Therapeutic Interventions for Prevention of Recurrent Ischemic Stroke

Patients who suffer ischemic stroke or transient ischemic attack (TIA) are at increased risk for subsequent cerebrovascular events. Secondary prevention is essential to reduce risks of recurrence and should include lifestyle modification to improve cardiovascular health, along with strict control of blood pressure, glucose, and lipids. Recurrent stroke in ischemic stroke patients is likely to be the same subtype as the initial stroke, and treatment should be unique to the stroke subtype and patient risk factors.

This article presents an overview of the recommendations for the secondary prevention of ischemic stroke or TIA and a review of the evidence supporting the role of antiplatelet therapy in managing the risk of recurrent noncardioembolic stroke. Although anticoagulants are recommended preventive treatment for cardioembolic stroke, they can increase the patient’s risk of bleeding complications and are not recommended for all subtypes of ischemic stroke. The American Heart Association/ American Stroke Association guidelines recommend 3 antiplatelet regimens for the secondary prevention of noncardioembolic ischemic stroke: aspirin (ASA), clopidogrel, and combined ASA + extended-release (ER) dipyridamole (DP). ASA + ER-DP is recommended over ASA alone.

Several studies have established the effectiveness of these 3 antiplatelet regimens as first-line options in the secondary prevention of noncardioembolic ischemic stroke. Clopidogrel monotherapy is a reasonable alternative for patients who cannot tolerate ASA. ASA + ER-DP has been shown to be more effective than ASA alone and does not increase the risk of bleeding. Effective secondary prevention must also address modifiable risk factors, such as obesity, smoking, and excessive alcohol consumption.

(Am J Manag Care. 2008;14:S212-S226)

Patients who experience a stroke or transient ischemic attack (TIA) face an increased risk of having another stroke1-3 or other vascular event.^3,4 Approximately one quarter of the 780,000 strokes that occur in the United States each year are recurrent.^2,5 Therefore, a principal goal in managing stroke or TIA patients is to prevent another cerebrovascular event. Recommended management for the secondary prevention of stroke includes addressing modifiable risk factors, initiating long-term antithrombotic therapy, and intervening surgically, when indicated.¹

Considerations for Secondary Prevention of Vascular Events

When considering the secondary prevention of vascular events, it is critical to recognize that ischemic events tend to recur in the same vascular beds; 75% to 79% of vascular events after a stroke are strokes,^5,6 and 76% to 84% of events after myocardial infarction (MI) are MI.⁵ Thus, primary poststroke prevention efforts should be geared toward preventing a recurrent stroke.⁵ Antithrombotic therapies should be selected according to their demonstrated efficacy in secondary stroke prevention, rather than myocardial protection.⁵

Stroke and TIA patients also bear an increased risk of suffering ischemic events in other vascular beds (eg, MI, ischemic limb),^3,4 and their risk of cardiovascular events should not be discounted. In poststroke years 1 through 10, the most common cause of death for stroke patients is cardiovascular disease (CVD).^3,7-10 In a recent study on secondary prevention of stroke in patients without known coronary heart disease (CHD), major coronary events exceeded recurrent strokes.¹¹ This suggests that many stroke patients have unrecognized CHD.¹² Although the primary concern when treating stroke patients should be preventing recurrent stroke, treatment plans should also consider the prevention of coronary events, especially for stroke patients who have a history of MI or peripheral arterial disease (PAD).

Cerebral vasculature appears to differ from that in other vascular beds, and stroke pathogenesis likely differs from the pathogenesis of CHD or PAD.⁵ For example, the association between stroke and dyslipidemia is not as well established as dyslipidemia’s association with CHD.^1,13 Stroke patients constitute a unique vascular disease population⁵; they may therefore require different preventive treatments than CHD or PAD patients. For example, certain antithrombotic agents are more likely to cause bleeding in stroke patients than in MI or PAD patients.⁵ The administration of warfarin at an anticoagulation intensity well tolerated by patients with CHD has been known to cause severe bleeding in stroke patients.⁵ The TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel– Thrombolysis in Myocardial Infarction) trial found that patients with a history of stroke or TIA were more prone to episodes of major bleeding.¹⁴ The choice of an antithrombotic therapy, therefore, should consider any adverse event risks specific to stroke patients.

