The-Efficacy-and-Tolerability of Sildenafil in Patients With Moderate-to-Severe Pulmonary Hypertension

Anil Bharani, Vivek Mathew, Ashutosh Sahu, Basant Lunia

Division of Cardiology, Department of Medicine,
M.G.M. Medical College and M.Y. Hospital, Indore

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. (Indian Heart J 2003; 55: 55–59)

Key Words: Pulmonary hypertension, Sildenafil, Echocardiography

Pulmonary arterial hypertension (PAH) is characterized by a progressive increase of pulmonary vascular resistance leading to right ventricular failure and death (WHO 1998).1,2 Pulmonary arterial hypertension includes primary pulmonary hypertension (PPH) with no apparent cause, PAH secondary to congenital shunt lesions, connective tissue disorders, and portal hypertension, druginduced PAH, and HIV-related PAH.1,2 The current therapeutic options available for PAH include anticoagulants, calcium-channel blockers, epoprostenol (prostacyclin), iloprost, beraprost, the endothelin receptor antagonist bosentan, and phosphodiesterase type-5 (PDE5) inhibitor sildenafil.3 However, in many parts of the world, therapeutic options for patients with PAH are limited in the absence of availability of prostacyclins3 and thus sildenafil could be a useful alternative. 

Sildenafil-induced inhibition of PDE5 increases the cellular levels of cGMP, potentiating vascular smooth muscle relaxation, particularly in the lungs where PDE5 is found in high concentrations.4 Sildenafil has been reported to inhibit hypoxia-induced pulmonary hypertension,5 cause sustained reduction in pulmonary artery pressures and pulmonary vascular resistance in PPH,6 blunt the rebound pulmonary hypertension seen following withdrawal of inhaled nitric oxide,7 lead to impressive clinical benefits in childhood PPH,8 and cause selective pulmonary vasodilatation in a lamb model of PAH.9

We report the results of a randomized, double-blind, placebo-controlled, crossover study designed to determine the efficacy of short-term oral administration of sildenafil on exercise capacity, symptoms, and Doppler-determined pulmonary artery pressures in NYHA class II–IV patients with PAH.

Methods

Selection of patients: Ten consecutive, symptomatic (NYHA class >II) patients with Doppler-estimated pulmonary systolic pressure >35 mmHg with normal left ventricular function and no reversible cause for PAH were taken up for the study. They gave well-informed written consent for participation in the study and all except one completed the study protocol. The institutional ethics committee approved the protocol. Patients were excluded if they had any contraindications to sildenafil therapy or if they had any reversible cause for pulmonary hypertension such as valvular heart disease.

Study design: The study was carried out at a large referral center of central India as a prospective, randomized, double-blind, crossover trial. To establish the diagnosis, patients were subjected to a thorough physical examination, routine laboratory evaluation, chest X-ray, electrocardiogram (ECG), and comprehensive echocardiographic evaluation at baseline. Before randomization, they were allowed a run-in period of one week after stoppage of their previous vasodilator therapy; they then received either sildenafil 25 mg 8 hourly or matching placebo for two weeks in a crossover design with a washout period of at least two weeks between the two therapies.

Outcome measures: The patients were evaluated for exercise capacity as indicated by the 6 min walking distance. The secondary measures of efficacy were change in symptoms and NHYA functional class, change in modified Borg dyspnea index10 (a measure of perceived breathlessness on a scale of 0 to 10, with higher values indicating more severe dyspnea), and change in resting pulmonary artery systolic pressures as estimated from Doppler tricuspid regurgitant jet velocities or from the gradient across the ventricular septal defect or patent ductus, wherever applicable.11 Echo-Doppler studies (GE Logic 500, MD, USA) were done by a single experienced observer who was blind to the therapy patients were receiving.

Statistical analysis: Changes in variables during treatment with sildenafil and placebo were analyzed with the paired Student’s t test. The null hypothesis was that there should be no significant difference in the exercise capacities and the pulmonary systolic pressures before and after 2 weeks of sildenafil therapy. A probability value of p<0.05 was considered significant.

Results

Baseline study group characteristics: There were 5 females and 4 males, 19 to 60 years of age, in NYHA functional classes II–IV, having pulmonary hypertension of varied etiologies. They were receiving conventional therapy including warfarin and nifedipine, and two patients were on diuretics and digoxin for treatment of heart failure (Table 1).

