Advertisement

Impact of eplerenone on major cardiovascular outcomes in patients with systolic heart failure according to baseline heart rate

  • Ken Lee ChinEmail author
  • Timothy Collier
  • Stuart Pocock
  • Bertram Pitt
  • John J. V. McMurray
  • Dirk J. van Veldhuisen
  • Karl Swedberg
  • John Vincent
  • Faiez Zannad
  • Danny Liew
Original Paper
  • 143 Downloads

Abstract

Background

Increased resting heart rate is a risk factor for cardiovascular mortality and morbidity. Mineralocorticoid receptor antagonists (MRAs) have been shown to improve cardiac sympathetic nerve activity, reduce heart rate and attenuate left ventricular remodelling. Whether or not the beneficial effects of MRA are affected by heart rate in heart failure patients with reduced ejection fraction (HFREF) is unclear.

Methods

We undertook a secondary analysis of data from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure study to assess if clinical outcomes, as well as the efficacy of eplerenone, varied according to heart rate at baseline.

Results

High resting heart rate of 80 bpm and above predisposed patients to greater risk of all outcomes in the trial, regardless of treatment allocation. The beneficial effects of eplerenone were observed across all categories of heart rate. Eplerenone reduced the risk of primary endpoint, the composite of cardiovascular death and hospitalisation for heart failure, by 30% (aHR 0.70; 95% CI 0.54–0.91) in subjects with heart rate ≥ 80 bpm, and by 48% (aHR 0.52; 95% CI 0.33–0.81) in subjects with heart rate ≤ 60 bpm. Eplerenone also reduced the risks of hospitalisation for heart failure, cardiovascular deaths and all-cause deaths independently of baseline heart rate.

Conclusions

Baseline heart rate appears to be an important predictor of major clinical outcome events in patients with HFREF, as has been previously reported. The benefits of eplerenone were preserved across all categories of baseline heart rate, without observed heterogeneity in the responses.

Keywords

ClinicalTrials.gov identifier: NCT00232180 Heart rate Aldosterone antagonists Aldosterone Heart failure 

Notes

Acknowledgements

The late Professor Henry Krum made substantial contributions to the study.

Funding

The EMPHASIS-HF Study was sponsored by Pfizer.

Compliance with ethical standards

Conflict of interest

Drs Pitt, McMurray, Swedberg, van Veldhuisen, Pocock, and Zannad were members of the EMPHASIS-HF Writing Committee and report having received fees and travel support in the past from the study sponsor, Pfizer Inc, for participation in and traveling to meetings of the committee. Dr Vincent is currently employed by Pfizer and owns stock in Pfizer Inc, the makers of eplerenone. Dr Pitt reports receiving fees for serving on the board of Novartis, consulting fees from Takeda, AstraZeneca, Boehringer Ingelheim, GE Healthcare, Relypsa, BG Medicine, Nile Therapeutics, Merck, Forest Laboratories, and Novartis, grant support from Forest Laboratories and Novartis, and stock options from Relypsa, BG Medicine, Nile Therapeutics, and Aurasenc and that his institution receives grant support from Forest Laboratories on his behalf and he and his institution receive grant support from Bayer. Dr Swedberg has received research support from Pfizer, Amgen, Novartis, and Servier. Dr Pocock reports receiving consulting fees from Servier, Amgen, AstraZeneca, and Novartis and that his institution receives grants from Servier and AstraZeneca on his behalf. Dr Zannad reports receiving fees for serving on the board of Boston Scientific, consulting fees from Novartis, Takeda, AstraZeneca, Boehringer Ingelheim, GE Healthcare, Relypsa, Servier, Boston Scientific, Bayer, Johnson & Johnson, and Resmed, and speaker’s fees from Pfizer and AstraZeneca and that his institution receives grant support from BG Medicine and Roche Diagnostics on his behalf. Dr Liew reports receiving grants and honoraria from Abbvie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Novartis, Pfizer, Sanofi and Shire. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

