Skip to main content

Advertisement

SpringerLink
Log in

Risk Stratification and Efficacy of Spironolactone in Patients with Heart Failure with Preserved Ejection Fraction: Secondary Analysis of the TOPCAT Randomized Clinical Trial

  • Original Article
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Purpose

We aimed to develop a simple risk score for patients with HFpEF and assessed the efficacy of spironolactone across baseline risk.

Methods

We developed risk stratification scheme for cardiovascular death in placebo arm of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial (TOPCAT). We screened candidate risk indicators and determined strong risk predictors using COX regression. The absolute risk reduction (ARR) in cardiovascular death with spironolactone was evaluated across baseline risk groups. COX regressions were performed to assess the hazard ratios (HRs) of spironolactone therapy for cardiovascular death and drug discontinuation in each risk category.

Results

A simple risk score scheme was constructed based on five risk indicators weighted by estimates from the model, including age, diastolic blood pressure, renal dysfunction, white blood cell, and left ventricular ejection fraction. The risk score scheme showed good discrimination in placebo cohort (C index=0.70). ARR with spironolactone therapy was observed only in patients at very high risk (7.9%). Spironolactone therapy significantly reduced the risk of cardiovascular death in the very high-risk group (HR: 0.57; 95%CI, 0.39–0.84; P =0.005 and P for interaction 0.03) but showed similar risk of drug discontinuation across risk categories (P for interaction=0.928).

Conclusion

This simple risk score stratifies patients with HFpEF by their baseline risk of cardiovascular death. Patients at very high risk derive great benefits from spironolactone therapy. This easy-to-use risk score provides a practical tool that can facilitate risk stratification and tailoring therapy for those who benefit most from spironolactone.

Trial Registration

ClinicalTrials.gov Identifier: NCT00094302.

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

Fig. 1
Fig. 2

Similar content being viewed by others

Availability of Data and Material

This study used TOPCAT trial data that are available to eligible researchers after registration.

Code Availability

Not applicable

References

  1. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–200.

    Article  Google Scholar 

  2. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. New Engl J Med. 2006;355:251–9.

    Article  CAS  Google Scholar 

  3. 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;70:776–803.

    Article  Google Scholar 

  4. Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, et al. Spironolactone for heart failure with preserved ejection fraction. New Engl J Med. 2014;370:1383–92.

    Article  CAS  Google Scholar 

  5. Cohen JB, Schrauben SJ, Zhao L, Basso MD, Cvijic ME, Li Z, et al. Clinical Phenogroups in Heart Failure With Preserved Ejection Fraction: Detailed Phenotypes, Prognosis, and Response to Spironolactone. JACC Heart Fail. 2020;8:172–84.

    Article  Google Scholar 

  6. Desai AS, Lewis EF, Li R, Solomon SD, Assmann SF, Boineau R, et al. Rationale and design of the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial: a randomized, controlled study of spironolactone in patients with symptomatic heart failure and preserved ejection fraction. Am Heart J. 2011;162:966–972.e10.

    Article  CAS  Google Scholar 

  7. Thorvaldsen T, Claggett BL, Shah A, Cheng S, Agarwal SK, Wruck LM, et al. Predicting Risk in Patients Hospitalized for Acute Decompensated Heart Failure and Preserved Ejection Fraction: The Atherosclerosis Risk in Communities Study Heart Failure Community Surveillance. Circ Heart Fail. 2017;10:e003992.

  8. Jones RC, Francis GS, Lauer MS. Predictors of mortality in patients with heart failure and preserved systolic function in the Digitalis Investigation Group trial. J Am Coll Cardiol. 2004;44:1025–9.

    Article  Google Scholar 

  9. Lee DS, Austin PC, Rouleau JL, Liu PP, Naimark D, Tu JV. Predicting mortality among patients hospitalized for heart failure: derivation and validation of a clinical model. JAMA. 2003;290:2581–7.

    Article  CAS  Google Scholar 

  10. Pocock SJ, Ariti CA, McMurray JJ, Maggioni A, Køber L, Squire IB, et al. Predicting survival in heart failure: a risk score based on 39 372 patients from 30 studies. Eur Heart J. 2013;34:1404–13.

    Article  Google Scholar 

  11. Kasahara S, Sakata Y, Nochioka K, Tay WT, Claggett BL, Abe R, et al. The 3A3B score: The simple risk score for heart failure with preserved ejection fraction - A report from the CHART-2 Study. Int J Cardiol. 2019;284:42–9.

    Article  Google Scholar 

  12. Wehner GJ, Jing L, Haggerty CM, Suever JD, Leader JB, Hartzel DN, et al. Routinely reported ejection fraction and mortality in clinical practice: where does the nadir of risk lie? Eur Heart J. 2020;41:1249–57.

    Article  Google Scholar 

  13. Jentzer JC, van Diepen S, Barsness GW, Henry TD, Menon V, Rihal CS, et al. Cardiogenic Shock Classification to Predict Mortality in the Cardiac Intensive Care Unit. J Am Coll Cardiol. 2019;74:2117–28.

    Article  Google Scholar 

  14. 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: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:e147–239.

    Article  Google Scholar 

  15. Bajaj NS, Kalra R, Gupta K, Aryal S, Rajapreyar I, Lloyd SG, et al. Leucocyte count predicts cardiovascular risk in heart failure with preserved ejection fraction: insights from TOPCAT Americas. ESC Heart Fail. 2020;7:1676–87.

