ACE Inhibitor and Angiotensin Receptor Blocker Use and Mortality in Patients with Chronic Kidney Disease

Molnar MZ, Kalantar-Zadeh K, Lott EH et al.
J Am Coll Cardiol. 2014 Feb 25;63(7):650-8

Background

Cardiovascular (CV) morbidity and mortality are more prevalent in patients with chronic kidney disease (CKD), than in populations without CKD.
Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs) are commonly prescribed in patients with comorbid conditions like coronary artery disease and congestive heart failure, because they have a favourable effect on mortality and CV outcomes [1-3]. These agents are thought to delay progression of kidney disease in patients with nondialysis-dependent CKD [4-10], but their effect on mortality in these patients is unclear, as conflicting results have been published.
This study examined the effect of ACEI/ARB administration on mortality in a large cohort of US veterans with non-dialysis-dependent CKD [11,12]. The cohort consisted of 141413 patients (26051 treated and 115362 untreated), of which a propensity score-matched cohort of 40494 patients (of whom half were exposed to ACEI/ARB) was used for the primary analyses. Median cohort time was 4.7 years (IQR: 3.6-5.2).

Main results

• Of 20247 patients who started ACEI/ARB treatment, only 8.4%, 17% and 66% still received their medication 100%, >90% and >50% of time respectively, during follow-up visits.
• In the propensity-score matched cohorts, mortality rate was 22.6 per 1000 patient-years (95%CI: 22.0-23.2) in the treated group and 26.5 per 1000 patient-years (95%CI: 25.9-27.2) in the untreated group.
• ACEI/ARB treatment was associated with lower mortality in both intention-to-treat (HR: 0.81, 95%CI: 0.78-0.84) and as-treated (OR: 0.37, 95%CI: 0.34-0.41) models.
• The benefit on mortality risk was consistent across different analysed subgroups, and independent on eGFR level, although a smaller benefit was seen in nondiabetic patients.
• In a sensitivity analysis on the full cohort, including patients who received ACEI/ARB more than 1 year after cohort entry, ACEI/ARB administration was also associated with a lower risk of mortality in both the intention-to-treat analysis (HR: 0.66, 95% CI: 0.64-0.68) and the as-treated analysis (OR: 0.48, 95% CI: 0.44-0.52).

Conclusion

In these non-dialysis-dependent patients with CKD, treatment with ACEI/ARB was associated with lower all-cause mortality, in different statistical models. Discontinuation rates of ACEI/ARB were high: less than 10% of patients received renewed prescriptions on all follow-up visits, and 66% at >50% of visits. This implies that the 19% reduction in mortality in the intention-to-treat analysis might be an underestimation of the true effect of these agents. Indeed the as-treated analyses showed a greater benefit of ACEI/ARB. ACEI/ARB may thus have benefits beyond renoprotection in this patient population. RCTs with a mortality endpoint will need to confirm this.

Editorial comment [13]

Adequate statistical techniques were applied to account for the inherent reasons that patients would be prescribed the treatment of interest. The observed effect might be an underestimation, since the treated population had a higher prevalence of CV disease, with associated higher risk  of mortality. However, it could also be postulated that these patients were monitored more closely, and may have received more intensive or better medical care.
The recently updated KDIGO guidelines recommend treatment with ACEI and ARB to slow down CKD progression in patients with hypertension and micro- or macroalbuminuria. The guideline does not distinguish between diabetic and non-diabetic CKD, based on earlier RCTs. Thus, the current finding that the observed effect of treatment was more pronounced in patients with diabetes needs to be interpreted with caution.
There is a need for more convincing mortality data in patients with CKD and predisposing conditions. Not only (CV) mortality data, but also end-stage renal disease should be analysed when evaluating the effect of interventions in CKD.

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