Differential Rates of Guideline-Directed Medical Therapy Modification in C-MIC and Control Patients: Results from the C-MIC II Trial

Abstract Background In the C-MIC II trial, C-MIC therapy improved outcomes in patients with heart failure (HF) with reduced ejection fraction (HFrEF). We evaluated whether differences in background HF medication adjustments influenced the observed benefits. Methods Ambulatory patients with chronic non-ischemic HFrEF receiving guideline-directed medical therapy (GDMT) were enrolled. The primary outcome was change in GDMT and diuretic intensity over 6 months. Treatment effects on left ventricular ejection fraction (LVEF), Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS), and 6-minute walk distance (6MWD) were assessed by baseline sodium-glucose cotransporter-2 inhibitor (SGLT2i) use for consistency. Results Among 65 patients, 25 (39%) had GDMT adjustments (C-MIC device: 44%; control 33%; p= 0.390). GDMT intensity increased in controls (Δ +0.36) but decreased (Δ -0.16; p= 0.100) in C-MIC group. Diuretic intensity decreased in C-MIC group (Δ -0.10) but increased in controls (Δ +0.12; p= 0.200). When stratified by baseline SGLT2i use, C-MIC therapy induced consistent improvements in LVEF (SGLT2i: +6% [95% CI 3–9; p<0.001] vs. without SGLT2i: +4% [95% CI 2–7; p=0.003]), KCCQ-OSS (SGLT2i: +42 points [95% CI 26–58; p<0.001] vs. without SGLT2i: +40 [95% CI 28–51; p<0.001]) and 6MWD (SGLT2i: +150 meters [95% CI 88–212; p<0.001] vs. without SGLT2i: +141 meters (95% CI 63–219; p<0.001]). Conclusion Medication intensity decreased in C-MIC–treated patients but increased in controls, driven primarily by escalation of diuretics, likely reflecting worsening HF. Consistent improvements in LVEF, 6MWD and KCCQ-OSS across SGLT2i subgroups suggest that the observed benefits are independent of background pharmacologic intensification.