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Diagnostic expansion in clinical trials: myocardial infarction, stroke, cancer recurrence, and metastases may not be the hard endpoints you thought they were

BMJ 2018; 362 doi: (Published 19 September 2018) Cite this as: BMJ 2018;362:k3783
  1. Go Nishikawa, instructor1,
  2. Vinay Prasad, assistant professor of medicine1
  1. 1Oregon Health Science University, Portland, Oregon, USA
  1. Correspondence to: V Prasad prasad{at}

What qualifies as disease in clinical trials may be getting so broad that outcomes are becoming less meaningful and harder to interpret, argue Go Nishikawa and Vinay Prasad

It is intuitive and obvious that no person desires a myocardial infarction, stroke, or recurrence or metastasis of a previously localised cancer. Reducing the risk of these endpoints is therefore used as the evidentiary basis of a wide range of drugs, devices, and surgical procedures. However, recent trials in cardiovascular and cancer medicine force us to revisit the assumption of their value as endpoints. Several studies have produced discordant results, with interventions that reduce myocardial infarction, stroke, or metastasis having no effect on cardiovascular death, health related quality of life, cancer related death, and overall mortality—four harder clinical endpoints.

Is the avoidance of myocardial infarction, stroke, and cancer recurrence or metastasis less meaningful than it used to be? Or has the severity of these events lessened, partly because of advances in imaging and assay sensitivity? As technology advances and diagnostic categories broaden we need to consider whether there comes a point when endpoints that are widely believed to be measures of patient centred outcomes become test based, non-clinical endpoints. We have selected four recent randomised trials that highlight how benefits hinge on the nature of events averted.

Trials with discordant results

The FOURIER trial compared the effect of evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), with placebo in patients with cardiovascular disease.1 The trial used a primary composite endpoint of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularisation and found a  benefit for the drug (1344/13 784 (9.8%) had reductions in the composite endpoint v 1563/13 780 (11.3%) with placebo; hazard ratio=0.85, 95% confidence interval 0.79 to 0.92; P<0.001). However, the drug had no favourable effect on …

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