a different antiplatelet agent from the one that the patient was taking when the most recent stroke occurred. It is also important to optimize the treatment of other major cardiovascular risk factors (eg, hypertension, dyslipidemia, diabetes). These issues are discussed in detail separately. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Treatment by ischemic mechanism' and "Overview of secondary prevention of ischemic stroke".)

ANTIPLATELET AGENTS

Aspirin — Aspirin, the most commonly used antiplatelet agent, inhibits the enzyme cyclooxygenase, reducing production of thromboxane A2, a stimulator of platelet aggregation. This interferes with the formation of thrombi, thereby reducing the risk of stroke. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

Aspirin is a first-line antiplatelet agent for the secondary prevention of ischemic stroke. (See 'Long-term treatment' above.)

Efficacy — The effectiveness of aspirin for preventing ischemic stroke and cardiovascular events is supported by high-quality data. A 2002 meta-analysis from the Antithrombotic Trialists Collaboration (ATC) included 195 randomized controlled trials of high-risk patients found that antiplatelet treatment led to a 25 percent relative risk reduction in nonfatal stroke compared with placebo [10]. Among the subset of patients with prior cerebrovascular disease (transient ischemic attack [TIA] or stroke), antiplatelet therapy reduced the risk of recurrent stroke, myocardial infarction (MI), or vascular death by 22 percent; the absolute benefit was 36 events prevented per 1000 patients treated for 29 months. The benefit of antiplatelet therapy was independent of sex, age (greater or less than 65), diabetes, and hypertension.

Similarly, a 2009 ATC meta-analysis of 16 placebo-controlled secondary prevention trials showed that aspirin reduced the risk of any serious vascular event by 19 percent and reduced the risk of ischemic stroke by 22 percent [11].

In addition to its benefit for secondary stroke prevention, treatment with aspirin decreases the risk of other cardiovascular events in a wide range of patients with established disease. Furthermore, there is considerable evidence that long-term aspirin use reduces the risk of death from certain cancers. (See "Overview of cancer prevention", section on 'Aspirin and other antiinflammatory drugs' and "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

Early benefit — In a 2016 pooled analysis of data from over 15,000 subjects in 12 trials evaluating aspirin for secondary prevention, the benefit of aspirin was strongest in the early weeks after TIA or ischemic stroke [12]. Aspirin reduced the relative risk of recurrent ischemic stroke within the first six weeks by 58 percent (1 versus 2.4 percent, absolute risk reduction 1.4 percent, hazard ratio [HR] 0.42, 95% CI 0.32-0.55). The benefit of aspirin in this time frame was greatest for the subgroup of patients with TIA or minor stroke (relative risk reduction of 80 percent, absolute risk reduction 0.7 percent, HR 0.19, 95% CI 0.11-0.34). Although the included secondary prevention trials treated few patients in the first days after the index stroke or TIA, similar risk reductions with aspirin were found in trials of aspirin for acute stroke and TIA, as reviewed separately. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Efficacy of aspirin'.)

Dose of aspirin — Given the apparent equivalent benefit of different doses of aspirin for ischemic stroke prevention, and the increased risk of bleeding complications with higher dose aspirin discussed below, we suggest a dose of 50 to 100 mg/day when using aspirin for the secondary prevention of noncardioembolic ischemic stroke. This recommendation is similar to the dose of 75 to 100 mg/day recommended by 2012 guidelines from the American College of Chest Physicians [1]. The 2021 American Heart Association/American Stroke Association guidelines recommend a dose of 50 to 325 mg daily [2].

●Dose and efficacy – The dose of aspirin in secondary stroke prevention studies ranged between 20 to 1300 mg. Most studies have found that 50 to 325 mg/day of aspirin is as effective as higher doses [10,13-18]. Furthermore, lower doses within this range appear to provide the same benefit as higher doses [10,14,18,19]. As an example, a review of 195 trials of secondary prevention by the ATC showed that doses of 75 to 150 mg/day produced the same risk reduction, compared with placebo, as doses of 150 to 325 mg/day [10]. In the ATC analysis of trials directly comparing aspirin <75 mg/day with aspirin ≥75 mg/day, there was no significant difference in effectiveness between the two regimens.

