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Effects of Different Doses of Sildenafil for Pulmonary Arterial Hypertension
Quick Takes
- Sildenafil, approved by the US FDA for the management of pulmonary arterial hypertension (PAH), has a recommended dose of 20 mg TID. Previously, a 5 mg TID dose was approved based on a randomized controlled trial showing similar improvements in 6-minute walk distance than the 20 mg TID dosing. Safety concerns arose particularly after pediatric data suggested an association of higher mortality with higher doses of sildenafil. To address these concerns, the US FDA required that the sponsor evaluate the effect of sildenafil and the risk of death in patients with PAH at different doses levels.
- This study evaluated the effect of sildenafil on the risk of death in adults with PAH at three different doses: 5 mg, 20 mg, and 80 mg orally TID. The study was prematurely terminated after the first interim analysis, after demonstrating noninferiority for the sildenafil 80 mg versus 5 mg dose.
- Based on results of this study, the US FDA revised the US label for sildenafil in the treatment of PAH, removing the recommendation for a 5 mg oral dose for adults, and reinforced the standard dosage of 20 mg TID. The revised label now permits titration of the dosage up to a maximum of 80 mg TID, as needed.
Study Questions:
For the treatment of pulmonary arterial hypertension (PAH), is sildenafil 80 mg TID noninferior to sildenafil 5 mg TID for all-cause mortality?
Methods:
This was a phase IIIB/IV, randomized, double-blind, parallel-group trial in adult patients with PAH. Patients were eligible if they were ≥18 and <75 years old, had idiopathic PAH, or PAH associated with connective tissue disease or PAH associated with congenital heart disease that had been corrected ≥12 months before randomization, had World Health Organization functional class II-IV symptoms, and a baseline 6-minute walk distance (6MWD) ≥50 m. Treatment with endothelin receptor antagonists was allowed if at a stable dose for >90 days. Patients were excluded if they were previously treated with phosphodiesterase inhibitors.
The primary objective was to demonstrate noninferiority of sildenafil 80 mg TID compared with 5 mg TID with respect to all-cause mortality. Prespecified secondary measures of efficacy included the time to first event of clinical worsening (defined as disease progression, hospitalization for PAH, or death) and change in 6MWD at months 6 and 12.
Results:
A total of 385 patients were included in this study (129 in the 5 mg group, 128 in the 20 mg group, and 129 in the 80 mg group). The baseline characteristics were similar across all three treatment groups. Idiopathic PAH (71.6%) was the most common diagnosis, 77.1% were female, and the mean age was 51.6 (± 15.2) years. Treatment adherence in the 5 mg, 20 mg, and 80 mg groups was 87.6%, 91.4%, and 80.5%, respectively.
The study was terminated prematurely after a planned interim analysis conducted in July 2020, when 50% of the predetermined mortality events had occurred. The data monitoring committee recommended stopping the study because the primary study objective of noninferiority of 80 mg of sildenafil compared with the 5 mg dose with respect to mortality was met, and safety concerns were raised because of an observed increase in mortality in the 5 mg dose cohort.
During a mean observation period of 32 months, 78 patients (20%) died. Of these, 34 (26.4%) were in the 5 mg cohort, 25 (19.5%) were in the 20 mg cohort, and 19 were (14.8%) in the 80 mg cohort. The hazard ratio (HR) for death was 0.5 for the primary analysis comparing all-cause mortality between the 80 mg group and the 5 mg sildenafil group (p value < 0.001 for noninferiority). In addition, the per-protocol population supported the findings of the primary efficacy results (HR, 0.51; p < 0.001 for noninferiority of the 80 mg sildenafil dose compared with the 5 mg dose).
The analysis of time to first clinical worsening event for the intention-to-treat population demonstrated superiority of sildenafil 80 mg compared with 5 mg (HR, 0.44; p < 0.001). The analysis of the per-protocol population also supports these results. The least-squares mean change in 6MWD from baseline to month 6 was highest for the 80 mg group (+31.2 m), followed by 20 mg (+27.3 m) and 5 mg (+12.2 m), with the 80 mg group achieving a significantly higher improvement in 6MWD than the 5 mg group for both the intention-to-treat and per-protocol populations (+18.9 m; p = 0.0201; and +24.3 m; p = 0.0031, respectively).
Conclusions:
This study shows that the mortality of patients with PAH who were treated with sildenafil at a dose of 80 mg TID was not higher than the mortality of patients who received sildenafil at a dose of 5 mg TID. Secondary analyses showed superiority of the 80 mg dose over the 5 mg dose for event-free survival and change in 6MWD from baseline at month 6.
Perspective:
Sildenafil citrate is approved for the treatment of PAH both in adults and children. The SUPER-1 trial tested the use of sildenafil 20 mg, 40 mg, and 80 mg TID in adults with PAH, showing similar improvements in the primary endpoint of 6MWD for all three doses. Later, a sildenafil dose of 5 mg TID was also approved for adults with PAH after a randomized controlled trial showed a similar improvement in 6MWD compared with a 20 mg TID dosing. Additionally, the STAR-1 trial, which tested the use of sildenafil in children with PAH, showed an improvement in 6MWD with doses of 10 mg, 20 mg, 40 mg, and 80 mg (weight-dependent doses). During the open-label extension study (STAR-2), a signal suggested association of higher doses of sildenafil and mortality. The current study is a response to these concerns and looked at the mortality difference between 80 mg and 5 mg TID of sildenafil in a noninferiority manner.
Hoeper et al. results in this multinational and multicenter study distinctly show that higher doses of sildenafil (80 mg) are noninferior to low doses of sildenafil (5 mg). The Kaplan-Meier curve shows separation of the three groups (80 mg, 20 mg. and 5 mg) with a numerical superiority of the 80 mg dose compared to the 5 mg dose. The secondary endpoint of clinical worsening events and change in 6MWD from baseline to 6 months reassures that the 80 mg dose of sildenafil is superior to the 5 mg dose. The results of this study led the Food and Drug Administration (FDA) to change the US label for sildenafil in the treatment of PAH by removing the 5 mg oral dose for adults, reinforcing the standard dose of 20 mg TID and permitting the up-titration of sildenafil to 20 mg.
The optimal dose of sildenafil in the treatment of PAH has been long debated. The current study gives additive information about the long-term use of sildenafil in PAH. The benefits seen in the secondary endpoints of time to clinical worsening and improvement in 6MWD support the possibility of up-titration to 80 mg TID in selected cases.
Clinical Topics: Heart Failure and Cardiomyopathies, Pulmonary Hypertension and Venous Thromboembolism, Statins, Pulmonary Hypertension
Keywords: Pulmonary Arterial Hypertension, Sildenafil Citrate
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