ACEI and ARBs in CKD: Should Anyone Not Receive Them?

Background: Underutilization of ACEIs and ARBs

The angiotensin-converting enzyme inhibitor (ACEI) captopril received US Food and Drug Administration approval in 1981. In 1993, Lewis and colleagues^[1] demonstrated that captopril slowed the progression of nephropathy among people with type 1 diabetes. Clinical trials have demonstrated mortality benefits from ACEIs, such that review articles on these benefits in patients with heart disease began appearing as early as 1995.^[2]

The presence of chronic kidney disease (CKD) is a recognized risk factor for heart disease.^[3] Patients with CKD are more likely to die a cardiovascular death than to live long enough to require dialysis.^[4] Finally, approximately one half of patients who initiate dialysis will die because of cardiovascular problems.^[5] So why, in these post-millennial decades, are we still publishing reports of underutilization of ACEIs and angiotensin II receptor blockers (ARBs) among people with compromised kidney function?

Could it be that ACEI/ARBs do not have the same mortality benefit in people with CKD or end-stage renal disease (ESRD) as seen in people with cardiac disease? In a word, no.

A recent analysis^[6] published in the Journal of the American College of Cardiology examined a population of 141,413 US veterans with CKD. The glomerular filtration rates (GFRs) of patients receiving their medications through the Veterans Affairs Outpatient Pharmacy were estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. From these, researchers identified patients with CKD (GFR > 60 mL/min with proteinuria, or GFR < 60 mL/min) who did not receive ACEIs or ARBs between 2002 and 2004. These patients were separated into 2 groups according to whether or not they received an ACEI or ARB during the following 2 years (2004 through 2006).

To allow the 2 groups to be more comparable, propensity scoring was used. Propensity scoring compares people taking and not taking ACEI or ARBs to determine factors associated with the use or nonuse of an ACEI/ARB. Two subgroups are then selected from the groups taking and not taking an ACEI/ARB who resemble each other with respect to those factors.

As seen in many other studies, ACEI/ARB use declined in patients as their eGFR declined. For every increase in estimated GFR (eGFR) of 10 mL/min, the likelihood of the use of ACEIs/ARBs rose by 13% (odds ratio, 1.13; 95% confidence interval [CI], 1.12-1.15; P < .001). When all patients initially identified as taking and not taking ACEIs/ARBs were compared, patients taking ACEIs/ARBs had a lower risk for mortality (hazard ratio, [HR], 0.81; 95% CI, 0.78-0.84). When the groups were restricted to those chosen by the propensity analysis, the beneficial association was strengthened (HR, 0.37; 95% CI 0.34-0.41). Therefore, the lower the eGFR, the greater the degree of underutilization.

If all patients regardless of baseline eGFR benefit from ACEIs/ARBs, why do we not give these medications to the people who need them the most? Could it be that ACEIs/ARBs provide less benefit to slowing nephropathy as eGFR at initiation declines?

This is also not the case. The RENAAL trial,^[7] published in 2001, randomly assigned patients with diabetic nephropathy to receive losartan or placebo and followed them for progression of kidney disease, ESRD, and mortality. Losartan lowered the risk for these events by 16% (P = .02).

A secondary analysis^[8] subsequently demonstrated that this benefit did not differ among groups based on kidney function at entry. Specifically, in all 3 tertiles of patients grouped by kidney function (creatinine values of 0.9-1.6, 1.6-2.0, and 2.1-3.6 mg/dL), losartan reduced the risk for ESRD by 24.6%, 26.3%, and 35.5%, respectively, over the mean follow-up of 3.4 years.

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