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Designing Future Clinical Trials in Heart Failure With Preserved Ejection Fraction: Lessons From TOPCAT

  • Clinical Trials (J Butler, Section Editor)
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Abstract

Purpose of Review

Spironolactone did not demonstrate benefit with respect to the primary composite endpoint in the global TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial in patients with chronic heart failure with preserved ejection fraction (HFpEF). We identify key lessons from the TOPCAT experience that can be applied to future HFpEF trials.

Recent Findings

Subsequent analyses of TOPCAT have revealed marked regional heterogeneity in patient profiles, event rates, drug adherence, and treatment effects. Significant regional variation may impact the success of global HFpEF trials. Given potential benefits in the Americas subgroup in TOPCAT, mineralocorticoid receptor antagonists can be considered in appropriately selected patients with HFpEF to reduce risk of heart failure hospitalization. A planned registry-based trial should provide additional evidence regarding the role of spironolactone in HFpEF.

Summary

The overall design, execution, and study oversight of TOPCAT have provided key insights into the conduct of future HFpEF trials.

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References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Ambrosy AP, Fonarow GC, Butler J, Chioncel O, Greene SJ, Vaduganathan M, et al. The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. J Am Coll Cardiol. 2014;63(12):1123–33. doi:10.1016/j.jacc.2013.11.053.

    Article  PubMed  Google Scholar 

  2. Edelmann F, Tomaschitz A, Wachter R, Gelbrich G, Knoke M, Dungen HD, et al. Serum aldosterone and its relationship to left ventricular structure and geometry in patients with preserved left ventricular ejection fraction. Eur Heart J. 2012;33(2):203–12. doi:10.1093/eurheartj/ehr292.

    Article  CAS  PubMed  Google Scholar 

  3. Weber KT. Aldosterone in congestive heart failure. N Engl J Med. 2001;345(23):1689–97. doi:10.1056/NEJMra000050.

    Article  CAS  PubMed  Google Scholar 

  4. •• Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2017; doi:10.1016/j.jacc.2017.04.025. The updated 2017 ACC/AHA/HFSA clinical practice guidelines for the management of patients with HF.

  5. Edelmann F, Wachter R, Schmidt AG, Kraigher-Krainer E, Colantonio C, Kamke W, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA. 2013;309(8):781–91. doi:10.1001/jama.2013.905.

    Article  CAS  PubMed  Google Scholar 

  6. Deswal A, Richardson P, Bozkurt B, Mann DL. Results of the randomized aldosterone antagonism in heart failure with preserved ejection fraction trial (RAAM-PEF). J Card Fail. 2011;17(8):634–42. doi:10.1016/j.cardfail.2011.04.007.

    Article  PubMed  Google Scholar 

  7. Pandey A, Garg S, Matulevicius SA, Shah AM, Garg J, Drazner MH, et al. Effect of mineralocorticoid receptor antagonists on cardiac structure and function in patients with diastolic dysfunction and heart failure with preserved ejection fraction: a meta-analysis and systematic review. J Am Heart Assoc. 2015;4(10):e002137. doi:10.1161/JAHA.115.002137.

    Article  PubMed  PubMed Central  Google Scholar 

  8. •• Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370(15):1383–92. doi:10.1056/NEJMoa1313731. The TOPCAT trial, a phase 3, international, double-blind, placebo-controlled trial of spironolactone in patients with HFpEF.

    Article  CAS  PubMed  Google Scholar 

  9. •• Pfeffer MA, Claggett B, Assmann SF, Boineau R, Anand IS, Clausell N, et al. Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. Circulation. 2015;131(1):34–42. doi:10.1161/CIRCULATIONAHA.114.013255. The pre-specified region-specific subgroup analysis of the TOPCAT trial demonstrated marked global heterogeneity in clinical profiles, event rates, and response to spironolactone.

    Article  CAS  PubMed  Google Scholar 

  10. de Denus S, O’Meara E, Desai AS, Claggett B, Lewis EF, Leclair G, et al. Spironolactone metabolites in TOPCAT—new insights into regional variation. N Engl J Med. 2017;376(17):1690–2. doi:10.1056/NEJMc1612601.

    Article  PubMed  Google Scholar 

  11. •• Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure With Preserved Ejection Fraction (SPIRRIT). https://clinicaltrials.gov/ct2/show/NCT02901184. Accessed May 21 2017. The SPIRRIT trial, a planned phase 4 registry-based RCT that will evaluate the efficacy of spironolactone in patients with HFpEF.

