Collaborative overview of randomised trials of antiplatelet therapy Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patientsBMJ 1994; 308 doi: https://doi.org/10.1136/bmj.308.6921.81 (Published 08 January 1994) Cite this as: BMJ 1994;308:81
- Antiplatelet Trialists' Collaboration
- Correspondence to: APT Statistical Secretariat, ICRF/BHF/MRC Clinical Trial Service Unit, Nuffield. Department of Clinical Medicine,Radcliffe Infirmary, Oxford OX2 6HE, or APT Clinical Secretariat,Department of Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU.
- Accepted 12 October 1993
Objective: To determine the effects of “prolonged” antiplatelet therapy (that is, given for one month or more) on “vascular events” (non-fatal myocardial infarctions, non-fatal strokes, or vascular deaths) in various categories of patients.
Design: Overviews of 145 randomised trials of “prolonged” antiplatelet therapy versus control and 29 randomised comparisons between such antiplatelet regimens.
Setting: Randomised trials that could have been available by March 1990.
Subjects: Trials of antiplatelet therapy versus control included about 70 000 “high risk” patients (that is, with some vascular disease or other condition implying an increased risk of occlusive vascular disease) and 30 000 “low risk” subjects from the general population. Direct comparisons of different antiplatelet regimens involved about 10 000 high risk patients.
Results: In each of four main high risk categories of patients antiplatelet therapy was definitely protective. The percentages of patients suffering a vascular event among those allocated antiplatelet therapy versus appropriately adjusted control percentages (and mean scheduled treatment durations and net absolute benefits) were: (a) among about 20 000 patients with acute myocardial infarction, 10% antiplatelet therapy v 14% control (one month benefit about 40 vascular events avoided per 1000 patients treated (2P< 0.00001)); (b) among about 20 000 patients with a past history of myocardial infarction, 13% antiplatelet therapy v 17% control (two year benefit about 40/1000 (2P<0.00001)); (c) among about 10 000 patients with a past history of stroke or transient ischaemic attack, 18% antiplatelet therapy v 22% control (three year benefit about 40/1000 (2P<0.00001)); (d) among about 20 000 patients with some other relevant medical history (unstable angina, stable angina, vascular surgery, angioplasty, atrial fibrillation, valvular disease, peripheral vascular disease, etc), 9% v 14% in 4000 patients with unstable angina (six month benefit about 50/1000 (2P<0.00001)) and 6% v 8% in 16 000 other high risk patients (one year benefit about 20/1000 (2P<0.00001)).
Reductions in vascular events were about one quarter in each of these four main categories and were separately statistically significant in middle age and old age, in men and women, in hypertensive and normotensive patients, and in diabetic and non: diabetic patients. Taking all high risk patients together showed reductions of about one third in non-fatal myocardial infarction, about one third in non-fatal stroke, and about one sixth in vascular death (each 2P<0.00001). There was no evidence that non-vascular deaths were increased, so in each of the four main high risk categories overall mortality was significantly reduced. The most widely tested antiplatelet regimen was “medium dose” (75-325 mg/day) aspirin. Doses throughout this range seemed similarly effective (although in an acute emergency it might be prudent to use an initial dose of 160-325 mg rather than about 75 mg). There was no appreciable evidence that either a higher aspirin dose or any other antiplatelet regimen was more effective than medium dose aspirin in preventing vascular events. The optimal duration of treatment for patients with a past history of myocardial infarction, stroke, or transient ischaemic attack could not be determined directly because most trials lasted only one, two, or three years (average about two years). Nevertheless, there was significant (2P<0.00001) further benefit between the end of year 1 and the end of year 3, suggesting that longer treatment might well be more effective.
Among low risk recipients of “primary prevention” a significant reduction of one third in non: fatal myocardial infarction was, however, accompanied by a non-significant increase in stroke. Furthermore, the absolute reduction in vascular events was much smaller than for high risk patients despite a much longer treatment period (4.4% antiplatelet therapy v 4.8% control; five year benefit only about four per 1000 patients treated) and was not significant (2P=0.09).
Conclusions: Among a much wider range of patients at high risk of occlusive vascular disease than is currently treated routinely, some years of antiplatelet therapy - with aspirin 75-325 mg/day or some other antiplatelet regimen (provided there are no contraindications) - offers worthwhile protection against myocardial infarction, stroke, and death. Significant benefit is evident not only among patients with unstable angina, suspected acute myocardial infarction, or a past history of myocardial infarction, stroke, or transient ischaemic attack, but also among many other categories of high risk patients (such as those having vascular procedures and those with stable angina or peripheral vascular disease). There is as yet, however, no clear evidence on the balance of risks and benefits of antiplatelet therapy in primary prevention among low risk subjects.
