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