Even lower doses may be effective, as demonstrated in the Dutch TIA Trial [20]. This study found similar efficacy for stroke prevention with 30 mg compared with 283 mg of aspirin per day in patients who had had a TIA or minor ischemic stroke. In the European Stroke Prevention Study-2 (ESPS-2), 50 mg of aspirin daily reduced stroke risk by 18 percent compared with placebo (29 strokes prevented per 1000 treated), an effect of comparable magnitude to the other trials cited above [14]. This benefit seen with very low-dose aspirin is consistent with laboratory observations that 30 mg of aspirin per day results in complete suppression of thromboxane A2 production [21].

●Dose and risk of bleeding – Lower doses of aspirin appear to be associated with less gastrointestinal toxicity [13,20,22]. In the United Kingdom TIA trial, for example, gastrointestinal hemorrhage occurred in 1.6 percent of patients on placebo, 2.6 percent on 300 mg aspirin, and 4.7 percent on 1200 mg aspirin [13]. A similar dose relationship was seen for milder gastrointestinal symptoms.

In an analysis of data from 31 randomized, controlled trials, aspirin doses ≤200 mg/day were associated with a significantly lower rate of major bleeding events compared with higher doses [23]. However, there was no difference in major bleeding when aspirin <100 mg/day was compared with 100 to 200 mg/day. When the overall rate of bleeding complications (including major, minor, and insignificant events) was considered, aspirin <100 mg/day was associated with a lower risk compared with the 100 to 200 mg/day and >200 mg/day groups.

A later meta-analysis of 22 randomized trials of low-dose aspirin (75 to 325 mg/day) versus placebo for cardiovascular prophylaxis reached similar conclusions within the low-dose range [24]. Compared with placebo, aspirin increased the relative risk of any major bleeding, major gastrointestinal bleeding, and intracranial bleeding by 1.7- to 2.1-fold. However, the absolute annual increase in risk for any major bleeding episode (mostly gastrointestinal) and for intracranial bleeding was 0.13 and 0.03 percent, respectively. Furthermore, there was no evidence of an increased risk of bleeding with "high" low-dose aspirin (>162 to 325 mg/day) compared with "low" low-dose aspirin (75 to 162 mg/day).

Aspirin resistance — Proposed mechanisms of aspirin resistance include reduced bioavailability (eg, poor compliance with therapy, reduced absorption, use of enteric-coated aspirin, inadequate dosing, drug interactions), genetic variability (eg, polymorphisms affecting cyclooxygenase-1 [COX-1], cyclooxygenase-2 [COX-2], thromboxane A2 synthase), and other factors (eg, increased isoprostane activity, accelerated platelet turnover from inflammation, infection, surgery, or stress) [8].

There is no established role for routine testing of patients for aspirin resistance/nonresponsiveness. Aspirin nonresponsiveness is rare in compliant patients and is not strongly associated with clinical outcomes in published studies. (See "Nonresponse and resistance to aspirin".)

Adverse effects — The main adverse effects of aspirin involve gastrointestinal toxicity (eg, ulceration, erosion) and an increased risk of gastrointestinal, intracranial, and systemic bleeding. Other adverse effects include renal complications (eg, renal insufficiency and renal failure), angioedema, bronchospasm, rash, hearing loss, tinnitus, hepatoxicity, and both allergic and pseudoallergic reactions. Salicylate toxicity may occur when higher salicylate levels are achieved. (See "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation".)

The potential use of aspirin desensitization to allow for the chronic use of aspirin in individuals who are known to be sensitive or "allergic" is discussed separately. (See "Introduction of aspirin to patients with aspirin hypersensitivity requiring cardiovascular interventions".)

Clopidogrel — Clopidogrel is a thienopyridine that inhibits adenosine diphosphate (ADP)-dependent platelet aggregation. Clopidogrel is a first-line antiplatelet agent for the secondary prevention of ischemic stroke. (See 'Long-term treatment' above.)

Efficacy — The CAPRIE trial randomly assigned 19,185 patients with recent stroke, MI, or symptomatic peripheral artery disease (divided roughly equally between these three enrolling diseases) to treatment with aspirin (325 mg) or clopidogrel (75 mg) [25]. The primary end point, a composite outcome of stroke, MI, or vascular death, was significantly reduced with clopidogrel treatment compared with aspirin treatment (5.3 versus 5.8 percent annually, relative risk reduction 8.7 percent, 95% CI 0.3-16.5 percent, absolute risk reduction 0.5 percent).

