Skip to main content

Advertisement

SpringerLink
Log in

Novel Endpoints for Heart Failure Clinical Trials

  • Clinical Trials (J Butler, Section Editor)
  • Published:
Current Heart Failure Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

With the growing prevalence of heart failure, there is a particular need to develop new pharmacologic treatments that can improve outcomes. While there are several approved therapies for heart failure with reduced ejection fraction, there is currently no approved agent for those with preserved ejection fraction. The current review aimed to explore the utility of alternate endpoints to mortality and hospitalization.

Recent Findings

There is increased interest in the use of alternative endpoints such as functional status and quality of life for heart failure drug development to focus on patients feeling better in addition to improving outcomes. This should ideally be measured using objective as well as subjective parameters.

Summary

While mortality and hospitalization remain important endpoints for clinical trials in heart failure, other more patient-centered outcomes are attractive alternatives yet how to best incorporate these in a trial setting remains to be elucidated.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

  1. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):1810–52. doi:10.1161/CIR.0b013e31829e8807.

    Article  PubMed  Google Scholar 

  2. Jencks SF, Williams MV, Coleman EA. Rehospitalizations among patients in the Medicare fee-for-service program. N Engl J Med. 2009;360(14):1418–28. doi:10.1056/NEJMsa0803563.

    Article  CAS  PubMed  Google Scholar 

  3. Fonarow GC, Stough WG, Abraham WT, Albert NM, Gheorghiade M, Greenberg BH, et al. Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF registry. J Am Coll Cardiol. 2007;50(8):768–77. doi:10.1016/j.jacc.2007.04.064.

    Article  PubMed  Google Scholar 

  4. Yancy CW, Lopatin M, Stevenson LW, De Marco T, Fonarow GC. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) database. J Am Coll Cardiol. 2006;47(1):76–84. doi:10.1016/j.jacc.2005.09.022.

    Article  PubMed  Google Scholar 

  5. Steinberg BA, Zhao X, Heidenreich PA, Peterson ED, Bhatt DL, Cannon CP, et al. Trends in patients hospitalized with heart failure and preserved left ventricular ejection fraction: prevalence, therapies, and outcomes. Circulation. 2012;126(1):65–75. doi:10.1161/circulationaha.111.080770.

    Article  PubMed  Google Scholar 

  6. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355(3):251–9. doi:10.1056/NEJMoa052256.

    Article  CAS  PubMed  Google Scholar 

  7. Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med. 2006;355(3):260–9. doi:10.1056/NEJMoa051530.

    Article  CAS  PubMed  Google Scholar 

  8. Holland DJ, Kumbhani DJ, Ahmed SH, Marwick TH. Effects of treatment on exercise tolerance, cardiac function, and mortality in heart failure with preserved ejection fraction. A meta-analysis. J Am Coll Cardiol. 2011;57(16):1676–86. doi:10.1016/j.jacc.2010.10.057.

    Article  PubMed  Google Scholar 

  9. Agarwal V, Briasoulis A, Messerli FH. Effects of renin-angiotensin system blockade on mortality and hospitalization in heart failure with preserved ejection fraction. Heart Fail Rev. 2013;18:429–37. doi:10.1007/s10741-012-9329-8.

    Article  CAS  PubMed  Google Scholar 

  10. Felker GM, Maisel AS. A global rank end point for clinical trials in acute heart failure. Circulation Heart failure. 2010;3(5):643–6. doi:10.1161/circheartfailure.109.926030.

    Article  PubMed  Google Scholar 

  11. Zanolla L, Zardini P. Selection of endpoints for heart failure clinical trials. Eur J Heart Fail. 2003;5(6):717–23.

    Article  PubMed  Google Scholar 

  12. Henkel DM, Redfield MM, Weston SA, Gerber Y, Roger VL. Death in heart failure: a community perspective. Circulation Heart failure. 2008;1(2):91–7. doi:10.1161/circheartfailure.107.743146.

    Article  PubMed  PubMed Central  Google Scholar 

  13. •• Butler J, Hamo CE, Udelson JE, Pitt B, Yancy C, Shah SJ et al. Exploring new endpoints for patients with heart failure with preserved ejection fraction. Circ Heart Fail. 2016;9:e003358. doi:10.1161/circheartfailure.116.003358. Proceedings from a meeting between clinicians, industry, and regulatory agencies to discuss the need for alternative endpoints in HFpEF clinical trials.

  14. Zannad F, Garcia AA, Anker SD, Armstrong PW, Calvo G, Cleland JG, et al. Clinical outcome endpoints in heart failure trials: a European Society of Cardiology Heart Failure Association consensus document. Eur J Heart Fail. 2013;15(10):1082–94. doi:10.1093/eurjhf/hft095.

