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Safety risks outweigh potential benefit of dual anti-platelet therapy for secondary stroke prevention – AGAIN!

Susan C Fagan, Pharm.D., FCCP, BCPS
Andrea N. Sikora, Pharm.D. Candidate, Univ. of Georgia College of Pharmacy
Robert C. Newsome, Pharm.D. Candidate, Univ. of Georgia College of Pharmacy
September, 2012

With the known devastating effects of stroke combined with the risk of recurrent stroke upwards of 30%, the temptation towards aggressive medical therapy is high. Further, The SAMMPRIS1 trial showed that aggressive medical management in patients with high-grade intracranial stenosis was superior to advanced endovascular intervention techniques and opened the possibility that dual anti-platelet therapy could be viable secondary prevention in other stroke subsets. Although the lack of benefit and increased danger associated with dual anti-platelet therapy for secondary stroke prevention had been documented in the MATCH2 trial, the investigators persisted in the Stroke Prevention of Small Subcortical Stroke (SPS3) to study the combination of clopidogrel and aspirin. They anticipated a lower bleeding rate in this study of lacunar strokes, which constitute 25% of ischemic stroke due to their exceptional attention to blood pressure control in this trial.3 In this homogeneous stroke subtype, resulting from small artery disease, the potential advantages of dual anti-platelet therapy in secondary prevention could be investigated.

The SPS34 trial included a racially diverse stroke population of 3020 patients with magnetic resonance imaging-documented lacunar strokes. Patients were randomized, in 2x2 factorial design to either clopidogrel 75 mg plus aspirin 325 mg or aspirin alone and either intense (<130 mmHg systolic) or “usual” (130-149 mmHg systolic) blood pressure control. The antiplatelet arms of the trial were stopped early when it was observed that dual anti-platelet therapy compared to aspirin alone exhibited no benefit and significant evidence of harm. The risk of recurrent stroke was 2.5% for dual anti-platelet therapy and 2.7% for aspirin alone (p=0.48) and the risk of hemorrhage was 2.1% for dual anti-platelet therapy compared to 1.1% for aspirin alone (p<0.001). The dual anti-platelet therapy group also showed higher rates of mortality (p=0.004), although the authors were quick to establish that this relationship was not due to an increased rate of intracerebral hemorrhage, the most feared complication of dual anti-platelet therapy. It was encouraging, however, that the overall recurrence rate was lower than predicted (4-11%) at a rate of 2.5% - 2.7% per year, so perhaps the close blood pressure control is having an important benefit. The blood pressure lowering part of SPS3 is continuing.

The SPS3 trial will have an impact on the care of patients with ischemic stroke:

  • Single-agent anti-platelet therapy suffices for secondary prevention of stroke in patients with previous lacunar stroke.

  • The SPS3 trial does not overshadow the SAMMPRIS findings (see ClotCare posting at and N Engl J Med (2012) 365:993-1003) that aggressive medical management for patients with tight intracranial stenosis improves secondary prevention but does highlight the necessity for continued follow-up to ensure that dual anti-platelet therapy is stopped after 3 months.

  • Dual anti-platelet therapy is still warranted for some patient sub-groups including patients with previous stroke and high-grade intracranial stenosis for up to 3 months and cardiovascular patients with percutaneous intervention with a drug-eluting stent for up to 1-year.

  • Evaluation of risk factors for intracranial hemorrhage in patients with previous ischemic stroke should be rigorous so that preventing ischemic stroke healthcare does not predispose patients to the often far more devastating outcome of intracerebral hemorrhage.


  1. Chimowitz MI et al. Stenting versus Aggressive Medical Therapy for Intracranial Stenosis. N Engl J Med 2011; September 7 (10.1056/NEJMoa1105335).

  2. Diener HC et al. 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 Jul 24-30;364(9431):331-7.

  3. Benavente OR et al. The Secondary Prevention of Small Subcortical Strokes (SPS3) study. Int J Stroke. 2011 Apr;6(2):164-75.

  4. The SPS3 Study Group. Effects of Clopidogrel Added to Aspirin in Patients with Recent Lacunar Stroke. N Engl J Med 2012; August 30 (10.1056/NEJMoa1204133).

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