The Long-Term Impact of Renin-Angiotensin System (RAS) Inhibition on Cardiorenal Outcomes (LIRICO): A Randomized, Controlled Trial

Abstract

Background: The comparative effectiveness of treatment with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or their combination in people with albuminuria and cardiovascular risk factors is unclear.

Methods: In a multicenter, randomized, open label, blinded end point trial, we evaluated the effectiveness on cardiovascular events of ACE or ARB monotherapy or combination therapy, targeting BP<130/80 in patients with moderate or severe albuminuria and diabetes or other cardiovascular risk factors. End points included a primary composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for cardiovascular causes and a revised end point of all-cause mortality. Additional end points included ESRD, doubling of serum creatinine, albuminuria, eGFR, BP, and adverse events.

Results: Because of slow enrollment, the trial was modified and stopped 41% short of targeted enrollment of 2100 participants, corresponding to 35% power to detect a 25% reduced risk in the primary outcome. Our analysis included 1243 adults, with median follow-up of 2.7 years. Efficacy outcomes were similar between groups (ACE inhibitor versus ARB, ACE inhibitor versus combination, ARB versus combination) as were rates of serious adverse events. The rate of permanent discontinuation for ARB monotherapy (6.3%) was significantly lower than for ACE inhibitor monotherapy (15.7%) or combined therapy (18.3%).

Conclusions: Patients may tolerate ARB monotherapy better than ACE inhibitor monotherapy. However, data from this trial and similar trials, although as yet inconclusive, show no trend suggesting differences in mortality and renal outcomes with ACE inhibitors or ARBs as dual or monotherapy in patients with albuminuria and diabetes or other cardiovascular risk factors.

Keywords: albuminuria; clinical trial; diabetic nephropathy; end-stage renal disease; mortality; renin angiotensin system.

Graphical abstract

Figure 1.

Overall, 1287 participants were randomized to the LIRICO trial. Consolidated Standards of Reporting Trials flow diagram of the Long-Term Impact of RAS Inhibition on Cardiorenal Outcomes study. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.

Figure 2.

Treatment group did not seem to influence the risk of the composite outcome of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for cardiovascular causes. Kaplan–Meier estimates of composite outcome according to treatment allocation. Number of events refers to the number of participants experiencing their first event of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for cardiovascular cause. ACE, angiotensin-converting enzyme; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.

Figure 3.

There was no evidence that the urinary albumin-to-creatinine ratio or eGFR was different between groups at any time point. Change in urine albumin-to-creatinine ratio and eGFR from baseline to study end. Data are expressed as estimated mean with 95% confidence interval. Comparative analyses are on the basis of a mixed model for repeated measurements, comparing the values over time between groups and accounting for within-participant correlation. P value for interaction between groups over time is shown. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.