Impact of quadruple guideline-directed medical therapy at discharge on thirty-day mortality in older adults with heart failure and reduced ejection fraction: a real-world registry

Background The implementation of quadruple guideline-directed medical therapy (GDMT) remains a challenge in clinical practice, particularly among older patients with heart failure and reduced ejection fraction. This vulnerable population is often underrepresented in clinical trials, and concerns regarding frailty and potential adverse events frequently lead to sub-optimal treatment at the time of hospital discharge. Purpose This study aimed to evaluate the association between discharge on quadruple guideline-directed medical therapy (four pillars) versus incomplete therapy (≤3 pillars) and 30-day all-cause mortality in patients aged ≥70 years with left ventricular ejection fraction ≤40%. Methods Retrospective observational study using an institutional acute decompensated heart failure registry (January 2022-July 2025). The exposure was discharge on quadruple therapy (renin–angiotensin system inhibitor, beta-blocker, mineralocorticoid receptor antagonist, and sodium–glucose cotransporter 2 inhibitor) versus incomplete therapy. Missing baseline covariates were handled using multiple imputation by chained equations (m=20). Thirty-day mortality was described using Kaplan-Meier curves and compared with the log-rank test. Because proportional hazards were not met for the main exposure, adjusted associations were estimated using Poisson regression with robust variance to obtain adjusted risk ratios. Treatment effect heterogeneity was explored with a causal forest model within an overlap-restricted subsample. Results The cohort included 1878 patients (mean age 77.7 years; mean ejection fraction 27.2%); 63.7% were discharged on quadruple therapy. In the 30-day mortality analysis (n=1.868), 163 deaths occurred: 35/1.197 (2.9%) in the quadruple-therapy group versus 128/671 (19.1%) in the incomplete-therapy group (log-rank p<0.001) (Figure 1). In adjusted analyses, incomplete therapy was associated with higher 30-day mortality (adjusted risk ratio 5.90; 95% confidence interval 4.05–8.58; p<0.001). In the overlap-restricted causal forest analysis (n=1830), the average treatment effect favoured quadruple therapy (absolute risk reduction 15.4 percentage points; 95% confidence interval 12.2-18.6; p<0.001), with variability across benefit quartiles (Figure 2). Conclusion (s) Among older adults with heart failure with reduced ejection fraction, discharge on quadruple guideline-directed medical therapy was associated with substantially lower 30-day mortality. These findings suggest that age alone should not be a barrier to treatment optimisation, as the benefits of the four-pillar regimen are substantial even in the elderly population during the high-risk post-discharge period.Figure 1.30-day mortality analysis.Figure 2.Causal forest analysis.