Association is not causation: treatment effects cannot be estimated from observational data in heart failure

Rush, C. J., Campbell, R. T., Jhund, P. S. , Petrie, M. C. and McMurray, J. J.V. (2018) Association is not causation: treatment effects cannot be estimated from observational data in heart failure. European Heart Journal, 39(37), pp. 3417-3438. (doi: 10.1093/eurheartj/ehy407) (PMID:30085087) (PMCID:PMC6166137)

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Aims: Treatment ‘effects’ are often inferred from non-randomized and observational studies. These studies have inherent biases and limitations, which may make therapeutic inferences based on their results unreliable. We compared the conflicting findings of these studies to those of prospective randomized controlled trials (RCTs) in relation to pharmacological treatments for heart failure (HF). Methods and results: We searched Medline and Embase to identify studies of the association between non-randomized drug therapy and all-cause mortality in patients with HF until 31 December 2017. The treatments of interest were: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, mineralocorticoid receptor antagonists (MRAs), statins, and digoxin. We compared the findings of these observational studies with those of relevant RCTs. We identified 92 publications, reporting 94 non-randomized studies, describing 158 estimates of the ‘effect’ of the six treatments of interest on all-cause mortality, i.e. some studies examined more than one treatment and/or HF phenotype. These six treatments had been tested in 25 RCTs. For example, two pivotal RCTs showed that MRAs reduced mortality in patients with HF with reduced ejection fraction. However, only one of 12 non-randomized studies found that MRAs were of benefit, with 10 finding a neutral effect, and one a harmful effect. Conclusion: This comprehensive comparison of studies of non-randomized data with the findings of RCTs in HF shows that it is not possible to make reliable therapeutic inferences from observational associations. While trials undoubtedly leave gaps in evidence and enrol selected participants, they clearly remain the best guide to the treatment of patients.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Jhund, Professor Pardeep and Petrie, Professor Mark and Campbell, Dr Ross and McMurray, Professor John and Rush, Dr Christopher
Authors: Rush, C. J., Campbell, R. T., Jhund, P. S., Petrie, M. C., and McMurray, J. J.V.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:European Heart Journal
Publisher:Oxford University Press
ISSN (Online):1522-9645
Published Online:01 August 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in European Heart Journal 39(37): 3417-3438
Publisher Policy:Reproduced under a Creative Commons License

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