Selecting the most effective stroke prevention strategy for patients with cerebrovascular disease is an acknowledged challenge. In addition to decisions about the appropriateness of carotid surgery or angioplasty and stenting, there is the often tricky matter of designing the most effective medical regimen.
Selecting the most effective stroke prevention strategy for patients with cerebrovascular disease is an acknowledged challenge. In addition to decisions about the appropriateness of carotid surgery or angioplasty and stenting (which we discussed in our article here), there is the often tricky matter of designing the most effective medical regimen.
Here we address questions that primary care clinicians frequently ask about the role of statins and antiplatelet agents in stroke prevention regimens. We also discuss strategies for situations in which optimal therapy fails to prevent recurrent stroke.
As in our first article, we review the best available data and then provide a summary of recommended, evidence-based management strategies.
What is the role of statins in stroke prevention?
Evidence supporting statin therapy. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial provides the best evidence to support the role of statins in secondary stroke prevention. Previous studies have demonstrated the benefit of statins in reducing stroke risk in patients with coronary artery disease.1 The SPARCL design was unique in that eligible patients had stroke or transient ischemic attack (TIA) without concomitant coronary artery dis-ease (CAD). Patients enrolled in SPARCL received either atorvastatin, 80 mg/d, or placebo beginning within 1 to 6 months of the index event.2 A small proportion of enrolled patients had hemorrhagic stroke (less than 2%); patients with cardioembolic stroke, disabling stroke, and uncontrolled hypertension were not included.
A significant reduction in fatal/nonfatal stroke and cardiovascular events over 5 years was observed in the treatment group. A post hoc analysis found a small increase in the incidence of hemorrhagic stroke in the group that received atorvastatin (2.3% vs 1.4%); however, this did not offset the overall benefit observed with statin use. A recent secondary analysis found that the incidence of hemorrhagic stroke was higher in those patients with hemorrhagic stroke as the entry event and was associated with male sex and increasing age.3 Table 1 summarizes the SPARCL study results. Possible mechanisms of action. The effects of statins in reducing recurrent stroke risk likely extend beyond simple reduction of low-density lipoprotein (LDL) cholesterol levels. Statin-mediated changes in vascular endothelial function, cell proliferation, inflammatory response, and platelet function may contribute to improved outcomes. Further study is required to better understand the relationship between statin use and hemorrhagic stroke.
Statins in acute stroke. Emerging data support the continuation of statin therapy in the acute phase of ischemic stroke. In patients who had been receiving statin therapy at the time of stroke and in whom the medication was subsequently discontinued, there was a significant increase in early neurological deterioration, infarct volume, and the likelihood of death or dependency at 3 months.4
What is the optimal antiplatelet regimen for stroke prophylaxis?
Primary prevention. A meta-analysis of 52,251 predominantly male patients failed to demonstrate that aspirin provided greater benefit than no aspirin for primary prevention of stroke in patients who were asymptomatic.5 The Women's Health Study demonstrated a significant 24% reduction in the risk of ischemic stroke over 10 years for women aged 45 years or older who received aspirin, 100 mg/d on alternating days.6 No other antiplatelet agents have been rigorously evaluated for primary stroke prevention.
Secondary prevention. Aspirin, clopidogrel, extended-release dipyridamole, and ticlopidine have demonstrated efficacy in large-scale clinical studies for the prevention of recurrent vascular events or stroke in patients with a history of noncardioembolic stroke.7 Aspirin, clopidogrel, and a formulation of extended-release dipyridamole plus low-dose aspirin are the agents in common use today. Ticlopidine has fallen out of favor because of its adverse event profile, which includes rash, diarrhea, and severe neutropenia. Clopidogrel has a similar biochemical structure and a more favorable side-effect profile; it has essentially replaced ticlopidine in routine clinical practice. Relevant facts pertinent to each of the commonly used antiplatelet formulations are summarized in Table 2.
Aspirin has been shown in several studies to be superior to placebo for secondary stroke prevention. In addition, aspirin is the only antiplatelet agent to be studied in the acute setting; a reduction in early stroke recurrence was seen when aspirin was given within 48 hours of symptom onset.8 However, there is no conclusive evidence that higher doses of aspirin provide increased efficacy; thus, the FDA has approved a dosage range of 50 to 325 mg/d.
