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Aspirin and Ticlopidine for Prevention of Recurrent Stroke in Black Patients a Randomized Trial

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Aspirin and Ticlopidine for Prevention of Recurrent Stroke in Black Patients a Randomized Trial ORIGINAL CONTRIBUTION Aspirin and Ticlopidine for Prevention of Recurrent Stroke in Black Patients A Randomized Trial Philip B. Gorelick, MD, MPH Context Blacks are disproportionately affected by stroke, and they are about 2 times DeJuran Richardson, PhD more likely than most other individuals in the United States to die of or experience stroke. Michael Kelly, MD Objective To determine the efficacy and safety of aspirin and ticlopidine to prevent recurrent stroke in black patients. Sean Ruland, DO Design, Setting, and Patients Randomized, double-blind, investigator-initiated, Elena Hung, MS multicenter trial of 1809 black men and women who recently had a noncardioembolic Yvonne Harris, MPA, CCRA ischemic stroke and who were recruited between December 1992 and October 2001 from 62 academic and community hospitals in the United States and followed up for Steven Kittner, MD, MPH up to 2 years. Sue Leurgans, PhD Intervention A total of 902 patients received 500 mg/d of ticlopidine and 907 re- for the African American Antiplatelet ceived 650 mg/d of aspirin. Stroke Prevention Study (AAASPS) Main Outcome Measures Recurrent stroke, myocardial infarction, or vascular death Investigators was the composite primary end point (according to intention-to-treat analysis). The LACKS ARE DISPROPORTION- secondary outcome was fatal or nonfatal stroke. ately affected by stroke, yet Results The blinded phase of the study was halted after about 6.5 years when futility they have been underrepre- analyses revealed a less than 1% probability of ticlopidine being shown superior to as- sented in clinical trials.1-8 Rec- pirin in the prevention of the primary outcome end point. The primary outcome of re- Bommendations for stroke prevention in current stroke, myocardial infarction, or vascular death was reached by 133 (14.7%) of this population have been based largely 902 patients assigned to ticlopidine and 112 (12.3%) of 907 patients assigned to aspi- rin (hazard ratio, 1.22; 95% confidence interval, 0.94-1.57). Kaplan-Meier curves for on trials that have included few black time to event for the primary outcome did not differ significantly (P=.12 by log-rank participants. This may not be an opti- test). Kaplan-Meier curves for time to the secondary outcome of fatal or nonfatal stroke mal practice because blacks are among approached a statistically significant reduction favoring aspirin over ticlopidine (P=.08 those with a higher prevalence of ma- by log-rank test). The frequency of laboratory-determined serious neutropenia was 3.4% jor cardiovascular risk factors, a differ- for patients receiving ticlopdine vs 2.2% for patients receiving aspirin (P=.12) and 0.3% ent distribution of atherosclerotic oc- vs 0.2% for thrombocytopenia, respectively (P=.69). One ticlopidine-treated patient clusive cerebral vascular lesions, developed thrombocytopenia, which was thought to be a case of possible thrombotic vascular biological differences such as thrombocytopenia purpura, and recovered after therapy with plasmapheresis. low renin hypertension, and a differ- Conclusions During a 2-year follow-up, we found no statistically significant differ- ent pattern of use of medical proce- ence between ticlopidine and aspirin in the prevention of recurrent stroke, myocardial dures and access to care8-13 that could infarction, or vascular death. However, there was a nonsignificant trend for reduction influence outcome. of fatal or nonfatal stroke among those in the aspirin group. Based on these data and the risk of serious adverse events with ticlopidine, we regard aspirin as a better treat- A subgroup analysis of the Ticlopi- ment for aspirin-tolerant black patients with noncardioembolic ischemic stroke. 14,15 dine Aspirin Stroke Study (TASS) JAMA. 2003;289:2947-2957 www.jama.com suggested a more favorable risk- benefit profile for nonwhites than Author Affiliations: Departments of Neurologic Sci- County Hospital, Chicago, Ill (Dr Kelly); and the De- whites. Specifically, among the 495 ences (Drs Gorelick, Ruland, and Leurgans, and Ms partment of Neurology, University of Maryland, Bal- black and 108 nonwhite and non- Harris) and Preventive Medicine (Dr Richardson and timore (Dr Kittner). Ms Hung), Rush Medical College, Chicago, Ill; De- Corresponding Author and Reprints: Philip B. Gorelick, partment of Mathematics and Computer Science, Lake MD, MPH, Center for Stroke Research, Rush Medi- For editorial comment see p 3005. Forest College, Lake Forest, Ill (Dr Richardson); De- cal College, 1645 W Jackson, Suite 400, Chicago, IL partment of Medicine, Division of Neurology, Cook 60612 (e-mail: [email