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  • Review Article
  • Published:

The need for increased pragmatism in cardiovascular clinical trials

Nature Reviews Cardiology volume 19, pages 737–750 (2022)Cite this article

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Abstract

The majority of cardiovascular randomized controlled trials (RCTs) test interventions in selected patient populations under explicitly protocol-defined settings. Although these ‘explanatory’ trial designs optimize conditions to test the efficacy and safety of an intervention, they limit the generalizability of trial findings in broader clinical settings. The concept of ‘pragmatism’ in RCTs addresses this concern by providing counterbalance to the more idealized situation underpinning explanatory RCTs and optimizing effectiveness over efficacy. The central tenets of pragmatism in RCTs are to test interventions in routine clinical settings, with patients who are representative of broad clinical practice, and to reduce the burden on investigators and participants by minimizing the number of trial visits and the intensity of trial-based testing. Pragmatic evaluation of interventions is particularly important in cardiovascular diseases, where the risk of death among patients has remained fairly stable over the past few decades despite the development of new therapeutic interventions. Pragmatic RCTs can help to reveal the ‘real-world’ effectiveness of therapeutic interventions and elucidate barriers to their implementation. In this Review, we discuss the attributes of pragmatism in RCT design, conduct and interpretation as well as the general need for increased pragmatism in cardiovascular RCTs. We also summarize current challenges and potential solutions to the implementation of pragmatism in RCTs and highlight selected ongoing and completed cardiovascular RCTs with pragmatic trial designs.

Key points

  • Most cardiovascular randomized controlled trials (RCTs) conducted to date have been ‘explanatory’, that is, designed to study the intervention in optimized conditions with selected patient populations and frequent protocolized assessments.

  • Although explanatory RCT designs increase validity, they limit the generalizability of trial findings, whereas a ‘pragmatic’ approach to RCTs yields findings more relevant to real-world practice.

  • In pragmatic RCTs, interventions are tested in patients who are broadly representative of the condition being studied, and the study is aligned with routine clinical care to reduce costs and organizational burden.

  • Although pragmatic RCTs tend to attenuate estimates of treatment effects, they do provide a more realistic understanding of population-level effectiveness and costs than explanatory trials.

  • Pragmatic trials can highlight barriers to the implementation of therapies and are better suited than explanatory RCTs to assessing the effects of implementation strategies and health-care policies at the population level.

  • Widespread implementation of pragmatic trials would require the development of technological infrastructure to collect and share data as well as regulatory guidelines amenable to findings derived from routinely collected data.

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Fig. 1: The PRECIS-2 wheel.
Fig. 2: Relative likelihood of biases and limitations in each type of clinical study.

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Authors and Affiliations

  1. Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA

    Muhammad Shariq Usman & Javed Butler

  2. Department of Medicine and Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada

    Harriette G. C. Van Spall

  3. Research Institute of St. Joe’s, Hamilton, Ontario, Canada

    Harriette G. C. Van Spall

  4. Population Health Research Institute, Hamilton, Ontario, Canada

    Harriette G. C. Van Spall

  5. Division of Cardiology, Duke University School of Medicine, Durham, NC, USA

    Stephen J. Greene, Robert J. Mentz & Muhammad Shahzeb Khan

  6. Duke Clinical Research Institute, Durham, NC, USA

    Stephen J. Greene & Robert J. Mentz

  7. Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center and Parkland Health and Hospital System, Dallas, TX, USA

    Ambarish Pandey & Darren K. McGuire

  8. DeMatteis Cardiovascular Institute, St Francis Hospital and Heart Center, Roslyn, NY, USA

    Ziad A. Ali

  9. Division of Cardiology, University of California Los Angeles, Los Angeles, CA, USA

    Gregg C. Fonarow

  10. Department of Cardiology, Saint Luke’s Mid America Heart Institute and the University of Missouri-Kansas City, Kansas City, MI, USA

