Current role of sildenafil citrate in the treatment of PAH

The increased pulmonary artery (PA) pressure found in PAH is due to disturbances in key vascular mediator pathways including relative deficiencies of vasodilators such as nitric oxide (NO) and prostacyclin, as well as exaggerated production of vasoconstrictors such as endothelin and thromboxanes.² Given the generally accepted role of pulmonary vasoconstriction in PAH, vasodilators such as bosentan, epoprostenol, iloprost, and sildenafil are a natural initial therapeutic choice.^2,3,4,5 

Sildenafil is a selective Phosphodiesterase-5 inhibitor that has been reported to be a potent pulmonary vasodilator.⁶ Sildenafil selectively inhibits phosphodiesterase 5 (PDE5 is abundant in pulmonary and penile tissue) which leads to stabilization of cyclic guanosine monophosphate (cGMP).⁷  cGMP is a second messenger of nitric oxide (NO). Stabilization of cGMP results in increasing nitric oxide (NO) at the tissue level leading to pulmonary vessel vasodilatation.^7,8  Nitric oxide has been considered the closest thing to an ideal vasodilator.² Sildenafil is a more potent acute pulmonary vasodilator than inhaled nitric oxide, however, sildenafil is not pulmonary vascular specific.²  Sildenafil administered orally has been shown to have beneficial effects in patients with PAH even during treatment with inhaled NO.⁷  In addition, sildenafil has been found to exert additive effects on pulmonary hemodynamics when used with inhaled iloprost.⁷  Sildenafil also prevents rebound pulmonary vasoconstriction on withdrawal of inhaled NO.²

Sildenafil was just approved this month (June 6, 2005) for the treatment of pulmonary arterial hypertension. According to Pfizer Inc., clinical trials have demonstrated that sildenafil (Revatio™) 20 mg taken three times daily was effective for the treatment of PAH in comparison to placebo. The most common side effects reported with therapy were headache, stomach upset, flushing, nosebleeds, and insomnia.³ 

Evidence:
M. Kataoka et al stated in a recent article (April 2005) that epoprostenol has become recognized as a therapeutic breakthrough in patients with primary pulmonary hypertension (PPH). However, a significant number of patients have become refractory to epoprostenol, leaving lung transplantation as the only remaining treatment option. The authors completed a study of 20 consecutive patients with PPH (mean pulmonary arterial pressure: 65+/-15 mmHg) who had received epoprostenol for greater than 1 year were included. Patients were divided into 2 groups (responders and non-responders to epoprostenol) Study conclusion: The combination therapy of epoprostenol and oral sildenafil was effective in patients with PPH refractory to continuous infusion of epoprostenol. The study suggested that sildenafil had a synergistic effect with epoprostenol even in patients with PPH refractory to epoprostenol. The authors also concluded that there is a possibility survival would be prolonged by additional therapy with sildenafil.⁴

A. Chockalingam and associates assessed the effects and optimal dosing of sildenafil in primary pulmonary hypertension (PPH). Methods: prospective study with 15 consecutive patients with severe symptomatic PPH of NYHA class III-IV. Therapy: Sildenafil was started at 50 mg twice daily x 4 weeks and increased to 100 mg bid for 4 more weeks in a step-up protocol. Results: NYHA class (baseline 3.8 +/- 0.4 vs. 4 weeks 2.4 +/- 0.5, p = 0.002), Borg dyspnea index (8.1 +/- 1.7 vs. 4.4 +/- 1.9, p = 0.0007), 6-min walk distance (234 +/- 44 vs. 377 +/- 128 m, p = 0.001) and pulmonary artery pressure (125 +/- 15 vs. 113 +/- 18 mm Hg p = 0.05) were significantly improved with sildenafil 50 mg bid at 4 weeks. (The higher dose did not produce further benefit.) Study conclusion: The authors concluded that sildenafil was well tolerated with no adverse effects. They also stated that therapy with sildenafil reduces symptoms, improves effort tolerance and controls refractory heart failure significantly by 2 weeks in 70% of patients at 50 mg twice daily.⁸

Lee AJ et al recently (May 2005) performed an extensive literature search to evaluate the efficacy of sildenafil for the treatment of pulmonary hypertension. Literature retrieval was accessed through MEDLINE (1977-March 2005), Cochrane Library, and International Pharmaceutical Abstracts (1977-March 2005) using the terms sildenafil and pulmonary hypertension. Only studies that included greater than 5 patients and were written in English were evaluated. The authors located eight hemodynamic studies and 12 clinical trials (1 retrospective, 3 double-blind, 8 open-label). Results: “Sildenafil was comparable to nitric oxide and at least as effective as iloprost or epoprostenol in terms of its pulmonary vasoreactivity. Combination therapy with iloprost, nitric oxide, or epoprostenol resulted in enhanced and prolonged pulmonary vascular effects. Clinical trials suggest that sildenafil improves exercise tolerance and New York Heart Association functional class, but large, randomized controlled trials are needed to confirm these findings.” Study conclusion: the authors stated that sildenafil was a promising and well-tolerated agent for the management of pulmonary hypertension, however; further well-designed trials are warranted to establish its place in the treatment of pulmonary hypertension.⁹