The benefit of clopidogrel over aspirin in the CAPRIE trial varied based on enrolling disease [25]. Most of the benefit was observed in patients with peripheral artery disease, and the difference in composite outcome between clopidogrel and aspirin treatment in patients with recent stroke and MI was not significant. However, the strength of these observations is limited since they are based on subgroup analyses.

Dose — The usual dose of clopidogrel monotherapy for secondary stroke prevention is 75 mg daily.

Clopidogrel resistance — Polymorphisms in the hepatic enzymes involved in the metabolism of clopidogrel (eg, CYP2C19, CYP1A2, CYP3A4) or within the platelet P2Y₁₂ receptor may affect the ability of clopidogrel to inhibit platelet aggregation. However, there are no convincing prospective data to support routine testing for clopidogrel resistance with in vitro tests of platelet function or genotyping in patients with cardiovascular disease, particularly for those with a history of stroke or TIA, and the role of platelet function testing remains unclear [2].

The issue of resistance/nonresponse to clopidogrel in cardiovascular disease is discussed in greater detail separately. (See "Clopidogrel resistance and clopidogrel treatment failure".)

Adverse effects — The side effect profile of clopidogrel is favorable compared with aspirin, with a slightly higher frequency of rash and diarrhea, but a slightly lower frequency of gastric upset or gastrointestinal bleeding [24]. Unlike its close relative ticlopidine (see 'Ticlopidine' below), severe neutropenia is not seen more frequently with clopidogrel than with aspirin [25].

Aspirin plus dipyridamole — Dipyridamole impairs platelet function by inhibiting the activity of adenosine deaminase and phosphodiesterase, which causes an accumulation of adenosine, adenine nucleotides, and cyclic adenosine monophosphate (AMP). Dipyridamole may also cause vasodilation.

The discussion below is focused on the role of the combination drug aspirin-extended-release dipyridamole, which is a first-line agent for the secondary prevention of ischemic stroke (see 'Long-term treatment' above). Immediate-release dipyridamole is not routinely recommended for secondary prevention of ischemic stroke, given the limited evidence supporting its effectiveness and the significant pharmacokinetic differences between it and extended-release dipyridamole.

Efficacy — The beneficial effects of aspirin and dipyridamole for secondary stroke prevention appear to be additive such that the combination of aspirin-extended-release dipyridamole is more effective than aspirin alone [14,26,27] and similar in effectiveness to clopidogrel [28].

●More effective than aspirin – In a meta-analysis of six randomized trials with 7648 patients, stroke risk was significantly reduced with aspirin plus dipyridamole (including immediate- and extended-release formulations of dipyridamole) compared with aspirin alone (relative risk 0.77, 95% CI 0.67-0.89) [26]. Nearly 80 percent of the patients in this meta-analysis came from just two trials, ESPS-2 and ESPRIT.

The ESPS-2 trial randomly assigned 6602 patients with a recent TIA or ischemic stroke to one of four groups: 200 mg extended-release dipyridamole alone given twice daily; 25 mg aspirin alone given twice daily; a combination of 25 mg aspirin plus 200 mg extended-release dipyridamole given twice daily; or placebo [14]. At 24 months of follow-up, the risk of stroke compared with placebo was reduced for both extended-release dipyridamole monotherapy (odds ratio [OR] 0.81, 95% CI 0.76-0.99) and aspirin monotherapy (OR 0.79, 95% CI 0.65-0.97). The benefit of combination aspirin-extended-release dipyridamole was greater still than the two components alone and greater than placebo (OR 0.59, 95% CI 0.48-0.73). The stroke rate was lower in the aspirin-extended-release dipyridamole group compared with the aspirin alone group (9.9 versus 12.9 percent, absolute risk reduction 3 percent) [14]. There was no difference in the risk of death or bleeding complications between the two groups, whereas both groups experienced a greater frequency of bleeding complications than the placebo group.

In the later ESPRIT trial, 2739 patients within six months of a TIA or minor stroke of presumed arterial origin were randomly assigned to open-label treatment with aspirin (30 to 325 mg/day) alone or aspirin plus dipyridamole (200 mg twice daily). The median aspirin dose was 75 mg/day in both treatment groups, and the dipyridamole formulation used by most patients (83 percent) was extended release rather than immediate release [27]. 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 less frequent in the aspirin plus dipyridamole group than the aspirin alone group (13 versus 16 percent, HR 0.80, 95% CI 0.66-0.98, absolute risk reduction 1.0 percent per year).

