Abstract：
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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; P<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]; P<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]; P=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.
UNASSIGNED: 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.
UNASSIGNED: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02060487.
UNASSIGNED: 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.
UNASSIGNED: 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; P<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]; P<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]; P=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.
UNASSIGNED: 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.
UNASSIGNED: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02060487.
摘要：
■西地那非，批准用于肺动脉高压（PAH），建议成人剂量为20mgTID，与美国食品和药物管理局先前批准的5毫克TID剂量。由于标签外使用较高剂量的常见安全问题，特别是在儿科数据将高剂量与死亡率增加联系起来之后.为了评估这一点，美国食品和药物管理局授权进行一项研究,评估不同剂量的西地那非对成人PAH患者死亡率的影响.
■这是随机的，双盲研究比较了西地那非在成人PAH患者中剂量为5,20或80mgTID。主要目标是80mg西地那非对全因死亡率的非劣效性。次要终点包括临床恶化的时间和6个月时6分钟步行距离的变化。计划在50%和75%的预期死亡率事件进行中期分析。在意向治疗人群中评估安全性和耐受性。
■这项研究在第一次中期分析后停止，证明80毫克西地那非与5毫克的非劣效性。在所有剂量组的385名患者中，78人死亡主要分析显示，与80mg西地那非和5mg相比，总生存率的风险比为0.51（99.7％CI，0.22-1.21；非劣效性P<0.001）。与5mg相比，80mg西地那非的临床恶化时间更受欢迎(风险比，0.44[99.7%CI，0.22-0.89]；P<0.001）。与5mg相比，西地那非80mg在6个月时改善了基线的6分钟步行距离（最小平方均值变化，18.9m[95%CI，2.99-34.86]；P=0.0201）。80毫克西地那非和20毫克之间的死亡率没有显着差异。临床恶化，和6分钟的步行距离。80mg西地那非的不良事件相关药物停药的数量更高。
■在检查PAH成人的全因死亡率时，80mg的西地那非不劣于5mg的西地那非。次要疗效终点有利于80mg西地那非超过5mg。根据这些发现,美国食品和药物管理局最近撤销了用于成人PAH的5mg西地那非的批准，强化20mgTID作为推荐剂量，现在允许剂量滴定高达80毫克TID，如果需要。
■URL：https://www。clinicaltrials.gov;唯一标识符:NCT02060487.
■这是随机的，双盲研究比较了西地那非在成人PAH患者中剂量为5,20或80mgTID。主要目标是80mg西地那非对全因死亡率的非劣效性。次要终点包括临床恶化的时间和6个月时6分钟步行距离的变化。计划在50%和75%的预期死亡率事件进行中期分析。在意向治疗人群中评估安全性和耐受性。
■这项研究在第一次中期分析后停止，证明80毫克西地那非与5毫克的非劣效性。在所有剂量组的385名患者中，78人死亡主要分析显示，与80mg西地那非和5mg相比，总生存率的风险比为0.51（99.7％CI，0.22-1.21；非劣效性P<0.001）。与5mg相比，80mg西地那非的临床恶化时间更受欢迎(风险比，0.44[99.7%CI，0.22-0.89]；P<0.001）。与5mg相比，西地那非80mg在6个月时改善了基线的6分钟步行距离（最小平方均值变化，18.9m[95%CI，2.99-34.86]；P=0.0201）。80毫克西地那非和20毫克之间的死亡率没有显着差异。临床恶化，和6分钟的步行距离。80mg西地那非的不良事件相关药物停药的数量更高。
■在检查PAH成人的全因死亡率时，80mg的西地那非不劣于5mg的西地那非。次要疗效终点有利于80mg西地那非超过5mg。根据这些发现,美国食品和药物管理局最近撤销了用于成人PAH的5mg西地那非的批准，强化20mgTID作为推荐剂量，现在允许剂量滴定高达80毫克TID，如果需要。
■URL：https://www。clinicaltrials.gov;唯一标识符:NCT02060487.
