Role of oral sildenafil in severe pulmonary arterial hypertension: Clinical efficacy and dose response relationship

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Abstract

Background

Sildenafil (phosphodiesterase type 5 inhibitor) has been shown to be effective in pulmonary arterial hypertension (PAH). We evaluated the efficacy and safety of oral sildenafil in patients of severe PAH with special emphasis on dose response relationship, time of onset of clinical response and its effects on different haemodynamic parameters.

Methods

Forty-four patients of severe PAH of either idiopathic pulmonary arterial hypertension [23 (51.7%)] or Eisenmenger syndrome [21 (48.3%)] were studied. All patients underwent six-minute walk test (SMWT) and echocardiography, while some also underwent cardiac catheterization. Sildenafil was started after a test dose and was gradually increased up to a target dose of 300 mg/day. Patients were followed-up 2 weekly for 10 weeks and monthly thereafter for functional class assessment and SMWT. Echocardiography and cardiac catheterization were repeated after at least 1 month of achieving maximal sildenafil dose (target dose or maximally tolerated dose). Drug safety and tolerability were assessed by monitoring patients for adverse effects including fundus examination.

Results

Mean follow-up duration was 18.7 ± 8.8 months (range 7–30 months). Mean maximum dose achieved was 276.1 ± 62.2 mg/day (range 75–300 mg/day). A significant improvement in NYHA class (2.54 ± 0.5 vs. 1.31 ± 0.4, p = 0.0001) and in SMWT distance (247.4 ±74.7 vs. 366.3 ± 93.8 m, p = 0.0001) was noted. All patients reported “feeling better” within 2 weeks of starting 12.5 mg thrice a day sildenafil. Marked improvement was noticed at 150 mg/day dose. Some minor additional benefit was noticed with further increase in the dose up to 225 mg/day. No further benefit was noted in improvement of NYHA class and SMWT distance by further increasing the dose of sildenafil. Haemoptysis as well as chest pain, if present, were also improved. On follow-up cardiac catheterization, a significant reduction in mean pulmonary arterial pressure (from 67.0 ± 10.2 to 56.9 ± 9.5 mm Hg, p = 0.001), PVRI (from 19.5 ± 7.0 to 11.1 ± 6.9 WU m2, p = 0.0001) and PVR/SVR ratio (0.6 ± 0.3 vs. 0.4 ± 0.2, p = 0.013) with increase in cardiac index (2.9 ± 1.1 l/min vs. 3.7 ± 1.1 l/min, p = 0.008) was noted. Systemic as well as pulmonary arterial oxygen saturations also improved significantly. Sildenafil was generally well tolerated, except for rhinorrhoea in 2, bodyache in 1 and headache in 1 patient. No visual symptom or change in fundus examination was noted.

Conclusions

Oral sildenafil improves functional capacity, haemodynamic parameters and is safe in patients with severe PAH. Benefits start as early as 2 weeks. The effects are dose related. A target dose of 150 mg/day appears to be optimal. Being very effective, widely available, relatively inexpensive, and very easy to use and very well tolerated without any major side effect, sildenafil may qualify as a first line medication for these patients.

Introduction

Pulmonary arterial hypertension (PAH) is a progressive disease with a poor prognosis. If not treated, it ultimately leads to right ventricular (RV) failure and death. Definitive treatment for PAH is either lung transplantation or heart lung transplantation. This therapy is neither available nor feasible for all patients. Other available therapeutic options are anticoagulants, calcium channel blockers, prostacycline, and endothelin receptor antagonist [1], [2]. But these are either very costly or have limited benefits or have poor acceptability among patients because of complex delivery systems. There is a need for an affordable, easily available, orally effective agent for the management of these patients. Recently, oral sildenafil (a specific phosphodiesterase-5 inhibitor which is widely used in the treatment of erectile dysfunction) has been shown to have promising results in this condition [3], [4], [5], [6], [7], [8], [9]. Because of its pulmonary vasodilatory property, sildenafil decreases pulmonary vascular resistance (PVR), increases cardiac output (CO), and decreases pulmonary capillary wedge pressure (PCWP). By these mechanisms it is beneficial in patients of PAH [10], [11], [12]. Data from experimental models of PAH, case reports and small studies suggest that sildenafil might be an effective pulmonary vasodilator [3], [4], [5], [8], [13], [14], [15], [16], [17], [18], [19]. Results of the few available randomized trials are also favorable [6], [7]. Presently, published experience is small and evolving. Time of onset of clinical response, optimal dose, clinical effects and safety of sildenafil on long-term use has not been well described. Also, its efficacy in PAH secondary to congenital heart diseases has not been well studied. Considering the only limited therapeutic options for this condition, recent demonstration of efficacy of sildenafil and some conflicting data in these studies, a good systematic evaluation of this drug is required to clarify the unanswered questions. This study has been planned with the objective to clarify these unanswered questions.

Section snippets

Selection of patients

From July 2003 to June 2005, 44 consecutive patients with severe PAH — pulmonary artery systolic pressure ≥70 mm Hg [20] were enrolled for study. Experimental nature of the drug was explained and informed consent was obtained from all the patients. The study protocol was approved by the Institutional Ethical Committee.

Results

A total of 44 consecutive patients with severe PAH were enrolled in the study between July 2003 to June 2005. Their baseline clinical characteristics are summarized in Table 1. There were 25 male and 19 female patients. The mean age was 25.9 ± 11.3 years (range 12–56 years). This group of patients represents a relatively stable patient population with severe PAH. Diagnoses were IPAH in 23 (51.7%) and Eisenmenger syndrome in rest of the 21 (48.3%) patients. Adjunctive medical therapy is shown in

Discussion

Sildenafil, which is currently approved for the treatment of erectile dysfunction, is emerging as a new promising therapeutic agent for the treatment of primary as well as secondary PAH [2], [7]. 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 PVR and PAP [14], [29]. Its clinical efficacy has been very well documented in patients of PAH due to IPAH [6],

Study limitations

Firstly, it was a non-randomized and non-placebo-controlled prospective study which has its own limitations. Secondly, we have not analyzed the serum level of sildenafil to objectively correlate the graded dose related effect of drug. Thirdly, follow-up cardiac catheterization was performed only in 20.5% patients.

Conclusions

Oral sildenafil is an effective and safe drug for the treatment of patients with severe PAH (IPAH and Eisenmenger syndrome). The effect of sildenafil is dose related with significant improvement in functional capacity. A target dose of 150 mg/day appears to be optimal. It decreases PA pressures, PVR with increase in cardiac output without significant effect on SVR. This study adds to the increasing body of data supporting therapeutic benefit from sildenafil in PAH and extends the management

Acknowledgments

We gratefully acknowledge Mr. Nageswar Lal and Mr. M. S. Rana, Senior Technical Officers for their valuable technical assistance in performing Six-Minute Walk Tests and Echocardiograms.

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