Long-term mortality benefit of renin-angiotensin system inhibitors in patients with chronic limb-threatening ischemia undergoing vascular intervention

Objective: The beneficial effect of renin-angiotensin system (RAS) inhibitors has been well-established in patients with cardiovascular disease; however, their effectiveness in patients with chronic limb-threatening ischemia (CLTI), a selected disease-burdened population, is largely unknown. The purpose of this study was to evaluate long-term outcomes of RAS inhibitor use in patients with CLTI undergoing a vascular intervention. Methods: For this study, all patients with CLTI undergoing a first-time revascularization (bypass or endovascular) were analyzed at our institution between 2005 and 2014. Patients discharged on an RAS inhibitor (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker) were compared with those not on an RAS inhibitor. The inverse probability of treatment weighting with additional regression analyses were used to determine the long-term risk of mortality and major adverse events. A sensitivity analysis was performed to assess the dose-related therapeutic response of RAS inhibitors (low-dose vs high-dose therapy). Results: Between 2005 and 2014, 1303 limbs from 1161 patients were identified. Of these patients, 52% were discharged on an RAS inhibitor, with 67% discharged on a high-dose therapy and 33% on a low-dose therapy. Patients discharged on an RAS inhibitor suffered more frequently from diabetes, hypertension, and myocardial infarction, whereas those not on an RAS inhibitor had more chronic kidney disease (all P < .05). There was no difference in the proportion of patients presenting with tissue loss. After adjustment for these and other baseline covariates, RAS inhibitor use was associated with less late mortality (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.65-0.94). Discharge on a high-dose RAS inhibitor was associated with lower mortality (HR, 0.70; 95% CI, 0.57-0.86), whereas a low-dose RAS inhibitor was not associated with less mortality (HR, 0.95; 95% CI, 0.73-1.24) compared with patients not prescribed an RAS inhibitor. This association remained significant when comparing high-dose with low-dose therapy (HR, 0.74; 95% CI, 0.55-0.98). No associations were found between RAS inhibitor use and major adverse limb event (HR, 0.95; 95% CI, 0.73-1.22), major amputation (HR, 0.82; 95% CI, 0.57-1.18), or reintervention (HR, 1.05; 95% CI, 0.85-1.31). These point estimates were not different for those on angiotensin-converting enzyme inhibitors vs angiotensin receptor blockers, nor were they affected by the type of revascularization. Conclusions: Patients with CLTI prescribed an RAS inhibitor at discharge demonstrated significantly less long-term mortality, whereas limb events were unaffected. These data indicate that, in these heavily burdened patients, the benefit is restricted to those on a high dose, which underscores the importance of attaining these doses.