Additional Considerations Unique to Ischemic Stroke Patients

Together, the American Heart Association (AHA) and American Stroke Association have established evidence-based guidelines for preventing stroke in patients who have a history of ischemic stroke or TIA.^1,12 A brief summary of these guidelines follows.

Recommendations Regarding Modifiable Risk FactorsSmoking.¹ Clinicians should urge ischemic stroke/TIA patients not to smoke and to avoid environmental smoke; counseling, nicotine products, and medications can help facilitate cessation.

Alcohol.¹ Light to moderate levels (≤2 alcoholic drinks/day for men and 1 drink/day for women) may be permitted, but heavier drinking should be discouraged.

Obesity.¹ Weight management through caloric limitation, physical activity, and behavioral counseling should be encouraged; the patient&#8217;s goals should include a body mass index of 18.5 to 24.9 kg/m² and a waist circumference of <35 inches for women and <40 inches for men.

Physical Activity.¹ Ischemic stroke/TIA patients able to engage in physical activity are encouraged to perform &#8805;30 minutes of moderate exercise on most days. A supervised therapeutic regimen is recommended for patients who have poststroke disability.

Diabetes.¹ Strict control of lipid levels and blood pressure is recommended for diabetic patients; angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) are preferred as first-line antihypertensives. Glycemic control must be strict and should target near-normal glucose levels and a hemoglobin A1C &#8804;7%. Note that excessively tight glucose control could result in hypoglycemia and an increased risk of mortality.

Hypertension. Antihypertensive treatment is recommended for all ischemic stroke/TIA patients past the hyperacute period, even for patients with no hypertensive history.¹ Reductions of ~10/5 mm Hg have proven beneficial.¹ Encourage lifestyle modifications known to reduce blood pressure.¹ Blood pressure targets and specific drug choices should be individualized, but evidence supports using diuretics, with or without ACE inhibitors or ARBs.^1,30

Cholesterol and Lipid Levels. Clinicians should follow National Cholesterol Education Panel III guidelines for lifestyle modification, diet, and medications for ischemic stroke/TIA patients with elevated cholesterol, comorbid CHD, or evidence of atherosclerotic origin.^1,12 Lipid-lowering statin therapy is recommended, with a goal of reducing low-density lipoprotein cholesterol (LDL-C) levels to <100 mg/dL and <70 mg/dL in very high-risk patients.^1,12 Patients with a low level of high-density lipoprotein cholesterol can be treated with niacin or gemfibrozil.^1,12 Although the relationship between lipid levels and ischemic stroke has not been as clearly established as the relationship between lipids and cardiac disease,^1,13 evidence supports lowering lipid levels to reduce the risks of initial^31-35 and recurrent stroke.⁷

Post-hoc analysis of the 4S (Scandinavian Simvastatin Survival Study) trial showed that patients with CHD who received simvastatin trended toward fewer strokes.¹³ This led to the analysis of stroke as a specified end point in the LIPID (Long-term Intervention with Pravastatin in Ischemic Disease), CARE (Cholesterol and Recurrent Events), and MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) trials.^31-33 These 3 studies, along with the Heart Protection Study, found that statins were associated with a reduced risk of stroke in patients with MI, unstable angina, or other vascular disease.^31-35

The recent SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial showed that statin therapy can reduce the risk of recurrent stroke in patients with a history of stroke or TIA.⁷ This study included 4731 patients who experienced stroke or TIA within the previous 1 to 6 months, had LDL-C levels between 100 mg/dL and 190 mg/dL, and no known CHD. Patients were randomized to 80 mg of atorvastatin per day or placebo.¹¹ Median follow-up was 4.9 years; 11.2% of statin-treated patients and 13.1% of Placebo-treated patients suffered fatal or nonfatal strokes (5-year absolute risk reduction [ARR], 2.2%; adjusted hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.71-0.99; P = 0.03; unadjusted P = .05).7 SPARCL also observed a 3.5% ARR for major cardiovascular events (HR, 0.80; 95% CI, 0.69-0.92; P = .002).¹¹ A prespecified analysis of 4162 patients found a relative risk reduction (RRR) of 18% in stroke risk for patients receiving atorvastatin compared with placebo (HR, 0.82; 95% CI, 0.90-0.98; P = .03).¹¹ Based on the findings of the SPARCL trial, AHA/American Stroke Association updated the lipid management section of the guidelines in 2008. To reduce risks of stroke and cardiovascular events, the guidelines now recommend statin therapy for all atherosclerotic ischemic stroke or TIA patients with an LDL-C level >100 and no known CHD.¹²

