Antiplatelet Trialists Research Articles

What have we learned from recent antiplatelet trials?

Aspirin's benefit in preventing vascular outcomes is well established. It reduces the relative risk for stroke, myocardial infarction, and vascular death by about 25% compared with placebo. Almost 10 years ago we learned that ticlopidine is more effective than aspirin (about 12% relative risk reduction for stroke or death). However, ticlopidine has important adverse effects. In 1996, the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial showed that clopidogrel, a new thienopyridine similar to ticlopidine, is also more effective than aspirin (by a similar amount) and is as safe as aspirin. Also in 1996, the European Stroke Prevention Study 2 (ESPS-2) showed that dipyridamole alone prevents stroke and that when combined with aspirin it is more effective, probably comparable to ticlopidine and clopidogrel. Dipyridamole combined with aspirin reduced the relative risk for stroke or death by about 13% compared with aspirin alone. Both clopidogrel and dipyridamole are safe but will cost more than aspirin. Aspirin also appears beneficial for acute stroke treatment. The Chinese Acute Stroke Trial (CAST) and the International Stroke Trial (IST) demonstrated that aspirin given at the time of an acute ischemic stroke reduces the risk for early death (about 5 less/1,000 treated), recurrence or death (about 10 less/1,000 treated), and dependence (about 5 less/1,000 treated). Overall, the benefits of aspirin in acute stroke treatment and stroke prevention are definite but modest. Combination therapy with antiplatelet agents that act through different mechanisms is a promising way to maximize the benefits of antiplatelet treatment.

Pl A2 polymorphism and efficacy of aspirin

Aspirin is widely used as an antiplatelet drug to prevent arterial thromboembolic events. 1 Antiplatelet Trialists' CollaborationCollaborative overview of randomised trials of antiplatelet therapy—I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 1994; 308: 81-106 Crossref PubMed Scopus (706) Google Scholar Aspirin acetylates irreversibly the enzyme cyclooxygenase (COX-1), and thereby inhibits the production of thromboxane A2 in platelets. However, the mechanism by which thromboxane A2 induces the expression of high-affinity receptor molecules for fibrinogen on the surface of platelets (the final common pathway of platelet activation) remains unknown.

Antiplatelet therapy in atherosclerotic cardiovascular disease

Arterial thrombosis frequently leads to death or disability from stroke, peripheral arterial disease, or myocardial infarction (MI). Treating the underlying causes of these diseases is the key to producing significant reduction in morbidity, mortality, and health care costs. Prevention of arterial thrombosis is the primary indication for antiplatelet therapy, and intense research has been conducted in the past decade to develop novel antiplatelet agents with favorable safety profiles. The results of the Antiplatelet Trialists' Collaboration, which definitively established the rationale for antiplatelet agents in the prevention of death, MI, and stroke, were an important stimulus for this research. This large meta-analysis combined data from 145 randomized trials and showed that antiplatelet therapy (most commonly aspirin, 75 to 325 mg/d) reduced the risk of vascular events, including nonfatal MI, non-fatal stroke, and vascular death, by 25% in patients at high risk for occlusive vascular disease. The limitations and adverse effects associated with traditional antiplatelet agents such as aspirin have prompted the search for newer antiplatelet agents. Clinical trials such as the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study, which was the first study to evaluate aspirin and clopidogrel in patients with cerebrovascular, cardiac, and peripheral arterial disease, have established the importance of newer antiplatelet effects in the management of patients with diseases associated with atherosclerosis. The pathophysiology of atherosclerosis, the mechanisms of action of antiplatelet agents, and the results of these and other clinical trials that document the value of antiplatelet agents in atherosclerosis are reviewed in this paper.

A Cost-effectiveness Analysis of Aspirin versus Oral Anticoagulants after Acute Myocardial Infarction in Italy

The recent publication of two large trials of secondary prevention of coronary artery disease with oral anticoagulants (WARIS and ASPECT) has caused a revival of the interest for this antithrombotic therapy in a clinical setting where the use of aspirin is common medical practice. Despite this, the preferential use of aspirin has been supported by an American cost-effectiveness analysis (JAMA 1995; 273: 965). Using the same parameters used in that analysis and incidence of events from the Antiplatelet Trialists Collaboration and the ASPECT study, we re-evaluated the economic odds in favor of aspirin or oral anticoagulants in the Italian Health System, which differs significantly in cost allocation from the United States system and is, conversely, similar to other European settings. Recalculated costs associated with each therapy were 2,150 ECU/ patient/year for oral anticoagulants and 2,187 ECU/patient/year for aspirin. In our analysis, the higher costs of oral anticoagulants versus aspirin due to a moderate excess of bleeding (about 10 ECU/ patient/year) and the monitoring of therapy (168 ECU/ patient/year) are more than offset by an alleged savings for recurrent ischemic syndromes and interventional procedures (249 ECU/ patient/year). Preference of aspirin vs. oral anticoagulants in a pharmaco-economical perspective is highly dependent on the geographical situation whereupon calculations are based. On a pure cost-effectiveness basis, and in the absence of data of direct comparisons between aspirin alone versus I.N.R.-adjusted oral anticoagulants, the latter are not more expensive than aspirin in Italy and, by cost comparisons, in other European countries in the setting of post-myocardial infarction.