Exercise capacity: The distance walked in 6 min at baseline and at the end of sildenafil or placebo therapies is given in Table 2. The patients showed a significant improvement in exercise capacity while on sildenafil therapy compared to placebo (p<0.005, Fig. 1A).

Symptoms and Borg dyspnea index: All the patients showed improvement in symptoms after 2 weeks of sildenafil therapy compared to placebo. The Borg dyspnea index of perceived exertion after the 6 min walk showed statistically significant improvement at the end of sildenafil therapy (p<0.01, Table 2, Fig. 1B). There was improvement in the NYHA class in only two patients. There was no mortality.

Pulmonary artery pressures: Table 2 gives the pulmonary artery systolic pressures as estimated from the Doppler studies. Sildenafil therapy was associated with significant reduction in the pulmonary artery pressures compared to placebo (p<0.005, Fig. 1C).

Side-effects and tolerance: Sildenafil therapy was tolerated well with no adverse effects reported during this short-term study. No substantial changes in heart rate or systemic arterial pressure were observed during sildenafil treatment. Two sexually active males included in the study experienced no change in overall sexual performance or libido during sildenafil therapy.

Discussion

Primary pulmonary hypertension is a rapidly progressive disease which is uniformly fatal if untreated. Until 1981, when heart–lung transplantation was introduced, no treatment was available. Challenged by the limited number of suitable donors and the complications associated with organ transplantation, the search for effective medical therapies is ongoing.1 Continuous epoprostenol infusions lead to improved symptoms, hemodynamics, and reduced mortality.12 The prostacyclin analogs iloprost13 and beraprost14 produce marked clinical benefits in patients with PAH. The orally administered endothelin receptor antagonist bosentan15 is reported to be effective and well tolerated in patients with PAH. While mortality benefits with these newer agents are yet to be ascertained, each therapy has certain limitations. Epoprostenol, the current gold standard of therapy for PPH, is associated with serious complications arising from the complex delivery system. Sildenafil, which is currently approved for the treatment of erectile dysfunction, is emerging as a new promising therapeutic agent for the treatment of secondary PAH and PPH.16,17 Through selective inhibition of PDE5, which is abundant in the lungs, sildenafil increases cellular levels of cGMP causing vascular smooth muscle relaxation leading to sustained reduction in pulmonary vascular resistance and pulmonary artery pressures.4,8,18 The salutary effects of sildenafil on symptoms and exercise performance in patients with PAH have been reported in small studies16,17 and in anecdotal case reports,8,18 which are comparable to those of the prostacyclins. However, large controlled trials with sildenafil to address the issue of improving survival in patients with PPH and PAH are not yet available. This short-term, double-blind, placebocontrolled, crossover study has demonstrated that oral sildenafil in a dosage of 25 mg 8 hourly improves exercise capacity, symptoms, and causes significant decrease in Doppler-estimated pulmonary artery pressures.

As in other trials performed on patients with PAH, the primary end-point of this study was the 6 min walking distance that has been shown to be an independent predictor of mortality.19.20 Following treatment, the distance observed in our patients was 96.67 m, which matches the effect observed with intravenous epoprostenol in NYHA class III–IV patients,20 and with beraprost21 in NYHA class II–III patients with PPH. Improvement in the 6 min walking distance was observed in all patients (NYHA class II–IV) in our study. However, improvement in the 6 min walk test was seen only in patients with PPH receiving beraprost but not in those with secondary PAH.21

Sildenafil alone16 or in combination with inhaled iloprost17 has been shown to improve exercise performance in patients with PPH and secondary PAH. The improvement in the 6 min walking distance was associated with a concomitant significant improvement in the perception of dyspnea, as assessed by a reduction of the Borg dyspnea score. Perceptual estimates, obtained by psychophysical ratio-scaling method such as the Borg dyspnea scale, are very useful in judging the perceptual variation and are complementary to physiological measurement of work capacity and physical performance.10 Despite improvement in symptoms and exercise capacity in all the patients, improvement in NYHA class was seen in only two patients. This was perhaps related to the shorter duration of our study. Similar observations were reported in patients with PAH who were treated with beraprost for 12 weeks.21