Recommendations for Surgical Management in Certain LVD Patients

Table 1

In patients with cardioembolic stroke, the primary focus is on anticoagulation ().¹ Absent a clear contraindication, atrial fibrillation (AF) patients who recently experienced stroke or TIA should be treated with oral anticoagulants, not antiplatelet therapy.¹ Ordinarily, AF patients should be initiated on oral anticoagulant therapy within 2 weeks of experiencing ischemic stroke or TIA.¹ An overall stroke RRR of 68% (95% CI, 50%-79%) has been demonstrated for patients with nonvalvular AF who receive adjusted-dose warfarin^1,36; the optimal international normalized ratio intensity is between 2.0 and 3.0.1 If patients with AF suffer ischemic stroke or TIA while taking anticoagulants, current evidence does not support increasing the intensity of the anticoagulate regimen or adding antiplatelet agents.¹

Treatment with oral anticoagulants is also recommended for patients with acute MI and left ventricular thrombus, rheumatic mitral valve disease, and prosthetic heart valves.¹ In patients with valvular heart disease, anticoagulants reduce&#8212;but do not eliminate&#8212;the likelihood of stroke¹; therefore, recommendations vary according to the heart valves affected. Concurrent use of oral anticoagulants and lower-dose aspirin (ASA) is recommended for patients with ischemic heart disease and for stroke and TIA patients with rheumatic mitral valve disease or mechanical prosthetic heart valves who develop an embolism while taking warfarin.¹ Evidence also supports concurrent use of anticoagulantsand dipyridamole (DP), alone or in combination with ASA for secondary prevention of stroke in patients with prosthetic heart valves.¹ For some patients, including those with dilated cardiomyopathy and mitral annular calcification, warfarin or antiplatelet therapy can be considered.¹ Warfarin can reduce the risk of stroke for patients with MI by 40% to 55%.1 Warfarin has demonstrated similar stroke-preventive effects in patients with nonischemic cardiomyopathy and ischemic heart disease.¹ Ischemic stroke and TIA patients with mitral valve prolapse have not been studied in randomized trials, but AHA/American Stroke Association guidelines indicate that antiplatelet therapy is reasonable for these patients.¹

Table 2

Recommendations for Antithrombotic Therapy in TIA or Noncardioembolic Stroke (Atherosclerotic, Lacunar, or Cryptogenic Infarcts) For all patients who suffer noncardioembolic ischemic stroke or TIA, the primary focus is antiplatelet therapy ().^1,12 AHA/American Stroke Association guidelines recommend antiplatelet agents rather than oral anticoagulants to reduce the risks of stroke recurrence and other cardiovascular events.^1,12 Oral anticoagulants are generally not recommended over antiplatelet agents for patients with noncardioembolic stroke,^1,12 because they have failed to demonstrate superior efficacy and they increase the patient&#8217;s risk of bleeding.¹

Antiplatelet therapy is associated with significant risk reductions (RRs) of 28% for nonfatal stroke and 16% for fatal stroke.^1,37 The US Food and Drug Administration (FDA) has approved 4 antiplatelet regimens for secondary ischemic stroke prevention: ASA, ticlopidine, clopidogrel, and combination ASA + DP.¹ Of these 4 regimens, 3 are considered acceptable options for initial therapy.¹ One study associated ticlopidine with a 21% RRR of stroke, but evidence is mixed regarding the reduction of composite outcomes; adverse events such as bleeding, neutropenia, and thrombotic thrombocytopenic purpura have been reported.¹ Clopidogrel monotherapy is comparable in efficacy and safety to ASA for secondary prevention of stroke, and it is recommended over ticlopidine because it is associated with fewer gastrointestinal symptoms and fewer incidents of hemorrhage.¹ The combination of ASA + extended-release (ER) DP is recommended over ASA monotherapy.^1,12