Antiplatelet drugs in secondary prevention of stroke: lessons from recent trials.

More than 50 randomized controlled trials have been conducted to determine the value of antiplatelet agents, most notably aspirin, for stroke prevention.1 Interpretation and comparison of trial results have been hampered by the studies' widely disparate patient populations, inclusion criteria, end points, and treatment protocols. Despite these difficulties, the efficacy of antiplatelet therapy in the prevention of ischemic cerebrovascular events is well established. By the late 1980s, many studies, including the French study known as AICLA(Accidents Ischemiques Cerebraux Lies a l'Atherosclerose), the first European Stroke Prevention Study(ESPS-1), and the first meta-analysis by the Antiplatelet Trialists' Collaboration, had demonstrated that antiplatelet therapy can significantly reduce the risk for fatal and nonfatal stroke among patients with a prior history of stroke or transient ischemic attack (TIA).2-4 In 1994, a second meta-analysis by the Antiplatelet Trialists' Collaboration concluded that antiplatelet therapy prevents between 20 and 30 nonfatal strokes for every 1,000 high-risk patients treated.5 Although the evidence of antiplatelet therapy's utility for secondary stroke prevention is compelling, questions have remained concerning the specifics of treatment. From a clinical standpoint, a primary question is whether the observed benefit of antiplatelet therapy justifies routine treatment of all eligible patients. If we assume that the answer is yes, other questions naturally follow:

Aspirin, ticlopidine, and warfarin: When and why

Aspirin inactivates prostaglandin G/H synthase, producing irreversible loss of cyclo-oxygenase activity. This produces permanent inhibition of platelet aggregation for the 8- to 10-day life of the platelet, prolonging the bleeding time and reducing aggregation of platelets within the vascular system. Other possible effects of aspirin include reduction in thrombin formation, the facilitation of plasminogen activation, and reduction in atherosclerotic progression. The antiplatelet trialists' collaboration published the updated results of a worldwide metaanalyses of trials of antiplatelet therapy in 1994.1 This analysis suggests that antiplatelet therapy reduces vascular mortality by 17% __+ 3% and nonfatal vascular events such as myocardial infarction and stroke by approximately 25%. In trials involving patients with transient ischemic attack (TIA) or minor stroke given any type of antiplatelet drugs, treatment reduced nonfatal stroke by 22%. Several issues and controversies remain regarding aspirin therapy. These include the optimal dose of aspirin, subgroups of patients that are more or less responsive to aspirin, including women and the elderly, and the effects of aspirin on the development of atherosclerosis and other factors contributing to stroke. Studies of aspirin compared with placebo have included doses ranging from 75 to 1,300 mg daily. 2 Significant benefits of 75 mg have been shown in comparison with placebo. Other studies have failed to show a difference between 30 and 280 mg aspirin daily. 3 Interestingly, in studies of primary prevention in reasonably healthy cohorts, specifically the US Physicians Health Survey, 4 325 mg aspirin on alternate days produced a 44% risk reduction for myocardial infarction, yet none for stroke. This raises the issue whether the mechanisms in coronary and cerebral ischemia are similar. The study also suggested an increased risk of brain hemorrhage in patients treated with aspirin. Approximately 15% of patients will have incomplete inhibition of platelet aggregation on 325 mg or less of aspirin daily, with improvement in their platelet inhibition with higher

Aspirin at any dose above 30 mg offers only modest protection after cerebral ischaemia.