    John A. Spertus

  11. Department of Cardiology (CVK), Berlin Institute of Health Center for Regenerative Therapies (BCRT), and German Centre for Cardiovascular Research (DZHK) Partner Site Berlin, Charité Universitätsmedizin, Berlin, Germany

    Stefan D. Anker

  12. Department of Medical Sciences, Uppsala University, Uppsala, Sweden

    Stefan K. James

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Contributions

M.S.U., Z.A.A., R.J.M. and M.S.K. researched data for the article. H.G.C.V., S.J.G., A.P., D.K.M. and S.K.J. contributed substantially to discussion of the content. M.S.U., D.K.M., R.J.M., G.C.F., J.A.S., S.D.A., J.B. and M.S.K. wrote the article. H.G.C.V., S.J.G., A.P., D.K.M., Z.A.A., G.C.F., J.A.S., S.D.A., J.B., S.K.J. and M.S.K. reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Muhammad Shahzeb Khan.

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H.G.C.V. is funded by the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada. S.J.G. has received research support from the Duke University Department of Medicine Chair’s Research Award, American Heart Association, Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Roche Diagnostics and Sanofi; and serves as a consultant for Amgen, Bayer, Bristol Myers Squibb, Merck, PharmaIN, Roche Diagnostics, Sanofi, Tricog Health, Urovant Pharmaceuticals and Vifor. D.K.M. reports honoraria for clinical trial leadership from AbbVie, Akebia, Arena, AstraZeneca, Boehringer Ingelheim, CSL Behring, Dynavax, Eidos, Esperion, Lexicon, Lilly USA, Merck & Co, Novo Nordisk, Otsuka, Pfizer and Sanofi, and honoraria for consultancy from Afimmune, Applied Therapeutics, Bayer, Boehringer Ingelheim, CSL Behring, Lilly USA, Merck & Co, Metavant, Novo Nordisk and Sanofi. Z.A.A. reports institutional research grants to Columbia University from Abbott and Cardiovascular Systems; and is a consultant for Abbott, Abiomed, AstraZeneca and Shockwave. R.J.M. reports receiving personal fees from Amgen, Bayer, Boehringer Ingelheim, Merck & Co and Novartis International; and receiving research support and honoraria from Abbott Laboratories, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly & Co, Boston Scientific Corporation, Cytokinetics, FAST BioMedical, Gilead Sciences, Innolife, Medtronic, Merck & Co, Novartis International, Relypsa, Respicardia, Windtree Therapeutics and ZOLL Medical Corporation. G.C.F. reports research support from the National Institutes of Health and consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Janssen, Medtronic, Merck and Novartis. J.A.S. is a consultant for Bayer, Janssen, Merck, Myokardia, Novartis, Terumo and United Healthcare; receives grant support from Janssen and Myokadia; and holds the copyright to the Peripheral Artery Questionnaire, Kansas City Cardiomyopathy Questionnaires and the Seattle Angina Questionnaire; and serves on the Board of Blue Cross/Blue Shield of Kansas City. S.D.A. declares grants or personal fees from Abbott Vascular, Actimed, Amgen, AstraZeneca, Bayer, Bioventrix, Boehringer Ingelheim, Brahms, Cardiac Dimensions, Cordio, Janssen, Occlutech, Respicardia, Servier, Vifor Int. and V-Wave. J.B. has served as a consultant for Abbott, Adrenomed, Arena Pharma, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Cardior, CVRx, Eli Lilly, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Sequana Medical, V-Wave Limited and Vifor. S.K.J. has received institutional research/grant support from AstraZeneca, Bayer, Janssen and Novartis. The other authors declare no competing interests.

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Usman, M.S., Van Spall, H.G.C., Greene, S.J. et al. The need for increased pragmatism in cardiovascular clinical trials. Nat Rev Cardiol 19, 737–750 (2022). https://doi.org/10.1038/s41569-022-00705-w

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