Evidence from the recent ESPRIT (European/ Australasian Stroke Prevention in Reversible Ischemia Trial) trial and a meta-analysis of previous data motivated the AHA/American Stroke Association Writing Committee for the Prevention of Stroke in Patients with Stroke and Transient Ischemic Attack to upgrade this recommendation to Class I, supported by grade B evidence.¹² The recently reported PRoFESS (Prevention Regimen for Effectively Avoiding Second Stroke) trial found no significant difference in efficacy between ASA + ER-DP and clopidogrel.³⁸

AHA/American Stroke Association guidelines state that there is not yet sufficient data regarding antiplatelet therapies other than ASA to make evidence- based recommendations of one over another, and choices should be individualized for each patient, taking into consideration patient allergies and comorbidities, possible side effects and costs of the medication, and rates of adherence.^1,12 New AHA/American Stroke Association guidelines are expected to be released by the end of 2008.

Use of Antiplatelet Agents in Secondary Prevention of Noncardioembolic Stroke

Many studies attest to the effectiveness of ASA,^1,37 which has a recurrent-event RR of approximately 13%-22%.37,^39-43 This relatively limited efficacy indicates that treatment with ASA alone may not be aggressive enough, which has justified investigating therapy with other antiplatelet agents.

Table 3

A meta-analysis of 195 randomized controlled trials conducted through 1997 (N = 135,640) found that most of the studies included ASA in at least one arm.³⁷ Trials compared ASA versus placebo, low- versus high-dose ASA, ASA versus another antiplatelet drug (monotherapy), and ASA versus a combination of ASA + another antiplatelet agent.³⁷ Antiplatelet therapy reduced the risks of nonfatal stroke by one quarter and vascular death by one sixth.³⁷ In patients with previous stroke or TIA, ARR of a vascular event was 36 (standard error, 6) per 1000 patients treated for 2 years.³⁷ No clear difference was observed in effects or serious vascular events between ASA and the other antiplatelet drugs studied.³⁷ In the placebo- controlled ASA trials, all ASA doses <325 mg produced a similar risk of major extracranial bleeding.³⁷ In 2 trials comparing different ASA dosing regimens, higher doses provided no additional benefit and increased the risk of nonfatal major gastrointestinal hemorrhage ().^44,45

In the UK-TIA (United Kingdom Transient Ischaemic Attack) trial, 2435 patients who suffered minor ischemic stroke or TIA were randomized to 600 mg of ASA twice daily, 300 mg of ASA once daily, or placebo; patients were followed from 1 to 7 years.⁴⁴ Risk of major stroke, MI, or vascular death was 15% lower in patients receiving ASA versus placebo, but a 1200-mg daily dose was no more effective than a 300-mg dose.⁴⁴ Intracranial hemorrhage occurred in 7 high-dose patients (6 fatalities) and 7 low-dose patients (4 fatalities); only 2 patients receiving placebo experienced an intracranial hemorrhage (1 fatality).⁴⁴ There were 39 incidents of gastrointestinal hemorrhage in patients receiving 1200 mg of ASA per day, 25 with 300 mg of ASA per day, and 9 with placebo.⁴⁴ The risks of other minor bleeding events were similarly higher in patients receiving ASA.⁴⁴

The Dutch TIA trial randomized 3131 patients who suffered TIA or nondisabling stroke to either 30 mg or 283 mg of ASA daily and compared outcomes of vascular death, nonfatal stroke, or nonfatal MI (mean follow-up, 2.6 years).⁴⁵ The composite outcome risk was 14.7% for patients using the 30-mg dose and 15.2% for those taking 283 mg; the trial concluded that the lower dose was no less effective.⁴⁵ Compared with the 283-mg group, the 30-mg group noted fewer incidents of minor bleeding (84 vs 49, respectively) and major bleeding (53 vs 40, respectively).⁴⁵

No evidence supports increasing the ASA dose for patients who suffer a stroke while being treated with ASA, and alternative antiplatelet agents have not been studied relative to this circumstance.¹ A subgroup analysis of the WARSS (Warfarin-Aspirin Recurrent Stroke Study) trial showed that continuing ASA therapy in patients whose treatment was initiated prior to suffering stroke was less effective than initiating ASA therapy after the incident event. For those patients who had a stroke despite receiving ASA at baseline, treatment with either ASA or warfarin resulted in similar recurrence rates at 2 years.⁴⁶

Clopidogrel

versus placebo, but the incidence of minor bleeding was slightly higher (3.6% vs 3.1%, respectively; P = .005).⁴⁹ Taken together, these data suggest that combination therapy with clopidogrel + ASA has a net benefit for secondary prevention of vascular events in patients with ACS.

