Clinical efficacy of phosphodiesterase-5 inhibitor tadalafil in Eisenmenger syndrome--a randomized, placebo-controlled, double-blind crossover study.

OBJECTIVES: In a randomized double-blind crossover trial, we compared the efficacy of phosphodiesterase-5 (PDE-5) inhibitor tadalafil with placebo in patients of Eisenmenger Syndrome (ES). The primary end point was the change in 6-minute walk test distance (6 MWD). Secondary end points were the effect of the drug on systemic oxygen saturation (SO(2) ), pulmonary vascular resistance (PVR), systemic vascular resistance (SVR), effective pulmonary blood flow (EPBF), and World Health Organization (WHO) functional class. BACKGROUND: ES is a disorder with limited treatment options. Uncontrolled studies have shown PDE-5 inhibitors to be beneficial in patients of ES. METHODS: Twenty-eight symptomatic adult patients of ES with weight ≥30 kg in WHO class II and III were enrolled. Patients were given 40 mg of tadalafil or matching placebo for 6 weeks followed by crossover to the other drug after a washout period of 2 weeks. Assessment of WHO class, exercise capacity by 6 MWD, and various hemodynamic parameters by cardiac catheterization was done at baseline, after 6 weeks and at the end of the study. RESULTS: All patients completed the study. There was significant increase in 6 MWD following drug administration compared with baseline (404.18 ± 69.54 m vs. 357.75 ± 73.25 m, P < .001). Compared with placebo, tadalafil produced significant decrease in PVR (-7.32 ± 1.58, P < .001), resulting in significant increase in EPBF (0.12 ± 0.05, P= .03), SO(2) % (1.72 ± 0.58, P= .007), and WHO functional class (1.96 ± 0.18 vs. 2.14 ± 0.44, P= .025), with no significant change in SVR (P= NS). CONCLUSION: In this first short-term placebo-controlled trial of tadalafil in patients of ES, the drug was well tolerated and significantly improved exercise capacity, functional class, SO(2) , and pulmonary hemodynamics.

Phosphodiesterase-5 inhibitor in Eisenmenger syndrome: a preliminary observational study.

BACKGROUND: Phosphodiesterase-5 inhibitors produce a significant decrease in pulmonary vascular resistance in patients with idiopathic pulmonary arterial hypertension. We studied the effects of tadalafil, a phosphodiesterase-5 inhibitor, on short-term hemodynamics, tolerability, and efficacy over a 12-week period in patients of Eisenmenger syndrome having a pulmonary vascular pathology similar to idiopathic pulmonary arterial hypertension. METHODS AND RESULTS: Sixteen symptomatic Eisenmenger syndrome patients (mean age, 25+/-8.9 years) were assessed hemodynamically at baseline and 90 minutes after a single dose of tadalafil (1 mg/kg body weight up to a maximum of 40 mg). The same dose was then continued daily for 12 weeks, and the patients were restudied. There was a significant decrease in mean pulmonary vascular resistance immediately (24.75+/-8.49 to 19.22+/-8.23 Woods units; P<0.005) and at 12 weeks (19.22+/-8.23 to 17.02+/-6.19 Woods units; P=0.03 versus 90 minutes). Thirteen of 16 patients (81.25%) showed a > or = 20% decrease in pulmonary vascular resistance and were defined as responders. The mean systemic oxygen saturation improved significantly both immediately (84.34+/-5.47% to 87.39+/-4.34%; P<0.005) and at 12 weeks (87.39+/-4.34% to 89.16+/-3.8%; P<0.02 versus 90 minutes) without a significant change in systemic vascular resistance. None of the patients had a fall in systemic arterial pressure, worsening of systemic oxygen saturation, or any adverse reactions to the drug. The mean World Health Organization functional class improved from 2.31+/-0.47 to 1.25+/-0.44 (P<0.0001), and the 6-minute walk distance improved from 344.56+/-119.06 to 387.56+/-117.18 m (P<0.001). CONCLUSIONS: Preliminary evaluation of tadalafil has shown efficacy and safety in selected patients with Eisenmenger syndrome, warranting further investigation in this subgroup of patients.