There is continuing debate about the relative efficacy of low (< 100 mg per day), medium (300 to 325 mg per day), and high (> 900 mg per day) doses of aspirin in patients after a transient ischaemic attack or non-disabling stroke. The purpose of this study was to resolve the issue. Thus a minimeta-analysis was performed on data from 10 randomised trials of aspirin only v control treatment in 6171 patients after a transient ischaemic attack or nondisabling stroke. The data on the trials were listed in an appendix of the report on the second cycle of the Antiplatelet Trialists' Collaboration. There was virtually no difference in relative risk reduction for low, medium, and high doses of aspirin (13%, 9%, and 14% respectively). This equivalence corresponds with the results of the UK-TIA trial in a direct comparison of 300 and 1200 mg. The Dutch TIA trial showed no difference in efficacy of 30 and 283 mg. It is concluded that aspirin at any dose above 30 mg daily prevents 13% (95% confidence interval 4-21) of vascular events and that there is a need for more efficacious drugs.

Aspirin and Other Platelet-Active Drugs: The Relationship Among Dose, Effectiveness, and Side Effects

Aspirin and Other Platelet-Active Drugs: The Relationship Among Dose, Effectiveness, and Side Effects

Antiplatelet treatment in elderly people with transient ischaemic attacks or ischaemic strokes

Strokes and transient ischaemic attacks become more common with advancing age, and their prognosis becomes worse. Because of the increase in the number of elderly subjects in most Western societies, atherothrombotic cerebrovascular disease is a significant health problem. It is important, therefore, to find effective treatments for both primary and secondary prevention. The Antiplatelet Trialists' Collaboration found that the reduction in vascular events as an end point in patients with a previous stroke or transient ischaemic attack was 22%.1 Antiplatelet drugs were equally effective in patients older and younger than 65 years, a result that was also seen in the European stroke prevention study.2 No study has, however, investigated the protective effect of antiplatelet drugs in patients older than 70 or 80. We analysed a subgroup of the 1306 Finnish patients participating in the European …

Omission of aspirin in patients following coronary artery bypass graft surgery.

Graft patency is a major factor contributing to the long-term results of coronary artery bypass graft (CABG) surgery. The systematic overview of the Antiplatelet Trialists' Collaboration provides unequivocal evidence that antiplatelet therapy reduces by nearly one-half the odds of coronary graft occlusion following CABG. We retrospectively reviewed patients undergoing CABG during 1993 at the Cardiothoracic Unit, Northern General Hospital, to determine the incidence of, and indications for, aspirin omission following CABG: 462 patients with isolated CABG, 75 patients with a combined CABG and a heart valve procedure and 21 patients with a combined CABG and other non-valve procedure. Thirty-six patients (7.5%) with isolated CABG and CABG combined with a non-valve procedure were not prescribed aspirin. The reasons for aspirin omission were categorized into three groups depending on whether omission was fully justified (group 1), possibly justified (group 2) or unjustified (group 3). Twenty-one patients were in groups 2 and 3, nine of whom were started on aspirin 2-6 weeks after discharge without any ill effect. Forty-two patients were discharged from hospital on a three month course of warfarin. Four months later four patients had died, 24 had changed to aspirin, 10 were still on warfarin and four were on neither drug. Aspirin was sometimes omitted without clear indications. Better provisions for supervision should be made by either the General Practitioner or Hospital Practitioner during the change-over period from oral anticoagulation to antiplatelet therapy in patients on a short course of warfarin.

Antiplatelet treatment for thromboprophylaxis: a step forward or backwards?

A recent meta-analysis from the Antiplatelet Trialists' Collaboration recommended that antilatelet treatment either alone or, for greater effect, in addition to other proved forms of thromboprophylaxis should be considered for patients at high risk of thromboembolism. This paper argues that the current evidence does not justify the adoption of aspirin or other antiplatelet treatment for venous thromboprophylaxis, especially when more effective alternatives exist. Furthermore, several issues relating to this latest meta-analysis need to be debated.

Antiplatelet therapy for thromboprophylaxis: the need for careful consideration of the evidence from randomised trials

Venous thromboses and pulmonary embolism remain an important cause of morbidity and mortality both in surgical patients and in immobilised medical patients.*RF 1-5* Various thromboprophylactic treatments have, therefore, been devised to prevent or limit thromboembolism. Our previous systematic overview (or meta-analysis) of randomised trials of perioperative subcutaneous heparin found that among surgical patients such treatment can roughly halve the risk not only of deep venous thrombosis but, more importantly, of pulmonary embolism6 (see fig 1). Subcutaneous heparin is now widely recommended for surgical or medical patients at high risk of venous occlusion.*RF 3-5* The recent Antiplatelet Trialists' Collaboration overview of the thromboprophylactic effects of antiplatelet therapy used prospectively determined criteria for trial inclusion and treatment comparisons that were similar to those of the previous heparin overview.*RF 6-8* The aim was to include all unconfounded properly randomised trials of antiplatelet versus no antiplatelet therapy (or of one antiplatelet regimen versus another) that could have been available for review by March 1990 in which deep venous thrombosis was systematically and unbiasedly monitored. (Parts I and III of the previous overview report give a fuller description of the methods used.1,7 The appropriateness of using “assumption free” statistical methods rather than the “random effects” model when combining trial results, as when combining results from different centres in a multicentre trial, has been discussed in detail previously.9,10) Such randomised trials were to be included whether or not the treatment comparison was “blinded” by placebo control. This was also the case in the heparin overview, where exclusion of informative “open” trials (in particular, the important open international multicentre trials coordinated by Professor V V Kakkar11) would have been equally inappropriate. Analyses confined to placebo controlled studies, which may be less subject to treatment dependent biases in the assessment …

