Are Hemodynamics Surrogate End Points in Pulmonary Arterial Hypertension?

• Published in: Circulation (New York, N.Y.) Vol. 130; no. 9; pp. 768 - 775
• Main Authors: Ventetuolo, Corey E., Gabler, Nicole B., Fritz, Jason S., Smith, K. Akaya, Palevsky, Harold I., Klinger, James R., Halpern, Scott D., Kawut, Steven M.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD by the American College of Cardiology Foundation and the American Heart Association, Inc 26.08.2014; Lippincott Williams & Wilkins
• Subjects: Adult; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Biomarkers; Blood and lymphatic vessels; Cardiology. Vascular system; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Familial Primary Pulmonary Hypertension; Female; Hemodynamics; Humans; Hypertension, Pulmonary - physiopathology; Male; Medical sciences; Middle Aged; Pneumology; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Randomized Controlled Trials as Topic; Hypertension; pulmonary heart disease; Lung disease; Respiratory disease; Lung; hypertension, pulmonary; Cardiovascular disease; Respiratory system; Artery; Pulmonary hypertension; trials; Blood vessel; Heart disease; Clinical trial; End; Circulatory system; Hemodynamics; Cardiology; hemodynamics
• DOI: 10.1161/CIRCULATIONAHA.114.009690
• ISSN: 0009-7322; 1524-4539

BACKGROUND—Although frequently assessed in trials and clinical practice, hemodynamic response to therapy has never been validated as a surrogate end point for clinical events in pulmonary arterial hypertension (PAH). METHODS AND RESULTS—We performed a patient-level pooled analysis of 4 randomized, placebo-controlled trials to determine whether treatment-induced changes in hemodynamic values at 12 weeks accounted for the relationship between treatment assignment and the probability of early clinical events (death, lung transplantation, atrial septostomy, PAH hospitalization, withdrawal for clinical worsening, or escalation in PAH therapy). We included 1119 subjects with PAH. The median (interquartile range) age was 48 years (37–59 years), and 23% were men. A total of 656 patients (59%) received active therapy (101 [15%] iloprost, 118 [18%] sitaxsentan, 204 [31%] sildenafil, and 233 [36%] subcutaneous treprostinil). Active treatment significantly lowered right atrial pressure, mean pulmonary artery pressure, and pulmonary vascular resistance and increased cardiac output and index (P<0.01 for all). Changes in hemodynamic values (except for right atrial pressure and mean pulmonary artery pressure) were significantly associated with the risk of a clinical event (P<0.02 for all). Although active treatment approximately halved the odds of a clinical event compared with placebo (P<0.001), changes in hemodynamics accounted for only 1.2% to 13.9% of the overall treatment effect. CONCLUSIONS—Treatment-induced changes in hemodynamics at 12 weeks only partially explain the impact of therapy on the probability of early clinical events in PAH. These findings suggest that resting hemodynamics are not valid surrogate end points for short-term events in PAH clinical trials.