References

  1. 1.
    Custodis F, Reil J-C, Laufs U, Böhm M (2013) Heart rate: a global target for cardiovascular disease and therapy along the cardiovascular disease continuum. J Cardiol 62:183–187CrossRefGoogle Scholar
  2. 2.
    Komajda M (2015) Heart rate in chronic heart failure: an overlooked risk factor. Eur Heart J 36:648–649CrossRefGoogle Scholar
  3. 3.
    Fox K, Borer JS, Camm AJ, Danchin N, Ferrari R, Sendon JLL, Steg PG, Tardif J-C, Tavazzi L, Tendera M, for the Heart Rate Working Group (2007) Resting heart rate in cardiovascular disease. J Am Coll Cardiol 50:823–830CrossRefGoogle Scholar
  4. 4.
    Custodis F, Schirmer SH, Baumhäkel M, Heusch G, Böhm M, Laufs U (2010) Vascular pathophysiology in response to increased heart rate. J Am Coll Cardiol 56:1973–1983CrossRefGoogle Scholar
  5. 5.
    Castagno D, Skali H, Takeuchi M, Swedberg K, Yusuf S, Granger CB, Michelson EL, Pfeffer MA, McMurray JJV, Solomon SD, for the CHARM Investigators (2012) Association of heart rate and outcomes in a broad spectrum of patients with chronic heart failure: results from the CHARM (Candesartan in heart failure: assessment of reduction in mortality and morbidity) program. J Am Coll Cardiol 59:1785–1795CrossRefGoogle Scholar
  6. 6.
    Kotecha D, Flather MD, Altman DG, Holmes J, Rosano G, Wikstrand J, Packer M, Coats AJS, Manzano L, Böhm M, van Veldhuisen DJ, Andersson B, Wedel H, von Lueder TG, Rigby AS, Hjalmarson Å, Kjekshus J, Cleland JGF, on behalf of the Beta-Blockers in Heart Failure Collaborative Group (2017) Heart rate and rhythm and the benefit of beta-blockers in patients with heart failure. J Am Coll Cardiol 69:2885–2896CrossRefGoogle Scholar
  7. 7.
    Böhm M, Swedberg K, Komajda M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L, on Behalf of the SHIFT Investigators (2010) 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 376:886–894CrossRefGoogle Scholar
  8. 8.
    Struthers AD (2002) Aldosterone: cardiovascular assault. Am Heart J 144:S2–S7CrossRefGoogle Scholar
  9. 9.
    Davies JI, Witham MD, Struthers AD (2005) Autonomic effects of spironolactone and MR blockers in heart failure. Heart Fail Rev 10:63–69CrossRefGoogle Scholar
  10. 10.
    Yee K, Struthers AD (1998) Aldosterone blunts the baroreflex response in man. Clin Sci (Lond) 95:687–692CrossRefGoogle Scholar
  11. 11.
    Kasama S, Toyama T, Kumakura H, Takayama Y, Ichikawa S, Suzuki T, Kurabayashi M (2003) Effect of spironolactone on cardiac sympathetic nerve activity and left ventricular remodeling in patients with dilated cardiomyopathy. J Am Coll Cardiol 41:574–581CrossRefGoogle Scholar
  12. 12.
    MacFadyen RJ, Barr CS, Struthers AD (1997) Aldosterone blockade reduces vascular collagen turnover, improves heart rate variability and reduces early morning rise in heart rate in heart failure patients. Cardiovasc Res 35:30–34CrossRefGoogle Scholar
  13. 13.
    Zannad F, McMurray JJV, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock S, Pitt B, for the EMPHASIS-HF Study Group (2011) Eplerenone in patients with systolic heart Failure and mild symptoms. N Engl J Med 364:11–21CrossRefGoogle Scholar
  14. 14.
    Zannad F, McMurray JJV, Drexler H, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pitt B (2010) Rationale and design of the eplerenone in mild patients hospitalization and survival study in heart failure (EMPHASIS-HF). Eur J Heart Fail 12:617–622CrossRefGoogle Scholar