    Article  PubMed  Google Scholar 

  15. Krumholz HM, Lin Z, Keenan PS, Chen J, Ross JS, Drye EE, et al. Relationship between hospital readmission and mortality rates for patients hospitalized with acute myocardial infarction, heart failure, or pneumonia. JAMA. 2013;309(6):587–93. doi:10.1001/jama.2013.333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. • US Government Publishing Office. Subpart H: accelerated approval of new drugs for serious or life-threatening illnesses. 2017 [available from: http://www.Ecfr.Gov/Cgi-bin/text-idx?SID=56d1f549ca3b4ce80ae9f17bffa625f2&mc=true&node=sp21.5.314.H&rgn=div6, accessed April 5, 2017. Guidelines from the FDA on accelerated drug approval.

  17. • EMA. European Medicines Agency Adaptive Pathways 2015 [Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000601.jsp, Accessed April 5, 2017. Guidelines from the European Medicine's Agency on Adaptive Pathway approach to drug development.

  18. O'Brien PC. Procedures for comparing samples with multiple endpoints. Biometrics. 1984;40(4):1079–87.

    Article  PubMed  Google Scholar 

  19. Finkelstein DM, Schoenfeld DA. Combining mortality and longitudinal measures in clinical trials. Stat Med. 1999;18(11):1341–54.

    Article  CAS  PubMed  Google Scholar 

  20. • Anker SD, Schroeder S, Atar D, Bax JJ, Ceconi C, Cowie MR, et al. Traditional and new composite endpoints in heart failure clinical trials: facilitating comprehensive efficacy assessments and improving trial efficiency. Eur J heart Fail. 2016;18(5):482–9. Discussion of novel composite endpoints for heart failure clinical trials.

    Article  PubMed  Google Scholar 

  21. Bohm M, Swedberg K, Komajda M, Borer JS, Ford I, Dubost-Brama A, et al. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet (Lond, Engl). 2010;376(9744):886–94. doi:10.1016/s0140-6736(10)61259-7.

    Article  Google Scholar 

  22. Drazner MH, Rame JE, Stevenson LW, Dries DL. Prognostic importance of elevated jugular venous pressure and a third heart sound in patients with heart failure. N Engl J Med. 2001;345(8):574–81. doi:10.1056/NEJMoa010641.

    Article  CAS  PubMed  Google Scholar 

  23. Lucas C, Johnson W, Hamilton MA, Fonarow GC, Woo MA, Flavell CM, et al. Freedom from congestion predicts good survival despite previous class IV symptoms of heart failure. Am Heart J. 2000;140(6):840–7. doi:10.1067/mhj.2000.110933.

    Article  CAS  PubMed  Google Scholar 

  24. Cooper HA, Dries DL, Davis CE, Shen YL, Domanski MJ. Diuretics and risk of arrhythmic death in patients with left ventricular dysfunction. Circulation. 1999;100(12):1311–5.

    Article  CAS  PubMed  Google Scholar 

  25. Fonarow GC, Peacock WF, Phillips CO, Givertz MM, Lopatin M. Admission B-type natriuretic peptide levels and in-hospital mortality in acute decompensated heart failure. J Am Coll Cardiol. 2007;49(19):1943–50. doi:10.1016/j.jacc.2007.02.037.

    Article  CAS  PubMed  Google Scholar 

  26. Maisel A, Mueller C, Adams K Jr, Anker SD, Aspromonte N, Cleland JG, et al. State of the art: using natriuretic peptide levels in clinical practice. Eur J Heart Fail. 2008;10(9):824–39. doi:10.1016/j.ejheart.2008.07.014.

    Article  CAS  PubMed  Google Scholar 

  27. Sharma R, Anker SD. The 6-minute walk test and prognosis in chronic heart failure—the available evidence. Eur Heart J. 2001;22(6):445–8. doi:10.1053/euhj.2000.2451.

    Article  CAS  PubMed  Google Scholar 

  28. Dries DL, Exner DV, Domanski MJ, Greenberg B, Stevenson LW. The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction. J Am Coll Cardiol. 2000;35(3):681–9.

    Article  CAS  PubMed  Google Scholar 

  29. Hillege HL, Girbes AR, de Kam PJ, Boomsma F, de Zeeuw D, Charlesworth A, et al. Renal function, neurohormonal activation, and survival in patients with chronic heart failure. Circulation. 2000;102(2):203–10.