●Efficacy similar to clopidogrel – The PRoFESS trial showed that clopidogrel monotherapy and aspirin-extended-release dipyridamole have similar risks and benefits for secondary stroke prevention [28]. The trial enrolled 20,332 patients with noncardioembolic ischemic stroke and randomly assigned them to treatment with either aspirin-extended-release dipyridamole (25/200 mg twice daily) or clopidogrel (75 mg once daily). At an average follow-up of 2.5 years, there was no difference between treatment with aspirin-extended-release dipyridamole or clopidogrel for the outcome of recurrent stroke (9.0 versus 8.8 percent, HR 1.01, 95% CI 0.92-1.11) or the composite outcome of stroke, MI, or vascular death (13.1 versus 13.1 percent, HR 0.99, 95% CI 0.92-1.07). Despite the nearly identical event rates for these outcomes, the trial failed to meet the prespecified noninferiority criteria for treatment with aspirin-extended-release dipyridamole. Among patients who had recurrent strokes, the rate of recurrent ischemic stroke was slightly lower in those assigned to aspirin-extended-release dipyridamole compared with clopidogrel (7.7 versus 7.9 percent), but hemorrhagic strokes were slightly increased (0.9 versus 0.5 percent). Thus, the net risk (ie, the combination of recurrent stroke plus major hemorrhage) was similar between aspirin-extended-release dipyridamole and clopidogrel (11.7 versus 11.4 percent; HR 1.03, 95% CI 0.95-1.11).

New or worsening heart failure was slightly less frequent in patients assigned to aspirin-extended-release dipyridamole compared with those assigned to clopidogrel; the difference was significant (1.4 versus 1.8 percent, 95% CI 0.62-0.96).

PRoFESS had a 2x2 factorial design in which the patients were also randomly assigned to telmisartan or placebo, the results of which are discussed elsewhere. (See "Antihypertensive therapy for secondary stroke prevention".)

Dose — Aspirin-extended-release dipyridamole, containing aspirin (25 mg) plus extended-release dipyridamole (200 mg), is given two times per day. Dipyridamole is also available as an immediate-release form, usually given as 50 to 100 mg three times per day, but this is seldom used alone for secondary stroke prevention.

The specific dipyridamole preparation may be important. In a meta-analysis cited above, the combination of aspirin and immediate-release dipyridamole was nonsignificantly better than aspirin alone for secondary prevention of stroke (relative risk 0.83, 95% CI 0.59-1.15) [26]. By contrast, extended release dipyridamole was used in all or the vast majority of patients in the much larger ESPS-2 and ESPRIT trials [14,27], and aspirin-extended-release dipyridamole led to a greater reduction in stroke risk compared with aspirin alone [26].

Adverse effects — Headache is the most common adverse effect of aspirin-extended-release dipyridamole, and one that most often leads to discontinuation of treatment. Other adverse reactions include abdominal pain, nausea, diarrhea, and vomiting.

Headache was the most frequent adverse event associated with aspirin-extended-release dipyridamole in two large clinical trials, ESPS-2 and ESPRIT [14,27]. In the PRoFESS trial, discontinuation due to headache was more frequent with aspirin-extended-release dipyridamole compared with clopidogrel (5.9 versus 0.9 percent) [28]. In a study of subjects aged 55 or older treated with the combination of aspirin-extended-release dipyridamole, headache developed in 39.7 percent after a single dose, and women were significantly more likely to develop headache than men (49.6 and 28.6 percent, respectively) [29]. The headaches associated with aspirin-extended-release dipyridamole treatment were mostly self-limited, and treatment of headache with acetaminophen was not significantly better than with placebo, as measured by response at two hours (75.5 and 69.4 percent). The overall incidence of headache declined markedly over seven days to less than 20 percent. Gastric upset and/or diarrhea requiring drug cessation was also more common with dipyridamole compared with aspirin or placebo in ESPS-2.

Notably, aspirin use was associated with significantly greater overall bleeding and gastrointestinal bleeding compared with dipyridamole or placebo in ESPS-2 and a subsequent meta-analysis [14,30]. In fact, in ESPS-2, the frequency of bleeding complications with dipyridamole was comparable to placebo.

