Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients

OBJECTIVE To determine the effects of antiplatelet therapy among patients at high risk of occlusive vascular events. DESIGN Collaborative meta-analyses (systematic overviews). INCLUSION CRITERIA Randomised trials of an antiplatelet regimen versus control or of one antiplatelet regimen versus another in high risk patients (with acute or previous vascular disease or some other predisposing condition) from which results were available before September 1997. Trials had to use a method of randomisation that precluded prior knowledge of the next treatment to be allocated and comparisons had to be unconfounded-that is, have study groups that differed only in terms of antiplatelet regimen. STUDIES REVIEWED 287 studies involving 135 000 patients in comparisons of antiplatelet therapy versus control and 77 000 in comparisons of different antiplatelet regimens. MAIN OUTCOME MEASURE "Serious vascular event": non-fatal myocardial infarction, non-fatal stroke, or vascular death. RESULTS Overall, among these high risk patients, allocation to antiplatelet therapy reduced the combined outcome of any serious vascular event by about one quarter; non-fatal myocardial infarction was reduced by one third, non-fatal stroke by one quarter, and vascular mortality by one sixth (with no apparent adverse effect on other deaths). Absolute reductions in the risk of having a serious vascular event were 36 (SE 5) per 1000 treated for two years among patients with previous myocardial infarction; 38 (5) per 1000 patients treated for one month among patients with acute myocardial infarction; 36 (6) per 1000 treated for two years among those with previous stroke or transient ischaemic attack; 9 (3) per 1000 treated for three weeks among those with acute stroke; and 22 (3) per 1000 treated for two years among other high risk patients (with separately significant results for those with stable angina (P=0.0005), peripheral arterial disease (P=0.004), and atrial fibrillation (P=0.01)). In each of these high risk categories, the absolute benefits substantially outweighed the absolute risks of major extracranial bleeding. Aspirin was the most widely studied antiplatelet drug, with doses of 75-150 mg daily at least as effective as higher daily doses. The effects of doses lower than 75 mg daily were less certain. Clopidogrel reduced serious vascular events by 10% (4%) compared with aspirin, which was similar to the 12% (7%) reduction observed with its analogue ticlopidine. Addition of dipyridamole to aspirin produced no significant further reduction in vascular events compared with aspirin alone. Among patients at high risk of immediate coronary occlusion, short term addition of an intravenous glycoprotein IIb/IIIa antagonist to aspirin prevented a further 20 (4) vascular events per 1000 (P<0.0001) but caused 23 major (but rarely fatal) extracranial bleeds per 1000. CONCLUSIONS Aspirin (or another oral antiplatelet drug) is protective in most types of patient at increased risk of occlusive vascular events, including those with an acute myocardial infarction or ischaemic stroke, unstable or stable angina, previous myocardial infarction, stroke or cerebral ischaemia, peripheral arterial disease, or atrial fibrillation. Low dose aspirin (75-150 mg daily) is an effective antiplatelet regimen for long term use, but in acute settings an initial loading dose of at least 150 mg aspirin may be required. Adding a second antiplatelet drug to aspirin may produce additional benefits in some clinical circumstances, but more research into this strategy is needed.

[1]  S. Hernández-Díaz,et al.  Association between aspirin and upper gastrointestinal complications: systematic review of epidemiologic studies. , 2001, British journal of clinical pharmacology.

[2]  A. Salam,et al.  Platelet glycoprotein IIb/IIIa receptor blockade in coronary artery disease , 2001, Current controlled trials in cardiovascular medicine.

[3]  R. Collins,et al.  Reliable assessment of the effects of treatment on mortality and major morbidity, I: clinical trials , 2001, The Lancet.

[4]  Deepak L. Bhatt,et al.  Current role of platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes. , 2000, JAMA.

[5]  Colin Baigent,et al.  Premature cardiovascular disease in chronic renal failure , 2000, The Lancet.

[6]  C. Sudlow,et al.  Thienopyridines or aspirin to prevent stroke and other serious vascular events in patients at high risk of vascular disease? A systematic review of the evidence from randomized trials. , 2000, Stroke.

[7]  C Warlow,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. , 2000, Stroke.

[8]  J. Danesh,et al.  Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial , 2000, The Lancet.

[9]  R. Stafford,et al.  Aspirin use is low among United States outpatients with coronary artery disease. , 2000, Circulation.

[10]  D. Gilligan,et al.  Frequency of anticoagulation for atrial fibrillation and reasons for its non-use at a Veterans Affairs medical center. , 2000, The American journal of cardiology.

[11]  E. Schryver Design of ESPRIT: An International Randomized Trial for Secondary Prevention after Non-Disabling Cerebral Ischaemia of Arterial Origin , 2000 .

[12]  C. Heeschen,et al.  Difficulties with oral platelet glycoprotein IIb/IIIa receptor antagonists , 2000, The Lancet.

[13]  R Brian Haynes,et al.  Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy: a randomised controlled trial , 1999, The Lancet.

[14]  S. Pocock,et al.  A Clinical Trial Comparing Three Antithrombotic-Drug Regimens after Coronary-Artery Stenting , 1998 .

