Hiatt William R, Money Samuel R, Brass Eric P
Section of Vascular Medicine, Divisions of Geriatrics and Cardiology, University of Colorado School of Medicine C/O Colorado Prevention Center, Denver, CO 80203, USA.
J Vasc Surg. 2008 Feb;47(2):330-336. doi: 10.1016/j.jvs.2007.10.009. Epub 2007 Dec 26.
Cilostazol, a phosphodiesterase III inhibitor, is indicated to treat the symptoms of intermittent claudication and increase walking distance in patients with peripheral arterial disease (PAD). At the time of approval, the United States Food and Drug Administration required an additional long-term safety study to evaluate the effect cilostazol on mortality.
A total of 1899 subjects with a clinical diagnosis of PAD and symptoms of claudication were screened for participation in a randomized, double-blinded, placebo-controlled safety study of cilostazol. The intent-to-treat (ITT) population, which was the primary analysis (n = 1435), was defined as all randomized patients who received at least one dose of study medication and included patients who were followed up >30 days after discontinuation of study drug. A total of 717 patients received cilostazol and 718 received placebo. Cilostazol was administered at a primary dose of 100 mg twice daily. The dose could be reduced to 50 mg twice daily if patients experienced an adverse event that might have been drug related.
Long-term adherence to study medication was poor, with >60% of participants discontinuing therapy by 36 months. The mortality analysis therefore focused on deaths during the period on-treatment, defined as the period during which the study drug was taken plus a 30-day follow-up period after dosing. Total patient-years of exposure were 1046 on-treatment for cilostazol and 1090 for placebo. On-treatment, there were 18 deaths on cilostazol and 19 deaths on placebo for a hazard ratio of 0.99 (95% confidence interval [CI], 0.52-1.88). Cardiovascular deaths on-treatment occurred in 14 patients on cilostazol and 14 on placebo. In the full ITT population at 36 months, there were 101 deaths, 49 on cilostazol and 52 on placebo, with hazard ratio of 0.94 (95% CI, 0.64-1.39). Thus, most deaths occurred >30 days after study drug discontinuation. Serious bleeding events affected 18 patients taking cilostazol in the on-treatment population and 22 taking placebo. The rates of bleeding events were similar in patients who used aspirin, aspirin plus clopidogrel, or anticoagulants at anytime during the course of the study
This long-term study demonstrated no safety signal for cilostazol on all-cause or cardiovascular mortality. The study, however, was underpowered to detect a small adverse impact of cilostazol on mortality (hazard ratio upper bound of the 95% CI was 1.88 in the on-treatment population). Serious bleeding events appeared not to be increased by cilostazol.
西洛他唑是一种磷酸二酯酶III抑制剂，被用于治疗间歇性跛行症状，并增加外周动脉疾病（PAD）患者的行走距离。在获批时，美国食品药品监督管理局要求进行一项额外的长期安全性研究，以评估西洛他唑对死亡率的影响。
总共筛选了1899名临床诊断为PAD且有跛行症状的受试者，参与一项关于西洛他唑的随机、双盲、安慰剂对照安全性研究。意向性治疗（ITT）人群是主要分析对象（n = 1435），定义为所有接受至少一剂研究药物的随机分组患者，包括在停用研究药物后随访超过30天的患者。共有717名患者接受西洛他唑治疗，718名患者接受安慰剂治疗。西洛他唑的初始剂量为每日两次，每次100毫克。如果患者出现可能与药物相关的不良事件，剂量可减至每日两次，每次50毫克。
研究药物的长期依从性较差，超过60%的参与者在36个月时停止治疗。因此，死亡率分析集中在治疗期间的死亡情况，治疗期定义为服用研究药物的时间段加上给药后30天的随访期。西洛他唑治疗组的总暴露患者年数为1046，安慰剂组为1090。在治疗期间，西洛他唑组有18例死亡，安慰剂组有19例死亡，风险比为0.99（95%置信区间[CI]，0.52 - 1.88）。治疗期间心血管死亡在西洛他唑组有14例患者，安慰剂组有14例。在36个月时的完整ITT人群中，有101例死亡，西洛他唑组49例，安慰剂组52例，风险比为0.94（95%CI，0.64 - 1.39）。因此，大多数死亡发生在研究药物停用30天之后。严重出血事件在治疗期人群中影响了18名服用西洛他唑的患者和22名服用安慰剂的患者。在研究过程中任何时候使用阿司匹林、阿司匹林加氯吡格雷或抗凝剂的患者中，出血事件发生率相似。
这项长期研究表明，西洛他唑在全因死亡率或心血管死亡率方面没有安全信号。然而，该研究检测西洛他唑对死亡率的微小不良影响的能力不足（治疗期人群中95%CI的风险比上限为1.88）。西洛他唑似乎不会增加严重出血事件的发生。
