Regular or "super-aspirins"? A review of thienopyridines or aspirin to prevent stroke - Commentary

PURPOSE: To review the evidence for the effectiveness and safety of the thi enopyridines (ticlopidine and clopidogrel) compared with aspirin for the pr evention of vascular events among patients at high risk of vascular disease . BACKGROUND: Atherosclerosis and resultant cardiovascular disease are import ant causes of morbidity and mortality in older people. In particular, ather osclerosis of the cerebral arteries can lead to transient ischemic attacks (TIAs) and stroke. Stroke ranks as the third-leading cause of death in the United States and in 1997 was responsible for over 150,000 fatalities.(1) I n addition to the mortality associated with this disease, stroke is also a leading source of long-term disability in survivors. Nearly 4.5 million str oke survivors are alive today,(1) highlighting the fact that primary, but a lso secondary, prevention are extremely important for minimizing the compli cations of this illness. For many years, aspirin has remained the single most cost-effective agent f or the treatment and prevention of coronary and cerebral arterial thrombosi s.(2,3) Despite its benefit, use of aspirin is associated with increased ri sk of bleeding, and treatment failures are known to occur. Therefore, for t hose patients who cannot tolerate or who experience treatment failure, a th erapeutic dilemma arises. One option has been the use of ticlopidine, a thi enopyridine antiplatelet agent initially approved for the secondary prevent ion of stroke but whose use has been limited by the significantly increased risk of adverse hematological effects.(4-6) Clopidogrel, an analogue of ti clopidine and the newest antiplatelet to be marketed for use in similar sit uations, appears to not carry this increased risk. The role of these so-cal led "super-aspirins" relative to traditional aspirin therapy remains ill de fined. A systematic review of the evidence is presented for the efficacy an d safety of ticlopidine and clopidogrel compared with aspirin for the preve ntion of vascular events among patients at high risk of vascular disease. DATA SOURCES: Specialized trial registers of the Cochrane Stroke Group and the Antithrombotic Trialist's Collaboration, MEDLINE, and Embase were searc hed. Additional unpublished information and data were sought from Sanofi, t he pharmaceutical company that developed and manufactures ticlopidine and c lopidogrel, as well as the principal investigators of the Clopidogrel versu s Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial,(7) the lar gest of the trials identified. STUDY SELECTION CRITERIA: All unconfounded randomized trials comparing eith er ticlopidine or clopidogrel with aspirin among patients at high risk of v ascular dis ease (those with symptoms of ischemia of the cerebral, coronary , or peripheral circulations) who were followed for at least 1 month for th e recurrence of vascular events were included. DATA EXTRACTION: Data were extracted from four completed randomized trials completed in the past 20 years, which included 22,656 patients.(7-10) Two a uthors independently extracted the data from these trials for the following information: the types of patients enrolled; the entry and exclusion crite ria; the randomization method; the number of patients originally allocated to the treatment and control groups; the method and duration of follow-up; the number of patients in each group lost to follow-up; information on comp liance with the treatment allocated; the definitions of outcome events; the number of outcome events in each treatment group; and any method used for blinding patients, treating clinicians, and outcome assessors to treatment allocation. Each trial's own definitions of the various outcome events were used. The p rimary outcome of effectiveness was vascular events, defined as stroke, myo cardial infarction, or death from a vascular cause. Secondary effectiveness outcomes were any stroke (ischemic or hemorrhagic), ischemic stroke, myoca rdial infarction, vascular death, or all-cause mortality. Adverse outcomes were hemorrhage (intracranial, extracranial, or gastrointestinal), neutrope nia, thrombocytopenia, skin rash, and diarrhea. The data were analyzed by intention-to-treat and the results described by o dds ratios and absolute risk reductions for the treatment group (thienopyri dine) and control group (aspirin). A weighted estimate of the odds ratio fo r each outcome was calculated using the Peto observed-minus-expected method . Absolute risk reductions were calculated using the risk difference and ex pressed as events prevented per 1,000 patients treated. Statistical heterog eneity between trials was assessed with a standard chi-squared test. MAIN RESULTS: Four completed trials involving a total of 22,656 patients we re identified. Aspirin was compared with ticlopidine in three trials (3,471 patients)(8-10) and with clopidogrel in one trial (19,185 patients).