Sildenafil therapy was associated with a significant decrease in Doppler-estimated tricuspid regurgitation velocities and pulmonary systolic pressures in our study. The available studies on sildenafil are few. In a young male with severe PAH, sildenafil 100 mg five times per day for 3 months led to a decrease in the Doppler-estimated pulmonary artery pressure from 120 mmHg to 90 mmHg with improvement in the myocardial oxygen consumption during exercise, and dramatic improvement in symptoms and aerobic capacity.18 Similarly, in the case of a 4-year year old girl with severe PPH with poor response to prostacyclin, oral sildenafil (2 mg/kg 4 hourly) led to a significant decrease in pulmonary artery pressures, rise in oxygen saturation, improved exercise capacity, and impressive clinical recovery, permitting discontinuation of prostacyclin and oxygen therapy.8

A recent study reported long-lasting reduction in the mean pulmonary artery pressure and pulmonary vascular resistance with sildenafil and additional improvement after iloprost inhalation in patients with PPH. No significant changes in heart rate or blood pressure were observed during the treatment.6 Another study reported impressive clinical benefits associated with combination therapy using oral sildenafil and inhaled iloprost in patients with severe PAH.17

In a randomized, double-blind, placebo-controlled study, sildenafil 100 mg given orally to ten healthy volunteers inhibited hypoxia-induced pulmonary hypertension, a response mediated through the eNOS–NO–cGMP pathway.5 Sildenafil has been reported to blunt the rebound pulmonary hypertension seen following withdrawal of inhaled nitric oxide.7,22 In lambs with acute pulmonary hypertension, sildenafil decreased the pulmonary artery pressure and pulmonary vascular resistance resulting from selective pulmonary vasodilatation.9 In a recent study, a single oral dose of sildenafil (75 mg) was found to be as effective and as selective a pulmonary vasodilator as inhaled nitric oxide in patients with severe PAH referred for heart–lung transplantation. Sildenafil was superior to nitric oxide in that it led to a greater increase in cardiac output and did not increase wedge pressure.23 Sildenafil was assessed for childhood and neonatal pulmonary hypertension (16 patients), given either acutely (0.25–0.5 mg/kg) prior to hemodynamic measurements in the cath lab, or chronically after gradual withdrawal of nitric oxide in refractory suprasystemic PAH, or for chronic treatment of PPH or PAH. During cardiac catheterization, the mean pulmonary artery pressure decreased (50±8 mmHg to 38±12 mmHg, p<0.05), and pulmonary vascular resistance decreased with no change in the mean systemic pressure or systemic vascular resistance. During chronic use, sildenafil attenuated the rise in pulmonary artery pressure, permitted discontinuation of nitric oxide and led to 200% improvement in the 6 min walk distance in the remaining patients.24

Sildenafil has been well tolerated without major sideeffects.3 We did not come across hypotension, syncope, or any other untoward effect attributable to sildenafil in our study. Our results concur with those of other studies to support the safety and impressive clinical benefits associated with sildenafil therapy in patients suffering from PPH or secondary PAH.6,8,17,18 Sildenafil therapy was not found to have any important hemodynamic effect in patients with stable coronary artery disease25 but caution must be exercised in patients receiving diuretics and/or nitrates.

To conclude, our study results show the beneficial effects of sildenafil in patients with PPH and secondary PAH in adults. These include significant improvement in exercise capacity as indicated by improvement in the 6 min walk distance, decrease in modified Borg dyspnea index of perceived exertion, and decrease in pulmonary artery systolic pressures. The drug is well tolerated with no substantial change in heart rate or blood pressure. The small sample size and short duration of the study are acceptable limitations. Large, long-term, randomized, multicenter trials are needed to answer questions regarding the long-term utility and survival benefits with the PDE5 inhibitor sildenafil in patients with PPH and secondary PAH.

Acknowledgments

We acknowledge the help received from Professor LK Mathur, Department of Biostatistics, M.G.M. Medical College, Indore, for statistical analysis and Mrs Prasanna Nair for secretarial assistance.