B.K. Sastry reported on the results of a study in April 2004. Study design: (n=22) randomized, double blind, crossover study that compared the efficacy of sildenafil with placebo in patients with primary pulmonary hypertension (PPH). The primary end point was the change in exercise time on a treadmill using the Naughton protocol. Patients were randomized to placebo or treatment with sildenafil: 25 to 100 mg tid on the basis of body weight. The evaluation was repeated after six weeks. Then patients were crossed over to alternate therapy. Final evaluation was performed after another six weeks of treatment. Results: Exercise time increased by 44% at the end of placebo phase to 686 +/- 224 s at the end of sildenafil phase (p < 0.0001). With sildenafil, cardiac index improved from 2.80 +/- 0.9 l/m2 to 3.45 +/- 1.1 l/m(2) (p < 0.0001), whereas pulmonary artery systolic pressure decreased insignificantly from 105.23 +/- 17.82 mm Hg to 98.50 +/- 24.38 mm Hg. Study conclusions: Sildenafil significantly improved exercise tolerance, cardiac index, and QOL in patients with PPH.¹⁰

Leuchte HH, et al reported on the results of a study in February 2004 that evaluated the acute hemodynamic response of iNO, iloprost aerosol, and oral sildenafil in 10 consecutive patients (prospective) with PPH during right-heart catheterization. Study results: iNO, iloprost aerosol, and sildenafil caused a significant fall in mean pulmonary artery pressure and pulmonary vascular resistance (PVR) [p < 0.05]. Study conclusion: All three substances (iNO, iloprost aerosol, and oral sildenafil) significantly improved pulmonary hemodynamics in patients with PPH with the most prominent hemodynamic effects and improvement of oxygenation observed with iloprost aerosol.⁷

Ng J, Finney SJ, et al stated that the use of inhaled NO for the treatment of PAH is limited by its mode of delivery and high costs. The authors reported that a patient with severe secondary PAH and right ventricular dysfunction who was previously stabilized with inhaled nitric oxide, was able to crossover to oral sildenafil therapy and maintain control of pulmonary hypertension, and expedited the discontinuation of respiratory and cardiovascular organ support. The authors concluded, “The relative pulmonary vascular specificity of oral sildenafil, and its low cost, makes it an attractive therapeutic alternative to inhaled nitric oxide, and warrants further study.”¹¹

Conclusion:
According to previous studies, sildenafil appears to be an important therapeutic addition for patients with pulmonary arterial hypertension. This agent has the advantage of having a low incidence of side effects, is easy to administer (oral dosage form), and is much cheaper compared to many of the alternatives. Also, according to Lee AJ et al, sildenafil was comparable to nitric oxide and at least as effective as iloprost or epoprostenol in terms of its pulmonary vasoreactivity.⁹ Finally, sildenafil may increase the overall survival rate in patients with PAH, and may have some utility as an alternative agent for patients refractory to other agents such as epoprostenol and inhaled nitric oxide.^2,4,7 The next logical step is to conduct larger, randomized trials in order to assess the long-term effects of sildenafil on clinically important outcomes and to further compare sildenafil against placebo or other PAH drugs.^5,12

2) Mehta S. Sildenafil for pulmonary arterial hypertension: exciting, but protection required. Chest. 2003 Apr; 123(4): 989-92.

3) Pfizer Inc. FDA Approves Pfizer’s Revatio as Treatment for Pulmonary Arterial Hypertension. . Accessed June 23, 2005.

4) Kataoka M, Satoh T, Manabe T, Anzai T, Yoshikawa T, Mitamura H, Ogawa S. Oral sildenafil improves primary pulmonary hypertension refractory to epoprostenol. Circ J. 2005 Apr;69(4):461-5.

5) Kanthapillai P, Lasserson T, Walters E. Sildenafil for pulmonary hypertension. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD003562.

6) Karatza AA, Bush A, Magee AG. Safety and efficacy of Sildenafil therapy in children with pulmonary hypertension. Int J Cardiol. 2005 Apr 20;100(2):267-73.

7) Leuchte HH, et al. Hemodynamic response to sildenafil, nitric oxide, and iloprost in primary pulmonary hypertension. Chest. 2004 Feb; 125(2): 580-6.

8) Chockalingam A, Gnanavelu G, Venkatesan S, Elangovan S, Jagannathan V, Subramaniam T, Alagesan R, Dorairajan S. Efficacy and optimal dose of sildenafil in primary pulmonary hypertension. Int J Cardiol. 2005 Mar 10;99(1):91-5.

9) Lee AJ, Chiao TB, Tsang MP. Sildenafil for pulmonary hypertension. Ann Pharmacother. 2005 May;39(5):869-84.

10) Sastry BK. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol, 2004 Apr;43 (7), pp. 1149-53.

11) Ng J, Finney SJ, Shulman R, Bellingan GJ, Singer M, Glynne PA. Treatment of pulmonary hypertension in the general adult intensive care unit: a role for oral sildenafil? Br J Anaesth. 2005 Jun;94(6):774-7.

12) American Heart Association rapid access journal report. Impotence drug may help children with fatal lung disorder. 06/23/2005. . Accessed: June 23, 2005.