Antiplatelet therapy protects a wider range of patients at high risk of occlusive vascular disease than is currently treated routinely: it should be considered for almost all with suspected acute myocardial infarction, unstable angina, or a history of myocardial infarction, angina, stroke, transient ischaemic attack, arterial bypass surgery, or angioplasty
There is, as yet, no clear evidence that antiplatelet therapy is indicated for routine use in “primary prevention” subjects at low risk of occlusive vascular events
Medium dose aspirin (75-325 mg/day) is the most widely tested antiplatelet regimen, and no other regimen appeared significantly more effective at preventing myocardial infarction, stroke, or death
Previous Antiplatelet Trials And Aims Of Current Overview
It is reliably established that antiplatelet therapy reduces the risk of vascular death by about one sixth and the risk of non-fatal myocardial infarction and stroke by about one third in patients with unstable angina, suspected acute myocardial infarction, or a past history of myocardial infarction, stroke, or a transient ischaemic attack.*RF 1-4* There remains uncertainty, however, whether antiplatelet therapy is beneficial in other patient populations at high risk of occlusive vascular disease or in certain subgroups of these “high risk” populations (for example, among women or among patients who are old, hypertensive, or diabetic). It is also uncertain whether the benefits of long term antiplatelet therapy would outweigh the side effects among subjects in whom the risks of occlusive vascular disease are much lower (for example, primary prevention in the general population with no relevant medical history) and which antiplatelet regimens are most effective.
The aim of this second cycle of the worldwide Antiplatelet Trialists' Collaboration1 was therefore to assess the effects of antiplatelet therapy in more detail and in a much wider range of circumstances than before. This paper (part I in a series of three reports) describes the methods used in the collaborative overview process and then provides systematic overviews of the effects of “prolonged” antiplatelet therapy (that is, given for at least one month) in subjects at high risk and at low risk of occlusive vascular disease. The trials in high risk subjects are then subdivided more finely by the category of patients who were to be studied (prior myocardial infarction, acute myocardial infarction, prior stroke or transient ischaemic attack, and various other categories of patients considered to be at particular risk of vascular events because of their medical history). Where possible, the patients in those trials in high risk are also subdivided by certain personal characteristics (age, sex, blood pressure, diabetes) or by the type of antiplatelet regimen tested (aspirin at various doses, dipyridamole, ticlopidine, etc). In addition, the directly randomised comparisons of different antiplatelet regimens are reviewed. Randomised comparisons of different durations of treatment were not available, but the effects of antiplatelet therapy during year 1, during year 2, and during later times are examined separately to help assess any additional effects of more prolonged therapy.
Parts II and III will report overviews of 53 trials of antiplatelet therapy to maintain vessel patency after vascular procedures(super5) and 77 trials to prevent venous thromboembolism after general and orthopaedic surgery.6
Evidence That Can Be Generalised To A Wide Range Of Patients
Reliable detection (or refutation) of the sort of moderate sized benefits observed previously with antiplatelet therapy requires reliable exclusion both of moderate biases and of moderate random errors, either of which might obscure (or mimic) moderate treatment effects. Each requirement may be difficult to meet adequately without a proper overview of the unconfounded randomised trials, particularly if the aim is not only to distil clear findings from the overall material but also (by appropriate subgroup analyses) to help assess the generalisability of those findings.7 8
Analyses of the effects of treatment in particular subgroups will mainly involve “vascular events” (that is, non-fatal myocardial infarctions, non-fatal strokes, or vascular deaths) rather than vascular deaths alone. This is because such subgroup analyses may be statistically more reliable for vascular events (where, overall, there is a 13 standard deviation difference in favour of antiplatelet therapy; see results) than for vascular deaths alone (where there is “only” a six standard deviation difference in favour of antiplatelet therapy). Even for vascular events, however, separate analyses of the effects in an excessively large number of small subgroups of patients studied could well generate some false negative results merely by chance. Paradoxically, therefore, unless there are good reasons for expecting a difference in the direction of the effects of treatment in different settings the approximate benefit of antiplatelet therapy in some small subgroup of patients may best be assessed indirectly by approximate extrapolation from the proportional effect observed in a much wider class of patients.9
Materials and methods
Identification of all unconfounded randomised trials
The aim was to seek collaboration between the coordinators of all unconfounded randomised trials, published or unpublished,10 11 that could have been available for review by March 1990, in which antiplatelet therapy was compared with no antiplatelet therapy, or in which one antiplatelet regimen was compared with another (with the exception) of trials of antiplatelet therapy for patients with subarachnoid haemorrhage12 14 or for preventing pre-eclampsia15 or migraine16. Trials were to be included only if they were believed to have been randomised in a manner that precluded prior knowledge of the next treatment (for example, where allocation was not alternate or based on odd or even dates), and they were considered to be unconfounded if one treatment group differed from another only in the treatment of interest. Thus a trial in which antiplatelet therapy plus heparin was compared with the same heparin regimen would have been included whereas a trial of antiplatelet therapy plus heparin versus no treatment (or of antiplatelet therapy versus anticoagulant therapy) would not.
