Secondary prevention of non-cardioembolic stroke

Background

The risk of stroke is increased in patients with previous transient ischemic attacks (TIAs) such that to avoid recurrence, practicing an appropriate secondary prevention strategy is pivotal.
Approximately one quarter of the 795,000 strokes that occur each year in the United States are recurrent events and the ratio is reported to be one in three according to European statistics collected by the World Health Organisation who evaluate the number of yearly incident strokes at 15 million and stroke as the third cause of death after myocardial infarction and cancer (1,2,3).  
Find here a review of the American Heart Association (AHA) guidelines regarding the management of modifiable risk factors, the use of antiplatelet agents, and the role of anticoagulation to prevent the recurrence of non-cardioembolic strokes (2011).

I - Risk factor management

Reduce hypertension by choosing a diuretic or the combination of a diuretic and an ACEI

Hypertension has been clearly established as a risk factor for stroke (4).
Reduction prevents recurrent strokes: Reduction of blood pressure with antihypertensive drugs was associated with a statistically significant reduction in the incidence of recurrent strokes (relative risk [RR], 0.76; 95% confidence interval [CI], 0.63 to 0.92) (5).
Due to the absence of large studies comparing the various antihypertensive drugs, the choice of a specific drug should be individualised. However limited data suggests that a diuretic or the combination of a diuretic and an ACEI are useful and has been given a class 1, evidence level A recommendation by the guidelines.

Target no less than 6.5% for HbA1c 

Diabetes has been clearly established as a risk factor for first stroke (6,7,8,9,10) but not as one for recurrent stroke. It has, in population-based studies, been shown to be an independent predictor of recurrent stroke; Eleven per cent of strokes and 9.1% of recurrent strokes have been estimated to be attributable to diabetes (11,12,13).
Indeed, the role of tight glycemic control in patients with diabetes and a history of cardiovascular disease, stroke, or additional vascular risk factors has been studied in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) which demonstrated an increased risk of death but no significant difference in the rate of nonfatal stroke or a composite end point of nonfatal heart attack, nonfatal stroke, and death due to a cardiovascular cause in patients randomised to the intensive treatment program (14). The Action in Diabetes and Vascular Disease (ADVANCE) showed no significant differences in the rate of death, or in the incidence of macro vascular events alone or nonfatal stroke (15) and the Veterans Affairs Diabetes (VADT) randomized clinical trials found no significant difference in the time to occurrence of major cardiovascular events or in the rate of death due to any cause. Based on the results of these trials, the guidelines recommend that the target for HbA1c should not be less than 6.5%.

Use statin therapy for the secondary prevention of stroke in patients without known CHD with evidence of atherosclerosis and LDL-C level >100 mg/d, with a target to reduce the LDL-C by half or to an LDL-C level of<70 mg/dL (16-17)

Dyslipidemia is a well-established risk factor for stroke. The AHA guidelines give a class 1 evidence level B for the following recommendation: However patients with concomitant coronary artery disease should be managed according to the most recent guidelines on dyslipidaemias (18, 19).

Urge smoking cessation or/and heavy drinkers to limit or stop their alcohol consumption.

The guidelines broadly support smoking cessation and limiting alcohol consumption in patients with previous stroke or TIAs even though they have issued a class 1, evidence level C recommendation. Smoking and exposure to passive smoke are established independent risk factors for primary ischemic stroke (20-30).
The association between alcohol consumption and recurrent stroke has been sparsely evaluated. Prior heavy alcohol use has been associated with an increased rate of stroke in patients with previous ischemic strokes (31). However no study has demonstrated that reduction of alcohol intake decreases risk of recurrent stroke. 
No specific recommendations have been issued by the guidelines regarding obesity physical activity or metabolic syndrome. Obesity has been primary studied in relation to the primary prevention of stroke (32-41), and no study has demonstrated that weight reduction reduces risk of stroke recurrence. 
The beneficial effects of a structured exercise program after stroke have been demonstrated by many studies but no study has shown that such programs reduce the incidence of subsequent stroke. Lastly, no randomized trial of secondary prevention therapy has been conducted among stroke patients with the metabolic syndrome.

II- Pharmaceutical strategies

Four antiplatelet drugs have been approved by FDA for the secondary prevention of stroke and are recommended in the guidelines. They include aspirin (acetylsalicylic acid - ASA), the combination of ASA and dipyridamole, clopidogrel, and ticlopidine. All these agents have been shown to reduce the relative risk of stroke, myocardial infarction (MI), or death by about 22% (42). However differences exist amongst these agents, which allow a more targeted use in any given patient. 