Concern that dipyridamole use might lead to increased rates of myocardial ischemia has been largely laid to rest by data from two large clinical trials (ESPS-2 and ESPRIT) and a meta-analysis [14,27,30,31]. This concern was related to the potential for dipyridamole to cause vasodilation of coronary vessels [32], and it first arose with the use of intravenous dipyridamole in cardiac stress testing [33]. However, accumulating data suggest that extended-release dipyridamole use for stroke prevention is not associated with an increased risk of myocardial ischemia or infarction. An analysis of data from ESPS-2 found that use of extended-release dipyridamole was not associated with increased cardiac ischemia or mortality in patients with a history of coronary artery disease [31], and a meta-analysis found that oral dipyridamole did not alter the rate of MI in patients with previous stroke or TIA, either when compared with control, or when administered in combination with aspirin and compared with aspirin alone [30]. In ESPRIT, the use of combination therapy with aspirin and dipyridamole, mainly extended-release dipyridamole, was associated with a nonsignificant decrease in the outcome of first cardiac event, and a significant decrease in the primary composite outcome that included death from all vascular causes and nonfatal MI [27].

Cilostazol — The antiplatelet agent cilostazol is a phosphodiesterase 3 inhibitor that increases cyclic AMP and leads to reversible inhibition of platelet aggregation and arterial vasodilation.

Efficacy — Several randomized controlled trials and meta-analyses have found that cilostazol is effective for preventing cerebral infarction [34-36].

In the CSPS trial of over 1000 patients from Japan, cilostazol (100 mg twice daily) compared with placebo reduced the risk of stroke (relative risk reduction [RRR] 42 percent, 95% CI 9.2-62.5 percent) [34]. The CSPS II trial randomly assigned 2757 patients in Japan with a recent noncardioembolic cerebral infarction to cilostazol (100 mg twice daily) or aspirin (81 mg daily) [35]. At a mean follow-up of 29 months, the yearly rates of recurrent stroke (infarction or hemorrhage) for cilostazol and aspirin were 2.7 and 3.7 percent (HR 0.74, 95% CI 0.56-0.98), confirming that cilostazol is noninferior to aspirin for stroke prevention. Annual rates of intracranial hemorrhage or other hemorrhage requiring hospitalization were lower with cilostazol than with aspirin (0.8 versus 1.8 percent, HR 0.46, 95% CI 0.30-0.71).

In the CASISP trial from China of 720 patients with recent ischemic stroke, the composite endpoint (any stroke, ischemic or hemorrhagic) at 12 to 18 months of follow-up was lower in the cilostazol group compared with the aspirin group (3.3 versus 5.6 percent), but this result was not statistically significant (HR 0.62, 95% CI 0.30-1.26) [37].

These data support the safety and efficacy of cilostazol for secondary stroke prevention in East Asian populations. However, there are as yet no high-quality data regarding the use of cilostazol for secondary stroke prevention in non-East Asian ethnic groups. Also, the twice daily dosing, lower tolerability, and higher cost of cilostazol compared with aspirin may limit its more widespread use for stroke prevention.

Dosing — The dose of cilostazol is 100 mg twice daily.

Adverse effects — In the CSPS II trial of cilostazol versus aspirin, headache, diarrhea, palpitation, dizziness, and tachycardia were more frequent with cilostazol, and more patients discontinued cilostazol than aspirin (20 versus 12 percent) [35]. Other potential adverse reactions include diarrhea, infection, and rhinitis.

Others

Ticlopidine — Ticlopidine is a thienopyridine with a chemical structure and mechanism of action similar to clopidogrel. Despite the evidence of benefit in randomized trials, ticlopidine is not considered a first-line antiplatelet agent for stroke prevention because of the risk of severe neutropenia and relatively high cost.

●Efficacy – The CATS trial enrolled over 1000 patients between one week and four months after ischemic stroke [38]. At a mean of 24 months, the primary composite end point of stroke, MI, and vascular death was lower with ticlopidine compared with placebo (10.8 versus 15.3 percent, RRR 30 percent). The benefit was smaller by intention-to-treat analysis (RRR 23 percent). The TASS trial compared ticlopidine (500 mg/d) with aspirin (1300 mg/d) in 3069 patients with a recent TIA or mild stroke [39]. At three-year follow-up, ticlopidine reduced the primary end point (nonfatal stroke or death) compared with aspirin (17 versus 19 percent). Ticlopidine also reduced the rate of fatal and nonfatal stroke compared with aspirin (10 versus 13 percent, respectively, RRR 21 percent, 95% CI 4-38).

