Large-scale Randomised Evidence
Reliable assessment of the treatment and prevention of cardiovascular disease
When important causes of vascular disease are assessed, their effects are sometimes so extreme that cause-effect relationships can be reliably inferred from observational studies of sufficiently large size. But, the effects of treatments may well involve only moderate improvements in mortality and major morbidity. Just a moderate survival improvement in vascular disease might, however, save tens of thousands of lives a year (and prevent much disability). So, even when the absolute gain is only moderate it is important not to get wrong answers. The best way to obtain reliable results about moderate treatment effects is by producing large-scale randomised evidence: large numbers avoid being misled by the play of chance and proper randomisation avoids being misled by biases.
As one way of achieving this aim, Oxford research groups pioneered the use of collaborative "meta-analyses" of previous randomised trials that had addressed much the same therapeutic question. These meta-analyses in vascular disease (in particular, those involving trials of antithrombotic, fibrinolytic and lipid-lowering therapy) have substantially influenced both worldwide clinical practice and future research strategies. In particular, the Cholesterol Treatment Trialists’ Collaboration has used individual patient data from large long-term statin trials to generate reliable evidence about the beneficial effects of lowering LDL-cholesterol on cardiovascular mortality and morbidity in many different types of patient in whom there had previously been uncertainty (e.g. women, the elderly, primary prevention and people with below-average cholesterol levels). It is now obtaining individual patient data on all of the other serious adverse events recorded in those trials to address concerns that have been raised (based chiefly on observational studies and case reports) about side-effects.
Oxford also established the use of very large streamlined randomised trials, or "mega-trials", to assess the effects of widely practicable treatments on mortality and major morbidity. Such trials typically randomise some tens of thousands of patients and, as a result, have provided clear and reliable information about the effects of many treatments (such as aspirin and fibrinolytic therapy for the emergency treatment of heart attacks, and statin therapy for a very wide range of patients with vascular disease, diabetes or hypertension irrespective of age, sex or presenting cholesterol level). The consequent widespread use of these effective treatments is preventing hundreds of thousands of premature deaths each year around the world. Most recently, Oxford showed that adding niacin to effective statin therapy does not produce benefit but does cause harm (including unexpected increases in hospitalisations due to bleeding and infections, as well as problems with glucose control). It has also shown, by contrast with previous trials of smaller size and/or shorter duration, that adding CETP inhibitor therapy to effective statin therapy further reduces the risk of cardiovascular events (although the benefit appears to relate to the LDL-reduction, with little impact from raising HDL-cholesterol). Now, Oxford is running further large-scale trials in patients at high risk of cardiovascular events due to pre-existing cardiovascular or renal disease. It is also taking the lead in an initiative to streamline guidance for the conduct of clinical trials.