No Firm Answers for Kidneys From LIRICO and VALID Studies on Utility of Dual RAS Blockade

Tejas P. Desai, MD


April 26, 2019

Despite previous conflicting studies about the utility of dual renin-angiotensin system (RAS) blockade in chronic kidney disease (CKD), researchers continue to investigate its utility. Earlier studies of dual RAS blockade have been plagued with poor recruitment, intolerable side effects, and/or poor outcomes.[1]

Nephrologists are a tenacious bunch, as is evidenced by a recently published pair of randomized clinical trials. The LIRICO[2] and VALID[3] trials are similar in many respects. They were conducted by Italian investigators, and patients were randomized to receive an angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blockers (ARBs), or both.

In the LIRICO trial, 1243 patients with moderate to severe albuminuria (albumin to creatinine ratio ≥ 300 mg/g) and diabetes were randomly assigned to one of three study arms—ACE inhibitor vs ARB, ACE inhibitor vs combination therapy, or ARB vs combination therapy—with a target blood pressure of < 130/80 mm Hg. In the VALID study, investigators randomly assigned far fewer patients with diabetes (103; 8% of patients in the LIRICO trial) and more severe albuminuria (albumin to creatinine ratio >1000 mg/g) to one of the same three study arms. The VALID protocol also targeted a blood pressure of < 130/80 mm Hg.


The LIRICO trial focused on nonrenal primary endpoints, death, and fatal and nonfatal myocardial infarctions and stroke, with renal endpoints as secondary outcomes. The VALID investigators took the opposite approach, primarily focusing on progression to end-stage renal disease and doubling of serum creatinine levels, and relegating the nonrenal-specific outcomes to secondary status.

The recruitment for the studies took place between 2007 and 2013, but the VALID study had a far longer duration of follow-up (4.5 years vs 2.7 years in LIRICO). Given the nearly 7-year enrollment period, it was no surprise that both studies reported funding challenges, with the LIRICO investigators having to amend their study protocol three times.

Where Do These Trials Leave Us?

Alas, the results of the studies leave us in no better position to answer the question of whether dual RAS blockade is beneficial in patients with CKD. The larger LIRICO study showed no improvements in either the primary or secondary endpoints in the dual RAS blockade arm. Monotherapy with either agent was similar to dual therapy over the approximately 3-year follow-up period. By contrast, the VALID trial showed a clear improvement in the primary renal endpoints for patients in the ARB arm, but there were no differences in either group regarding the secondary endpoints. The infographic (above) provides further details.

Both the LIRICO and VALID trials failed to answer the question of the utility of dual ACE inhibitor/ARB blockade in patients with diabetic kidney disease. Although the VALID trial did show improvements in renal endpoints using an ARB, its small sample size calls this result into question. Both LIRICO and VALID were plagued with slow and/or poor enrollment, which may explain the study duration of nearly 7 years and may have had a detrimental effect on the studies themselves. Lack of funding may also have played a deleterious role in conducting these investigations because the ACE inhibitors and ARBs used in the trials were likely generic drugs.

Overall, LIRICO and VALID don't move the needle in any direction regarding dual RAS blocking therapy in patients with CKD and broach the question of whether future trials (and their associated expenses and resources) should be undertaken.

In the interim, how do nephrologists navigate the dual RAS blockade option? What patient population would be considered optimal for the dual therapeutic option?

Previous studies[1] reported hyperkalemia as a pronounced adverse effect, so is "dual" therapy actually "triple" therapy with a concomitant potassium-binding resin (eg, patiromer)? What do you do in your practice? Share with us in the comments below.

Follow Tejas P. Desai, MD, on Twitter: @nephondemand

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