  15. 15.
    Rawles JM (1990) What is meant by a “controlled” ventricular rate in atrial fibrillation? Br Heart J 63:157–161CrossRefGoogle Scholar
  16. 16.
    Atwood JE, Myers J, Sullivan M, Forbes S, Friis R, Pewen W, Callaham P, Hall P, Froelicher V (1988) Maximal exercise testing and gas exchange in patients with chronic atrial fibrillation. J Am Coll Cardiol 11:508–513CrossRefGoogle Scholar
  17. 17.
    Floras JS, Ponikowski P (2015) The sympathetic/parasympathetic imbalance in heart failure with reduced ejection fraction. Eur Heart J 36:1974–1982CrossRefGoogle Scholar
  18. 18.
    Böhm M, Perez A-C, Jhund PS, Reil JC, Komajda M, Zile MR, McKelvie RS, Anand IS, Massie BM, Carson PE, McMurray JJV, on behalf of the I-Preserve Committees and Investigators (2014) Relationship between heart rate and mortality and morbidity in the irbesartan patients with heart failure and preserved systolic function trial (I-Preserve). Eur J Heart Fail 16:778–787CrossRefGoogle Scholar
  19. 19.
    Kaye D, Lefkovits J, Jennings GL, Bergin P, Broughton A, Esler MD (1995) Adverse consequences of high sympathetic nervous activity in the failing human heart. J Am Coll Cardiol 26:1257–1263CrossRefGoogle Scholar
  20. 20.
    Greene SJ, Vaduganathan M, Wilcox JE, Harinstein ME, Maggioni AP, Subacius H, Zannad F, Konstam MA, Chioncel O, Yancy CW, Swedberg K, Butler J, Bonow RO, Gheorghiade M, on behalf of the EVEREST Trial Investigators (2013) The prognostic significance of heart rate in patients hospitalized for heart failure with reduced ejection fraction in sinus rhythm: insights from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: outcome Study With Tolvaptan) trial. J Am Coll Cardiol HF 1:488–496Google Scholar
  21. 21.
    Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L, on behalf of the SHIFT Investigators (2010) Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 376:875–885CrossRefGoogle Scholar
  22. 22.
    Vazir A, Claggett B, Jhund P, Castagno D, Skali H, Yusuf S, Swedberg K, Granger CB, McMurray JJV, Pfeffer MA, Solomon SD (2015) Prognostic importance of temporal changes in resting heart rate in heart failure patients: an analysis of the CHARM program. Eur Heart J 36:669–675CrossRefGoogle Scholar
  23. 23.
    Bertomeu-González V, Núñez J, Núñez E, Cordero A, Fácila L, Ruiz-Granell R, Quiles J, Sanchis J, Bodí V, Miñana G, Bertomeu V, Llàcer A (2010) Heart rate in acute heart failure, lower is not always better. Int J Cardiol 145:592–593CrossRefGoogle Scholar
  24. 24.
    Rienstra M, Van Gelder IC, Van den Berg MP, Boomsma F, Hillege HL, Van Veldhuisen DJ (2006) A comparison of low versus high heart rate in patients with atrial fibrillation and advanced chronic heart failure: effects on clinical profile, neurohormones and survival. Int J Cardiol 109:95–100CrossRefGoogle Scholar
  25. 25.
    Swedberg K, Zannad F, McMurray JJV, Krum H, van Veldhuisen DJ, Shi H, Vincent J, Pitt B, for the EMPHASIS-HF Study Investigators (2012) Eplerenone and atrial fibrillation in mild systolic heart failure Results from the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) Study. J Am Coll Cardiol 59:1598–1603CrossRefGoogle Scholar
  26. 26.