Patients with stroke appear to have a different response to antiplatelet agents than patients with ACS. In comparison to monotherapy using clopidogrel or ASA, the dual antiplatelet regimen of clopidogrel + ASA has not demonstrated incremental protective benefit against recurrent stroke or TIA.^50-52 Furthermore, clopidogrel + ASA may increase the risk of bleeding in patients with stroke, possibly because their cerebral vessels have increased vulnerability.^1,5,8 In the TRITON-TIMI 38 study, major bleeding occurred in more patients with a history of stroke or TIA (prasugrel, 5.0%; clopidogrel, 2.9%) than in those without this cerebrovascular history (prasugrel, 2.3%; clopidogrel, 1.8%).¹⁴ The rate of bleeding associated with prasugrel was enough to nullify any benefit it might offer in preventing further coronary ischemia in patients with stroke.¹⁴

Table 4

Two studies compared combination clopidogrel + ASA versus monotherapy with ASA or clopidogrel in preventing vascular events in stroke or TIA patients without ACS (). The MATCH (Management of Atherothrombosis with Clopidogrel in High-risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke) trial evaluated clopidogrel + ASA versus clopidogrel + placebo,⁵⁰ and CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance) studied clopidogrel + ASA versus ASA + placebo.^51,52

The MATCH trial enrolled 7599 patients who recently experienced ischemic stroke or TIA, had at least 1 other risk factor for recurrence, and were already being treated with clopidogrel (75 mg/day).⁵⁰ Subjects were randomized to ASA (75 mg/day) or placebo, while continuing clopidogrel, for 18 months.⁵⁰ The clopidogrel + ASA combination did not demonstrate significantly greater efficacy than clopidogrel monotherapy (RRR, 6.4%; P = .244) in preventing the primary composite end point (ischemic stroke, MI, vascular death, or rehospitalization secondary to an ischemic event).^1,5,50 The incidence of life-threatening bleeding was double in the combination therapy group (2.6% vs 1.3%; P <.0001), and there was a significant increase in episodes of major bleeding.^5,50 The difference between the 2 regimens in the number of life-threatening bleeding episodes (47) was greater than the difference in the number of primary outcome events (40),^5,50 suggesting a poor risk-to-benefit ratio.¹ More than 50% of enrolled subjects were SVD patients, who possibly derive less benefit from antiatherothrombotic therapy and might be more susceptible to bleeding.⁵⁰ The effect this has on study results, however, is unclear.

The 28-month CHARISMA trial randomly allocated 15,603 patients to clopidogrel (75 mg/day) or placebo, in addition to ASA (75-162 mg/day). Patients had CVD or multiple risk factors for atherothrombotic events, although not all patients had an index vascular event.^4,12,51 Overall, ASA + clopidogrel did not prove to be significantly more effective than ASA + placebo in reducing the incidence of the primary composite end point (ischemic stroke, MI, or cardiovascular death).^5,51 In a prespecified subgroup analysis of 12,153 patients with documented coronary disease, PAD, ischemic stroke, or TIA within the previous 5 years, the combination of ASA + clopidogrel was slightly more effective than ASA alone in reducing risk for the primary end point (6.9% vs 7.9%, respectively; RR, 0.88; P = .046).^5,12,51 In patients who experienced previous cerebrovascular events, the benefit of combination therapy as secondary prevention did not reach statistical significance.^12,51 In patients using combination therapy, moderate bleeding increased significantly (2.1% vs 1.3%; RR, 1.62; P <.001).^5,51 A post-hoc secondary prevention analysis of 9478 CHARISMA patients with previous MI, ischemic stroke, or symptomatic PAD determined a composite end point rate of 7.3% with clopidogrel + ASA versus 8.8% with placebo + ASA (HR, 0.83; P = .01).⁵² It was again noted that moderate bleeding increased significantly in patients using the combination regimen (2.0% vs 1.3%; P = .004).⁵² Another post-hoc analysis of 593 CHARISMA subjects with a history of AF found that their risk of stroke increased with clopidogrel + ASA use (HR, 1.03; 95% CI, 0.49-2.10).⁵³ The authors concluded that this combination is not superior to ASA alone in treating patients with AF.⁵³

