Khouri Charles, Lepelley Marion, Bailly Sebastien, Blaise Sophie, Herrick Ariane L, Matucci-Cerinic Marco, Allanore Yannick, Trinquart Ludovic, Cracowski Jean-Luc, Roustit Matthieu
Pharmacovigilance Unit, Grenoble Alpes University Hospital, Grenoble, France; Clinical Pharmacology Department, INSERM CIC1406, Grenoble Alpes University Hospital, Grenoble, France; HP2 Laboratory, U1042 INSERM, Grenoble Alpes University, Grenoble, France.
Pharmacovigilance Unit, Grenoble Alpes University Hospital, Grenoble, France.
Lancet Rheumatol. 2019 Dec;1(4):e237-e246. doi: 10.1016/S2665-9913(19)30079-7.
Several pharmacological treatments are available for secondary Raynaud's phenomenon, but there is uncertainty regarding the best options. We aimed to assess and compare the benefits and harms of treatments available for secondary Raynaud's phenomenon.
We did a systematic review and network meta-analysis of randomised controlled trials (RCTs) of pharmacological treatments. We searched for systematic reviews published in MEDLINE and the Cochrane Database of Systematic Reviews up to Jan 31, 2017, and for RCTs published from inception to Sept 24, 2019 in MEDLINE, Embase, and ClinicalTrials.gov. We included double-blind RCTs (parallel or crossover) that compared two or more pharmacological treatments or placebo in patients with secondary Raynaud's phenomenon. Individual patient data were obtained for one unpublished RCT. Three researchers independently screened the texts and extracted the data. Efficacy outcomes included severity (on a ten-point scale), daily frequency, and mean duration of Raynaud's phenomenon attacks. We also examined tolerability and acceptability. Pairwise meta-analyses and Bayesian random-effects network meta-analyses were used to synthesise data. This study is registered with PROSPERO (CRD42017057518).
We included 58 RCTs in the analysis, comprising 3867 patients (3540 [91·5%] with secondary Raynaud's phenomenon) and 15 classes of drugs. Phosphodiesterase 5 (PDE5) inhibitors were more effective than placebo for frequency (mean difference -0·36 [95% credibility interval -0·69 to -0·04]), severity (-0·34 [-0·66 to -0·03]), and duration (-3·42 [-6·62 to -0·29]) of attacks (low to moderate level of evidence). Calcium channel blockers (CCBs) were superior to placebo for frequency (-0·35 [-0·67 to -0·02]) and severity (-0·84 [-1·25 to -0·45]) of attacks (low level of evidence). For severity of attacks, selective serotonin-reuptake inhibitors (-1·54 [-2·68 to -0·41]; very low level of evidence) and oral prostacyclin receptor agonists (-0·48 [-0·80 to -0·16]; low level of evidence) were superior to placebo. No other drug classes were significantly superior to placebo with regard to efficacy outcomes. Compared with placebo, tolerability was lower for PDE5 inhibitors (incidence rate ratio for serious adverse events or early study exit due to adverse events 3·30 [95% CrI 1·49 to 7·55]) and CCBs (3·13 [1·33 to 7·04]). For all outcomes, global heterogeneity and between-study variance ranged from low (I=0% and τ=0·0 for attack severity and duration) to moderate (I=41% and τ=0·2 for tolerability). The overall risk of bias was judged to be low in 22 (38%), high in ten (17%), and unclear in 26 (45%) RCTs.
PDE5 inhibitors and CCBs are the most effective pharmacological options, albeit with moderate efficacy and a low level of evidence. Current evidence does not support the use of any other drug in secondary Raynaud's phenomenon.
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有几种药物治疗方法可用于继发性雷诺现象，但关于最佳选择仍存在不确定性。我们旨在评估和比较可用于继发性雷诺现象的治疗方法的益处和危害。
我们对药物治疗的随机对照试验（RCT）进行了系统评价和网状Meta分析。我们检索了截至2017年1月31日发表在MEDLINE和Cochrane系统评价数据库中的系统评价，以及从创刊至2019年9月24日发表在MEDLINE、Embase和ClinicalTrials.gov上的RCT。我们纳入了双盲RCT（平行或交叉），这些试验比较了两种或更多种药物治疗或安慰剂在继发性雷诺现象患者中的效果。获取了一项未发表的RCT的个体患者数据。三名研究人员独立筛选文本并提取数据。疗效结局包括严重程度（采用十分制）、每日发作频率和雷诺现象发作的平均持续时间。我们还检查了耐受性和可接受性。采用成对Meta分析和贝叶斯随机效应网状Meta分析来综合数据。本研究已在PROSPERO注册（CRD42017057518）。
我们在分析中纳入了58项RCT，包括3867例患者（3540例[91.5%]为继发性雷诺现象患者）和15类药物。磷酸二酯酶5（PDE5）抑制剂在发作频率（平均差值 -0.36 [95%可信区间 -0.69至 -0.04]）、严重程度（-0.34 [-0.66至 -0.（此处原文有误，推测应为-0.03）]）和持续时间（-3.42 [-6.62至 -0.29]）方面比安慰剂更有效（证据质量为低至中等）。钙通道阻滞剂（CCB）在发作频率（-0.35 [-0.67至 -0.02]）和严重程度（-0.84 [-1.25至 -0.45]）方面优于安慰剂（证据质量低）。对于发作严重程度，选择性5-羟色胺再摄取抑制剂（-1.54 [-2.68至 -0.41]；证据质量极低）和口服前列环素受体激动剂（-0.48 [-0.80至 -0.16]；证据质量低）优于安慰剂。在疗效结局方面，没有其他药物类别明显优于安慰剂。与安慰剂相比，PDE5抑制剂（严重不良事件或因不良事件导致早期研究退出的发生率比值 3.30 [95% CrI 1.49至7.55]）和CCB（3.13 [1.33至7.04]）的耐受性较低。对于所有结局，总体异质性和研究间方差范围从低（发作严重程度和持续时间的I = 0%且τ = 0.0）到中等（耐受性的I = 41%且τ = 0.2）。在22项（38%）RCT中，总体偏倚风险被判定为低，在10项（17%）中为高，在26项（45%）中不明确。
PDE5抑制剂和CCB是最有效的药物选择，尽管疗效中等且证据质量低。目前的证据不支持在继发性雷诺现象中使用任何其他药物。
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