Ramipril and Cardiovascular Outcomes in Patients on Maintenance Hemodialysis: The ARCADIA Multicenter Randomized Controlled Trial

Abstract

Background and objectives: Renin-angiotensin system (RAS) inhibitors reduce cardiovascular morbidity and mortality in patients with CKD. We evaluated the cardioprotective effects of the angiotensin-converting enzyme inhibitor ramipril in patients on maintenance hemodialysis.

Design, setting, participants, & measurements: In this phase 3, prospective, randomized, open-label, blinded end point, parallel, multicenter trial, we recruited patients on maintenance hemodialysis with hypertension and/or left ventricular hypertrophy from 28 Italian centers. Between July 2009 and February 2014, 140 participants were randomized to ramipril (1.25-10 mg/d) and 129 participants were allocated to non-RAS inhibition therapy, both titrated up to the maximally tolerated dose to achieve predefined target BP values. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the single components of the primary end point, new-onset or recurrence of atrial fibrillation, hospitalizations for symptomatic fluid overload, thrombosis or stenosis of the arteriovenous fistula, and changes in cardiac mass index. All outcomes were evaluated up to 42 months after randomization.

Results: At comparable BP control, 23 participants on ramipril (16%) and 24 on non-RAS inhibitor therapy (19%) reached the primary composite end point (hazard ratio, 0.93; 95% confidence interval, 0.52 to 1.64; P=0.80). Ramipril reduced cardiac mass index at 1 year of follow-up (between-group difference in change from baseline: -16.3 g/m2; 95% confidence interval, -29.4 to -3.1), but did not significantly affect the other secondary outcomes. Hypotensive episodes were more frequent in participants allocated to ramipril than controls (41% versus 12%). Twenty participants on ramipril and nine controls developed cancer, including six gastrointestinal malignancies on ramipril (four were fatal), compared with none in controls.

Conclusions: Ramipril did not reduce the risk of major cardiovascular events in patients on maintenance hemodialysis.

Clinical trial registry name and registration number: ARCADIA, NCT00985322 and European Union Drug Regulating Authorities Clinical Trials Database number 2008-003529-17.

Keywords: ACE inhibitors; Ramipril; cardiovascular events; hemodialysis; renin angiotensin system.

Copyright © 2021 by the American Society of Nephrology.

Figures

Graphical abstract

Figure 1.

Study flow diagram. CV, cardiovascular.

Figure 2.

Cumulative incidence of the primary composite outcome. Kaplan–Meier survival curves showing the risk of progression to the primary composite end point of cardiovascular death, acute myocardial infarction, or stroke in the ramipril group and non-RAS inhibitor group. Hazard ratios (crude and adjusted for age, sex, previous cardiovascular events or RAS inhibitor therapy, and presence of diabetes and left ventricular hypertrophy at inclusion) are reported in the figure. Only one event from the composite end point per participant, whichever occurred first, was included in the analysis. The number of participants at risk is shown in the bottom table. Blue line indicates the ramipril group; red line indicates the non-RAS inhibitor group. HR, hazard ratio; RAS, renin-angiotensin system.

Figure 3.

Risk of progression to the single components of the primary composite end point, according to treatment arm. Kaplan–Meier survival curves showing the risk of the first occurrence of either (A) cardiovascular death, (B) nonfatal acute myocardial infarction, or (C) nonfatal stroke, considered as single end points in the ramipril group and non-RAS inhibition group. Hazard ratios (crude and adjusted for age, sex, previous cardiovascular events or RAS inhibitor therapy, and presence of diabetes and left ventricular hypertrophy at inclusion) are reported in the three panels. The number of participants at risk is shown in the bottom table. Blue line indicates the ramipril group; red line indicates the non-RAS inhibitor group.

Figure 4.

Pre- and postdialysis systolic and diastolic BP over time (A and B), cardiac mass index at baseline and at 1 and 2 years after randomization (C), and serum potassium levels over time (D) in the two treatment groups. All data are expressed as mean±SEM. Blue indicates ramipril and red indicates non-RAS inhibitor therapy. *P<0.05 versus baseline; P values for between-groups comparisons are reported in the figure.