    Article  CAS  PubMed  Google Scholar 

  30. Horwich TB, Patel J, MacLellan WR, Fonarow GC. Cardiac troponin I is associated with impaired hemodynamics, progressive left ventricular dysfunction, and increased mortality rates in advanced heart failure. Circulation. 2003;108(7):833–8. doi:10.1161/01.cir.0000084543.79097.34.

    Article  CAS  PubMed  Google Scholar 

  31. Latini R, Masson S, Anand IS, Missov E, Carlson M, Vago T, et al. Prognostic value of very low plasma concentrations of troponin T in patients with stable chronic heart failure. Circulation. 2007;116(11):1242–9. doi:10.1161/circulationaha.106.655076.

    Article  CAS  PubMed  Google Scholar 

  32. Peacock WF, De Marco T, Fonarow GC, Diercks D, Wynne J, Apple FS, et al. Cardiac troponin and outcome in acute heart failure. N Engl J Med. 2008;358(20):2117–26. doi:10.1056/NEJMoa0706824.

    Article  CAS  PubMed  Google Scholar 

  33. Chen J, Johnson G, Hellkamp AS, Anderson J, Mark DB, Lee KL, et al. Rapid-rate nonsustained ventricular tachycardia found on implantable cardioverter-defibrillator interrogation: relationship to outcomes in the SCD-HeFT (Sudden Cardiac Death in Heart Failure trial). J Am Coll Cardiol. 2013;61(21):2161–8. doi:10.1016/j.jacc.2013.02.046.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Doval HC, Nul DR, Grancelli HO, Varini SD, Soifer S, Corrado G, et al. Nonsustained ventricular tachycardia in severe heart failure. Independent marker of increased mortality due to sudden death. GESICA-GEMA investigators. Circulation. 1996;94(12):3198–203.

    Article  CAS  PubMed  Google Scholar 

  35. Poole JE, Johnson GW, Hellkamp AS, Anderson J, Callans DJ, Raitt MH, et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med. 2008;359(10):1009–17. doi:10.1056/NEJMoa071098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Daubert JP, Zareba W, Cannom DS, McNitt S, Rosero SZ, Wang P, et al. Inappropriate implantable cardioverter-defibrillator shocks in MADIT II: frequency, mechanisms, predictors, and survival impact. J Am Coll Cardiol. 2008;51(14):1357–65. doi:10.1016/j.jacc.2007.09.073.

    Article  PubMed  Google Scholar 

  37. Francis DP, Shamim W, Davies LC, Piepoli MF, Ponikowski P, Anker SD, et al. Cardiopulmonary exercise testing for prognosis in chronic heart failure: continuous and independent prognostic value from VE/VCO(2)slope and peak VO(2). Eur Heart J. 2000;21(2):154–61. doi:10.1053/euhj.1999.1863.

    Article  CAS  PubMed  Google Scholar 

  38. Guyatt GH, Sullivan MJ, Thompson PJ, Fallen EL, Pugsley SO, Taylor DW, et al. The 6-minute walk: a new measure of exercise capacity in patients with chronic heart failure. Can Med Assoc J. 1985;132(8):919–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Cahalin LP, Mathier MA, Semigran MJ, Dec GW, DiSalvo TG. The six-minute walk test predicts peak oxygen uptake and survival in patients with advanced heart failure. Chest. 1996;110(2):325–32.

    Article  CAS  PubMed  Google Scholar 

  40. Forleo GB, Santini L, Campoli M, Malavasi M, Scaccia A, Menichelli M, et al. Long-term monitoring of respiratory rate in patients with heart failure: the Multiparametric Heart Failure Evaluation in Implantable Cardioverter-Defibrillator Patients (MULTITUDE-HF) study. J Interv Card Electrophysiol Int J Arrhythm Pacing. 2015;43(2):135–44. doi:10.1007/s10840-015-0007-3.

    Article  Google Scholar 

  41. Goetze S, Zhang Y, An Q, Averina V, Lambiase P, Schilling R, et al. Ambulatory respiratory rate trends identify patients at higher risk of worsening heart failure in implantable cardioverter defibrillator and biventricular device recipients: a novel ambulatory parameter to optimize heart failure management. J Interv Card Electrophysiol Int J Arrhythm Pacing. 2015;43(1):21–9. doi:10.1007/s10840-015-9983-6.

    Article  Google Scholar 

  42. Small RS, Wickemeyer W, Germany R, Hoppe B, Andrulli J, Brady PA, et al. Changes in intrathoracic impedance are associated with subsequent risk of hospitalizations for acute decompensated heart failure: clinical utility of implanted device monitoring without a patient alert. J Card Fail. 2009;15(6):475–81. doi:10.1016/j.cardfail.2009.01.012.

