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Genotype-based clinical trials in cardiovascular disease

Nature Reviews Cardiology volume 12, pages 475–487 (2015)Cite this article

Subjects

Key Points

  • Substantial progress has been made in the field of pharmacogenomics, with advances in genotyping and sequencing technology, and by the routine collection of DNA samples to study the drug-response phenotype

  • Genetic markers associated with drug toxicity and drug efficacy can be identified by candidate gene, genome-wide association, and next-generation sequencing studies

  • The potential of targeting the right patient with the right drug, and FDA labelling guidance to use pharmacogenetic markers, have provided new impetus to conduct genotype-based randomized clinical trials (RCTs)

  • Prospective approaches using a pharmacogenetic-based strategy with enrichment or adaptive designs are being increasingly used in cardiovascular RCTs

  • Clinical adoption of pharmacogenetics in the practice of cardiovascular medicine will become a reality when a transition has been made from conducting genetic association studies to rigorously performed genotype-based RCTs

Abstract

Consensus practice guidelines and the implementation of clinical therapeutic advances are usually based on the results of large, randomized clinical trials (RCTs). However, RCTs generally inform us on an average treatment effect for a presumably homogeneous population, but therapeutic interventions rarely benefit the entire population targeted. Indeed, multiple RCTs have demonstrated that interindividual variability exists both in drug response and in the development of adverse effects. The field of pharmacogenomics promises to deliver the right drug to the right patient. Substantial progress has been made in this field, with advances in technology, statistical and computational methods, and the use of cell and animal model systems. However, clinical implementation of pharmacogenetic principles has been difficult because RCTs demonstrating benefit are lacking. For patients, the potential benefits of performing such trials include the individualization of therapy to maximize efficacy and minimize adverse effects. These trials would also enable investigators to reduce sample size and hence contain costs for trial sponsors. Multiple ethical, legal, and practical issues need to be considered for the conduct of genotype-based RCTs. Whether pre-emptive genotyping embedded in electronic health records will preclude the need for performing genotype-based RCTs remains to be seen.

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Figure 1: Genotyping and sequencing strategies to identify pharmacogenetic markers associated with drug efficacy (response versus no response) and drug toxicity.
Figure 2: Some possible prospective biomarker-based clinical trial designs.

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Acknowledgements

Supported in part by Mayo Transplant Scholarly Award (N.L.P.), U01 GM61388 (The Pharmacogenetics Research Network). The TAILOR-PCI study is funded in part by the Mayo Clinic Centre for Individualized Medicine, and the Mayo Clinic Division of Cardiology. We thank Ms Luanne Wussow (Mayo Clinic, Rochester, MN, USA) for her assistance with the preparation of this manuscript.

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  1. Division of Cardiovascular Diseases, Department of Internal Medicine, 200 First Street SW, Rochester, 55905, MN, USA

    Naveen L. Pereira & Charanjit S. Rihal

  2. Department of Biomedical Statistics and Informatics, Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, 55905, MN, USA

    Daniel J. Sargent

  3. Peter Munk Cardiac Centre and Heart and Stroke Richard Lewer Centre, University of Toronto, 585 University Avenue, Toronto, M5G 2N2, ON, Canada

    Michael E. Farkouh

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N.L.P. researched data for the article. N.L.P., D.J.S., and C.S.R. provided substantial contributions to discussion of the content. N.L.P., D.J.S., M.E.F., and C.S.R. wrote and reviewed/edited the article before submission.

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Pereira, N., Sargent, D., Farkouh, M. et al. Genotype-based clinical trials in cardiovascular disease. Nat Rev Cardiol 12, 475–487 (2015). https://doi.org/10.1038/nrcardio.2015.64

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