protected]). ©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, June 11, 2003—Vol 289, No. 22 2947 Downloaded From: https://jamanetwork.com/ on 10/01/2021 PREVENTION OF RECURRENT STROKE IN BLACK PATIENTS black study participants, there was a dose of 650 mg/d in accordance with Primary and Secondary 24.1% relative risk reduction (RRR) for the recommendations by Barnett et al.22 Hypotheses stroke and death at 2 years favoring Eligibility criteria included black (Af- The primary hypothesis of this ran- ticlopidine (500 mg/d) over aspirin rican American) race; 29-85 years of age domized, double-blind, investigator- (1300 mg/d), and 10% fewer serious ad- inclusive; noncardioembolic ischemic initiated clinical trial was that ticlopi- verse events (SAEs).15 Overall in TASS, stroke with onset at least 7 days but not dine (500 mg/d) was more effective than there was a 12% RRR for nonfatal stroke more than 90 days; cranial computed aspirin (650 mg/d) in preventing the or death from any cause (P=.05) favor- tomographic scan or magnetic reso- composite outcome of recurrent stroke, ing ticlopidine at 3 years. nance image of the brain consistent with myocardial infarction, or vascular death The current study was designed in occurrence of the entry cerebral in- (death due to ischemic or hemor- 1993, with the belief that a targeted re- farct; measurable neurological deficit rhagic stroke, myocardial infarction, current stroke prevention study for that correlates at onset with entry ce- sudden death, pulmonary embolism, blacks was justified given their dispro- rebral infarct; informed consent; and heart failure, visceral or limb infarc- portionate stroke burden, promising availablity of patient to be followed up tion, or a vascular procedure or opera- data for ticlopidine as a recurrent stroke in an outpatient treatment program.16 tion) among blacks with noncardioem- preventive treatment in nonwhites, and Exclusion criteria included tran- bolic ischemic stroke who were the lack of previous substantial repre- sient ischemic attack, subarachnoid followed up for up to 2 years. The pre- sentation of blacks in stroke clinical hemorrhage, cardiac source embo- specified secondary hypotheses were trials. The primary outcome of the Af- lism, iatrogenic stroke, nonatheroscle- that the incidence of the outcome end rican American Antiplatelet Stroke Pre- rotic stroke, postoperative stroke oc- points of recurrent stroke or death; non- vention Study (AAASPS) was the com- curring within 30 days of operation, or fatal or fatal stroke; recurrent stroke, posite end point of recurrent stroke, carotid endarterectomy as primary myocardial infarction, or death from all myocardial infarction, or vascular death. treatment measure for entry cerebral in- causes; vascular death; death from all farct; mean arterial blood pressure causes; or myocardial infarction would METHODS higher than 130 mm Hg on 3 consecu- be lower in ticlopidine-treated pa- A description of the design and meth- tive days; modified Barthel index of less tients compared with aspirin-treated pa- ods of AAASPS has been reported pre- than 10; history of dementia or neuro- tients followed up for up to 2 years. viously16 in accordance with criteria pro- degenerative disease; severe comorbid posed by the Consolidated Standards of condition (eg, cancer) judged to limit Randomization Reporting Trials.17,18 That article16 in- survival during 2-year follow-up; en- The ratio of those receiving ticlopi- cluded a discussion of barriers to black rollment in another clinical trial; al- dine and aspirin was 1:1, and the se- participation in clinical trials and how lergy or sensitivity to study drugs; quence was stratified by site to bal- they were overcome,12,19,20 the rationale woman of childbearing potential; gas- ance the treatment groups. All study for study drug selection, relationships trointestinal tract bleeding, bleeding personnel were masked (blinded) from established with primary care physi- diathesis, or platelet or other hemato- treatment assignment with the excep- cians, management of cardiovascular risk logic abnormality (judged to be a con- tion of 1 study statistician who devel- factors, and other major aspects of the traindication for administration of study oped the randomization algorithm. Af- study. The diagnosis of stroke and stroke drugs) currently active or clinically ac- ter written informed consent was subtype was determined after review of tive in the past year; hematuria or posi- obtained, local study site personnel source documents and case report forms tive stool guaiac test related to major called a dedicated automated tele- and by application of criteria from the bleeding source; and prolonged pro- phone registration system for AAASPS, Trial of ORG 10172 in Acute Stroke thrombin time or partial thromboplas- which was operated by the Moffitt Can- Treatment (TOAST)21 by local princi- tin time, blood urea
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