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Covariate adjusted reanalysis of the I-Preserve trial

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Abstract

Background

The CHARM-Preserved trial suggested that the renin-angiotensin system (RAS) inhibitor candesartan might have been beneficial in heart failure with preserved ejection fraction (HFpEF); however, this hypothesis was not supported by the findings of I-Preserve with irbesartan.

Aims

To re-analyse the results of I-Preserve, adjusting for imbalances in baseline variables that may have influenced the trial outcomes.

Methods

Cox proportional hazards models with covariate adjustment for baseline variables, including age, sex, medical history, physiological and laboratory variables.

Results

In I-Preserve, 763 (37.0%) participants in the placebo group and 742 (35.9%) in the irbesartan group experienced the primary composite outcome (death from any cause or hospitalization for heart failure, myocardial infarction, unstable angina, arrhythmia, or stroke). The prespecified analysis of this outcome, stratifying for the use of ACEi at baseline, gave a hazard ratio (HR) of 0.95 (95% confidence interval, 0.86–1.05); p = 0.35. Adjusting the effect of treatment for key prognostic baseline variables, gave a HR of 0.89 (0.80–0.99); p = 0.033. Similar findings were observed for the composite of cardiovascular death or HF hospitalization.

Conclusion

Adjusting for imbalances in baseline variables that influence outcomes (or the response to therapy or both) can improve the power around the estimate of the effect of treatment and may alter its statistical significance. Along with the CHARM-Preserved results, these findings suggest that angiotensin-receptor blockers may have a modest effect in HFpEF.

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Acknowledgements

JPF is supported by the French National Research Agency Fighting Heart Failure (ANR-15-RHU-0004), by the French PIA project “Lorraine Université d’Excellence” GEENAGE (ANR-15-IDEX-04-LUE) programmes, and the Contrat de Plan Etat Région Lorraine and FEDER IT2MP.

Funding

JJVM, MCP, and PSJ are supported by a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217. JPF is funded by an ESC research grant for collaboration with the University of Glasgow. All other authors report no specific funding for this project.

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Authors and Affiliations

  1. BHF Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK

    João Pedro Ferreira, Pooja Dewan, Pardeep S. Jhund, Mark C. Petrie & John J. V. McMurray

  2. National Institute of Health and Medical Research (INSERM), Center for Clinical Multidisciplinary Research 1433, INSERM U1116, French Clinical Research Infrastructure Network (F-CRIN) Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists (INI-CRCT), University of Lorraine, Regional University Hospital of Nancy, Nancy, France

    João Pedro Ferreira, Kévin Duarte & Faiez Zannad

  3. Department of Internal Medicine. Renal, Vascular and Diabetes Laboratory, Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain

    Ana Lorenzo-Almorós

  4. Cardiovascular Division, Department of Cardiology, Washington Veterans Affairs Medical Center, Washington, DC, USA

    Peter E. Carson

  5. Department of Medicine, Western University, London, ON, Canada

    Robert McKelvie

  6. Service de Cardiologie, Hôpital Saint Joseph, Paris, France

    Michel Komajda

  7. Medical University of South Carolina and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina, USA

    Michael Zile

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  1. João Pedro Ferreira
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  2. Pooja Dewan
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  3. Pardeep S. Jhund
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  7. Peter E. Carson
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  8. Robert McKelvie
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  10. Michael Zile
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  12. John J. V. McMurray
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Corresponding author

Correspondence to John J. V. McMurray.

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Ferreira, J.P., Dewan, P., Jhund, P.S. et al. Covariate adjusted reanalysis of the I-Preserve trial. Clin Res Cardiol 109, 1358–1365 (2020). https://doi.org/10.1007/s00392-020-01632-x

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  • DOI: https://doi.org/10.1007/s00392-020-01632-x

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