Aspirin + Extended-release DipyridamoleDP, a phosphodiesterase inhibitor, has a different mechanism of action than the other antiplatelet therapies. Whereas ASA inhibits thromboxane formation, DP raises intracellular levels of cyclic adenosine monophosphate and cyclic guanosine monophosphate (cGMP), for an antiaggregation effect.⁴² By increasing cGMP, DP may augment downstream signaling pathways of nitric oxide, which aids in endothelial protection.5 ER-DP has advantages over an immediate-release formulation. Immediate-release DP has a half-life of 40 minutes, and plasma concentration would decline rapidly.⁵ ER-DP also produces better gastrointestinal absorption in patients.⁵

Table 5

A pivotal study showed that ASA + ER-DP was significantly more effective than ASA alone in secondary prevention of stroke and conveyed a similarly low risk of severe bleeding ().⁴² ESPS-2 (European Stroke Prevention Study) randomized 6602 patients who recently experienced ischemic stroke or TIA to 1 of 4 therapies: ASA (25 mg twice daily), ER-DP (200 mg twice daily), ASA + ER-DP, or placebo. Patients were followed for 2 years⁴² and monitored for primary end points (stroke, death) or a combined end point of stroke and death together.⁴² Compared with placebo, stroke risk was reduced 18.1% with ASA monotherapy (P = .013), 16.3% with ER-DP monotherapy (P = .039), and 37% with ASA + ER-DP (P <.001).⁴² RRR of stroke was 23.1% with combination therapy versus ASA alone (P = .006) and 24.7% versus ER-DP alone (P = .002).^5,42 ASA + ER-DP therapy also reduced risk of the combined end point of stroke or death by 24% (P <.001) and the risk of TIA by 35.9% (P <.001).⁴² The most common adverse event associated with ER-DP was headache, reported by 37% of the ERDP cohort and 38% of the ASA + ER-DP cohort, versus 33% of patients receiving ASA monotherapy and 32% of patients receiving placebo.⁴² All-site bleeding and gastrointestinal bleeding were significantly more common in patients who received ASA as monotherapy or in combination with ERDP (P <.001).⁴² DP did not significantly increase bleeding over ASA.^1,42 Patients receiving combination therapy and patients receiving ASA alone had similar incidence rates of severe or fatal bleeding (1.6% vs 1.2%, respectively).^5,42 Total incidence of bleeding was 8.2% in patients receiving ASA versus 8.7% in patients receiving ASA + ER-DP.⁴² A post-hoc analysis of ESPS-2 data for cardiac patients who received ER-DP showed no increase in risk for MI, angina, or mortality.^1,5

A recent open-label study confirmed the findings of ESPS-2.^5,8,43 ESPRIT (European/Australasian Stroke Prevention in Reversible Ischemia Trial) randomized 2739 patients with recent TIA or minor ischemic stroke to ASA or ASA + DP (separately or as a fixed-dose combination).⁴³ Each patient&#8217;s physician determined the daily dose of ASA, which ranged from 30 to 325 mg (median, 75 mg/day); DP was administered at a dose of 200 mg twice daily.⁴³ Of patients randomized to ASA + DP, 83% received ER-DP.43 Mean follow-up was 3.5 years.⁴³ Although treatment allocation was not blinded, outcome assessment was blinded.⁴³

On intention-to-treat analysis, the incidence rate of the composite primary outcome (nonfatal MI, nonfatal stroke, vascular death, or major bleeding complication) was significantly lower in patients receiving ASA + DP than in those using ASA alone (12.7% vs 15.7%, respectively; HR, 0.80; 95% CI, 0.66-0.98).⁴³ The ASA + DP group noted 35 major bleeding complications versus 53 for the ASA cohort (HR, 0.67; 95% CI, 0.44-1.02).⁴³ More patients on combination ASA + DP discontinued therapy than those receiving ASA alone; this was primarily because of adverse effects, most notably headache.⁴³

The investigators also conducted a meta-analysis that included the ESPRIT trial data and findings from 5 previous studies comparing ASA with ASA + DP; 4 of the 6 studies evaluated only the immediaterelease formulation of DP. The meta-analysis demonstrated an overall RR of 0.82 for composite stroke, MI, or vascular death in patients receiving combination therapy (95% CI, 0.74-0.91), and an RRR of 18% compared with ASA monotherapy.⁴³

