Very Different Results from RCT and Observational Studies?

The CLAHRC WM Director lives only a few doors down from the Edgbaston golf course. The club house is a fine Georgian building and was the home of William Withering – a member of the Lunar Society and the person who discovered the cardiac-stimulating drug digitalis (digoxin). Foxglove plants, the natural source of digitalis, still grow in profusion. The CLAHRC WM Director prescribed this medicine frequently when working as a junior doctor on the medical wards. However, the drug fell from grace when many observational studies showed that use of the medicine was associated with an increased risk of death in patients with heart failure. However, a recent meta-regression [1] from Birmingham, London and Melbourne showed that the more care that was taken to reduce the risk of bias, the smaller the estimated increase in mortality, ending up with RCTs showing a neutral effect. The source of bias is obvious – doctors prescribe the medicine for their sickest patients, and the observable prognostic factors pick up only a proportion of the increased risk. The residual prognostic factors are subtle clues that experienced doctors can sense in a tacit way.

The accompanying editorial [2] uses these data to rubbish observational evidence, rather spectacularly missing a more subtle point – the greater the care taken in observational evidence, the more the risk of bias can be mitigated. Further mitigation is possible by adjusting for bias, using the method of Turner et al.,[3] thereby reducing point estimates and widening confidence limits into credible limits. We are considering using digoxin as an examplar of the method.

As for William Withering’s medicine; well it appears not to increase death rates after all, while both the observational and RCT evidence suggests that it reduces the need for admission. Two hundred and thirty years after his discovery, the scientific principles of the Englightenment that Withering espoused continue to refine our understanding of the medical uses of digoxin.

— Richard Lilford, CLAHRC WM Director


  1. Ziff OJ, Lane DA, Samra M, et al. Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data. BMJ. 2015; 351: h4451.
  2. Cole GD & Francis DP. Trials are best, ignore the rest: safety and efficacy of digoxin. BMJ. 2015; 351: h4662.
  3. Turner RM, Spiegelhalter DJ, Smith GC, Thompson SG. Bias modelling in evidence synthesis. J R Stat Soc Ser A Stat Soc. 2009;172(1):21-47.

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