Randomized Trials Versus Common Sense and Clinical Observation: JACC Review Topic of the Week
Authors: John J V McMurray
Renato D Lopes
Alexander C Fanaroff
Manesh R Patel
C Michael Gibson
John H Alexander
Christopher B Granger
Robert A Harrington
Robert M Califf
Stephan Windecker
Adrian F Hernandez
Deepak L Bhatt
Journal: Journal of the American College of Cardiology (2020)
Discipline: CLINICAL MEDICINE
Keywords: observational studies; randomized controlled trials; real-world data; surrogate endpoints.
Affiliations: Penn Cardiovascular Outcomes, Quality and Evaluative Research Center, Leonard Davis Institute, and Cardiovascular Medicine Division, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: https://twitter.com/ACFanaroff., Verily Life Sciences (Alphabet), South San Francisco, California., Department of Medicine, Stanford University, Stanford, California., Division of Cardiology and Duke Clinical Research Institute, Duke University, Durham, North Carolina., British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland., Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, Massachusetts., Department of Cardiology, Bern University Hospital, Inselspital, University of Bern, Bern, Switzerland., Cardiovascular Division, Beth Israel Deaconess Medical, Harvard Medical School, Boston, Massachusetts., Division of Cardiology and Duke Clinical Research Institute, Duke University, Durham, North Carolina. Electronic address: .

Abstract:  Concerns about the external validity of traditional randomized clinical trials (RCTs), together with the widespread availability of real-world data and advanced data analytic tools, have led to claims that common sense and clinical observation, rather than RCTs, should be the preferred method to generate evidence to support clinical decision-making. However, over the past 4 decades, results from well-done RCTs have repeatedly contradicted practices supported by common sense and clinical observation. Common sense and clinical observation fail for several reasons: incomplete understanding of pathophysiology, biases and unmeasured confounding in observational research, and failure to understand risks and benefits of treatments within complex systems. Concerns about traditional RCT models are legitimate, but randomization remains a critical tool to understand the causal relationship between treatments and outcomes. Instead, development and promulgation of tools to apply randomization to real-world data are needed to build the best evidence base in cardiovascular medicine. 

Retracted: No

PubPeer comments:
 **Problems in comparing observational studies and RCTs on vitamins E and C** Fanaroff listed examples where observational studies and RCTs diverged and interpreted that the latter reflect true outcomes [1]. However, they stated that the size of the RCT matters and that a patientu2019s individual response to any intervention will be dependent on a multitude of factors, yet these issues were not considered when comparing observational studies and RCTs. One of their examples was vitamin E and cardiovascular events. A few highly publicized cohort studies associated higher vitamin E intake with lower cardiovascular disease risk. The PHS-II and HOPE trials [2,3] were cited as a refutation of that association [1]. However, the PHS-II trial recruited physicians, which means upper-class population far from the average population in health-related life styles. Furthermore, the PHS-II and HOPE trials recorded 1661 and 1600 deaths, respectively. Although size is an important issue in RCTs [1], Fanaroff ignored the ATBC Study on vitamin E that recorded 3571 deaths [4,5], which is more than the two cited RCTs combined. Large size makes subgroup comparisons reasonable. The ATBC Study recruited male smokers over all social classes and is much more representative of the ordinary population than PHS-II. In the ATBC Study, there was strong evidence that the effect of vitamin E supplementation on total mortality was heterogeneous (P = 0.0005)[4]. This evidence of heterogeneity challenges the interpretation that PHS-II and HOPE trials prove that vitamin E supplementation uniformly has no effects on health [1]. It is also an irony that while Fanaroff emphasizes focus on RCTs when considering vitamin E intakes, the US dietary recommendations base u201cestimated average requirementu201d of vitamin E on in vitro hemolysis in young males; a surrogate endpoint without any validity [5]. Another of their examples was vitamin C, which did not influence mortality in the PHS-II trial [2]. However, there may be heterogeneity also in the effects of vitamin C on health. A meta-analysis of 14 randomized trials found that vitamin C did not prevent post-operative atrial fibrillation in US trials, yet there was strong evidence of effect in non-US trials [6]. The explanation for the divergent findings is not evident, yet possibly the greater wealth in the USA is reflected as better hospital care such that the effect of vitamin C administration is therefore less influential, or there might be other cultural explanations. In any case, there is no basis to consider that the PHS-II trial proves that no-one can benefit from vitamin C administration. References 1. Fanaroff AC, Califf RM, Harrington RA, et al. Randomized Trials Versus Common Sense and Clinical Observation. J Am Coll Cardiol. 2020;76:580-589. https: doi.org 10.1016 j.jacc.2020.05.069 http: www.ncbi.nlm.nih.gov pmc articles pmc7384793 2. Sesso HD, Buring JE, Christen WG, et al. Vitamins E and C in the prevention of cardiovascular disease in men: the Physiciansu2019 Health Study II randomized controlled trial. JAMA 2008;300:2123u20132133. https: doi.org 10.1001 jama.2008.600 3. Lonn E, Bosch J, Yusuf S, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 2005;293:1338-47. https: doi.org 10.1001 jama.293.11.1338 4. Hemilu00e4 H, Kaprio J. Modification of the effect of vitamin E supplementation on the mortality of male smokers by age and dietary vitamin C. Am J Epidemiol. 2009;169:946-53. https: doi.org 10.1093 aje kwn413 https: www.ncbi.nlm.nih.gov pmc articles PMC2661323 5. Hemilu00e4 H. Vitamin E and mortality in male smokers of the ATBC Study: implications for nutritional recommendations. Front Nutr. 2020;7:36. https: doi.org 10.3389 fnut.2020.00036 https: www.ncbi.nlm.nih.gov pmc articles PMC7136753 6. Hemilu00e4 H, Suonsyrju00e4 T. Vitamin C for preventing atrial fibrillation in high risk patients: a systematic review and meta-analysis. BMC Cardiovasc Disord. 2017;17:49. https: doi.org 10.1186 s12872-017-0478-5 https: www.ncbi.nlm.nih.gov pmc articles PMC5286679 ,