The AAASPS trial compared ticlopidine (500 mg/day) with aspirin (650 mg/day) in 1809 Black patients with noncardioembolic ischemic stroke [40]. At two-year follow-up, there was no significant difference in the primary end point (stroke, MI, vascular death) between ticlopidine and aspirin.

●Dose – The dose of ticlopidine is 250 mg twice daily. The drug is no longer available in the United States.

●Adverse effects – The most serious complication of ticlopidine therapy is severe neutropenia, which occurs in approximately 1 percent of patients. Thus, patients must have a complete blood count with differential prior to treatment initiation and then weekly for the first three months of therapy; more frequent monitoring is recommended for patients whose absolute neutrophil counts are consistently declining or are 30 percent less than baseline. Other common side effects, which occur more frequently with ticlopidine than aspirin, are rash and diarrhea.

Triflusal — Triflusal is an antiplatelet agent that is structurally related to aspirin. It is available as a licensed pharmaceutical in some European and Latin American countries but is considered investigational in the United States. In a randomized trial with 2113 patients, the effectiveness of triflusal (600 mg/day) was similar to aspirin (325 mg/day) at preventing vascular events after stroke, but it did have a lower rate of hemorrhagic complications [41]. Similar findings were noted in a smaller randomized trial and a meta-analysis of four trials [42,43]. It is not clear whether triflusal would have had a lower rate of hemorrhagic complications than lower-dose aspirin [44].

Dual antiplatelet therapy — The short-term use of dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is beneficial compared with aspirin alone in some patients with acute ischemic stroke syndromes (algorithm 1 and algorithm 2), as reviewed elsewhere. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".)

However, evidence from randomized trials suggests that long-term DAPT has no such benefit for stroke risk reduction, but rather appears to be harmful due to an increased risk of bleeding.

Aspirin plus clopidogrel — For the vast majority of patients with ischemic stroke, the long-term use of DAPT with aspirin and clopidogrel does not offer greater benefit for stroke prevention than either agent alone but does substantially increase the risk of bleeding complications [45-49].

●The MATCH trial enrolled 7599 patients with stroke or TIA who also had some additional "high-risk" feature, defined as prior MI, prior stroke (in addition to the index event), diabetes, angina, or symptomatic peripheral artery disease [45]. Patients were randomly assigned to the combination of clopidogrel (75 mg daily) plus aspirin (75 mg daily) or clopidogrel (75 mg daily) alone. Follow-up was 18 months. Compared with clopidogrel alone, aspirin plus clopidogrel treatment did not reduce the risk of major vascular events (relative risk reduction 6.4 percent, 95% CI -4.6 to 16.3 percent) but did result in more life-threatening bleeding complications, mainly intracranial and gastrointestinal. Over the 18-month trial period, there was an absolute excess of 1.3 percent for life-threatening hemorrhage (95% CI 0.6-1.9) and an additional 1.3 percent for major hemorrhage in patients assigned combination therapy. Overall, treatment with aspirin and clopidogrel compared with clopidogrel alone might prevent 10 ischemic events per 1000 at the cost of 13 life-threatening hemorrhages per 1000 treated.

There are several limitations of MATCH. For instance, 54 percent of MATCH subjects qualified for trial entry because of a lacunar stroke, a stroke subtype that has the lowest recurrence risk [50]. Furthermore, data regarding interaction between treatment and stroke mechanism were not reported, raising the question of whether combination therapy might still play a role in particular stroke subtypes.

●The CHARISMA trial evaluated aspirin plus clopidogrel versus aspirin alone in 15,603 patients with either documented cardiovascular disease (coronary, ischemic cerebrovascular, or peripheral arterial) or, in 21 percent of patients, multiple atherothrombotic risk factors (eg, diabetes, hypertension, primary hypercholesterolemia, current smoking, asymptomatic carotid stenosis ≥70 percent) [46]. Patients were randomly assigned to low-dose aspirin (75 to 162 mg/day) plus either clopidogrel (75 mg/day) or placebo. At a median follow-up of 28 months, combined aspirin plus clopidogrel treatment did not reduce the risk of the composite end point (MI, stroke of any cause, or death from cardiovascular causes) compared with aspirin alone (6.8 versus 7.3 percent, relative risk 0.93, 95% CI 0.83-1.05), but did increase in moderate bleeding (2.1 versus 1.3 percent) and severe bleeding (1.7 versus 1.3 percent), although the latter did not reach statistical significance.

