BACKGROUND: The impact of treatment with vasodilators on the survival of patients with pulmonary arterial hypertension (PAH) remains uncertain. Despite several clinical trials have been carried out in the last 15 years, their primary objective was not to assess mortality but the changes on surrogate end points. METHODS AND RESULTS: We reviewed the results of all clinical trials with vasodilators in PAH and the main results of different metaanalysis. Clinical trials and systematic reviews confirm that vasodilator therapies in patients with PAH who are non-vasoreactive produce a consistent, statistically significant but a marginal effect on exercise capacity assessed by the six-minute walk test. The weighted mean difference (95% CI) achieved with epoprostenol (EPO) or other prostacyclin analogues (PCA), endothelin receptor antagonists (ETRA) and phosphodiesterase-type-5 inhibitors (PDE5-I) was 35.4 m (17.3-53.5), 46.1 m (38.1-54.2) and 33.8 m (24.8-42.7), respectively. When considering the cumulative effects within each drug family, no class of drug produced a statistically significant reduction in all cause mortality. The relative risk rates (95% CI) conferred by EPO or PCA, ETRA and PDE5-I were 0.66 (0.36-1.21), 0.48 (0.19-1.23) and 0.65 (0.16-2.67), respectively. INTERPRETATION: Further trials utilizing similar classes of drugs, and following similar trial designs are unlikely to yield different results or offer any more clinical benefits. Given that PAH is a fatal disease this raises concerns about whether they are ethical to conduct or not. Future trials will need to utilize clinical endpoints rather than the ones that are easy to administer and will need to include longer durations of study and other strategies to test the durability of effect.
BACKGROUND: The impact of treatment with vasodilators on the survival of patients with pulmonary arterial hypertension (PAH) remains uncertain. Despite several clinical trials have been carried out in the last 15 years, their primary objective was not to assess mortality but the changes on surrogate end points. METHODS AND RESULTS: We reviewed the results of all clinical trials with vasodilators in PAH and the main results of different metaanalysis. Clinical trials and systematic reviews confirm that vasodilator therapies in patients with PAH who are non-vasoreactive produce a consistent, statistically significant but a marginal effect on exercise capacity assessed by the six-minute walk test. The weighted mean difference (95% CI) achieved with epoprostenol (EPO) or other prostacyclin analogues (PCA), endothelin receptor antagonists (ETRA) and phosphodiesterase-type-5 inhibitors (PDE5-I) was 35.4 m (17.3-53.5), 46.1 m (38.1-54.2) and 33.8 m (24.8-42.7), respectively. When considering the cumulative effects within each drug family, no class of drug produced a statistically significant reduction in all cause mortality. The relative risk rates (95% CI) conferred by EPO or PCA, ETRA and PDE5-I were 0.66 (0.36-1.21), 0.48 (0.19-1.23) and 0.65 (0.16-2.67), respectively. INTERPRETATION: Further trials utilizing similar classes of drugs, and following similar trial designs are unlikely to yield different results or offer any more clinical benefits. Given that PAH is a fatal disease this raises concerns about whether they are ethical to conduct or not. Future trials will need to utilize clinical endpoints rather than the ones that are easy to administer and will need to include longer durations of study and other strategies to test the durability of effect.
Authors: Mark R Nicolls; Shiro Mizuno; Laima Taraseviciene-Stewart; Laszlo Farkas; Jennnifer I Drake; Aysar Al Husseini; Jose G Gomez-Arroyo; Norbert F Voelkel; Herman J Bogaard Journal: Pulm Circ Date: 2012-10 Impact factor: 3.017