Correspondence:

Dr Anil Bharani,
119, Ravindra Nagar,
Indore 452018.
e-mail: tanmaybharani@eth.net

References

  1. Rich S. Executive summary from the World Symposium on Primary-Pulmonary Hypertension 1998. Available from http/www.who.int/ncd/cvd/pph.html

  2. British Cardiac Society Guidelines and Medical Practice Committee. Recommendations on the management of pulmonary hypertension in clinical practice. Heart 2001; 86 (Suppl): I1–I13

  3. Kothari SS, Bahl VK. Primary pulmonary hypertension—an update. Indian Heart J 2002; 54: 255–260

  4. Sanchez LS, de la Monte SM, Filippov G, Jones RC, Zapol WM, Bloch KD. Cyclic-GMP-binding, cyclic-GMP-specific phosphodiesterase (PDE5) gene expression is regulated during rat pulmonary development. Pediatr Res 1998; 43: 163–168

  5. Zhao L, Mason NA, Morrell NW, Kojonazarov B, Sadykov A, Maripov A, et al. Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation 2001; 104: 424–428

  6. Wilkens H, Guth A, Konig J, Forestier N, Cremers B, Hennen B, et al. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation 2001; 104: 1218–1222

  7. Mychaskiw G, Sachdev V, Heath BJ. Sildenafil (viagra) facilitates weaning of inhaled nitric oxide following placement of a biventricular assist device. J Clin Anesth 2001; 13: 218–220

  8. Abrams D, Schulze-Neick I, Magee AG. Sildenafil as a selective pulmonary vasodilator in childhood primary pulmonary hypertension. Heart 2000; 84: E4

  9. Weimann J, Ullrich R, Hromi J, Fujino Y, Clark MW, Bloch KD, et al. Sildenafil is a pulmonary vasodilator in awake lambs with acute pulmonary hypertension. Anesthesiology 2000; 92: 1702 –1712

  10. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982; 14: 377–381

  11. Oh JK, Seward JB, Tajik AJ. The echo manual. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 1999. p. 215

  12. Galie N, Manes A, Branzi A. Medical therapy of pulmonary hypertension. The prostacyclins. Clin Chest Med 2001; 22: 529–537

  13. Hoeper MM, Galie N, Simonnean G, Rubin LJ. New treatments for  pulmonary arterial hypertension. Am J Respir Crit Care Med 2002; 165: 1209–1216

  14. Nagaya N, Shimizu Y, Satoh T, Oya H, Uematsu M, Kyotani S, et al. Oral beraprost sodium improves exercise capacity and ventilatory efficiency in patients with primary or thromboembolic pulmonary hypertension. Heart 2002; 87: 340–345

  15. Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, et al. Bosentan therapy for pulmonary artery hypertension. N Engl J Med 2002; 346: 896–903

  16. Watanabe H, Ohashi K, Takeuchi K, Yamashita K, Yokoyama T, Tran QK, et al. Sildenafil for primary and secondary pulmonary hypertension. Clin Pharmacol Ther 2002; 71: 398–402

  17. Ghobrani HA, Weidmann R, Rose F, Olscherski H, Schermuly RT, Weissmann N. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 2002; 136: 515–522

  18. Prasad S, Wilkinson J, Gatzoulis MA. Sildenafil in primary pulmonary hypertension. N Engl J Med 2000; 343: 1342

  19. Miyamoto S, Nagaya N, Satoh T, Kyotani S, Sakamaki F, Fujita M, et al. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med 2000; 161: 487–492

  20. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary-Pulmonary Hypertension Study Group. N Engl J Med 1996; 334: 296–302

  21. Galie N, Humbert M, Vachiery JL, Vizza CD, Kneussl M, Manes A, et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, doubleblind, placebo-controlled trial. J Am Coll Cardiol 2002; 39: 1496–1520

  22. Atz AM, Wessel DL. Slidenafil ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology 1999; 91: 307–310

  23. Michelakis ED, Tymchak W, Lien D, Dasilva L, Hashimoto K, Archer SL. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension [Abstr]. J Am Coll Cardiol 2002; 39 (Suppl): 1081

  24. Erickson S, Reyes J, Bohn D, Adatia I. Sildenafil (Viagra) in childhood and neonatal pulmonary hypertension [Abstr]. J Am Coll Cardiol 2002; 39 (Suppl): 1097–1098

  25. Arruda-Olson AM, Mahoney DW, Nehra A, Leckel M, Pellikka PA. Cardiovascular effects of sildenafil during exercise in men with known or probable coronary artery disease: a randomized crossover trial. JAMA 2002; 287: 719–725