Sustained adherence to ESC guideline-recommended medications is associated with lower long-term mortality in heart failure and reduced ejection fraction: Insights from the EPICAL2 cohort

What is known and objective The real-life prognostic impact on long-term survival of continuous or discontinuous adherence to ESC guideline-recommended drugs in heart failure with reduced ejection fraction (HFrEF) patients has rarely been investigated. Here, we present the long-term association of longitudinal prescription of guideline-recommended drugs with 3-year all-cause and cardiovascular (CV) mortality in HFrEF patients. Methods We used data from the EPICAL2 cohort study of 624 hospitalized HFrEF patients. Using the sequence analysis, we classified patients into five groups of long-term adherence according to the continuity/discontinuity of their prescription adherence to guidelines over a 3-year follow-up, as follow: 316 (50.6%) patients in the sustained adherence group, 163 (26.1%) in the sustained non-adherence group, 79 (12.6%) in the adherence to non-adherence group, 43 (6.9%) in the non-adherence to adherence group and 23 (3.7%) in the multiple switches group. The associations between all-cause mortality and CV mortality and the adherence groups were determined by Cox and Fine-Gray models, respectively. To account for immortal time bias, we performed a landmark analysis at 24 months. Patients who died, prior to the landmark time, were excluded from this analysis and long-term adherence groups were redefined. Results and discussion After adjustment for confounding factors, as compared to the sustained non-adherence group, the sustained adherence group showed lower all-cause and CV mortality (hazard ratio HR = 0.37 [0.25-0.56] and sub-distribution hazard ratio SHR = 0.33 [0.20-0.56]). Both clinical outcomes were also significantly improved in the adherence to non-adherence group (HR = 0.25 [0.13-0.45] and SHR = 0.20 [0.10-0.41]), the non-adherence to adherence (HR = 0.24 [0.11-0.55] and SHR = 0.11 [0.04-0.30]), and for the multiple switches group (HR = 0.13 [0.07-0.51] and SHR = 0.12 [0.08-0.43]). Results from landmark analysis were comparable to the main results. What is new and conclusion As in all observational studies, our results may be affected by residual confounding related to unmeasured confounders, although we attempted to adjust for many confounders. Even a discontinuous prescription of the recommended drugs over time was associated with better long-term outcomes. In other words, whatever the time of HFrEF evolution, prescribing recommended drugs at some point was always better than never prescribing.