Clopidogrel, 75 mg/d, was shown in the Clopidogrel versus Aspirin in Patients at Risk for Ischemic Events (CAPRIE) trial to be superior to aspirin, 325 mg/d, in patients with stroke, myocardial infarction (MI), or peripheral artery disease (PAD) for the composite end point of ischemic stroke, acute MI, or vascular death.9 However, the beneficial effect of clopidogrel was primarily attributable to results from the PAD group (relative risk reduction [RRR], 23.8%). In contrast, in those patients for whom ischemic stroke was the qualifying event, the difference was much smaller (RRR, 7.3%) and not statistically significant.
The European/Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) randomly assigned patients with TIA or noncardioembolic minor stroke to receive treatment with either aspirin alone (30 to 325 mg/d) or in combination with dipyridamole (200 mg bid).10 The intention-to-treat analysis for the primary outcome of death from all vascular causes, nonfatal stroke, nonfatal MI, or major bleeding complication reached statistical significance, with the results favoring the combination therapy. Combined dipyridamole and aspirin conferred an absolute risk reduction of 1% per year compared with aspirin alone. However, patients assigned the combination of aspirin and dipyridamole discontinued trial medication more frequently than did those assigned aspirin alone, mostly because of headache. The lack of statistical significance for the on-treatment analysis, the study's open-label design, and the use of low-dose aspirin (30 mg/d) in approximately 45% of patients has led to cautious acceptance of these results.
The Prevention Regimen For Effectively avoiding Second Strokes (PRoFESS) study randomly assigned 20,332 patients with noncardioembolic stroke to receive either aspirin (25 mg) plus extended-release dipyridamole (200 mg) twice daily or clopidogrel (75 mg) once daily; the patients were followed for an average of 2.5 years. The study found no difference between the 2 groups with respect to either the primary outcome measure of recurrent stroke or the secondary outcome of stroke, MI, or vascular death.11
Determination of the optimal, evidence-based regimen for secondary stroke prevention is challenging because trials of antiplatelet agents have involved patients with heterogeneous vascular risk profiles and because composite end points have been used in the placebo-controlled and comparative studies. Moreover, the largest clinical trial of antiplatelet therapy for secondary stroke prevention to date (PRoFESS) did not demonstrate a significant difference between 2 commonly prescribed agents. It is unlikely that one antiplatelet agent is truly superior to another for secondary prevention. Therefore, adverse-effect profiles, cost, and coexisting vascular disease heavily influence the choice of antiplatelet therapy in individual patients.
When is combination antiplatelet therapy warranted for secondary prevention of ischemic stroke?
The only combination therapy that has been approved by the FDA for secondary stroke prevention is extended-release dipyridamole and aspirin. No other combination anti- platelet therapy has demonstrated evidence of benefit that outweighs risk. Studies of clopidogrel plus aspirin. The Management of ATherothrombosis with Clopidogrel in High-risk patients with recent TIA or ischemic stroke (MATCH) trial compared clopidogrel, 75 mg/d, with the combination of aspirin, 325 mg/d and clopidogrel, 75 mg/d, in patients with stroke, TIA, or other vascular risk factors.12 No significant reduction in the composite end point of stroke, MI, vascular death, or rehospitalization for an ischemic event was seen in the combination antiplatelet arm at 18 months. Moreover, the combination of clopidogrel and aspirin was associated with a significantly higher rate of life-threatening bleeding episodes than clopidogrel alone (2.6% vs 1.3%).
The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial compared the combination of aspirin and clopidogrel with aspirin alone in patients with MI, stroke, PAD, or multiple atherothrombotic risk factors.13 No significant reduction in stroke, MI, or vascular death was observed (P = .22). Although severe bleeding was not higher in the combination group (P = .09), moderate bleeding was statistically higher in those patients who received combination therapy (P < .001).
The results of these large clinical trials demonstrate that the combination of aspirin and clopidogrel provides no reduction in recurrent ischemic events while increasing the risk of bleeding over that incurred with monotherapy. Thus, the combination of aspirin and clopidogrel should not be used for routine secondary stroke prevention.
