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
General Considerations
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
If a patient’s initial stroke is ischemic, another level of complexity is added to treatment decisions. Ischemic stroke comprises several pathogenic subtypes. The main etiologic subtypes are large vessel disease (LVD), small vessel disease (SVD, also called lacunar), cardioembolic, other known cause (eg, hypercoagulable state, arterial dissection), and cryptogenic (unknown cause).¹ Some risk factors vary according to ischemic stroke subtype. Risk factors more commonly associated with SVD are smoking,^15-17 diabetes,^15,18 an elevated white blood cell count,¹⁵ and possibly hypertension (evidence of this is not conclusive).¹⁹ Strong risk factors for LVD include smoking,^16,17,20,21 abdominal obesity,^15,22 dyslipidemia,^20,21,23,24 infection/inflammation,^25,26 and hyperhomocysteinemia.²⁷ Infection/inflammation^25,26 and von Willebrand factor¹⁵ are strong risk factors for cardioembolic stroke.^25,26 Effective secondary prevention depends heavily on addressing modifiable risk factors.

Ischemic stroke subtypes differ in severity and cause varying degrees of impairment; for example, SVD is associated with a lower 5-year mortality rate and better functional outcomes,²⁸ whereas cardioembolic stroke has the highest 5-year mortality rate (>80%).²⁸ The risk of stroke recurrence also varies according to ischemic stroke subtype. SVD is associated with a lower 30-day risk of recurrence, and LVD stroke conveys the highest 30-day risk of recurrence. ²⁸ Approximately 60% to 70% of first recurrent strokes are the same subtype as the initial stroke.^28,29

The stroke-patient population is heterogeneous, and treatment strategies may need to be uniquely tailored not only to the ischemic stroke subtype but also to the patient. Some LVD stroke patients with severe carotid artery stenosis, extracranial vertebral artery stenosis, or hemodynamically significant intracranial stenosis will benefit from surgical or endovascular interventions.¹ Anticoagulant agents are recommended for cardioembolic stroke patients with a high-risk source of embolism, whereas antiplatelet agents are preferred for other stroke subtypes.¹ Treatment decisions should always consider the subtype of the initial ischemic stroke, and they should be individualized with regard to the patient’s modifiable risk factors.

AHA/American Stroke Association Guidelines for Secondary Prevention of Stroke
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 Factors
Smoking.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’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 ≥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 ≤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
Extracranial Carotid Disease.¹ Carotid endarterectomy (CEA) is recommended for patients with severe ipsilateral (≥70%) carotid artery stenosis who have experienced ischemic stroke or TIA within the previous 6 months; surgery should be performed within 2 weeks of findings. CEA is also recommended in patients with moderate ipsilateral carotid artery stenosis (50%-69%), depending on age, sex, comorbidities, and the severity of initial symptoms. For patients with symptomatic severe carotid artery stenosis, carotid artery balloon angioplasty and stenting should be considered if stenosis would be difficult to access by CEA or is radiationinduced, if comorbid conditions make CEA highrisk, and if restenosis follows a prior CEA.

Extracranial Vertebrobasilar Disease.¹ Endovascular therapy (eg, angioplasty, stenting) can be performed in patients with symptomatic extracranial vertebral stenosis who demonstrate stroke or TIA symptoms despite treatment with antithrombotics, statins, and other medical therapies.

Intracranial Atherosclerosis.¹ Endovascular therapy in patients with hemodynamically significant intracranial stenosis who experience symptoms despite medical treatment is considered investigational.

Recommendations for Antithrombotic Therapy in Cardioembolism
In patients with cardioembolic stroke, the primary focus is on anticoagulation (Table 1).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—but do not eliminate—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 anticoagulants
and 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

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 (Table 2).^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’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
Aspirin
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.

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 (Table 3).^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
Clopidogrel has a different mechanism of action than ASA; clopidogrel inhibits platelet aggregation induced by adenosine diphosphate.³⁹ Monotherapy with either clopidogrel or ASA reduces ischemic events in patients with disease in other vascular beds; thus, clopidogrel is well-suited to patients whose medical history includes CHD or PAD.^5,37,39 The pivotal CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trial demonstrated that clopidogrel monotherapy was more effective than ASA monotherapy in reducing overall risk in a heterogeneous population; the difference in efficacy did not reach statistical significance in the subgroup of stroke patients studied, however. ^1,5,39 CAPRIE randomized 19,185 patients with symptomatic vascular disease (including MI, PAD, or ischemic stroke) to clopidogrel (75 mg/day) or ASA (325 mg/day), with a mean follow-up of 1.91 years and a composite outcome of ischemic stroke, MI, or vascular death.³⁹ Intention-to-treat analysis demonstrated an 8.7% overall RRR for patients receiving clopidogrel versus ASA (P = .043).³⁹ The RRR in the PAD subgroup was 23.8% (P = .0028) versus 7.3% in the stroke subgroup (no significance, P = .26),^5,39 suggesting that the overall benefit derived mainly from patients with PAD.⁵Dual therapy of clopidogrel + ASA for up to 12 months is more effective than ASA monotherapy in patients with acute coronary syndromes (ACS)^1,47-49 and is recommended for patients with coronary stents.¹² The CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial enrolled 12,562 patients with ACS who presented within 24 hours of symptom onset and had no ST-segment elevation.⁴⁷ Patients were allocated randomly to clopidogrel (300-mg loading dose, 75 mg/day thereafter) or placebo, combined with ASA (75-325 mg/day), for a mean of 9 months.⁴⁷ The primary composite outcome (cardiovascular death, nonfatal MI, or stroke) occurred in 9.3% of the clopidogrel + ASA group versus 11.4% of the placebo + ASA group (RR, 0.80; P <.001).⁴⁷ Significantly more patients receiving clopidogrel versus placebo experienced major bleeding (3.7% vs 2.7%, respectively; RR, 1.38; P = .001).⁴⁷

The CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis in Myocardial Infarction) trial included 3491 patients with ST-segment elevation who presented to the hospital within 12 hours of MI onset.⁴⁸ Patients were randomly allocated to clopidogrel (300-mg loading dose, 75 mg/day thereafter) or placebo, combined with ASA (150-325 mg first day, 75-162 mg/day thereafter); all patients had been scheduled to undergo angiography within 48 to 92 hours.⁴⁸ Clopidogrel conferred an ARR of 6.7% and an RRR of 36% (P <.001) in the primary composite end point (occluded infarct-related artery on angiography, death or recurrent MI before angiography).⁴⁸ Clopidogrel reduced the odds of recurrent MI by 30% (P = .08); there was no significant difference in the incidence of bleeding between the 2 groups.⁴⁸

The COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) study enrolled 45,892 patients with acute MI hospitalized within 24 hours of symptom onset; 93% demonstrated ST-segment elevation.⁴⁹ Patients were randomized to clopidogrel (75 mg/day) or placebo, along with ASA (162 mg/day), until discharge or for up to 4 weeks of hospitalization (mean, 15 days in survivors).⁴⁹ The clopidogrel group saw a 9% proportional reduction in composite outcome of death, reinfarction, or stroke (P = .002).⁴⁹ The incidence of major bleeding did not increase significantly with 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

Two studies compared combination clopidogrel + ASA versus monotherapy with ASA or clopidogrel  in preventing vascular events in stroke or TIA patients without ACS (Table 4). 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 Dipyridamole
DP, 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