[15]  Rose Anne Kenny,et al.  Prevalence of atrial fibrillation and eligibility for anticoagulants in the community , 1998, The Lancet.

[16]  David P Miller,et al.  Long‐Term Protection from Myocardial Ischemic Events in a Randomized Trial of Brief Integrin β3 Blockade with Percutaneous Coronary Intervention , 1998 .

[17]  D. Singer,et al.  Recent national patterns of warfarin use in atrial fibrillation. , 1998, Circulation.

[18]  M. Pfisterer,et al.  Safe use of platelet GP IIb/IIIa inhibitors. , 1998, American heart journal.

[19]  J. Colwell Aspirin Therapy in Diabetes , 1997, Diabetes Care.

[20]  Zheng-Ming Chen,et al.  CAST: randomised placebo-controlled trial of early aspirin use in 20 000 patients with acute ischaemic stroke , 1997, The Lancet.

[21]  Peter Sandercock,et al.  The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19 435 patients with acute ischaemic stroke , 1997, The Lancet.

[22]  R. More,et al.  Antiplatelet rather than anticoagulant therapy with coronary stenting , 1997, The Lancet.

[23]  David Schultz,et al.  A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) , 1996, The Lancet.

[24]  J. Herbert,et al.  The Antiaggregating and Antithrombotic Activity of Ticlopidine Is Potentiated by Aspirin in the Rat , 1996, Thrombosis and Haemostasis.

[25]  M. Kaste,et al.  Aspirin dose in stroke prevention: beautiful hypotheses slain by ugly facts. , 1996, Stroke.

[26]  M. Galanski,et al.  Controlled trial of high-versus low-dose aspirin treatment after percutaneous transluminal angioplasty in patients with peripheral vascular disease , 1994, The clinical investigator.

[27]  Radcliffe Infirmary,et al.  Collaborative overview of randomised trials of antiplatelet therapy - III: Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients , 1994, BMJ.

[28]  Collaborative overview of randomised trials of antiplatelet therapy - II: Maintenance of vascular graft or arterial patency by antiplatelet therapy , 1994, BMJ.

[29]  Walker,et al.  Collaborative overview of randomised trials of antiplatelet therapy Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients , 1994 .

[30]  Eaft Study Group Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke , 1993, The Lancet.

[31]  F. Violi,et al.  Effect of Picotamide on the Clinical Progression of Peripheral Vascular Disease A Double‐Blind Placebo‐Controlled Study , 1993 .

[32]  B. Norrving,et al.  Low-dose aspirin and stroke. , 1993, Stroke.

[33]  M. Lavezzari,et al.  Indobufen in the Prevention of Thromboembolic Complications in Patients With Heart Disease A Randomized, Placebo‐Controlled, Double‐Blind Study , 1993, Circulation.

[34]  J. Slattery,et al.  Antithrombotic therapy in acute ischaemic stroke: an overview of the completed randomised trials. , 1993, Journal of neurology, neurosurgery, and psychiatry.

[35]  N. Edvardsson,et al.  Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris , 1992, The Lancet.

[36]  V. Fuster,et al.  Low-dose aspirin and stroke. "It ain't necessarily so". , 1992, Stroke.

[37]  F. Ferris Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report 14. ETDRS Investigators. , 1992, JAMA.

[38]  M. Thun,et al.  Aspirin use and reduced risk of fatal colon cancer. , 1991, The New England journal of medicine.

[39]  A. Algra,et al.  A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. , 1991, The New England journal of medicine.

[40]  P. Wolf,et al.  Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. , 1991, Stroke.

[41]  J. Wittes,et al.  Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. , 1991, JAMA.

[42]  A. Paganini-Hill,et al.  Aspirin use and chronic diseases: a cohort study of the elderly. , 1989, BMJ.

[43]  C. Patrono,et al.  Aspirin and human platelets: from clinical trials to acetylation of cyclooxygenase and back. , 1989, Trends in pharmacological sciences.

[44]  L. Bolognese,et al.  RANDOMISED TRIAL OF INTRAVENOUS STREPTOKINASE, ORAL ASPIRIN, BOTH, OR NEITHER AMONG 17 187 CASES OF SUSPECTED ACUTE MYOCARDIAL INFARCTION: ISIS-2 , 1988, The Lancet.

[45]  G. Rasmanis,et al.  EFFECTS OF INTERMITTENT TREATMENT WITH ASPIRIN ON THROMBOXANE AND PROSTACYCLIN FORMATION IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION , 1988, The Lancet.

[46]  G. Davı̀,et al.  Clinical pharmacology of platelet cyclooxygenase inhibition. , 1985, Circulation.

[47]  B. Massie Antithrombotic therapy in heart failure: new perspectives , 2000 .

[48]  J. Welch MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience. , 1999, European heart journal.

[49]  Hans-Christoph Diener,et al.  European Stroke Prevention Study 2. Efficacy and safety data. , 1997, Journal of the neurological sciences.

[50]  G. FitzGerald,et al.  Inhibition of thromboxane formation in vivo and ex vivo: implications for therapy with platelet inhibitory drugs. , 1987, Blood.