●The SPS3 trial evaluated over 3000 patients with subcortical (ie, lacunar) stroke confirmed by magnetic resonance imaging (MRI) [51]. The arm testing the combination of aspirin plus clopidogrel versus aspirin alone was terminated before completion because of a higher frequency of bleeding events (mostly systemic) and a higher mortality rate in patients assigned to DAPT compared with those assigned to aspirin only. In the final analysis, subjects treated with aspirin plus clopidogrel compared with aspirin alone had a significantly increased annual rate of both major hemorrhage (2.1 versus 1.1 percent, HR 1.97, 95% CI 1.41-2.71) and all-cause mortality (2.1 versus 1.4 percent, HR 1.52, 95% CI 1.14-2.04) [49]. Furthermore, treatment with aspirin and clopidogrel compared with aspirin alone in did not reduce the risk of recurrent stroke [49].

Cilostazol plus aspirin or clopidogrel — The potential utility of DAPT using cilostazol was explored in the open-label CSPS.com trial in Japan, which enrolled 1884 adult patients with noncardioembolic ischemic stroke who had ≥50 percent stenosis of a major intracranial or extracranial artery, or two or more vascular risk factors [52]. The patients were assigned in a 1:1 ratio to antiplatelet monotherapy using either aspirin or clopidogrel, or to DAPT using cilostazol combined with either aspirin or clopidogrel [52]. During a median follow-up of 1.4 years, the rate of recurrent ischemic stroke was lower for the DAPT group compared with the monotherapy group (3 versus 7 percent, HR 0.49, 95% CI 0.31-0.76). The rates of serious adverse events and bleeding events were similar between the groups. Limitations to this trial include early stopping before reaching the planned 4000 enrollment due to slow recruitment, resulting in a lower number of event rates, the varying combinations of antiplatelet medications and dosages of aspirin, and the unblinded treatment.

Combination antiplatelet and anticoagulant therapy — Aspirin combined with low-dose rivaroxaban (2.5 orally twice a day) is another reasonable treatment option for some patients with non-lacunar, non-cardioembolic ischemic stroke and evidence of systemic atherosclerosis.

This approach is based primarily on the results of the COMPASS trial, which randomly assigned over 27,000 patients with stable coronary artery disease or peripheral arterial disease to one of three treatment arms: one, rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily; two, rivaroxaban 5 mg twice daily; or three, aspirin 100 mg daily [53]. Patients with a history of lacunar stroke or with cardioembolic stroke requiring anticoagulation were excluded from enrollment. The mean follow-up was 23 months. Compared with those assigned to aspirin alone, patients assigned to rivaroxaban plus aspirin had a decrease in the annualized composite outcome of cardiovascular mortality, stroke, or myocardial infarction (4.1 versus 5.4 percent, absolute risk reduction [ARR] 1.3 percent, HR 0.76, 95% CI 0.66 to 0.86) and a decrease in ischemic stroke (0.7 versus 1.4 percent, ARR 0.7 percent, HR 0.51, 95% CI 0.38-0.68). Similarly, in the subgroup of 1032 patients with prior stroke, aspirin and rivaroxaban decreased the composite rate of cardiovascular death, stroke, or myocardial infarction (3.7 percent, versus 6.5 percent with aspirin alone, ARR 2.8 percent, HR 0.57, 95% CI 0.34-0.96) [54]; thus, the ARR for patients with prior stroke was more than double that observed for the overall trial cohort.

As expected, those assigned to combination therapy in COMPASS had an increase in major bleeding events (3.1 versus 1.9 percent, absolute risk increase 1.2 percent, HR 1.70, 95% CI 1.40-2.05), with the gastrointestinal tract being the most common site of major bleeding [53]. However, there was no difference between the two groups in fatal bleeding (0.2 versus 0.1 percent) or intracranial bleeding (0.2 percent in both arms).