Settings in which dual antiplatelet therapy is appropriate. The combination of clopidogrel plus aspirin has been effective in patients with an acute coronary syndrome (ACS) and in those who have recently undergone coronary revascularization with angioplasty and stenting.14 Combination antiplatelet therapy has also been used empirically in the periprocedural period in patients who undergo carotid artery stenting or intracranial stent placement. However, dual antiplatelet therapy has not been prospectively evaluated after extracranial or intracranial stent-assisted revascularization.
What can be done when recurrent stroke occurs despite optimal therapy?
Secondary stroke prevention therapies are not perfect, and a certain percentage of patients have recurrent stroke despite modification of vascular risk factors or use of antiplatelet agents. In such patients, re-evaluation for common stroke mechanisms, such as cardiac disease or extracranial carotid disease, is important to guide preventive strategies, and modification of vascular risk factors should continue.15 In addition, one may consider less common causes of stroke, such as inherited or acquired prothrombotic conditions, which may require different preventive strategies.
Inherited and environmental factors likely reduce the effectiveness of standard stroke prevention strategies. Studies such as the Ischemic Stroke Genetics Study (ISGS) are under way to better understand the inherited contribution to so-called common stroke.
Pharmacological evidence of aspirin resistance in patients with stroke has been demonstrated, but how this relates to clinical recurrence or prevention of recurrence remains unclear. One study suggested that about 7% of patients with stroke may have primary aspirin resistance and that secondary aspirin resistance may develop in an additional 4%.16 However, because the clinical relevance of pharmacological aspirin resistance is not clear, assessing platelet function in patients who experience recurrent stroke while receiving aspirin is not currently indicated.
Recommendations for Patients With Recurrent Stroke:
1. Amarenco P, Labreuche J, Lavallee P, Touboul PJ. Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke. 2004;35:2902-2909.
2. Stroke Prevention by Aggressive Reduction in Cholestrol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549-559.
3. Goldstein LB, Amarenco P, Szarek M, et al. Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study. Neurology. 2007 Dec 12 [Epub ahead of print].
4. Blanco M, Nombela F, Castellanos M, et al. Statin treatment withdrawal in ischemic stroke: a controlled randomized study. Neurology. 2007;69:904-910.
5. Hart RG, Halperin JL, McBride R, et al. Aspirin for the primary prevention of stroke and other major vascular events. Meta-analysis and hypotheses. Arch Neurol. 2000;57:326-332.
6. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005;352:1293-1304.
7. 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;10:153-161.
8. Chen ZM, Sandercock P, Pan HC, et al. Indications for early aspirin use in acute ischemic stroke: a combined analysis of 40,000 randomized patients from the Chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups. Stroke. 2000;31:1240-1249.
9. CAPRIE steering committee. A randomized, blinded trial of clopidogrel versus aspirin in patients at risk for ischemic events (CAPRIE). Lancet. 1996;348:1329-1339.
10. ESPRIT Study Group, Halkes PH, van Gijn J, et al. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomized controlled trial [published correction appears in Lancet. 2007;369:274]. Lancet. 2006;367:1665-1673.
11. Sacco R, Diener HC, Yusuf S; for the PRoFESS Investigators. Prevention Regimen For Effectively avoiding Second Strokes (PRoFESS) Trial: comparison of a fixed-dose combinaion of extended-release depyridamole plus asa with clopidogrel. Presented at: the European Stroke Conference; May 14, 2008; Nice, France.
12. 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;364:331-337.
13. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for prevention of atherothrombotic events. N Engl J Med. 2006;354:1706-1717.
14. Keller T, Squizzato A, Middeldorp S. Clopidogrelplus aspirin versus aspirin alone for preventing cardiovascular disease. Cochrane Database Syst Rev. 2007;(3):CD005158.
15. 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: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Stroke. 2006;37:577-617.
16. Berrouschot J, Schwetlick B, von Twickel G, et al. Aspirin resistance in secondary stroke prevention. Acta Neurol Scand. 2006;113:31-35.
17. Chan FK, Ching JY, Hung LC, et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med. 2005;352:238-244.