Abstract: Objective To investigate the characteristics and independent risk factors of adverse drug reactions associated with combined renin-angiotensin-aldosterone system (RAAS) inhibitors and β-blockers therapy in patients with heart failure, and to evaluate the impact of a risk factor based stratified management strategy on treatment safety and efficacy. Methods A prospective observational study was conducted. A total of 120 patients with heart failure admitted to Yan’an University Xianyang Hospital from February 2024 to May 2025 were enrolled and divided into a standard monitoring group and a routine management group, with 60 cases in each group according to management strategies. After balancing confounding factors by propensity score matching (PSM), 103 patients were finally enrolled, including 52 cases in the standard monitoring group and 51 cases in the routine management group. All patients were treated with RAAS inhibitors combined with β -blockers. The two groups were compared in terms of adverse reaction incidence, treatment discontinuation rate, 6 month target dose attainment rate, proportion of patients with more than 30% reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP), and 30 day readmission rate. Results Among 103 patients with heart failure, the overall incidence of drug related adverse reactions was 49.51%, predominantly hypotension (28.16%), renal function deterioration (22.33%), bradycardia (18.45%) and hyperkalemia (16.50%). A total of 20.39% of patients experienced two or more concurrent adverse reactions. Multivariate Logistic regression analysis revealed that age over 65 years and high dose RAAS inhibitors therapy were independent risk factors for hypotension. Comorbid diabetes mellitus, combined spironolactone administration and baseline estimated glomerular filtration rate (eGFR) < 60 mL·min^-1·1.73 m^-2 were independent risk factors for hyperkalemia. Baseline eGFR < 60 mL·min^-1·1.73 m^-2 and high dose RAAS inhibitors were independent risk factors for renal function deterioration, and high dose β-blockers was an independent risk factor for bradycardia (P < 0.05).Compared with the routine management group, the standardized monitoring group had lower total adverse reaction incidence, treatment discontinuation rate and 30 day readmission rate, and higher 6 month target dose attainment rate and proportion of patients with NT-proBNP reduction exceeding 30% (P < 0.05). Conclusion Combination therapy with RAAS inhibitors and β-blockers in heart failure is associated with a high incidence of adverse reactions, which frequently co-occur. Advanced age, renal impairment, diabetes mellitus, and high dose drug regimens are independent risk factors for adverse reactions related to this combination therapy; a risk factor-guided stratified management strategy significantly enhances both the safety and effectiveness of therapy and improves short term clinical outcomes.