Relevant randomised trials were identified by computer aided literature searches (Medline and Current Contents), by manual searches of journals, by scrutiny of the reference lists of trial and review articles, by scrutiny of abstracts and meeting proceedings, by collaboration with the trials register of the International Committee on Thrombosis and Haemostasis, by inquiry among colleagues (particularly those who had coordinated other such studies), and by inquiry of various manufacturers of antiplatelet agents. This process and the correspondence with collaborating trialists that it engendered (see below) took several years. The aim was to include trials of agents whose primary mode of action on the vascular system was thought to be through inhibition of platelet aggregation or adhesion, or both: cyclo-oxygenase inhibitors (aspirin, flurbiprofen, ibuprofen, indobufen, naproxen, sulphinpyrazone, triflusal), phosphodiesterase inhibitors (dipyridamole, E5510, RA233), platelet calcium ion channel inhibitors (suloctidil), phospholipase inhibitors (hydroxychloroquine), thromboxane synthetase inhibitors, receptor blockers, or both (dazoxiben, piracetam, picotamide, ridogrel, sulotroban, daltroban, GR32191), and agents with direct effects on platelet membranes (ticlopidine). Agents known also to have a major vasodilating action (such as epoprostenol, oxpentifylline, ketanserin, naftidrofuryl) or major anticoagulant action (such as heparin or warfarin) were not to be included.
Definition of outcome measures
In this report the effects of antiplatelet therapy were to be assessed principally in terms of their effects on vascular events, defined as non-fatal myocardial infarctions, non-fatal strokes, or vascular deaths. Outcome events were to be counted as “non-fatal” only if the patient subsequently survived to the end of the study treatment period scheduled for that patient: otherwise, only the death was to be counted. Survivors could have suffered more than one type of non-fatal event. Causes of death were subdivided into “non-vascular” (that is, definitely non-vascular) and “vascular” (that is, definitely or possibly vascular, which includes all deaths attributed to cardiac, cerebral, haemorrhagic, embolic, other vascular, or unknown causes). Myocardial infarctions and strokes were to be counted if the investigator considered them to be either probable or definite. Transient ischaemic attacks (in brain or eye), angina, and “possible” myocardial infarctions or strokes were not to be counted as outcomes. Strokes (including subarachnoid haemorrhages) were to be counted only if symptoms persisted for at least 24 hours, and were subdivided into haemorrhagic (including those of “probably” haemorrhagic aetiology) and other (including those of probably ischaemic or of unknown aetiology). “Major” bleeds were those non-cerebral bleeds that required transfusion.
In trials among patients having vascular surgery or angioplasty or those having renal shunts or fistulas established, information on vessel or graft patency was sought (see part II5, and among all trials in which deep venous thromboses were looked for prospectively (usually among surgical patients) information on deep venous thromboses and pulmonary emboli was also sought (see part III6. Pulmonary emboli were to be counted if considered “probable” or “definite” by the investigator. There were differences between studies in the definitions of outcome measures, but because retrospective reclassification would have been impracticable (and potentially biased) the definitions preferred by the original investigators in each study were generally retained. The heterogeneity that this entailed does not invalidate the main overview results.17
“Summary data” from all contributing trials
For all studies that might have been randomised controlled trials of antiplatelet therapy a few simple details of trial design were requested from the principal investigators (including the exact method of treatment allocation, whether control patients received placebo, any other “blinding” of treatment allocation or outcome assessment, and the scheduled duration of trial treatment and of patient recruitment). Summary data were requested on the numbers of patients allocated to each treatment group and on the numbers of these who had suffered each of the outcomes of interest. These summary data were checked for internal consistency and for consistency with any published reports of the trials. When the data did not include information about outcome among all patients initially randomised or about all the outcomes of interest during the scheduled period of follow up, extra details were sought by correspondence with the principal investigators so that “intention to treat” analyses could be conducted. Before the final analyses, the data to be used were printed out for each trialist to check again.
Individual patient data from certain trial categories
For the trials among “low risk” subjects (that is, of primary prevention of vascular events) or among particular categories of “high risk” patients (those with unstable angina, acute myocardial infarction, prior myocardial infarction, stroke or transient ischaemic attack) data were sought for each individual randomised patient. These concerned certain baseline entry characteristics (age or date of birth, sex, blood pressure, and whether diabetic or not); the allocated treatments; and the dates of randomisation, of the scheduled end of trial treatment, of the actual end of trea