University of Utah, Moran Eye Center, Salt Lake City, 84132, USA.
BMJ. 2012 Feb 21;344:e554. doi: 10.1136/bmj.e554.
To assess the ocular effects and safety profile of chronic sildenafil oral dosing in patients with pulmonary arterial hypertension.
12 week, double masked, randomised, placebo controlled, phase III trial with open label extension.
53 institutions worldwide.
277 adults with idiopathic pulmonary arterial hypertension or pulmonary arterial hypertension associated with connective tissue disease or after congenital heart disease repair (mean pulmonary artery pressure ≥25 mm Hg; pulmonary capillary wedge pressure ≤15 mm Hg at rest).
During the double masked study, oral sildenafil 20 mg, 40 mg, or 80 mg or placebo (1:1:1:1) three times daily for 12 weeks was added to baseline drug treatment. In the extension study, the placebo, 20 mg and 40 mg groups received 40 mg three times daily titrated to 80 mg three times daily at week 6. After unmasking, the dose was titrated according to clinical need.
Ocular safety (ocular examinations, visual function tests, participants' reports of adverse events, and visual disturbance questionnaire completed by investigators) by treatment group at 12 weeks, 24 weeks, 18 months, and yearly.
Findings of the objective assessments-that is, intraocular pressure and visual function tests (visual acuity, colour vision, and visual field)-were similar across groups (20 mg, n=69; 40 mg, n=67; 80 mg, n=71; placebo, n=70). No clinically significant changes occurred between baseline and 12 weeks, except for an efficacy signal in contrast sensitivity for the sildenafil 40 mg three times daily group. In right eyes, changes in intraocular pressure from baseline to week 12 ranged from a mean of -0.5 (95% confidence interval -1.3 to 0.2) mm Hg with placebo, -0.2 (-0.9 to 0.5) mm Hg with sildenafil 40 mg, and -0.1 (-0.7 to 0.5) mm Hg with 80 mg to 0.3 (-0.4 to 0.9) mm Hg with sildenafil 20 mg (the approved dose for pulmonary arterial hypertension). Mean changes from baseline to week 12 in contrast sensitivity in right eyes were -0.02 (SD 0.12) in the sildenafil 20 mg three times daily group compared with -0.05 (0.18) in the placebo group (P=0.044). Percentages of participants with deterioration in visual acuity (Snellen) from baseline to week 12 ranged from 10% (n=7) in the placebo group to 3% (n=2) in the sildenafil 20 mg three times daily group; the same percentages had visual field changes from normal to abnormal during the period in these two groups. The investigators did not deem any findings on colour vision assessment to be clinically significant. Findings of the objective assessments in the 40 mg and 80 mg three times daily sildenafil treatment groups and in left eyes were not substantially different, nor were any measures different throughout the open label extension compared with week 12. However, objective data were limited after month 18, as most participants had missing data or visual parameters were no longer collected by investigators. Incidence of ocular adverse events reported on the case report forms and assessed by the investigator was low with all doses, but a modest, dose related incidence of chromatopsia, cyanopsia, photophobia, and visual disturbance was reported with 80 mg three times daily consistent with the indicated dosing for erectile dysfunction. Retinal haemorrhages, captured on funduscopy, occurred in 2% (4/207) of sildenafil treated participants and none in the placebo group during the double masked study and in 4% (10/259) during the open label extension.
Sildenafil dosing up to 80 mg three times daily is safe and well tolerated from an ocular perspective in patients with pulmonary arterial hypertension. Daily chronic dosing in this patient population was not associated with visual change and had no detrimental effect on best corrected visual acuity, contrast sensitivity, colour vision, or visual field, or on slit lamp examinations, funduscopy, or intraocular pressure during the duration of this study.
Clinical trials NCT00644605 and NCT00159887.
评估慢性西地那非口服给药对肺动脉高压患者的眼部影响和安全性。
12 周、双盲、随机、安慰剂对照、开放标签扩展的 III 期试验。
全球 53 个机构。
277 名特发性肺动脉高压或与结缔组织病相关的肺动脉高压或先天性心脏病修复后（平均肺动脉压≥25mmHg；静息时肺毛细血管楔压≤15mmHg）的成年人。
在双盲研究中，口服西地那非 20mg、40mg 或 80mg 或安慰剂（1:1:1:1）每日 3 次，共 12 周。在扩展研究中，安慰剂、20mg 和 40mg 组在第 6 周时开始服用 40mg 每日 3 次，滴定至 80mg 每日 3 次。在揭盲后，根据临床需要调整剂量。
治疗组在 12 周、24 周、18 个月和每年的眼部安全性（眼部检查、视觉功能测试、参与者报告的不良事件和研究者完成的视觉障碍问卷）。
客观评估结果（即眼压和视觉功能测试（视力、色觉和视野））在各组之间相似（20mg，n=69；40mg，n=67；80mg，n=71；安慰剂，n=70）。除了 40mg 每日 3 次组的对比敏感度有疗效信号外，与基线相比，在 12 周时没有发现临床意义上的变化。右眼的眼压从基线到第 12 周的变化范围为：安慰剂组平均下降 0.5mmHg（95%置信区间-1.3 至 0.2mmHg），40mg 西地那非组下降 0.2mmHg（-0.9 至 0.5mmHg），80mg 西地那非组下降 0.1mmHg（-0.7 至 0.5mmHg），20mg 西地那非（肺动脉高压的批准剂量）组下降 0.3mmHg（-0.4 至 0.9mmHg）。右眼对比敏感度从基线到第 12 周的平均变化在 20mg 每日 3 次组为-0.02（SD 0.12），安慰剂组为-0.05（0.18）（P=0.044）。从基线到第 12 周，视力（Snellen）恶化的参与者比例在安慰剂组为 10%（n=7），在 20mg 每日 3 次组为 3%（n=2）；在这两组中，同样有视野从正常变为异常的百分比。研究者认为色觉评估的任何发现都没有临床意义。40mg 和 80mg 每日 3 次西地那非治疗组和左眼的客观评估结果没有明显差异，在开放标签扩展期间与第 12 周相比，任何措施都没有变化。然而，由于大多数参与者的数据缺失或研究者不再收集视觉参数，18 个月后客观数据有限。报告的眼部不良事件的发生率在所有剂量下都较低，但与 80mg 每日 3 次相关的发生率适度、剂量相关的色觉异常、蓝视、畏光和视觉障碍发生率报告与用于治疗勃起功能障碍的指示剂量一致。在双盲研究期间，视网膜出血在 2%（4/207）的西地那非治疗参与者中发生，安慰剂组中无此情况；在开放标签扩展期间，4%（10/259）的参与者中发生。
肺动脉高压患者每日慢性服用西地那非 80mg 三次是安全且耐受良好的，从眼部角度来看。在这项研究的持续时间内，每日慢性给药与视觉变化无关，也不会对最佳矫正视力、对比敏感度、色觉或视野、裂隙灯检查、眼底检查或眼压产生不利影响。
临床试验 NCT00644605 和 NCT00159887。
