Effects of clopidogrel added to aspirin in patients with recent lacunar stroke.

BACKGROUND Lacunar infarcts are a frequent type of stroke caused mainly by cerebral small-vessel disease. The effectiveness of antiplatelet therapy for secondary prevention has not been defined. METHODS We conducted a double-blind, multicenter trial involving 3020 patients with recent symptomatic lacunar infarcts identified by magnetic resonance imaging. Patients were randomly assigned to receive 75 mg of clopidogrel or placebo daily; patients in both groups received 325 mg of aspirin daily. The primary outcome was any recurrent stroke, including ischemic stroke and intracranial hemorrhage. RESULTS The participants had a mean age of 63 years, and 63% were men. After a mean follow-up of 3.4 years, the risk of recurrent stroke was not significantly reduced with aspirin and clopidogrel (dual antiplatelet therapy) (125 strokes; rate, 2.5% per year) as compared with aspirin alone (138 strokes, 2.7% per year) (hazard ratio, 0.92; 95% confidence interval [CI], 0.72 to 1.16), nor was the risk of recurrent ischemic stroke (hazard ratio, 0.82; 95% CI, 0.63 to 1.09) or disabling or fatal stroke (hazard ratio, 1.06; 95% CI, 0.69 to 1.64). The risk of major hemorrhage was almost doubled with dual antiplatelet therapy (105 hemorrhages, 2.1% per year) as compared with aspirin alone (56, 1.1% per year) (hazard ratio, 1.97; 95% CI, 1.41 to 2.71; P<0.001). Among classifiable recurrent ischemic strokes, 71% (133 of 187) were lacunar strokes. All-cause mortality was increased among patients assigned to receive dual antiplatelet therapy (77 deaths in the group receiving aspirin alone vs. 113 in the group receiving dual antiplatelet therapy) (hazard ratio, 1.52; 95% CI, 1.14 to 2.04; P=0.004); this difference was not accounted for by fatal hemorrhages (9 in the group receiving dual antiplatelet therapy vs. 4 in the group receiving aspirin alone). CONCLUSIONS Among patients with recent lacunar strokes, the addition of clopidogrel to aspirin did not significantly reduce the risk of recurrent stroke and did significantly increase the risk of bleeding and death. (Funded by the National Institute of Neurological Disorders and Stroke and others; SPS3 ClinicalTrials.gov number, NCT00059306.).

[1]  R. Conwit,et al.  Clinical features and racial/ethnic differences among the 3020 participants in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial. , 2013, Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association.

[2]  Christopher S Coffey,et al.  Sample size re-estimation in an on-going NIH-sponsored clinical trial: the secondary prevention of small subcortical strokes experience. , 2012, Contemporary clinical trials.

[3]  O. Benavente,et al.  Effect of Addition of Clopidogrel to Aspirin on Mortality: Systematic Review of Randomized Trials , 2012, Stroke.

[4]  Á. Chamorro,et al.  Terutroban versus aspirin in patients with cerebral ischaemic events (PERFORM): a randomised, double-blind, parallel-group trial , 2011, The Lancet.

[5]  R. Conwit,et al.  The Secondary Prevention of Small Subcortical Strokes (SPS3) Study , 2011, International journal of stroke : official journal of the International Stroke Society.

[6]  G. Moneta.  Bleeding Complications With Dual Antiplatelet Therapy Among Patients With Stable Vascular Disease or Risk Factors for Vascular Disease: Results From the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) Trial , 2011 .

[7]  Irene Katzan,et al.  Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the american heart association/american stroke association. , 2011, Stroke.

[8]  S. Yusuf,et al.  Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. , 2010, The New England journal of medicine.

[9]  Salim Yusuf,et al.  Effect of clopidogrel added to aspirin in patients with atrial fibrillation. , 2009, The New England journal of medicine.

