Determinants of the survival benefit associated with statins in patients with acute heart failure

Abstract

Aims: The benefit of statins in patients with heart failure (HF) remains controversial and the mechanism of action is largely speculative. We investigated the determinants of the survival benefit associated with statins in HF patients.

Methods and results: We enrolled 1680 acute HF patients receiving statins and 2157 patients not receiving statins admitted between 2009 and 2016. The left ventricular (LV) global longitudinal strain (GLS) was assessed as a measure of myocardial contractility. The primary outcome was 5 year all-cause mortality. Statin therapy was independently associated with improved survival in patients with HF with preserved ejection fraction (HFpEF) [adjusted hazard ratio (HR) 0.781, 95% confidence interval (CI) 0.621-0.981, P = 0.034], but not in those with HF with reduced EF (HFrEF) (adjusted HR 0.881, 95% CI 0.712-1.090, P = 0.244). Mortality reduction associated with statin therapy was significant in patients with ischaemic HF (adjusted HR 0.775, 95% CI 0.607-0.989, P = 0.040), but not in those with non-ischaemic HF (adjusted HR 0.895, 95% CI 0.734-1.092, P = 0.275). The relative magnitude of survival benefit with statin therapy increased as LV-EF and LV-GLS increased, with a steeper dose-response relationship in patients with ischaemic HF. In the subgroup of patients with ischaemic HF, survival benefit with statin therapy was confined to those ≤75 years of age.

Conclusions: Our study suggests that the survival benefit of statins is confined to patients with HFpEF and those with ischaemic HF. Myocardial contractility may modulate the prognostic effects of statins in HF patients, particularly when the aetiology is ischaemic rather than non-ischaemic.

Trial registration: ClinicalTrials.gov NCT03513653.

Keywords: Heart failure; Mortality; Myocardial function; Statins.

Conflict of interest statement

None.

© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Figures

Figure 1

Study population. Flow chart of this study is presented. EF, ejection fraction; GLS, global longitudinal strain; LV, left ventricle; RV, right ventricle; STRATS‐AHF, Strain for Risk Assessment and Therapeutic Strategies in Patients with Acute Heart Failure.

Figure 2

Hazard ratios for mortality in statin users vs. non‐users according to type and aetiology of heart failure. Multivariable‐adjusted survival curves demonstrating the difference in all‐cause mortality between statin users and non‐users at 5 year follow‐up. Note a smaller mortality reduction with statin therapy in the HFrEF group (A) compared with that in the HFpEF group (B). Mortality reduction with statin therapy was also smaller in non‐ischaemic HF group (D) than ischaemic HF group (C). Adjusted comparisons were based on multivariate Cox regression models. HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.

Figure 3

Relative magnitude of survival benefit with statin therapy by left ventricular systolic function. Cox regression analysis showing the multivariable‐adjusted relative hazard ratios (solid line) and 95% confidence intervals (shaded area). Note that the magnitude of mortality reduction with statin therapy substantially increased as LV‐EF increased in the overall study patients (A). This association was more pronounced in patients with ischaemic HF (B) than those with non‐ischaemic HF (C). Similar associations were found for LV‐GLS (D–F). HF, heart failure; LV‐EF, left ventricular‐ejection fraction; LV‐GLS, left ventricular‐global longitudinal strain.

Figure 4

Relative magnitude of survival benefit with statin therapy by right ventricular systolic function. Cox regression analysis showing the multivariable‐adjusted relative hazard ratios (solid line) and 95% confidence intervals (shaded area). Note that the magnitude of mortality reduction with statin therapy substantially decreased as RV‐FAC increased in the overall study patients (A). The magnitude of association between RV‐FAC and survival benefit was similar in both ischaemic (B) and non‐ischaemic HF groups (C). The magnitude of mortality reduction with statin therapy decreased as RV‐GLS increased in the overall study patients, with a less steep slope (D) than in the case of RV‐FAC. The magnitude of this association was more evident in ischaemic HF group (E) than non‐ischaemic HF group (F). HF, heart failure; RV‐FAC, right ventricular‐fractional area change; RV‐GLS, right ventricular‐global longitudinal strain.

Figure 5

Forest plot depicting multivariable‐adjusted subgroup analyses. Forest plots of adjusted hazard ratios for the relationship between relevant subgroups and all‐cause mortality according to statin therapy in patients with ischaemic HF (A) and those with non‐ischaemic HF (B). Interaction P values are shown. The hazard ratio within each stratum was adjusted for the independent variables shown in Table2. CI, confidence interval; DM, diabetes mellitus, HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HL, hyperlipidaemia; HR, hazard ratio; HTN, hypertension; LV‐EF, left ventricular‐ejection fraction; LV‐GLS, left ventricular‐global longitudinal strain. Take home figure: Postulated associations between aetiology of heart failure, myocardial contractility, and effect of statin therapy. Ischaemic aetiology for HF and LV and RV myocardial contractility may be associated with the magnitude of survival benefits with statin therapy in patients with acute HF. HF, heart failure; LV, left ventricular; RV, right ventricular.