The Effects of Pantoprazole on Kidney Outcomes: Post Hoc Observational Analysis from the COMPASS Trial

Abstract

Key Points:

1. In this post hoc analysis of a randomized controlled trial, the proton pump inhibitor pantoprazole led to a faster rate of eGFR decline as compared with placebo.

2. Additional studies are needed to determine the effect of proton pump inhibitors on those at higher risk of adverse kidney outcomes.

Background: Observational studies have found an association between proton pump inhibitor use and worsening kidney function. It is unclear whether these associations are causal. We conducted post hoc analyses to determine the effect of pantoprazole on kidney function using data from the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial, a 17,598-participant randomized trial comparing pantoprazole (8791) with placebo (8807).

Methods: The primary outcome was the rate of eGFR change. Rate of eGFR change was based on the two eGFR measures available: the eGFR at randomization and at the open-label extension study that enrolled at trial conclusion. Secondary outcomes included incident CKD (defined by eGFR <60 ml/min per 1.73 m² at open-label extension or case report forms) as well as AKI, acute nephritis, and nephrotic syndrome.

Results: Eight thousand nine hundred ninety-one of the 17,598 participants randomized to pantoprazole/placebo (51%) had eGFR recorded at baseline and open-label extension enrollment and were included in the rate of eGFR change population (mean age 67 [SD 8] years, 22% female, mean baseline eGFR 75 [SD 17.5] ml/min per 1.73 m²). The mean duration between randomization and open-label extension eGFR was 3.3 (SD 0.8) years. The placebo rate of eGFR change was −1.41 (SD 4.45) ml/min per 1.73 m² per year. The pantoprazole rate of eGFR change was −1.64 (SD 4.47) ml/min per 1.73 m² per year. In adjusted analyses, pantoprazole had a 0.27 ml/min per 1.73 m² per year greater decline in eGFR (95% confidence interval [CI], 0.11 to 0.43). The odds ratio for the effect of pantoprazole on incident CKD was 1.11 (95% CI, 0.98 to 1.25) and on AKI was 0.89 (95% CI, 0.65 to 1.21). There were five nephrotic syndrome outcomes recorded and one event of acute nephritis.

Conclusions: In this post hoc analysis of the COMPASS trial, pantoprazole resulted in a statistically significant greater rate of eGFR decline as compared with placebo.

Clinical Trial registry name and registration number:: Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS), NCT01776424.

Graphical abstract

Figure 1

Flow diagram illustrating the analysis population for each kidney outcome. (A) Mean rate of eGFR change. (B) CKD composite outcome. (C) Other kidney outcomes (AKI, acute nephritis, and nephrotic syndrome). ASA, aspirin; PPI, proton pump inhibitor; Riva, rivaroxaban.

Figure 2

Distribution (percent of participants) of rate of change of eGFR (ml/min per 1.73 m² per year, CKD-EPI) by treatment group (placebo versus pantoprazole). CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration.

Figure 3

Mean rate of eGFR change (ml/min per 1.73 m² per year) pantoprazole as compared with placebo by subgroup and overall population in fully adjusted analyses (adjusting for stratification factors of center and rivaroxaban/ASA randomization as well as age as a continuous variable, baseline eGFR as a continuous variable, diabetes, hypertension, race—Black race relative to all other races, and sex). CAD, coronary artery disease; eGFR, eGFR in ml/min per 1.73 m²; PAD, peripheral arterial disease.