    Ferreira JP, Rossignol P, Machu J-L, Sharma A, Girerd N, Anker SD, Cleland JG, Dickstein K, Filippatos G, Hillege HL, Lang CC, ter Maaten JM, Metra M, Ng L, Ponikowski P, Samani NJ, van Veldhuisen DJ, Zwinderman AH, Voors AA, Zannad F (2017) Mineralocorticoid receptor antagonist pattern of use in heart failure with reduced ejection fraction: findings from BIOSTAT-CHF. Eur J Heart Fail 19:1284–1293CrossRefGoogle Scholar
  27. 27.
    Komajda M, Anker SD, Cowie MR, Filippatos GS, Mengelle B, Ponikowski P, Tavazzi L, on behalf of the QUALIFY Investigators (2016) Physicians’ adherence to guideline-recommended medications in heart failure with reduced ejection fraction: data from the QUALIFY global survey. Eur J Heart Fail 18(5):514–522CrossRefGoogle Scholar
  28. 28.
    Savarese G, Carrero J-J, Pitt B, Anker SD, Rosano GMC, Dahlström U, Lund LH (2018) Factors associated with underuse of mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction: an analysis of 11 215 patients from the Swedish Heart Failure Registry. Eur J Heart Fail.  https://doi.org/10.1002/ejhf.1182 CrossRefPubMedGoogle Scholar
  29. 29.
    Banka G, Heidenreich PA, Fonarow GC (2013) Incremental cost-effectiveness of guideline-directed medical therapies for heart failure. J Am Coll Cardiol 61:1440–1446CrossRefGoogle Scholar
  30. 30.
    Rohde LE, Bertoldi EG, Goldraich L, Polanczyk CA (2013) Cost-effectiveness of heart failure therapies. Nat Rev Cardiol 10:338–354CrossRefGoogle Scholar
  31. 31.
    Bapoje SR, Bahia A, Hokanson JE, Peterson PN, Heidenreich PA, Lindenfeld J, Allen LA, Masoudi FA (2013) Effects of mineralocorticoid receptor antagonists on the risk of sudden cardiac death in patients with left ventricular systolic dysfunction: a meta-analysis of randomized controlled trials. Circ Heart Fail 6:166–173CrossRefGoogle Scholar
  32. 32.
    Rossello X, Ariti C, Pocock SJ, Ferreira JP, Girerd N, McMurray JJV, van Veldhuisen DJ, Pitt B, Zannad F (2018) Impact of mineralocorticoid receptor antagonists on the risk of sudden cardiac death in patients with heart failure and left ventricular systolic dysfunction: an individual patient-level meta-analysis of three randomized-controlled trials. Clin Res Cardiol.  https://doi.org/10.1007/s00392-00018-01378-00390 (Epub ahead of print) CrossRefPubMedGoogle Scholar
  33. 33.
    Böhm M, Borer J, Ford I, Gonzalez-Juanatey JR, Komajda M, Lopez-Sendon J, Reil J-C, Swedberg K, Tavazzi L (2013) Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study. Clin Res Cardiol 102:11–22CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Ken Lee Chin
    • 1
    Email author
  • Timothy Collier
    • 2
  • Stuart Pocock
    • 2
  • Bertram Pitt
    • 3
  • John J. V. McMurray
    • 4
  • Dirk J. van Veldhuisen
    • 5
  • Karl Swedberg
    • 6
    • 7
  • John Vincent
    • 8
  • Faiez Zannad
    • 9
  • Danny Liew
    • 1
  1. 1.Department of Epidemiology and Preventive Medicine, CCRE TherapeuticsMonash University/Alfred HospitalMelbourneAustralia
  2. 2.London School of Hygiene and Tropical MedicineLondonUK
  3. 3.University of MichiganAnn ArborUSA
  4. 4.University of GlasgowGlasgowUK
  5. 5.University Medical CentreGroningenThe Netherlands
  6. 6.University of GothenburgGothenburgSweden
  7. 7.National Heart and Lung InstituteImperial CollegeLondonUK
  8. 8.PfizerNew YorkUSA
  9. 9.Nancy UniversityNancyFrance

Personalised recommendations