Surrogate end points in pulmonary arterial hypertension: assessing the response to therapy

Abstract

Recent discoveries in the disease pathophysiology of pulmonary arterial hypertension have been translated into effective therapies tested in clinical trials. The studies have focused on surrogate and intermediate end points, thought to reflect quantity and quality of life, respectively. The authors present the necessary requirements for establishing the reliability and validity of such end points before they may be used dependably. The authors also review the available data, strengths, and weaknesses of potential end points in pulmonary arterial hypertension.

Figure A

The intervention and surrogate act in the single causal pathway of PAH to morbidity or mortality. This setting has the greatest potential for the surrogate end point to be valid. Situations in which surrogates may fail include: B. The surrogate is not in the causal pathway of PAH. C. Of several causal PAH disease pathways to morbidity and mortality, the intervention affects only the pathway mediated through the surrogate. D. The surrogate is not in the pathway of the intervention’s effect or is insensitive to its effect. E. The intervention has mechanisms of action (either beneficial or adverse) independent of the disease process of PAH. Dotted lines = mechanisms of action that might exist. Adapted from Fleming TR and DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med 1996;125:605–613.