Randomized Trials of Antiplatelet Therapy

Cathie LM Sudlow, Colin N Baigent Clinical Trial Service Unit and Epidemiological Studies Unit University of Oxford Radcliffe Infirmary Oxford 0X2 6HE United Kingdom 

Vascular disease is of major importance worldwide as a cause both of death and disability, mainly in middle-aged and elderly individuals. Ischemic heart disease and stroke are the two leading causes of deadi in the developing world, as well as in the developed world, and accounted for around one fiflh of the 50 million deaths worldwide in 1990 (1). Cardiovascular disorders caused almost 10% of all disability worldwide in 1990 (2), and projections suggest that by the year 2020 this will have risen to 15%, with almost all of the increase occurring in developing countries (3). 

The main global priorities for reducing the increasing burden of vascular disease are primary prevention 

Colin Baigent is a UK Medical Research Coimcil Scientist and coordinator of the Antithrombotic Trialists Collaboration. His interests include the treatment and prevention of cardiovascular disease and the causes of such disease in chronic renal failure. 

The overwdielming majority of recent iiiqrrovements in outcome in cardiovascular diseases have been only moderate in size. Relative risk reductions of only about 10 or 20% (typically generating absolute differences in a major outcome of a few percent at most) are therefore the most that should generally be anticipated. To detect such moderate-sized differences reliably, both moderate biases and moderate random errors must be excluded. This requires large-scale randomized evidence, which may take the form of a single megatrial, or, as for antiplatelet therapy, a meta-analysis of all the available randomized trials 

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Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002 324 71-86. 

Randomized trials have been completed assessing the role of antiplatelet therapy with aspirin for primary stroke prevention. The use of aspirin in patients with no history of stroke or ischemic heart disease reduced the incidence of non-fatal myocardial infarction (MI) but not of stroke. A meta-analysis of eight trials found that the risk of stroke was slightly increased with aspirin use, especially hemorrhagic stroke. Major bleeding risk was also increased with aspirin use.4 Aspirin is beneficial in the primary prevention of MI, but not for primary stroke prevention. 

Among the more recently developed antiplatelet agents, GP Ilb/nia receptor antagonists have the potential to produce substantial iiihibition of platelet function. A small excess of intracranial bleeds has been observed in randomized trials of these agents, but the number of events was small, and as yet there are too few data to draw reliable conclusions about the size of any hazard, particularly among patients also receiving other antithrombotic treatments or fibrinolytic therapy (37). 

Urban P Macaya C, Rupprecht HJ, et al. Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients the multicenter aspirin and ticlopidine trial after intracoronary stenting (MATTIS). Circulation 1998 98 2126-2132. 

Steinhubl SR, Berger PB, Mann JT III, et al. CREDO Investigators. Clopidogrel for the reduction of events during observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention a randomized controlled trial. J Am Med Assoc 2002 288 241 1-2420. 

More recently, Tran and Anand conducted a systematic review of the literature in an effort to summarize the best evidence for oral antiplatelet therapy in patients with cerebrovascular disease, CAD, and PAD. This review included 111 trials (42 of which included patients with PAD, n = 9214) and concluded that patients with PAD should use ASA (160 to 325 mg/day) or clopidogrel (75 mg/day) when ASA is not tolerated or contraindicated. This is in concordance with the recommendations of the Seventh American College of Chest Physicians (ACCP) Conference on Antithrombotic and Thrombolytic Therapy which recommends lifelong ASA (75 to 325 mg/day) over clopidogrel, ticlopidine, and no antithrombotic therapy in patients with PAD. Unfortunately, no data are currently avaUable from large, clinical, randomized trials that ASA, or any other antiplatelet therapies, can actually prevent or delay the progression of PAD. ... 

Tomaselh GF (2015) Introduction to a compendium on sudden cardiac death epidemiology, mechanisms, and management. Circ Res 116 1883-1886 Udell JA, Bonaca MP, Collet JP et al (2016) Long-term dual antiplatelet therapy for secondary prevention of cardiovascular events in the subgroup of patients with previous myocardial infarction a collaborative meta-analysis of randomized trials. Eur Heart J 37 390-399 Unudurthi SD, Hund TJ (2016) Late sodium current dysregulation as a causal factor in arrhythmia. Expert Rev Cardiovasc Ther 14 545-547... 

Ding XL, Xie C, Jiang B, Gao J, Zhang LL, Zhang H, et al. Efficacy and safety of adjunctive cilostazol to dual antiplatelet therapy after stent implantation an updated meta-analysis of randomized controlled trials. J Cardiovasc Pharma T May 2013 18(3) 222-8. 

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