Similar findings for risk reduction of ischemic stroke were reported in the COMMANDER-HF trial, which randomly assigned over 5000 patients with chronic heart failure, left ventricular ejection fraction ≤40 percent, coronary artery disease, elevated plasma natriuretic peptide level, and no atrial fibrillation to receive rivaroxaban 2.5 mg twice daily or placebo [55]. At baseline, approximately 93 percent of the patients were on aspirin (alone or in combination with a thienopyridine), and approximately 35 percent were taking DAPT. During a median follow-up of 21 months, there was no significant difference in all-cause mortality between the rivaroxaban and placebo groups, but the risk of stroke was reduced in the group assigned to rivaroxaban (2 versus 3 percent, ARR 1 percent, HR 0.66, 95% CI 0.47-0.95). The risk of major bleeding was higher in the rivaroxaban group (3.3 versus 2.0 percent), but there was no significant difference between groups for fatal bleeding (0.4 percent in both groups) or for bleeding into a critical space (0.5 versus 0.8 percent).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Stroke (The Basics)" and "Patient education: Medicines after an ischemic stroke (The Basics)")

●Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)" and "Patient education: Transient ischemic attack (Beyond the Basics)" and "Patient education: Ischemic stroke treatment (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Acute antiplatelet therapy – The use of antiplatelet therapy in the acute period of ischemic stroke and transient ischemic attack (TIA), including the short-term use of dual antiplatelet therapy (DAPT), is discussed in detail elsewhere (algorithm 1 and algorithm 2). (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".)

●Options for long-term antiplatelet therapy – Aspirin, clopidogrel, and the combination of aspirin-extended-release dipyridamole are all acceptable options for preventing recurrent noncardioembolic ischemic stroke. Cilostazol is a reasonable option for patients of East Asian ethnicity, and for all patients if the other agents are not available or tolerated. (See 'Aspirin' above and 'Clopidogrel' above and 'Aspirin plus dipyridamole' above.)

●Our recommendations – For secondary prevention of stroke in patients with a history of noncardioembolic stroke or TIA of atherothrombotic, lacunar (small vessel occlusive type), or cryptogenic type, we recommend treatment with an antiplatelet agent using either aspirin, clopidogrel, or aspirin-extended-release dipyridamole (Grade 1A). We suggest antiplatelet therapy using either clopidogrel (75 mg daily) as monotherapy or the combination of aspirin-extended-release dipyridamole (25 mg/200 mg twice a day), rather than aspirin alone (Grade 2B). The choice between clopidogrel and aspirin-extended-release dipyridamole is dependent mainly on patient tolerance and contraindications. Aspirin is appropriate for patients who cannot afford or tolerate clopidogrel or aspirin-extended-release dipyridamole. (See 'Aspirin' above and 'Clopidogrel' above and 'Aspirin plus dipyridamole' above.)

●Aspirin dose – Although the optimal dose of aspirin is uncertain, there is no compelling evidence that any specific dose is more effective than another, and fewer gastrointestinal side effects and bleeding occur with lower doses (≤325 mg a day). We recommend a dose of 50 to 100 mg daily when using aspirin for the secondary prevention of ischemic stroke (Grade 1B). (See 'Dose of aspirin' above.)

●Limited role for long-term dual antiplatelet therapy – For most patients with a noncardioembolic stroke or TIA, we recommend not using aspirin and clopidogrel in combination for long-term stroke prevention, given the lack of greater efficacy compared with clopidogrel alone and the substantially increased risk of bleeding complications (Grade 1A). (See 'Aspirin plus clopidogrel' above.)

Possible exceptions include patients with concurrent indications for dual antiplatelet therapy (eg, selected patients with a recent acute myocardial infarction, other acute coronary syndrome, or arterial stent placement including carotid stenting); these are discussed elsewhere. (See "Acute ST-elevation myocardial infarction: Antiplatelet therapy" and "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy" and "Antithrombotic therapy for elective percutaneous coronary intervention: General use" and "Long-term antiplatelet therapy after coronary artery stenting in stable patients" and "Overview of carotid artery stenting".)

●Role of combined antiplatelet and anticoagulant therapy – For high-risk patients with noncardioembolic, nonlacunar stroke and evidence of peripheral, coronary, or cerebrovascular atherosclerosis, aspirin combined with low-dose rivaroxaban (2.5 orally twice a day) is a reasonable treatment option. (See 'Combination antiplatelet and anticoagulant therapy' above.)

●Atrial fibrillation – Prevention of recurrent cardioembolic stroke in patients with atrial fibrillation is discussed separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants".)