75 mg of ASA

Aspirin is an irreversible, non-selective cyclooxygenase inhibitor. The use of ASA for the secondary prevention of any type of stroke (hemorrhagic or ischemic) is associated with a relative risk reduction of 15% (95% CI, 6% to 23%) (43) and the benefit appears to be similar for doses ranging from 50 mg to 1500 mg (44).
Since there is no dose-response relationship and lower doses of ASA are associated with lower gastrointestinal side effects, the use of 75 mg of ASA is recommended in the guidelines.
From a health care standpoint, Aspirin is the most cost effective of any of the recommended drugs. 
The annual risk of serious GI bleeding in patients who use ASA <325 mg daily for prolonged periods is 0.4%, which is 2.5 times the risk for nonusers.

The combination of ASA and dipyridamole may be more effective than ASA alone but may cause more hemorrhages 

Dipyridamole is an inhibitor of adenosine uptake and results in reduced platelet aggregation. In addition, dipyridamole also augments cGMP production in the vascular smooth muscle leading to vasodilation. The efficacy of ASA/dipyridamole in the secondary prevention of stroke was tested  against placebo in three separate studies: 
The European Stroke Prevention Study (ESPS1) found 33% relative risk reduction compared with placebo (45). This trial included patients with a recent TIA or stroke and investigated the effects of ASA/dipyridamole on the risk of subsequent stroke and death from any cause. In the treatment group there was a significant 33% relative risk reduction compared with placebo (p<0.001).
The European Stroke Prevention Study 2 (ESPS2) (46) found that 25mg twice daily and dipyridamole are associated with similar clinical efficacy and their effects are additive: trial assessed the efficacy of low-dose aspirin, modified-release dipyridamole and their combination on ischemic stroke, death or a combination of stroke and death in patients with prior TIA or stroke. The risk of subsequent stroke was decreased by 18% with aspirin alone (p = 0.013); 16% with dipyridamole alone (p = 0.039); and 37% with the combination therapy (p < 0.001). Compared with aspirin alone, the combination therapy reduced the risk of stroke by 23% (P<0.006) and stroke or death by 13% (P<0.056). Thus ASA 25mg twice daily and dipyridamole are associated with similar clinical efficacy and their effects are additive. Headache and gastrointestinal symptoms were more common in the ASA plus dipyridamole group in the ESPS-2 trial. 
The aspirin plus dipyridamole versus aspirin alone after cerebral ischemia of arterial origin (ESPIRIT) found combination is superior to ASA alone (47). The trial assessed the efficacy of ASA/dipyridamole versus ASA alone on stroke recurrence, MI, vascular death or major bleeding in men and women with a TIA or ischemic stroke within the past 6 months. The authors report a hazard ratio of 0.80 (95% Cl 0.66 to 0.98), indicating that the combination is superior to ASA alone. Major bleeding was also more common among patients assigned to ASA and extended-release dipyridamole (4.1% compared with 3.6%) groups as compared to the clopidogrel group in the PRoFESS trial, but this difference did not meet statistical significance.

Clopidogrel is as effective as ASA or combination ASA/dipyridamole. Compared to ASA, there is less gastrointestinal symptoms and hemorrhages but more diarrhea and rash with clopidogrel. Intolerance to ASA because of allergy or gastrointestinal side effects makes clopidogrel an appropriate choice.

Clopidogrel is an irreversible antagonist of the platelet P2Y12 ADP receptor and inhibits platelet activation and aggregation. Clopidogrel has not been compared with placebo for secondary prevention of stroke in any randomised trial.
However, in the clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) and the aspirin and extended release dipyridamole versus clopidogrel for recurrent stroke (PRoFESS) trials clopidogrel has been compared with ASA and ASA/dipyridamole, respectively (48, 49). Clopidogrel is probably as effective as ASA and the combination ASA/dipyridamole, as observed in the CAPRIE48 and PRoFESS49 trials. Indeed, CAPRIE assessed the efficacy of clopidoposite end point of ischemic stroke, myocardial infarction, or vascular death in patients with a recent ischemic stroke, recent myocardial infarction, or symptomatic peripheral arterial disease. It showed a statistically significant (p = 0.043) relative-risk reduction of 8.7% in favor of clopidogrel (95% confidence interval 0.3 -16.5). However, in a subgroup analysis of patients who had entered CAPRIE after a stroke this benefit was not observed. Of note, CAPRIE also showed that the safety profile of clopidogrel is similar to that of ASA. There was no difference in the incidence of neutropenia among patients assigned to clopidogrel, compared with ASA or placebo, in published trials.
PRoFESS was designed to assess the efficacy of ASA/dipyramidamole and clopidogrel in reducing the risk of recurrent stroke in patients with history of ischemic stroke. While more intracranial hemorrhages were recorded on ASA/dipyridamole than on clopidogrel (hazard ratio, 1.42; 95% CI, 1.11 to 1.83), no significant difference was observed in the net risk of recurrent stroke or major hemorrhagic event, suggesting equal efficacy of the two treatments.

