Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, Germany (M.M.H.).
German Center for Lung Research, Biomedical Research in End-Stage and Obstructive Lung Disease Hanover (BREATH), Germany (M.M.H.).
Circulation. 2024 Jun 18;149(25):1949-1959. doi: 10.1161/CIRCULATIONAHA.123.068107. Epub 2024 May 16.
Sildenafil, approved for pulmonary arterial hypertension (PAH), has a recommended adult dose of 20 mg TID, with a previously approved 5-mg TID dose by the US Food and Drug Administration. Safety concerns arose because of common off-label use of higher doses, particularly after pediatric data linked higher doses to increased mortality. To assess this, the Food and Drug Administration mandated a study evaluating the effects of various sildenafil doses on mortality in adults with PAH.
This randomized, double-blind study compared sildenafil at doses of 5, 20, or 80 mg TID in adults with PAH. The primary objective was noninferiority of 80 mg of sildenafil versus 5 mg for all-cause mortality. Secondary end points included time to clinical worsening and change in 6-minute walk distance at 6 months. Interim analyses were planned at 50% and 75% of the anticipated mortality events. Safety and tolerability were assessed in the intention-to-treat population.
The study was halted after the first interim analysis, demonstrating noninferiority for 80 mg of sildenafil versus 5 mg. Of 385 patients enrolled across all dose groups, 78 died. The primary analysis showed a hazard ratio of 0.51 (99.7% CI, 0.22-1.21; <0.001 for noninferiority) for overall survival comparing 80 mg of sildenafil with 5 mg. Time to clinical worsening favored 80 mg of sildenafil compared with 5 mg (hazard ratio, 0.44 [99.7% CI, 0.22-0.89]; <0.001). Sildenafil at 80 mg improved 6-minute walk distance from baseline at 6 months compared with 5 mg (least square mean change, 18.9 m [95% CI, 2.99-34.86]; =0.0201). No significant differences were found between 80 mg of sildenafil and 20 mg in mortality, clinical worsening, and 6-minute walk distance. Adverse event-related drug discontinuations were numerically higher with 80 mg of sildenafil.
Sildenafil at 80 mg was noninferior to sildenafil at 5 mg when examining all-cause mortality in adults with PAH. Secondary efficacy end points favored 80 mg of sildenafil over 5 mg. On the basis of these findings, the Food and Drug Administration recently revoked the approval of 5 mg of sildenafil for adults with PAH, reinforced 20 mg TID as the recommended dose, and now allows dose titration up to 80 mg TID, if needed.
URL: https://www.clinicaltrials.gov; Unique identifier: NCT02060487.
西地那非已获美国食品药品监督管理局（FDA）批准用于肺动脉高压（PAH），推荐成人剂量为一日三次 20 毫克，此前已批准一日三次 5 毫克剂量。由于常见的超说明书剂量的使用，特别是儿科数据表明较高剂量与死亡率增加相关，故引起了安全性方面的担忧。为了评估这一点，FDA 要求进行一项研究，评估不同剂量西地那非对 PAH 成人患者死亡率的影响。
这项随机、双盲研究比较了 PAH 成人患者一日三次 5、20 或 80 毫克西地那非的疗效。主要终点为 80 毫克西地那非与 5 毫克西地那非相比非劣效性的全因死亡率。次要终点包括 6 个月时临床恶化时间和 6 分钟步行距离的变化。计划在预计死亡率事件的 50%和 75%时进行中期分析。以意向治疗人群评估安全性和耐受性。
在第一次中期分析后，该研究停止，80 毫克西地那非与 5 毫克西地那非相比显示出非劣效性。在所有剂量组的 385 名入组患者中，78 人死亡。主要分析显示，80 毫克西地那非与 5 毫克西地那非相比，总生存率的风险比为 0.51（99.7%置信区间，0.22-1.21；<0.001 表示非劣效性）。与 5 毫克西地那非相比，80 毫克西地那非的临床恶化时间更优（风险比，0.44[99.7%置信区间，0.22-0.89]；<0.001）。80 毫克西地那非与 5 毫克西地那非相比，6 分钟步行距离自基线在 6 个月时改善（最小平方均数变化，18.9 米[95%置信区间，2.99-34.86]；=0.0201）。80 毫克西地那非与 20 毫克西地那非相比，死亡率、临床恶化和 6 分钟步行距离无显著差异。80 毫克西地那非的药物相关停药不良事件发生率较高。
在检查 PAH 成人患者的全因死亡率时，80 毫克西地那非与 5 毫克西地那非相比非劣效。次要疗效终点显示 80 毫克西地那非优于 5 毫克西地那非。基于这些发现，FDA 最近撤销了 5 毫克西地那非用于 PAH 成人患者的批准，强化了一日三次 20 毫克为推荐剂量，并允许在需要时将剂量滴定至一日三次 80 毫克。
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