[10]  M. Ezekowitz,et al.  Combination antiplatelet therapy for secondary stroke prevention: enhanced efficacy or double trouble? , 2009, The American journal of cardiology.

[11]  Deepak L. Bhatt,et al.  Aspirin to Prevent Cardiovascular Disease: The Association of Aspirin Dose and Clopidogrel With Thrombosis and Bleeding , 2009, Annals of Internal Medicine.

[12]  A. Rabinstein.  Aspirin and Extended-Release Dipyridamole versus Clopidogrel for Recurrent Stroke , 2009 .

[13]  Samy Suissa,et al.  Drug–drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding , 2007, Canadian Medical Association Journal.

[14]  Patrice Cacoub,et al.  Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. , 2006, The New England journal of medicine.

[15]  R. Hart,et al.  Avoiding Central Nervous System Bleeding During Antithrombotic Therapy: Recent Data and Ideas , 2005, Stroke.

[16]  W. Feuerhake,et al.  Incidence, 30-day case-fatality rate, and prognosis of stroke in Iquique, Chile: a 2-year community-based prospective study (PISCIS project) , 2005, The Lancet.

[17]  J. Wardlaw,et al.  What causes lacunar stroke? , 2005, Journal of Neurology, Neurosurgery & Psychiatry.

[18]  H. Diener,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 , 2004, The Lancet.

[19]  S. Yusuf,et al.  Effects of Aspirin Dose When Used Alone or in Combination With Clopidogrel in Patients With Acute Coronary Syndromes: Observations From the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Study , 2003, Circulation.

[20]  Gustavo Saposnik,et al.  Stroke in South America: a systematic review of incidence, prevalence, and stroke subtypes. , 2003, Stroke.

[21]  C. Wolfe,et al.  Incidence and case fatality rates of stroke subtypes in a multiethnic population: the South London Stroke Register , 2002, Journal of neurology, neurosurgery, and psychiatry.

[22]  Olaf Gefeller,et al.  Epidemiology of Ischemic Stroke Subtypes According to TOAST Criteria: Incidence, Recurrence, and Long-Term Survival in Ischemic Stroke Subtypes: A Population-Based Study , 2001, Stroke.

[23]  S. Yusuf,et al.  Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. , 2001, The New England journal of medicine.

[24]  P. R. R. Ecurrent,et al.  EFFECTS OF CLOPIDOGREL IN ADDITION TO ASPIRIN IN PATIENTS WITH ACUTE CORONARY SYNDROMES WITHOUT ST-SEGMENT ELEVATION , 2001 .

[25]  R. Havlik,et al.  Characterization of risk factors for vascular dementia , 1999, Neurology.

[26]  O. Benavente,et al.  Survey of the causes of stroke among Mexican Americans in South Texas. , 1998, Texas medicine.

[27]  R. Sacco,et al.  Race-ethnic differences in stroke risk factors among hospitalized patients with cerebral infarction , 1995, Neurology.

[28]  J. Rothrock,et al.  Impact of race and ethnicity on ischemic stroke. The University of California at San Diego Stroke Data Bank. , 1995, Stroke.

[29]  O. D. Del Brutto,et al.  Stroke Subtypes Among Hispanics Living in Guayaquil, Ecuador: Results From the Luis Vernaza Hospital Stroke Registry , 1993, Stroke.

[30]  J. Lodder,et al.  Prognosis for Survival, Handicap and Recurrence of Stroke in Lacunar and Superficial Infarction , 1993 .

[31]  R. Mayeux,et al.  Clinical determinants of dememtia related to stroke , 1993, Annals of neurology.

[32]  J. Bogousslavsky,et al.  The Lausanne Stroke Registry: analysis of 1,000 consecutive patients with first stroke. , 1988, Stroke.

[33]  S. Haffner,et al.  A comparison of three indicators for identifying Mexican Americans in epidemiologic research. Methodological findings from the San Antonio Heart Study. , 1986, American journal of epidemiology.