Cochrane Vascular, University of Edinburgh, Edinburgh, UK.
Department of Health Registry Research and Development, Norwegian Institute of Public Health, Bergen, Norway.
Cochrane Database Syst Rev. 2021 Jun 30;6(6):CD003748. doi: 10.1002/14651858.CD003748.pub5.
Peripheral arterial disease (PAD) affects between 4% and 12% of people aged 55 to 70 years, and 20% of people over 70 years. A common complaint is intermittent claudication (exercise-induced lower limb pain relieved by rest). These patients have a three- to six-fold increase in cardiovascular mortality. Cilostazol is a drug licensed for the use of improving claudication distance and, if shown to reduce cardiovascular risk, could offer additional clinical benefits. This is an update of the review first published in 2007.
To determine the effect of cilostazol on initial and absolute claudication distances, mortality and vascular events in patients with stable intermittent claudication.
The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and AMED databases, and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registries, on 9 November 2020.
We considered double-blind, randomised controlled trials (RCTs) of cilostazol versus placebo, or versus other drugs used to improve claudication distance in patients with stable intermittent claudication.
Two authors independently assessed trials for selection and independently extracted data. Disagreements were resolved by discussion. We assessed the risk of bias with the Cochrane risk of bias tool. Certainty of the evidence was evaluated using GRADE. For dichotomous outcomes, we used odds ratios (ORs) with corresponding 95% confidence intervals (CIs) and for continuous outcomes we used mean differences (MDs) and 95% CIs. We pooled data using a fixed-effect model, or a random-effects model when heterogeneity was identified. Primary outcomes were initial claudication distance (ICD) and quality of life (QoL). Secondary outcomes were absolute claudication distance (ACD), revascularisation, amputation, adverse events and cardiovascular events.
We included 16 double-blind, RCTs (3972 participants) comparing cilostazol with placebo, of which five studies also compared cilostazol with pentoxifylline. Treatment duration ranged from six to 26 weeks. All participants had intermittent claudication secondary to PAD. Cilostazol dose ranged from 100 mg to 300 mg; pentoxifylline dose ranged from 800 mg to 1200 mg. The certainty of the evidence was downgraded by one level for all studies because publication bias was strongly suspected. Other reasons for downgrading were imprecision, inconsistency and selective reporting. Cilostazol versus placebo Participants taking cilostazol had a higher ICD compared with those taking placebo (MD 26.49 metres; 95% CI 18.93 to 34.05; 1722 participants; six studies; low-certainty evidence). We reported QoL measures descriptively due to insufficient statistical detail within the studies to combine the results; there was a possible indication in improvement of QoL in the cilostazol treatment groups (low-certainty evidence). Participants taking cilostazol had a higher ACD compared with those taking placebo (39.57 metres; 95% CI 21.80 to 57.33; 2360 participants; eight studies; very-low certainty evidence). The most commonly reported adverse events were headache, diarrhoea, abnormal stools, dizziness, pain and palpitations. Participants taking cilostazol had an increased odds of experiencing headache compared to participants taking placebo (OR 2.83; 95% CI 2.26 to 3.55; 2584 participants; eight studies; moderate-certainty evidence).Very few studies reported on other outcomes so conclusions on revascularisation, amputation, or cardiovascular events could not be made. Cilostazol versus pentoxifylline There was no difference detected between cilostazol and pentoxifylline for improving walking distance, both in terms of ICD (MD 20.0 metres, 95% CI -2.57 to 42.57; 417 participants; one study; low-certainty evidence); and ACD (MD 13.4 metres, 95% CI -43.50 to 70.36; 866 participants; two studies; very low-certainty evidence). One study reported on QoL; the study authors reported no difference in QoL between the treatment groups (very low-certainty evidence). No study reported on revascularisation, amputation or cardiovascular events. Cilostazol participants had an increased odds of experiencing headache compared with participants taking pentoxifylline at 24 weeks (OR 2.20, 95% CI 1.16 to 4.17; 982 participants; two studies; low-certainty evidence).
AUTHORS' CONCLUSIONS: Cilostazol has been shown to improve walking distance in people with intermittent claudication. However, participants taking cilostazol had higher odds of experiencing headache. There is insufficient evidence about the effectiveness of cilostazol for serious events such as amputation, revascularisation, and cardiovascular events. Despite the importance of QoL to patients, meta-analysis could not be undertaken because of differences in measures used and reporting. Very limited data indicated no difference between cilostazol and pentoxifylline for improving walking distance and data were too limited for any conclusions on other outcomes.
