Covariate adjusted reanalysis of the I-Preserve trial
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ORIGINAL PAPER
Covariate adjusted reanalysis of the I‑Preserve trial João Pedro Ferreira1,2 · Pooja Dewan1 · Pardeep S. Jhund1 · Ana Lorenzo‑Almorós3 · Kévin Duarte2 · Mark C. Petrie1 · Peter E. Carson4 · Robert McKelvie5 · Michel Komajda6 · Michael Zile7 · Faiez Zannad2 · John J. V. McMurray1 Received: 18 January 2020 / Accepted: 11 March 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
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. Keywords Heart failure with preserved ejection fraction · Irbesartan · Covariate adjustment · Treatment effects
Introduction Although it is commonly stated that heart failure with preserved ejection fraction (HFpEF) is a condition for which no treatment has yet been shown to reduce morbidity or
mortality, in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved trial, fewer individuals treated with candesartan experienced the composite outcome of a first admission to hospital for worsening heart failure or death from cardiovascular causes:
* John J. V. McMurray [email protected] 1
BHF Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK
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), Uni
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