Efficacy and safety of PDE-5 inhibitor tadalafil in pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a life threatening disease for which phosphodiesterase-5 inhibitor sildenafil is recently approved. We aimed to evaluate the efficacy and safety of tadalafil, a long acting congener of sildenafil, in treatment of PAH related to previous left to right shunt lesions. METHODS: In this blinded, cross over study, 11 patients with severe PAH related to congenital left to right shunt lesions (Eisenmenger syndrome) were randomly assigned to tadalafil (20 mg daily) or placebo for 4 weeks period, separated by a wash out period of at least 2 weeks. They were symptomatic with a six minute walk distance (6MWD)>or=50 m. The change in 6MWD, echo-Doppler determined pulmonary artery systolic pressure (PASP), WHO Class and modified Borg Dyspnea Index (BDI) were assessed after each therapy. RESULTS: Eight patients who completed the study protocol were analyzed. Tadalafil was associated with a significant increase in 6MWD (mean 409.25 SD 40.25 m vs 319.37 SD 42.39 m, p<0.0001), reduction in PASP (88.75 SD 23.26 mmHg vs 109.5 SD 23.78 mmHg, p<0.0001), improvement in BDI (4.62 SD 2.56 vs 6.37 SD 2.61, p=0.021) and WHO Class (6 patients vs 2 patients), compared to placebo. Tadalafil was well tolerated with no significant untoward effects. CONCLUSIONS: Tadalafil, in patients with PAH related to previous congenital left to right shunt lesions, lead to a significant improvement in exercise capacity (6MWD), PASP and WHO Class with reduced perceived exertion and was well tolerated.

The efficacy and tolerability of sildenafil in patients with moderate-to-severe pulmonary hypertension.

BACKGROUND: Pulmonary arterial hypertension is a life-threatening disease for which continuous intravenous infusion of prostacyclin has proved effective. However, it carries the risk of serious complications arising from the complex delivery system. Prostacyclin analogs, endothelin antagonists, and the phosphodiesterase-5 inhibitor sildenafil are emerging promising therapies. This study was aimed at evaluating the utility of oral sildenafil in patients with pulmonary hypertension of varied etiology, poorly controlled on conventional treatment. METHODS AND RESULTS: Ten consecutive patients with pulmonary hypertension, either primary or related to previous left-to-right shunts, thromboembolism, or interstitial lung disease, poorly controlled on conventional therapy such as warfarin, calcium antagonists, digitalis, and diuretics, were included. A thorough clinical, laboratory, and comprehensive echo Doppler evaluation was performed before enrollment in the trial to establish the diagnosis and obtain baseline data. Subjects received sildenafil 25 mg 8 hourly, or a matching placebo for two weeks each, in a randomized, double-blind, crossover design. A run-in period of two weeks was permitted between the two therapies during which patients continued to receive the conventional therapy without any vasodilator. At the end of each therapy period, the patients were evaluated for symptoms, New York Heart Association class, distance covered during the 6 min walk test, rating of modified Borg dyspnea score, and systolic pulmonary artery pressure using echo Doppler. The differences in the above variables at the end of sildenafil and placebo therapies were compared. Nine patients completed the study protocol. Sildenafil, compared to placebo, was associated with improved exercise tolerance as determined by the 6 min walk test (266.67+/-131.45 m v. 170+/-105 m; p<0.005), decrease in modified Borg dyspnea score (3.56+/-1.01 v. 5.11+/-1.45; p<0.01), decrease in Doppler-estimated pulmonary artery systolic pressures (55.33+/-16.52 mmHg v. 75.33+/-19.75 mmHg; p<0.005), improvement in New York Heart Association class (2 patients), and improvement in symptoms. Sildenafil was well tolerated with no untoward effects; further, no significant changes in heart rate or blood pressure occurred during the study period. CONCLUSIONS: Sildenafil improves exercise capacity and symptoms, and decreases pulmonary artery pressures in patients with primary or secondary pulmonary hypertension of varied etiology.