Review: Antiplatelet agents reduce risks for death, stroke, myocardial infarction, deep venous thrombosis, and arterial occlusion

Source Citation Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy—I: Prevention of death, myocardial infarction, and stroke by prolonged ant...

Antiplatelet prophylaxis Combination treatment may cause bleeding

EDITOR, - The Antiplatelet Trialists' Collaboration has carried out an important meta-analysis of antiplatelet prophylaxis used to reduce venous thrombosis and pulmonary embolism.1 The results section of the abstract of the paper states: “Information on adding antiplatelet therapy to heparin was limited but, at least for pulmonary embolism, suggested more protection from the combination than from heparin alone.” We suggest that consideration should be given to possible harmful effects of the combination of aspirin and heparin. The authors found a 62 (SD 33)% reduction in the odds of pulmonary embolism after the combined treatment compared with the same dose of heparin. They also noted a 12 (22)% reduction in the odds of deep vein thrombosis. They do not, however, present any comparisons of total mortality or of complications. We therefore made these comparisons, using data from individual trials given in appendix 1. We found that total mortality was higher with combination treatment than with heparin alone (table). Although this increase was not significant (neither was the reported reduction in pulmonary embolism), it is worrying when considered together with the much higher rate of complications related to bleeding after the combination treatment. In absolute terms the possible benefits of combination treatment could well be …

Antiplatelet Agents for Stroke Prevention

Data from the Antiplatelet Trialists’ collaboration are reviewed showing that aspirin is effective in reducing vascular outcomes in patients with atherosclerosis, with a relative risk reduction of about 30% for stroke, 22% for stroke and death, and 15 % for vascular mortality. Apparently 900 and 1,300 mg aspirin are similar in efficacy. Whether low-dose aspirin, such as 75 or 30 mg a day, is as effective as 900–1,300 mg in preventing strokes is less certain. Complications are more frequent with high doses than with low doses of aspirin. The Ticlopidine Aspirin Stroke Study showed, in the first year, a 41 % risk reduction for stroke and death and a 46% risk reduction for stroke and stroke death with ticlopidine compared to aspirin. The superiority of ticlopidine in the reduction of strokes was seen in both males and females. Except for a reversible severe neutropenia in 0.9% of patients on ticlopidine, side effects related to ticlopidine were relatively benign and reversible. The Canadian American Ticlopidine Study compared ticlopidine to placebo in patients with major strokes. The primary outcome cluster of stroke, myocardial infarction and vascular death showed a risk reduction of about 30% in the ticlopidine group, providing strong evidence that ticlopidine delivers a clinically important reduction in the risk of thromboembolic events in patients with a history of thromboembolic stroke. The modest, reversible risk of neutropenia, affecting less than 1 % of patients, makes the benefit-risk ratio of ticlopidine a reasonable one. The issue of the ''wearing off’ of the beneficial effect of antiplatelet agents is a pertinent one. A cursory review of published data suggests that the beneficial effect of antiplatelet therapy diminishes over time. The Antiplatelet Trialists'' overview analysis shows an apparent trend towards a greater effect during the early years of treatment, but they emphasize some difficulties in this interpretation. They conclude that the data on this issue are incomplete and it may be prudent to continue antiplatelet therapy indefinitely in patients who remain at high risk for atherothrombotic vascular events. The issues of odds reductions, risk reductions and absolute risk of vascular events in particular patients are discussed. Finally, clopidogrel is a newly developed analog of ticlopidine that is more potent in antiplatelet antiaggregation and is better tolerated. This promising new platelet antiaggregation agent is presently being evaluated for efficacy and safety in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study. The CAPRIE study is briefly described.

Collaborative worldwide overviews of randomized trials.