    Article  PubMed  Google Scholar 

  43. Abraham WT, Adamson PB, Bourge RC, Aaron MF, Costanzo MR, Stevenson LW, et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet (Lond, Engl). 2011;377(9766):658–66. doi:10.1016/s0140-6736(11)60101-3.

    Article  Google Scholar 

  44. Abraham WT, Stough WG, Pina IL, Linde C, Borer JS, De Ferrari GM, et al. Trials of implantable monitoring devices in heart failure: which design is optimal? Nat Rev Cardiol. 2014;11(10):576–85. doi:10.1038/nrcardio.2014.114.

    Article  PubMed  Google Scholar 

  45. Redfield MM, Anstrom KJ, Levine JA, Koepp GA, Borlaug BA, Chen HH, et al. Isosorbide mononitrate in heart failure with preserved ejection fraction. N Engl J Med. 2015;373:2314–24. doi:10.1056/NEJMoa1510774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Piette JD, List J, Rana GK, Townsend W, Striplin D, Heisler M. Mobile health devices as tools for worldwide cardiovascular risk reduction and disease management. Circulation. 2015;132(21):2012–27. doi:10.1161/circulationaha.114.008723.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Rector TS, Kubo SH, Cohn JN. Validity of the Minnesota Living with Heart Failure questionnaire as a measure of therapeutic response to enalapril or placebo. Am J Cardiol. 1993;71(12):1106–7.

    Article  CAS  PubMed  Google Scholar 

  48. Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart failure. J Am Coll Cardiol. 2000;35(5):1245–55.

    Article  CAS  PubMed  Google Scholar 

  49. Allen LA, Gheorghiade M, Reid KJ, Dunlay SM, Chan PS, Hauptman PJ, et al. Identifying patients hospitalized with heart failure at risk for unfavorable future quality of life. Circ Cardiovasc Qual Outcomes. 2011;4(4):389–98. doi:10.1161/circoutcomes.110.958009.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Belardinelli R, Capestro F, Misiani A, Scipione P, Georgiou D. Moderate exercise training improves functional capacity, quality of life, and endothelium-dependent vasodilation in chronic heart failure patients with implantable cardioverter defibrillators and cardiac resynchronization therapy. Eur J Cardiovasc Prev Rehabil Off J Eur Soc Cardiol Working Groups Epidemiol Prev Card Rehabil Exerc Physiol. 2006;13(5):818–25. doi:10.1097/01.hjr.0000230104.93771.7d.

    Google Scholar 

  51. Nazarian S, Maisel WH, Miles JS, Tsang S, Stevenson LW, Stevenson WG. Impact of implantable cardioverter defibrillators on survival and recurrent hospitalization in advanced heart failure. Am Heart J. 2005;150(5):955–60. doi:10.1016/j.ahj.2005.01.012.

    Article  PubMed  Google Scholar 

  52. Bayram M, De Luca L, Massie MB, Gheorghiade M. Reassessment of dobutamine, dopamine, and milrinone in the management of acute heart failure syndromes. Am J Cardiol. 2005;96(6a):47g–58g. doi:10.1016/j.amjcard.2005.07.021.

    Article  CAS  PubMed  Google Scholar 

  53. Teerlink JR, Cotter G, Davison BA, Felker GM, Filippatos G, Greenberg BH, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet (Lond, Engl). 2013;381(9860):29–39. doi:10.1016/s0140-6736(12)61855-8.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Cardiology, Stony Brook University, T-16, Room 080, Stony Brook, NY, 11794, USA

    Carine E. Hamo & Javed Butler

  2. Center for Cardiovascular Innovation, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Mihai Gheorghiade

Authors
  1. Carine E. Hamo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mihai Gheorghiade
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Javed Butler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Javed Butler.

Ethics declarations

Conflict of Interest

Carine E. Hamo declares no conflict of interest.

Javed Butler has been a consultant to Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Relypsa, ZS Pharma, and Janssen.

Mihai Gheorghiade declares potential conflicts from Bayer, other from Novartis, other from J&J, other from cardiocell, and Stealth BioTherapeutics.

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.

Additional information

This article is part of the Topical Collection on Clinical Trials

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hamo, C.E., Gheorghiade, M. & Butler, J. Novel Endpoints for Heart Failure Clinical Trials. Curr Heart Fail Rep 14, 210–216 (2017). https://doi.org/10.1007/s11897-017-0334-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11897-017-0334-z

Keywords

Search

Navigation