  12. Ferreira JP, Girerd N, Rossignol P, Zannad F. Geographic differences in heart failure trials. Eur J Heart Fail. 2015;17(9):893–905. doi:10.1002/ejhf.326.

    Article  PubMed  Google Scholar 

  13. Bristow MR, Enciso JS, Gersh BJ, Grady C, Rice MM, Singh S, et al. Detection and management of geographic disparities in the TOPCAT trial: lessons learned and derivative recommendations. JACC Basic Transl Sci. 2016;1(3):180–9. doi:10.1016/j.jacbts.2016.03.001.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Greene SJ, Gheorghiade M. Same protocol, different continents, different patients: should we continue to conduct global heart failure trials? Eur J Heart Fail. 2015;17(9):875–8. doi:10.1002/ejhf.335.

    Article  PubMed  Google Scholar 

  15. Vaduganathan M, Butler J, Gheorghiade M. Transforming drug development in heart failure: navigating the regulatory crossroads. Circ Heart Fail. 2016;9(10) doi:10.1161/CIRCHEARTFAILURE.116.003192.

  16. Gheorghiade M, Vaduganathan M, Greene SJ, Mentz RJ, Adams KF Jr, Anker SD, et al. Site selection in global clinical trials in patients hospitalized for heart failure: perceived problems and potential solutions. Heart Fail Rev. 2014;19(2):135–52. doi:10.1007/s10741-012-9361-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Harinstein ME, Butler J, Greene SJ, Fonarow GC, Stockbridge NL, O’Connor CM, et al. Site selection for heart failure clinical trials in the USA. Heart Fail Rev. 2015;20(4):375–83. doi:10.1007/s10741-015-9473-z.

    Article  CAS  PubMed  Google Scholar 

  18. Kelly JP, Mentz RJ, Mebazaa A, Voors AA, Butler J, Roessig L, et al. Patient selection in heart failure with preserved ejection fraction clinical trials. J Am Coll Cardiol. 2015;65(16):1668–82. doi:10.1016/j.jacc.2015.03.043.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Anjan VY, Loftus TM, Burke MA, Akhter N, Fonarow GC, Gheorghiade M, et al. Prevalence, clinical phenotype, and outcomes associated with normal B-type natriuretic peptide levels in heart failure with preserved ejection fraction. Am J Cardiol. 2012;110(6):870–6. doi:10.1016/j.amjcard.2012.05.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Greene SJ, Fonarow GC, Solomon SD, Subacius HP, Ambrosy AP, Vaduganathan M, et al. Influence of atrial fibrillation on post-discharge natriuretic peptide trajectory and clinical outcomes among patients hospitalized for heart failure: insights from the ASTRONAUT trial. Eur J Heart Fail. 2017;19(4):552–62. doi:10.1002/ejhf.674.

    Article  CAS  PubMed  Google Scholar 

  21. Patel RB, Vaduganathan M, Shah SJ, Butler J. Atrial fibrillation in heart failure with preserved ejection fraction: insights into mechanisms and therapeutics. Pharmacol Ther. 2016; doi:10.1016/j.pharmthera.2016.10.019.

  22. Vaduganathan M, Michel A, Hall K, Mulligan C, Nodari S, Shah SJ, et al. Spectrum of epidemiological and clinical findings in patients with heart failure with preserved ejection fraction stratified by study design: a systematic review. Eur J Heart Fail. 2016;18(1):54–65. doi:10.1002/ejhf.442.

    Article  PubMed  Google Scholar 

  23. Anand IS, Claggett B, Liu J, Shah AM, Rector TS, Shah SJ, et al. Interaction between spironolactone and natriuretic peptides in patients with heart failure and preserved ejection fraction: from the TOPCAT trial. JACC Heart Fail. 2017;5(4):241–52. doi:10.1016/j.jchf.2016.11.015.

    Article  PubMed  Google Scholar 

  24. D’Elia E, Vaduganathan M, Gori M, Gavazzi A, Butler J, Senni M. Role of biomarkers in cardiac structure phenotyping in heart failure with preserved ejection fraction: critical appraisal and practical use. Eur J Heart Fail. 2015;17(12):1231–9. doi:10.1002/ejhf.430.

    Article  PubMed  Google Scholar 

  25. Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail. 2010;3(5):588–95. doi:10.1161/CIRCHEARTFAILURE.109.930701.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Kraigher-Krainer E, Shah AM, Gupta DK, Santos A, Claggett B, Pieske B, et al. Impaired systolic function by strain imaging in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2014;63(5):447–56. doi:10.1016/j.jacc.2013.09.052.

