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Study objective: To evaluate the impact of a medication optimization clinic (MOC) on GDMT and outcomes for patients with HFrEF versus usual care. Design: Retrospective evaluation of a multi-site MOC was conducted. Setting: Large health system with academic and community hospitals. Participants: Patients with HFrEF referred to MOC by their cardiologist versus usual care. Interventions: GDMT use managed by an advanced practice provider or clinical pharmacist through weekly telemedicine visits. Main outcome measures: The primary outcome was HF hospitalization. Cardiovascular hospitalization and all-cause mortality were also assessed. Kaplan−Meier Curve, Cumulative Incidence Function, and competing risk analysis with regression models were conducted. Results: 1419 patients in MOC group were compared to 5116 control patients. GDMT use was significantly higher in MOC: quadruple therapy (49 % vs. 19 %; p < 0.0001), angiotensin-receptor neprilysin inhibitor (62 % vs. 45 %; p < 0.0001), beta blocker (92 % vs. 88 %; p < 0.0001), mineralocorticoid receptor antagonist (69 % vs. 45 %; p < 0.0001), and sodium glucose cotransporter-2 inhibitor (68 % vs. 35 %; p < 0.0001). Competing risk analyses showed that HF and CV hospitalizations were significantly lower at all times points (3, 6, and 12 months) for MOC vs. control (p < 0.001). All-cause mortality was significantly lower at 6 months (p = 0.006) and 12 months (p < 0.001), but did not differ at 3 months (p = 0.35), for MOC vs. control. Conclusions: MOC was associated with improved GDMT and lower risks of hospitalizations due to HF and any cardiovascular cause, and all-cause mortality in patients with HFrEF.