Vascular disease meta analyses

Many medical questions about the efficacy and safety of specific treatments cannot be addressed by looking at the results of a single randomized trial, and instead depend on combining the results of many trials that have studied that question. The combination of data from many trials is achieved through the use of meta-analysis. Such meta-analyses are typically done by combining the summary results from each trial in order to achieve an overall summary of the effects of a treatment. Our group specialises, however, in obtaining detailed and complete data from each individual participant included in each of the relevant trials, and then analysing the resulting dataset (which is generally very large) to obtain more comprehensive analyses of how treatment efficacy and safety varies in different clinical circumstances.
We are now using this method to study the effects of: statin therapy on various conditions (such as muscle pain) that have been linked to treatment (but where the link is unproven); alteplase (a ‘clot-busting’ drug) after stroke; low-dose aspirin to prevent a first heart attack or stroke in apparently healthy people, and angiotensin-receptor blockers in Marfan Syndrome (a condition that causes the main artery leaving the heart to expand dangerously).

The aim of this programme of meta-analyses is to determine in detail, for a wide range of individuals, the benefits and risks of several of the most important drugs used for the treatment and prevention of cardiovascular disease. In each meta-analysis, after identifying randomized trials relevant to the particular question of interest, we set up a collaboration among the principal investigators and trial sponsors, and a secretariat in PHRU then coordinates the collection of individual participant data (IPD), data checking, analysis and publication. In each case, new trial evidence is incorporated as it is published, and new analyses are published as the data mature. This approach differs from most other meta-analyses of individual patient data in the subject area of cardiovascular disease, which are generally set up to answer a specific question and are not maintained long-term. Our approach allows us to maintain up-to-date summaries of present knowledge, to respond to requests for new analyses (eg, in response to safety concerns from regulatory authorities), and to influence the formulation of new trial proposals to address gaps or uncertainties in the evidence highlighted by our meta-analyses.
We generally limit our attention to topics for which IPD are likely to be available. Although this approach is very labour intensive, the advantages of achieving access to IPD are that they often provide a more accurate understanding of treatment effects and disease mechanisms. In particular, they allow assessment of the effects of a drug: (i) on particular outcomes (eg, distinguishing between atherosclerotic and non-atherosclerotic cardiac events, or vascular and non-vascular causes of death) defined similarly in each trial, where possible, or if not with a good understanding of how phenotyping of events differs between trials; (ii) on particular types of trial participants, and (iii) over time, which often allows the net effects of treatment to be understood in terms of benefits and hazards occurring on different timescales.
We are coordinating meta-analyses of randomized trials in 4 main areas: (1) the Cholesterol Treatment Trialists’ (CTT) Collaboration, which is undertaking an additional cycle of data collection in order to examine the effects of statin regimens on adverse events such as muscle pain, new-onset diabetes mellitus, haemorrhagic stroke, and other conditions that have been reported – in non-randomized studies – to be associated with statin therapy; (2) the Stroke Thrombolysis Trialists’ (STT) Collaboration, which is currently examining how the results of CT (or MR) scans taken prior to randomization to alteplase vs placebo (or open control) influence functional outcomes; (3) the Antithrombotic Treatment Trialists’ (ATT) Collaboration, which is conducting an updated meta-analysis of data from trials of aspirin vs placebo (or open control) for the primary prevention of cardiovascular disease; and (4) the Marfan Treatment Trialists’ (MTT) Collaboration, which is examining the effects of angiotensin receptor blockers on aortic root size within 10 randomized trials.