    Article  Google Scholar 

  16. Solomon SD, Claggett B, Lewis EF, Desai A, Anand I, Sweitzer NK, et al. Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction. Eur Heart J. 2016;37:455–62.

    Article  CAS  Google Scholar 

  17. Ramalho SHR, Claggett BL, Sweitzer NK, Fang JC, Shah SJ, Anand IS, et al. Impact of pulmonary disease on the prognosis in heart failure with preserved ejection fraction: the TOPCAT trial. Eur J Heart Fail. 2020;22:557–9.

    Article  Google Scholar 

  18. Agostoni P, Magini A, Andreini D, Contini M, Apostolo A, Bussotti M, et al. Spironolactone improves lung diffusion in chronic heart failure. Eur Heart J. 2005;26:159–64.

    Article  CAS  Google Scholar 

  19. Cikes M, Claggett B, Shah AM, Desai AS, Lewis EF, Shah SJ, et al. Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction: The TOPCAT Trial. JACC Heart Fail. 2018;6:689–97.

    Article  Google Scholar 

  20. 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;5:241–52.

    Article  Google Scholar 

  21. Elkholey K, Papadimitriou L, Butler J, Thadani U, Stavrakis S. Effect of Obesity on Response to Spironolactone in Patients with Heart Failure with Preserved Ejection Fraction. Am J Cardiol. 2021. https://doi.org/10.1016/j.amjcard.2021.01.018

  22. Zile MR, Baicu CF, Ikonomidis JS, Stroud RE, Nietert PJ, Bradshaw AD, et al. Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin. Circulation. 2015;131:1247–59.

    Article  CAS  Google Scholar 

  23. Kasner M, Westermann D, Lopez B, Gaub R, Escher F, Kühl U, et al. Diastolic tissue Doppler indexes correlate with the degree of collagen expression and cross-linking in heart failure and normal ejection fraction. J Am Coll Cardiol. 2011;57:977–85.

    Article  CAS  Google Scholar 

  24. Ravassa S, Trippel T, Bach D, Bachran D, González A, López B, et al. Biomarker-based phenotyping of myocardial fibrosis identifies patients with heart failure with preserved ejection fraction resistant to the beneficial effects of spironolactone: results from the Aldo-DHF trial. Eur J Heart Fail. 2018;20:1290–9.

    Article  CAS  Google Scholar 

  25. Steiner J, Guglin M. BNP or NTproBNP? A clinician’s perspective. Int J Cardiol. 2008;129:5–14.

    Article  Google Scholar 

Download references

Acknowledgements

We thank the staff and participants of the TOPCAT study and ARIC study for their contributions. We express our appreciation to Shuyi Wang, MD, for her generous assistance in manuscript editing.

Funding

This work was supported by the National Natural Science Foundation of China (81600206 to ZXD; 81870195 to LXX) and Natural Science Foundation of Guangdong Province (2016A030310140 to ZXD; 2016A020220007 and 2019A1515011582 to LXX).

Author information

Author notes

  1. Yifen Lin and Xiangbin Zhong contributed equally to this work.

Authors and Affiliations

  1. Cardiology Department, First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China

    Yifen Lin, Xiangbin Zhong, Menghui Liu, Shaozhao Zhang, Zhenyu Xiong, Yiquan Huang, Yongqiang Fan, Xingfeng Xu, Yue Guo, Yuqi Li, Xiuting Sun, Huimin Zhou, Daya Yang, Xiaomin Ye, Xinxue Liao & Xiaodong Zhuang

  2. NHC Key Laboratory of Assisted Circulation (Sun Yat-Sen University), Guangzhou, China

    Yifen Lin, Xiangbin Zhong, Menghui Liu, Shaozhao Zhang, Zhenyu Xiong, Yiquan Huang, Yongqiang Fan, Xingfeng Xu, Yue Guo, Yuqi Li, Xiuting Sun, Huimin Zhou, Daya Yang, Xiaomin Ye, Xinxue Liao & Xiaodong Zhuang

Authors
  1. Yifen Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiangbin Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Menghui Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shaozhao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhenyu Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yiquan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yongqiang Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xingfeng Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yue Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yuqi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Xiuting Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Huimin Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Daya Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Xiaomin Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Xinxue Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Xiaodong Zhuang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LXX, ZXD, and LYF contributed to the conception or design of the work. All authors were responsible for the acquisition, analysis, and interpretation of data. LYF, ZXB, and ZSZ drafted the manuscript. Critical revision of the manuscript for important intellectual content were performed by all authors. All authors agreed with the content of the article to be submitted.

Corresponding authors

Correspondence to Xinxue Liao or Xiaodong Zhuang.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Ethics Approval

The institutional review board at each participating center approved the study protocol.

Consent to Participate

All patients provided written informed consent.

Consent for Publication

All authors have reviewed and agree with the content of the article for publication.

Disclaimer

The supporting organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(PDF 691 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lin, Y., Zhong, X., Liu, M. et al. Risk Stratification and Efficacy of Spironolactone in Patients with Heart Failure with Preserved Ejection Fraction: Secondary Analysis of the TOPCAT Randomized Clinical Trial. Cardiovasc Drugs Ther 36, 323–331 (2022). https://doi.org/10.1007/s10557-021-07178-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-021-07178-y

Keywords

Search

Navigation