Results of the PRoFESS trial were presented in May 2008 at the XVII European Stroke Conference.38 This randomized, double-blind trial (N = 20,332) compared the efficacy of 2 antiplatelet therapies in secondary prevention of recurrent stroke.³⁸ Recurrent stroke rates were similar in patients receiving ER-DP + ASA and clopidogrel therapy (9.0% vs 8.8%, respectively); no significant differences were observed in the incidence of the composite end point (stroke, MI, or vascular death) between ER-DP + ASA and ASA monotherapy (13.1% vs 13.1%, respectively).³⁸ Ischemic strokes occurred less often in patients receiving ER-DP + ASA compared with ASA (7.7% vs 7.9%, respectively), whereas hemorrhagic strokes occurred more often (0.8% vs 0.4%, respectively).38 More major hemorrhagic events occurred in the ERDP + ASA cohort than in the ASA group (4.1% vs 3.6%, respectively; HR, 1.15; 95% CI, 1.00-1.32), but no significant difference was found in the benefitto- risk ratio expressed as combined recurrent stroke and major hemorrhage (11.7% vs 11.4%, respectively; HR, 1.03; 95% CI, 0.95-1.11).³⁸

Evidence to date does not support differential effectiveness of antiplatelet therapies¹ among the different noncardioembolic subtypes. Ongoing trials, including SPS3 (Secondary Prevention of Small Subcortical Strokes) and ARCH (Aortic Arch Related Cerebral Hazard), should seek further understanding in this area.

Conclusion

In ischemic stroke and TIA patients, preventing subsequent cerebrovascular events is a primary goal of treatment. An individual&#8217;s risk factors for recurrent stroke should be addressed, implementing lifestyle modifications and controlling blood pressure and levels of glucose and lipids.¹

Other secondary prevention treatments for ischemic stroke patients should be geared toward preventing recurrence of a stroke that is the same subtype as the initial event. Patients who experience LVD stroke&#8212;particularly with carotid bifurcation area stenosis&#8212;can benefit from surgical or endovascular interventions.¹ Anticoagulants are recommended for most cardioembolic stroke types.¹ For other ischemic stroke subtypes, FDA-approved antiplatelet agents are recommended and preferred over anticoagulants,^1,12 which can increase the risk of bleeding complications.¹

ASA, clopidogrel, and ASA + ER-DP are recognized as accepted first-line options for secondary prevention of noncardioembolic ischemic stroke.^1,8 For patients who cannot tolerate regimens containing ASA, clopidogrel monotherapy is a reasonable alternative.^1,12 Although dual antiplatelet therapy with ASA + clopidogrel has been shown to benefit patients with ACS,^1,12 it is not recommended as secondary prevention therapy in stroke or TIA patients because of the incrementally increased risk of hemorrhage without benefit of additional protection.¹ Growing evidence supports using combination ASA + ER-DP over ASA monotherapy in the ischemic stroke population because it provides additional benefit and has a similar safety profile,^1,12 although the PRoFESS trial did not confirm a clear advantage to using this agent rather than clopidogrel.

Author Affiliation: Vanderbilt Stroke Center, Nashville, TN.

Funding Source: This supplement was supported by Boehringer Ingelheim.

Author Disclosures: Consultant/Speakers’ bureau: Bristol-Myers Squibb/Sanofi, Investigator/Speakers’ bureau/Consultant: Boehringer Ingelheim; Investigator/Speakers’ bureau: Pfizer.

Authorship Information: Concept, design, and drafting of the manuscript and critical revision of the manuscript for important intellectual content.

Address Correspondence to: Howard S. Kirshner, MD, SelectHealth, 9502 Carriage Chase Ln, Sandy, UT 04092. E-mail: howard.kirshner@vanderbilt.edu.

1. Sacco RL, Adams R, Albers G, et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: cosponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of the guidelines. Stroke. 2006;37(2):577-617.2. American Heart Association/American Stroke Association. Heart Disease and Stroke Statistics, 2008 Update At-a-Glance. http://www.americanheart.org/downloadable/heart/1200082005246HS_Stats%202008.final.pdf. Accessed March 27, 2008.