    Article  PubMed  Google Scholar 

  27. Shah SJ, Katz DH, Selvaraj S, Burke MA, Yancy CW, Gheorghiade M, et al. Phenomapping for novel classification of heart failure with preserved ejection fraction. Circulation. 2015;131(3):269–79. doi:10.1161/CIRCULATIONAHA.114.010637.

    Article  PubMed  Google Scholar 

  28. Vaduganathan M, Patel RB, Butler J, Metra M. Integrating electronic health records into the study of heart failure: promises and pitfalls. Eur J Heart Fail. 2017 (in press).

  29. Blecker S, Katz SD, Horwitz LI, Kuperman G, Park H, Gold A, et al. Comparison of approaches for heart failure case identification from electronic health record data. JAMA Cardiol. 2016;1(9):1014–20. doi:10.1001/jamacardio.2016.3236.

    Article  PubMed  Google Scholar 

  30. Jonnalagadda SR Adupa AK, Garg RP, Corona-Cox J, Shah SJ. Text mining of the electronic health record: an information extraction approach for the automated identification and subphenotyping of HFpEF patients for clinical trials. J Cardiovasc Transl Res. 2017 (in press).

  31. Bhatt DL, Mehta C. Adaptive designs for clinical trials. N Engl J Med. 2016;375(1):65–74. doi:10.1056/NEJMra1510061.

    Article  PubMed  Google Scholar 

  32. Pfeffer MA, Braunwald E. Treatment of heart failure with preserved ejection fraction: reflections on its treatment with an aldosterone antagonist. JAMA Cardiol. 2016;1(1):7–8. doi:10.1001/jamacardio.2015.0356.

    Article  PubMed  Google Scholar 

  33. Mitter SS, Shah SJ. Spironolactone for management of heart failure with preserved ejection fraction: whither to after TOPCAT? Curr Atheroscler Rep. 2015;17(11):64. doi:10.1007/s11883-015-0541-6.

    Article  PubMed  Google Scholar 

  34. ACCESS CV, Patel MR, Armstrong PW, Bhatt DL, Braunwald E, Camm AJ, et al. Sharing data from cardiovascular clinical trials—a proposal. N Engl J Med. 2016;375(5):407–9. doi:10.1056/NEJMp1605260.

    Article  Google Scholar 

  35. Taichman DB, Backus J, Baethge C, Bauchner H, de Leeuw PW, Drazen JM, et al. Sharing clinical trial data—a proposal from the International Committee of Medical Journal Editors. N Engl J Med. 2016;374(4):384–6. doi:10.1056/NEJMe1515172.

    Article  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Ravi B. Patel & Sanjiv J. Shah

  2. Ahmanson-UCLA Cardiomyopathy Center, University of California Los Angeles, Los Angeles, CA, USA

    Gregg C. Fonarow

  3. Division of Cardiology, Stony Brook University, Stony Brook, NY, USA

    Javed Butler

  4. Brigham and Women’s Heart & Vascular Center and Harvard Medical School, 75 Francis St, Boston, MA, USA

    Muthiah Vaduganathan

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  1. Ravi B. Patel
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  4. Javed Butler
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Correspondence to Muthiah Vaduganathan.

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Conflict of Interest

Ravi B. Patel and Muthiah Vaduganathan declare no conflicts of interest.

Sanjiv J. Shah reports receiving research support from the National Institutes of Health (R01 HL107577, R01 HL127028), the American Heart Association (16SFRN28780016, 15CVGPSD27260148), Actelion, AstraZeneca, Corvia, and Novartis and serving as a consultant for Actelion, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiora, Eisai, Gilead, Ironwood, Merck, MyoKardia, Novartis, Sanofi, and United Therapeutics.

Gregg C. Fonarow reports significant consulting for Novartis and modest consulting for Amgen, Janssen, Novartis, Medtronic, and St. Jude Medical; Dr. Fonarow holds the Eliot Corday Chair of Cardiovascular Medicine at UCLA and is also supported by the Ahmanson Foundation (Los Angeles, CA).

Javed Butler has received research support from the NIH and European Union, and has been a consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Novartis, Relypsa, ZS Pharma, Medtronic, Merck, and CVRx.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Clinical Trials

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Patel, R.B., Shah, S.J., Fonarow, G.C. et al. Designing Future Clinical Trials in Heart Failure With Preserved Ejection Fraction: Lessons From TOPCAT. Curr Heart Fail Rep 14, 217–222 (2017). https://doi.org/10.1007/s11897-017-0336-x

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  • DOI: https://doi.org/10.1007/s11897-017-0336-x

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