<b>Monotherapy Survival Benefit: Challenging GDMT Dogma in Tolerance-Limited Heart Failure</b>

Background: Heart failure (HF) management in resource-limited settings remains poorly characterized, particularly regarding outcomes associated with medication tolerance and burden. Methods: This multicenter, cross-sectional study analyzed 7,404 patients from Algerian cardiology registries (2017–2025), identifying 315 with HFrEF/HFmEF. Patients were stratified by GDMT burden: Group 0 (no therapy, *n*=125), Group 1 (monotherapy, *n*=108), Group 2 (dual therapy, *n*=64), and Group 3+ (triple therapy, *n*=18). Mortality rates and comorbidity interactions were assessed. Results: Prevalence of HFrEF/HFmEF was 4.25%. Mortality demonstrated a U-shaped association: Group 0 (2.44%), Group 1 (1.96%), Group 2 (3.33%), and Group 3+ (22.22%) (*p*<0.001). High-burden patients (Groups 2–3+) had 2.3-fold higher mortality vs. low-burden (RR 2.27, 95% CI 1.15–4.48). Comorbidity stratification revealed striking disparities: atrial fibrillation patients in Group 3+ had 60% mortality vs. 0% without AF (*p*=0.003), while ischemic HF patients in Group 0 exhibited 4.0% mortality vs. 1.33% in non-ischemic counterparts. Medication patterns showed ACEi/ARB dominance in Group 1 (40.7%) and high diuretic use in Group 3+ (55.6%). Conclusions: In this North African cohort, HF mortality followed a U-shaped curve by treatment intensity, with highest risk in untreated and intensively treated patients. Monotherapy demonstrated protective effects in tolerance-limited individuals, while atrial fibrillation identified a high-risk phenotype. These findings advocate for personalized, comorbidity-adapted HF management in resource-constrained settings.