4. Diener HC. Update on clopidogrel and dual antiplatelet therapy: neurology. Eur Heart J. 2006;8(suppl G):G15-G19.

6. Jamieson DG, Parekh A, Ezekowitz MD. Review of antiplatelet therapy in secondary prevention of cerebrovascular events: a need for direct comparisons between antiplatelet agents. J Cardiovasc Pharmacol Ther. 2005;10(3):153-161.

2000;31(9):2080-2086.

9. Hartmann A, Rundek T, Mast H, et al. Mortality and causes of death after first ischemic stroke: the Northern Manhattan Stroke Study. Neurology. 2001;57(11):2000-2005.

11. Amarenco P, Bogousslavsky J, Callahan A 3rd; Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355(6):549-559.

13. Pedersen TR, Kjekshus J, Pyorala K, et al. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian simvastatin survival study (4S). Am J Cardiology. 1998;81(3):333-335.

15. Ohira T, Shahar E, Chambless LE, Rosamond WD, Mosley TH Jr, Folsom AR. Risk factors for ischemic stroke subtypes: the Atherosclerosis Risk in Communities Study. Stroke. 2006;37(10):2493-2498.

2003;34(8):2050-2059.

18. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24(1):35-41.

20. Laloux P, Galanti L, Jamart J. Lipids in ischemic stroke subtypes. Acta Neurol Belg. 2004;104(1):13-19.

22. Suk SH, Sacco RL, Boden-Albala B, et al; Northern Manhattan Stroke Study. Abdominal obesity and risk of ischemic stroke: the Northern Manhattan Stroke Study. Stroke. 2003;34(7):1586-1592.

24.Vibo R, Korv J, Roose M, et al. Acute phase proteins and oxidised low-density lipoprotein in association with ischemic stroke subtype, severity and outcome. Free Radic Res. 2007;41(3):282-287.

26. Grau AJ, Buggle F, Lichy C, Brandt T, Becher H, Rudi J. Helicobacter pylori infection as an independent risk factor for cerebral ischemia of atherothrombotic origin.

27. Eikelboom JW, Hankey GJ, Anand SS, Lofthouse E, Staples N, Baker RI. Association between high homocyst(e)ine and ischemic stroke due to large- and smallartery disease but not other etiologic subtypes of ischemic stroke. Stroke. 2000;31(5):1069-1075.

29. Shin DH, Lee PH, Bang OY. Mechanisms of recurrence in subtypes of ischemic stroke: a hospital-based followup study. Arch Neurol. 2005;62(8):1232-1237.

31. Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339(19):1349-1357.

33. Waters DD, Schwartz GG, Olsson AG, et al. Effects of atorvastatin on stroke in patients with unstable angina or non-Q-wave myocardial infarction: a Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) substudy. Circulation. 2002;106(13):1690-1695.

placebo-controlled trial. Lancet. 2002;360(9326):7-22.

36. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch InternMed. 1994;154(13):1449-1457.

38. PRoFESS results announced at XVII European Stroke Conference. PharmaLive.com, May 14, 2008.

39. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348(9038):1329-1339.

41. Algra A, van Gijn J. Cumulative meta-analysis of aspirin efficacy after cerebral ischaemia of arterial origin. J Neurol Neurosurg Psychiatry. 1999;66(2):255.

43. Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A; ESPRIT Study Group. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial

44. Farrell B, Godwin J, Richards S,Warlow C. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry.

45. The Dutch TIA Trial Study Group. A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. N Engl J Med. 1991;325(18):1261-1266.

Conference; February 13-15, 2003; Phoenix, Arizona. Abstract 100698.

48. Sabatine MS, Cannon CP, Gibson CM, et al; CLARITYTIMI 28 Investigators. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352(12):1179-1189.

50. Diener HC, Bogousslavsky J, Brass LM, et al; MATCH investigators. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364(9431):331-337.

52. Bhatt DL, Flather MD, Hacke W, et al; CHARISMA investigators. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in

53. Hart RG, Bhatt DL, Hacke W, et al; CHARISMA investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of stroke in patients with a history of atrial fibrillation: subgroup analysis of the CHARISMA randomized trial. Cerebrovasc Dis. 2008;25(4):344-347.

Download PDF: Therapeutic Interventions for Prevention of Recurrent Ischemic Stroke