外周动脉疾病（PAD）影响 55 至 70 岁人群的 4%至 12%，影响 70 岁以上人群的 20%。常见的抱怨是间歇性跛行（下肢疼痛，休息后缓解）。这些患者的心血管死亡率增加了三到六倍。西洛他唑是一种被批准用于改善跛行距离的药物，如果能降低心血管风险，可能会提供额外的临床益处。这是对 2007 年首次发表的综述的更新。
确定西洛他唑对稳定间歇性跛行患者初始和绝对跛行距离、死亡率和血管事件的影响。
Cochrane 血管专题检索员检索了 Cochrane 血管专业注册库、CENTRAL、MEDLINE、Embase、CINAHL 和 AMED 数据库，以及世界卫生组织国际临床试验注册平台和 ClinicalTrials.gov 试验注册库，检索日期为 2020 年 11 月 9 日。
我们考虑了双盲、随机对照试验（RCT），比较了西洛他唑与安慰剂或其他用于改善稳定间歇性跛行患者跛行距离的药物。
两位作者独立评估试验的选择，并独立提取数据。如有分歧，通过讨论解决。我们使用 Cochrane 偏倚风险工具评估风险偏倚。使用 GRADE 评估证据的确定性。对于二分类结局，我们使用比值比（OR）及其 95%置信区间（CI），对于连续结局，我们使用均数差（MD）及其 95%CI。我们使用固定效应模型或当存在异质性时使用随机效应模型进行数据合并。主要结局是初始跛行距离（ICD）和生活质量（QoL）。次要结局是绝对跛行距离（ACD）、血运重建、截肢、不良事件和心血管事件。
我们纳入了 16 项双盲、RCT（3972 名参与者），比较了西洛他唑与安慰剂，其中 5 项研究还比较了西洛他唑与己酮可可碱。治疗时间从 6 周到 26 周不等。所有参与者都有 PAD 引起的间歇性跛行。西洛他唑的剂量范围为 100mg 至 300mg；己酮可可碱的剂量范围为 800mg 至 1200mg。由于强烈怀疑存在发表偏倚，所有研究的证据确定性都降低了一个级别。其他降级的原因包括不精确、不一致和选择性报告。
与服用安慰剂的患者相比，服用西洛他唑的患者 ICD 更高（MD 26.49m；95%CI 18.93 至 34.05；1722 名参与者；6 项研究；低确定性证据）。我们报告了 QoL 措施的描述性结果，因为研究中缺乏足够的统计细节来合并结果；在西洛他唑治疗组中，QoL 可能有所改善（低确定性证据）。与服用安慰剂的患者相比，服用西洛他唑的患者 ACD 更高（39.57m；95%CI 21.80 至 57.33；2360 名参与者；8 项研究；极低确定性证据）。最常报告的不良事件是头痛、腹泻、异常粪便、头晕、疼痛和心悸。与服用安慰剂的患者相比，服用西洛他唑的患者发生头痛的几率更高（OR 2.83；95%CI 2.26 至 3.55；2584 名参与者；8 项研究；中等确定性证据）。很少有研究报告其他结局，因此无法得出关于血运重建、截肢或心血管事件的结论。
西洛他唑和己酮可可碱在改善步行距离方面没有差异，无论是 ICD（MD 20.0m，95%CI -2.57 至 42.57；417 名参与者；1 项研究；低确定性证据）还是 ACD（MD 13.4m，95%CI -43.50 至 70.36；866 名参与者；2 项研究；极低确定性证据）。一项研究报告了 QoL；研究作者报告治疗组之间的 QoL 没有差异（极低确定性证据）。没有研究报告血运重建、截肢或心血管事件。与服用己酮可可碱的患者相比，服用西洛他唑的患者在 24 周时发生头痛的几率更高（OR 2.20；95%CI 1.16 至 4.17；982 名参与者；2 项研究；低确定性证据）。
西洛他唑已被证明可改善间歇性跛行患者的步行距离。然而，服用西洛他唑的患者发生头痛的几率更高。关于西洛他唑对严重事件（如截肢、血运重建和心血管事件）的有效性，证据不足。尽管 QoL 对患者很重要，但由于使用和报告的措施不同，无法进行荟萃分析。非常有限的数据表明，西洛他唑与己酮可可碱在改善步行距离方面没有差异，关于其他结局的数据也非常有限，无法得出任何结论。
