Effect of Renin-Angiotensin System Inhibitors on the Comparative Nephrotoxicity of NSAIDs and Opioids during Hospitalization

Abstract

Background: Nonsteroidal anti-inflammatory drugs (NSAIDS) are increasingly important alternatives to opioids for analgesia during hospitalization as health systems implement opioid-minimization initiatives. Increasing NSAID use may increase AKI rates, particularly in patients with predisposing risk factors. Inconclusive data in outpatient populations suggests that NSAID nephrotoxicity is magnified by renin-angiotensin system inhibitors (RAS-I). No studies have tested this in hospitalized patients.

Methods: Retrospective, active-comparator cohort study of patients admitted to four hospitals in Philadelphia, Pennsylvania. To minimize confounding by indication, NSAIDs were compared to oxycodone, and RAS-I were compared to amlodipine. We tested synergistic NSAID+RAS-I nephrotoxicity by comparing the difference in AKI rate between NSAID versus oxycodone in patients treated with RAS-I to the difference in AKI rate between NSAID versus oxycodone in patients treated with amlodipine. In a secondary analysis, we restricted the cohort to patients with baseline diuretic treatment. AKI rates were adjusted for 71 baseline characteristics with inverse probability of treatment-weighted Poisson regression.

Results: The analysis included 25,571 patients who received a median of 2.4 days of analgesia. The overall AKI rate was 23.6 per 1000 days. The rate difference (RD) for NSAID versus oxycodone in patients treated with amlodipine was 4.1 per 1000 days (95% CI, -2.8 to 11.1), and the rate difference for NSAID versus oxycodone in patients treated with RAS-I was 5.9 per 1000 days (95% CI, 1.9 to 10.1), resulting in a nonsignificant interaction estimate: 1.85 excess AKI events per 1000 days (95% CI, -6.23 to 9.92). Analysis in patients treated with diuretics produced a higher, albeit nonsignificant, interaction estimate: 9.89 excess AKI events per 1000 days (95% CI, -5.04 to 24.83).

Conclusions: Synergistic nephrotoxicity was not observed with short-term NSAID+RAS-I treatment in the absence of concomitant diuretics, suggesting that RAS-I treatment may not be a reason to choose opioids in lieu of NSAIDs in this population. Synergistic nephrotoxicity cannot be ruled out in patients treated with diuretics.

Graphical abstract

Figure 1.

Exclusions applied to obtain the primary and sensitivity analysis cohorts. CCB, calcium channel blocker (amlodipine); NSAID, nonsteroidal anti-inflammatory drug; Oxy, oxycodone; RAS, renin-angiotensin system inhibitors.

Figure 2.

Interaction estimates from the primary analysism, sensitivity analyeses, and prespecified subgroups. (A) Interaction measures on the ratio scale (ratio of rate ratios [RRR]). Each point represents an RRR estimate, with 95% CI represented by the capped bars. Values above one favor excess AKI with NSAID+RAS-I. (B) Interaction measures on the difference scale (difference in differences [DID]). Each point represents a DID estimate, with 95% CI represented by the capped bars. Values above zero favor excess AKI with NSAID+RAS-I. IPTW, inverse probability of treatment weighting; MV, multivariable.