Regression to the Mean in SYMPLICITY HTN-3: Implications for Design and Reporting of Future Trials.

Regression to the mean (RTM) describes the tendency for an extreme measurement on 1 occasion to become less extreme when measured again. RTM may affect clinical trial data interpretation when the outcome measure has high variability. We investigated RTM in the SYMPLICITY HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension) trial of renal denervation versus a sham procedure. Analysis of covariance was performed on the 6-month change in systolic blood pressure, estimating a mean treatment difference of -4.11 mm Hg (95% confidence interval: -8.44 to 0.22 mm Hg; p = 0.064), which was similar to the unadjusted difference but with a smaller confidence interval. RTM occurred in both arms, but it had a negligible effect on the observed treatment difference. A second example concerns changes in hemoglobin A1c in a nonrandomized study. These findings emphasize the importance of incorporating RTM and analysis of covariance into the design and reporting of clinical studies of how treatments affect time changes in quantitative outcomes. (Renal Denervation in Patients With Uncontrolled Hypertension [SYMPLICITY HTN-3]; NCT01418261).