(7) A recent TIA or ischemic stroke was the qualifying event in 9,840 patients, a recent myocardial infarction in 6,302 patients, and symptomatic peripheral arterial disease in 6,514 patients. The average age of the patients was ap proximately 63, with approximately two-thirds of the patients being male an d white. The duration of follow-up ranged from 12 to 40 months. For all patients at high risk of vascular disease, pooled results demonstra ted that therapy with a thienopyridine produced a modest decrease in the od ds of a serious vascular event compared with aspirin (12% vs 13% for aspiri n; odds ratio (OR) 0.91, 95% confidence interval (CI) 0.84-0.98; P =.01), c orresponding to prevention or delay of 11 vascular events per 1,000 patient s treated for approximately 2 years (95% CI 2-19). The odds of suffering an y stroke were reduced in favor of the thienopyridine group (5.7% vs 6.4%; O R 0.88, 95% CI 0.79-0.98) compared with aspirin, corresponding to a prevent ion or delay of seven strokes per 1,000 patients treated for 2 years (95% C I 1-13). Nonsignificant trends in favor of thienopyridines compared with as pirin were also noted for reduction in ischemic stroke (OR 0.90, 95% CI 0.8 1-1.01), myocardial infarction (OR 0.88, 95% CI 0.76-1.01), vascular or unk nown cause of death (OR 0.93, 95% CI 0.82-1.06), and death from any cause ( OR 0.95, 95% CI 0.85-1.05). Analyses restricted to patients presenting with stroke or TW demonstrated t hat thienopyridines and aspirin produced similar benefits for the composite of all vascular events (16.8% for thienopyridine vs 18.3% far aspirin; OR 0.90, 95% CI 0.81-1.00), corresponding to the avoidance of 14 (95% CI 1-29) serious Vascular events per 1,000 patients treated for about 2 years. The risk of any stroke was decreased in the thienopyridine group compared with aspirin (10.4% for thioenopyridine vs 12.0% for aspirin; OR 0.86, 95% CI 0. 75-0.97), corresponding to 16 (95% CI 3-28) strokes avoided per 1,000 patie nts treated. Antiplatelet therapy with thienopyridines and aspirin produced similar risk s for intracranial hemorrhage (0.3% for thienopyridine vs 0.4% for aspirin; OR 0.82, 95% CI 0.53-1.27) and extracranial hemorrhage (8.8% for thienopyr idine vs 8.9% for aspirin; OR 1.00, 95% CI 0.91-1.09). Compared with aspiri n, thienopyridines were associated with significant reductions in the odds of gastrointestinal hemorrhage (1.8% for thienopyridine vs 2.5% for aspirin ; OR 0.71, 95% CI 0.59-0.86) and indigestion/nausea/vomiting (14.8% for thi enopyridine vs 17.1% for aspirin; OR 0.84, 95% CI 0.78-0.90) but the odds o f diarrhea or skin rash were increased in the thienopyridine group. Compare d with aspirin, clopidogrel was associated with a mild excess of skin rash (6.0% vs 4.6%; OR 1.3, 95% CI 1.2-1.5) and diarrhea (4.5% vs 3.4%, OR 1.3, 95% CI 1.2-1.6). Compared with aspirin, ticlopidine was associated with a m oderate excess of skin rash (11.8% vs 5.5%, OR 2.2, 95% CI 1.7-2.9) and dia rrhea (20.4% vs 9.9%, OR 2.3, 95% CT 1.9-2.8). Importantly, the risk of exc ess neutropenia was increased in the ticlopidine group (2.3% for: ticlopidi ne vs 0.8% for aspirin; OR 2.7, 95% CI 1.5-4.8). No increased risk was obse rved with clopidogrel compared with aspirin (0.1% vs 0.2%; OR 0.63, 95% CI 0.29-1.36). CONCLUSIONS: This systematic review demonstrates that, compared with aspiri n, thienopyridines are only modestly more effective in preventing serious v ascular events in high risk patients. For patients who are intolerant of, o r allergic to aspirin, the available safety and efficacy data suggest that clopidogrel is an appropriate, but more-expensive, alternative antiplatelet drug. It appears safer than ticlopidine and as safe as aspirin but it shou ld not replace aspirin as the first-choice antiplatelet agent for all patie nts. Further studies are necessary to determine which, if any, particular t ypes of patients would benefit most and least from clopidogrel instead of a spirin.