The validity of using changes in serum creatinine as surrogate endpoints for outcomes in heart failure was examined in 301 patients in the Diuretic Optimization Strategies Evaluation trial.

Decreases in serum creatinine, when incorrectly assumed to be linearly related to outcomes, were paradoxically associated with a substantially increased risk for adverse events.

Worsening in serum creatinine during the randomized intervention was not associated with an increase in adverse outcomes.

Improvement in renal function during the randomized intervention was strongly associated with poor outcomes.

The practice of using mild to moderate-sized changes in serum creatinine as an endpoint in heart failure clinical trials may be inappropriate.