Formal overviews (or meta-analyses) are now widely accepted as the most reliable way to evaluate the evidence from several randomized controlled trials that have all assessed a particular form of therapy. If a limited amount of trial data has accumulated, overviews can be undertaken at a relatively simple level, assembling just summary data extracted from published reports. Such overviews are likely to be incomplete and biased and may (because of the restricted number of analyses that are possible) not answer all the clinically important questions that might be addressed. Where a particularly large body of data from randomized trials has accumulated, more thorough and detailed overview analyses are needed. Such detailed reviews are greatly facilitated if a collaborative group of all the trialists is formed. Such groups have sought to collate individual patient data (a very few key items for every patient randomized). A central statistical secretariat then coordinates the process of data collection, checking, and analysis. Analyses are presented to the whole group for discussion and final reports are published in the name of the whole group. Experience from two very large groups that have followed this model, the Antiplatelet Trialists' Collaboration and the Early Breast Cancer Trialists' Collaborative Group, has shown that detailed collaborative overviews have many benefits: the results are particularly clear and therefore have substantial public health impact; the areas of statistical and medical agreement on the evidence can be defined; the areas of uncertainty (and hence future research priorities) are clarified; and the group can disseminate the results particularly widely and rapidly.

The gastrointestinal toxicity of aspirin: an overview of randomised controlled trials.

The proven benefit of aspirin in the secondary prevention of cardiovascular disease and its possible value in primary prevention must be weighted against its potential hazards. This paper is an overview of the gastrointestinal toxicity of aspirin, its most serious complication after intracerebral haemorrhage. Information on toxicity has been drawn only from randomised trials, thus avoiding the potential biases of observational studies. All randomised placebo controlled trials listed in the Anti-platelet Trialists Collaboration where a direct aspirin-placebo comparison was possible were included. Twenty-one trials were included, all but one of secondary prevention. There were over 75,000 person years of aspirin exposure. The pooled odds ratios for categories of gastrointestinal bleeding (e.g. haematemesis, melaena) were between 1.5-2.0; fatal bleeds were very rare. The risk of peptic ulcers was 1.3 and of upper gastrointestinal symptoms 1.7. These risks were lower than those found in observational studies. Attributable disease rates are also presented. For haematemesis for example they varied from 0.2-1.0 per 1000 person years. Toxicity was dose related. Aspirin does have significant gastrointestinal toxicity, although this is rarely fatal. More recent work has demonstrated the efficacy of low doses of aspirin (75 mg daily) but there is limited information yet available on its toxicity.

Long‐term antiplatelet therapy for the prevention of vascular disease

To estimate the effects of prolonged antiplatelet therapy on the primary and secondary incidence of vascular disease. Twenty-five randomised trials in 29,000 patients with a history of vascular disease (the Antiplatelet Trialists' Collaboration) and two randomised trials in 27,000 individuals without a history of vascular disease (the British doctors' and American physicians' studies). The Antiplatelet Trialists' Collaboration obtained data from all randomised trials of secondary prevention completed before January 1988. The British doctors' and American physicians' studies are the only two completed randomised trials of primary prevention. Data from the secondary prevention trials were provided by the Antiplatelet Trialists' Collaboration. Data from the primary prevention trials were extracted from the final published reports of these studies. In the secondary prevention trials, antiplatelet therapy reduced the rate of vascular disease by about 15% and the incidence of non-fatal myocardial infarction and stroke by about 30%. In the American physicians' study, but not the British doctors' study, the incidence of non-fatal myocardial infarction was also reduced. In neither primary prevention trial was there evidence of reduced rates of non-fatal stroke or vascular death; overall, fatal or disabling strokes were slightly more frequent among those assigned aspirin. For patients with a history of vascular disease, the benefits of antiplatelet therapy appear to outweigh any risks. Among 100 such patients, antiplatelet therapy for two years would prevent one death and two major non-fatal events. The balance of benefits and risks for individuals without a history of vascular disease is less clear because there is no firm evidence of a net reduction in either vascular death or disabling non-fatal vascular events among those treated with aspirin.

A review of secondary coronary prevention with dipyridamole and aspirin

A large number of placebo-controlled trials of antiplatelet drugs have been carried out. A summary of the results of AMIS, CDP, ISIS-2, PARIS I and II and the Antiplatelet Trialists' Collaboration is presented. It is concluded that two fatal events and three non-fatal events will be averted for every 100 patients given a 2-year course of antiplatelet agents, starting promptly after myocardial infarction.

Invitation: Anti-platelet Trialists Collaboration (APT) Invitation to participate in a worldwide overview of trials of antiplatelet agents in vascular diseases

Invitation: Anti-platelet Trialists Collaboration (APT) Invitation to participate in a worldwide overview of trials of antiplatelet agents in vascular diseases