Ticlopidine may be more efficacious than ASA in secondary stroke prevention; however its side effects limit its use (including diarrhea, skin rash and severe reversible neutropenia <2%). Ticlopidine has also been linked to the occurrence of thrombotic thrombocytopenic purpura.

Ticlopidine is an irreversible antagonist of the platelet P2Y12 ADP receptor which inhibits platelet activation and aggregation. To assess its efficacy in terms of secondary prevention of stroke, ticlopidine was compared to placebo in the Canadian American Ticlopidine Study in Thromboembolic Stroke (CATS) 50 trial and to aspirin in the Ticlopidine Aspirin Stroke Study Group (TASS) (50) and Aspirin and ticlopidine for prevention of recurrent stroke in black patients AAASPS52 trials.
The CATS study (51) reported a 23% in the first event of recurrence of stroke. It assessed the efficacy of ticlopidine on the risk of subsequent stroke, myocardial infarction, or vascular death in patients with a recent thromboembolic stroke. Authors reported a relative risk reduction [RRR] of 23% (95% confidence interval 1% to 41%) in the primary outcome - the first event of recurrence of stroke. Importantly, the benefit was observed in both men and women (relative risk reductions 28.1%, p = 0.037, and 34.2%, p = 0.045, respectively).  
TASS compared the efficacy of ticlopidine and ASA in patients with a recent transient or mild persistent focal cerebral or retinal ischemia for the secondary prevention of stroke.  While ticlopidine appeared to be more effective than ASA with a relative risk reduction of 12% (95% confidence interval 2% to 26%) it caused significantly higher incidence of side effects, including diarrhea, skin rash and severe reversible neutropenia than ASA. Rate of GI bleeding with ticlopidine is equal or less than that with ASA.
The AAASPS (52) trial compared the efficacy of ASA and ticlopidine in African American patients with a recent thromboembolic stroke on the recurrence of stroke, MI, or vascular death. No statistically significant difference was found between the ticlopidine and ASA groups. Considering the risk of serious adverse events with ticlopidine the trial recommended ASA over ticlopidine for ASA-tolerant African American patients with previous non-cardioembolic ischemic stroke. 

Combination therapy of ASA and clopidogrel is no better than either drug alone, however bleeding risk is increased. 

The efficacy of ASA/clopidogrel was assessed in the Aspirin and clopidogrel compared with clopidogrel alone after ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH) (53) and the Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events (CHARISMA) (54) trials. 
The MATCH trial compared the effects of the combination of ASA plus clopidogrel and clopidogrel alone on the risk of ischemic stroke, MI, vascular death, or rehospitalization for any central or peripheral ischemic event in patients with recent TIA or ischemic stroke. No statistically significant benefit was observed with the combination treatment versus clopidogrel alone. Furthermore, the risk of major hemorrhage was significantly increased with ASA/clopidogrel, with a 1.3% absolute increase in life-threatening bleeding.
CHARISMA compared the efficacy of aspirin/clopidogrel and aspirin in patients with clinically evident cardiovascular disease or multiple risk factors for the prevention of MI, stroke, or death due to cardiovascular causes. Overall no statistically significant benefit was observed in the combination treatment, and a subgroup analysis of patients who entered after a stroke showed increased bleeding risk. 

The use of antiplatelet agents is recommended over anticoagulation for the secondary prevention of stroke (class 1, level of evidence A).

The efficacy of anticoagulation therapy on recurrent non-cardioembolic stroke was assessed in the Stroke Prevention in Reversible Ischemia Trial Study Group (SPIRIT) (55,56), in a
comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke (WARSS) (57) and the ESPRIT trials.
SPIRIT compared high intensity anticoagulation with warfarin (INR 3.0-4.0) versus ASA. Because of the increased risk of bleeding in the warfarin group this study was stopped early.
The efficacy of lower-intensity anticoagulation with warfarin (INR 1.4 to 2.8) versus ASA 325 mg daily on recurrent stroke or death was investigated in WARSS, which showed no significant difference in the efficacy or the rates of major bleeding.
ESPRIT - a reformulation of SPIRIT - compared medium intensity anticoagulation with warfarin (INR 2.0-3.0) versus ASA alone or the combination of ASA/dipyridamole. This trial was stopped early because of the superiority of ASA/dipyridamole versus ASA alone. Analysis of the data showed that overall the warfarin group did not have a statistically significant reduction in the ischemic events but was associated with significantly higher rate of major bleeding (HR, 2.56; 95% CI, 1.48 to 4.43) compared with ASA alone.

Conclusion

Added to the specific risk factor management regarding hypertension, lipids, diabetes and smoking/drinking described above, a recommended pharmaceutical strategy would consist in 75 mg of ASA, or a combination of ASA and dipyridamole or clopidogrel. 
Efficacy, safety profile, cost effectiveness, patient characteristics and preference should be factored in deciding on the appropriate approach in a given patient.