Commentary on Complications of Immunosuppressive Treatments for Glomerulonephritis

Teaching Statement

The reliable assessment of adverse drug effects, including complications of immunosuppressive therapies, optimally synthesizes data from multiple sources, including safety signals from preclinical studies and clinical development, adverse events from randomized trials supporting regulatory approval, and outcomes detected in postapproval studies and pharmacosurveillance programs. Randomized trial data are valuable for assessing drug safety, because these studies can separate the effect of a drug from the characteristics of the people who receive it and use standardized procedures to collect adverse events. Greater precision in risk assessment may be achieved by combining adverse event data across randomized studies in meta-analysis. Nonetheless, the exclusive use of randomized trial data to evaluate harm due to medications has some important limitations.

(1) Trials tend to enroll relatively healthy participants and exclude those with multiple comorbidities, who may be more susceptible to the adverse effects of a novel drug.

(2) Trials tend to include comprehensive monitoring procedures to maximize safety. Although these procedures are designed to protect the safety of study participants, they are typically not reflective of monitoring procedures in real world clinical practice.

(3) Trials may include an insufficient number of participants to reliably estimate the rate of uncommon events.

(4) Trials may be of insufficient duration to observe long-term adverse outcomes.

A classic example showing the discrepancy between assessing drug safety in randomized trials and nonrandomized studies is the occurrence of hyperkalemia due to spironolactone treatment (1,2). In a randomized trial of 1663 patients with systolic heart failure, the incidence of serious hyperkalemia in the spironolactone group was low and nearly identical to that in the placebo group. In contrast, a large observational study reported that spironolactone use was associated with an estimated 20-fold greater risk of serious hyperkalemia. This difference in harm most likely reflects the intensive monitoring procedures of the randomized trial, which frequently measured serum potassium levels and reduced or held spironolactone for even small increases in potassium. In contrast, the procedures for monitoring serum potassium levels in clinical practice are less stringent and more variable.

Observational studies can provide important drug safety data that may not be easily obtained from trials. These studies can evaluate large numbers of users and nonusers of particular medications under real world conditions to identify rare and unintended adverse effects that may have been missed in trials. Observational studies are also useful for assessing the harms of medications among patients who have serious comorbidities that would prevent inclusion in trials, including advanced kidney disease. The primary limitation of observational studies of medication use is that potential differences in the characteristics of users versus nonusers of the medication could affect the frequency of adverse outcomes (i.e., confounding). This limitation can be reduced but not eliminated by careful measurement of potential confounding characteristics and comprehensive adjustment for these characteristics in the analysis.

Disclosures

None.