The first Russian experience of sildenafil application in patients with idiopathic pulmonary hypertension

Over the last decade, the interest in the treatment of idiopathic pulmonary hypertension (IPAH) has greatly increased because of the development and implementation of innovative therapeutic approaches. One of the modern drug groups for the treatment of pulmonary arterial hypertension are phosphodiesterase type 5 inhibitors (PDE5), which can cause pulmonary vasodilation via a NO-dependent mechanism.The aim of the research was to study the efficacy and safety of sildenafil treatment in patients with IPAH received 16-week course and to study sildenafil impact on clinical, hemodynamic and functional status.Material and methods: 20 patients with IPAH (mean age 40.9±11.5 years) functional class (FC) II-IV (WHO), who were receiving standard therapy (anticoagulants, diuretics, glycosides, calcium antagonists), were prescribed sildenafil 20 mg three times a day for 16 weeks. Initially, and after 16 weeks of treatment we studied FC, and the results of the six-minute walk test (6MWT), transthoracic echocardiography (ECHO), right heart catheterization (RHC) and laboratory tests to determine the safety of the therapy were carried out, as well.Results: the group of patients had 6MWT distance of 344±116 m at the beginning of the study. For about 90% of the patients suffered from dizziness, 75% - from the pain in the heart, 65% of the patients had edema and 35% - hepatomegaly. The patients suffered from severe pulmonary hypertension according to the functional and hemodynamic status. The estimated pulmonary artery systolic pressure (PASP) according to ECHO results was 89.6±22 mm Hg. According to the data from RHC we noted the elevation of mean pulmonary arterial pressure (mPAP) to 56.3±19 mm Hg, of pulmonary vascular resistance (PVR) to 1218±709 dyne/sec x per x cm-5 and the decrease in cardiac output (CO) - 3.4±0.8 l/min/m2.There were slight increasing in 6MWT distance (+23 m, p>0.05) and a statistically significant improvement in clinical status in comparison with the initial data: dizziness - 71%, heart pain - 38%, edema and hepatomegaly were observed in 15% and 14% (p<0.05) of the cases, respectively, during 4 weeks of therapy. ECHO showed statistically significant reduction of estimated PASP - 83±14 mm Hg (p<0.05). We noted a statistically significant increase in 6MWT distance +112 towards 16 week of treatment in comparison with the initial data (p<0.05). We noted a statistically significant reduction of PASP (from 89.6±23.1 mm Hg to 75.2±14 mm Hg, p<0.05), according to the data from ECHO. At the end of 16 weeks of sildenafil treatment all patients demonstrated no edema and hepatomegaly; dizziness was diagnosed only in 26% of the cases (p<0.05), heart pain - in 10%. Sildenafil treatment demonstrated statistically significant dynamics of key hemodynamic characteristics using RHC - mPAP (-9,3 mm Hg), PVR (235 dyne/sec x per x cm-5), CO (-0.4 l/min/m2).On the background of sildenafil therapy the patients had following side effects: palpitations - 3 patients (15%), hot flashes - 2 patients (10%), headache - 1 patient (5%), systemic hypotension - 3 patients (15%). All mentioned side effects occurred within the first 2-3 days of therapy and were minor and did not cause dose correction.Conclusions. The application of sildenafil in dose of 60 mg per day in patients with IPAH within 16 weeks had resulted in a significant increase in 6MWT, improvement of FC and hemodynamic parameters according to the data from ECHO and RHC. Therapy characterized by a good tolerance and accompanied by no clinically significant side-effects.

idiopathic pulmonary hypertension, phosphodiesterase type 5 inhibitors, sildenafil

1. Российские рекомендации по диагностике и лечению легочной гипертензии. 2007.

2. Morrell N.W, Adnot S, Archer S.L et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54: S20-31.

3. Corbin J.D, Francis S.H. Pharmacology of phosphodiesterase-5 inhibitors. Int J Clin Pract 2002; 56: 453-9.

4. Benza R.L, Miller D.P, Gomberg-Maitland M et al. Predicting survival in pulmonary arterial hypertension. Insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation 2010; 122: 164-72.

5. Galie N, Hoeper M.M, Humbert M et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT) Eur Heart J 2009; 30 (20): 2493-537.

6. Чазова И.Е., Авдеев С.Н., Царева Н.А. и др. Клинические рекомендации по диагностике и лечению легочной гипертензии. Терапевт. архив. 2014; 9: 4-23.

7. Беленков Ю.Н., Чазова И.Е. Первичная легочная гипертензия. М.: Нолидж, 1999.

8. Galie N, Rubin L.J, Hoeper M.M et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double - blind, randomized controlled trial. Lancet 2008; 371: 2093-100.

9. Mc Laughlin V.V, Archer S, Badesch D.B et al. ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension: A Report of the American College of Cardiology Foundation Task Force of Expert Consensus Documents and the American Heart Association Developed in Collaboration With the American College of Chest Physicians; American Thoracic Society and the Pulmonary Hypertension Association J Am Coll Cardiol 2009; 53; 1573-619.

10. Gresser U, Gleiter C.H. Erectile dysfunction: Comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil, and tadalafil: Review of the literature. Eur J Med Res 2002; 7: 435-46.

11. Galie N, Ghofrani H.A, Torbicki A et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005; 353 (20): 2148-57.

12. Zeng W.J, Sun Y.J, Gu Q et al. Impact of sildenafil on survival of patients with idiopathic pulmonary arterial hypertension. J Clin Pharmacol 2012; 52 (9): 1357-64-f.

13. Michelakis E.D, Tymchak W, Noga M et al. Long - term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension. Circulation 2003; 108: 2066-9.

14. Lee A.J, Chiao T.B, Tsang M.P. Sildenafil for pulmonary hypertension. Ann Pharmacother 2005; 39 (5): 869-84.

15. Prasad S, Wilkinson J, Gatzoulis M.A. Sildenafil in pulmonary hypertension. N Engl J Med 2000; 343: 1342.

16. Chockalingam A, Gnanavelu G, Venkatesan S et al. Efficacy and optimal dose of sildenafil in primary pulmonary hypertension. Int J Cardiol 2005; 99 (1): 91-5.

17. Волков А.В., Юдкина Н.Н., Курмуков И.А. и др. Влияние силденафила на клинические проявления и гемодинамические показатели у больных легочной артериальной гипертензией, ассоциированной с системными ревматическими заболеваниями. Системные гипертензии. 2014; 11 (3): 61-5.

18. Янулевич О.С., Ковалев И.А., Соколов А.А., Кривощеков Е.В. Использование ингибитора фосфодиэстеразы при лечении резидуальной легочной гипертензии у детей после хирургической коррекции врожденных пороков сердца.. Кардиология. 2012; 3.