Barnes Hayley, Brown Zoe, Burns Andrew, Williams Trevor
Department of Respiratory Medicine, The Alfred Hospital, Commercial Rd, Melbourne, Australia, 3004.
Cochrane Database Syst Rev. 2019 Jan 31;1(1):CD012621. doi: 10.1002/14651858.CD012621.pub2.
Pulmonary hypertension (PH) comprises a group of complex and heterogenous conditions, characterised by elevated pulmonary artery pressure, and which left untreated leads to right-heart failure and death. PH includes World Health Organisation (WHO) Group 1 pulmonary arterial hypertension (PAH); Group 2 consists of PH due to left-heart disease (PH-LHD); Group 3 comprises PH as a result of lung diseases or hypoxia, or both; Group 4 includes PH due to chronic thromboembolic occlusion of pulmonary vasculature (CTEPH), and Group 5 consists of cases of PH due to unclear and/or multifactorial mechanisms including haematological, systemic, or metabolic disorders. Phosphodiesterase type 5 (PDE5) inhibitors increase vasodilation and inhibit proliferation.
To determine the efficacy of PDE5 inhibitors for pulmonary hypertension in adults and children.
We performed searches of CENTRAL, MEDLINE, Embase, CINAHL, and Web of Science up to 26 September 2018. We handsearched review articles, clinical trial registries, and reference lists of retrieved articles.
We included randomised controlled trials that compared any PDE5 inhibitor versus placebo, or any other PAH disease-specific therapies, for at least 12 weeks. We include separate analyses for each PH group.
We imported studies identified by the search into a reference manager database. We retrieved the full-text versions of relevant studies, and two review authors independently extracted data. Primary outcomes were: change in WHO functional class, six-minute walk distance (6MWD), and mortality. Secondary outcomes were haemodynamic parameters, quality of life/health status, dyspnoea, clinical worsening (hospitalisation/intervention), and adverse events. When appropriate, we performed meta-analyses and subgroup analyses by severity of lung function, connective tissue disease diagnosis, and radiological pattern of fibrosis. We assessed the evidence using the GRADE approach and created 'Summary of findings' tables.
We included 36 studies with 2999 participants (with pulmonary hypertension from all causes) in the final review. Trials were conducted for 14 weeks on average, with some as long as 12 months. Two trials specifically included children.Nineteen trials included group 1 PAH participants. PAH participants treated with PDE5 inhibitors were more likely to improve their WHO functional class (odds ratio (OR) 8.59, 95% confidence interval (CI) 3.95 to 18.72; 4 trials, 282 participants), to walk 48 metres further in 6MWD (95% CI 40 to 56; 8 trials, 880 participants), and were 22% less likely to die over a mean duration of 14 weeks (95% CI 0.07 to 0.68; 8 trials, 1119 participants) compared to placebo (high-certainty evidence). The number needed to treat to prevent one additional death was 32 participants. There was an increased risk of adverse events with PDE5 inhibitors, especially headache (OR 1.97, 95% CI 1.33 to 2.92; 5 trials, 848 participants), gastrointestinal upset (OR 1.63, 95% CI 1.07 to 2.48; 5 trials, 848 participants), flushing (OR 4.12, 95% CI 1.83 to 9.26; 3 trials, 748 participants), and muscle aches and joint pains (OR 2.52, 95% CI 1.59 to 3.99; 4 trials, 792 participants).Data comparing PDE5 inhibitors to placebo whilst on other PAH-specific therapy were limited by the small number of included trials. Those PAH participants on PDE5 inhibitors plus combination therapy walked 19.66 metres further in six minutes (95% CI 9 to 30; 4 trials, 509 participants) compared to placebo (moderate-certainty evidence). There were limited trials comparing PDE5 inhibitors directly with other PAH-specific therapy (endothelin receptor antagonists (ERAs)). Those on PDE5 inhibitors walked 49 metres further than on ERAs (95% CI 4 to 95; 2 trials, 36 participants) (low-certainty evidence). There was no evidence of a difference in WHO functional class or mortality across both treatments.Five trials compared PDE5 inhibitors to placebo in PH secondary to left-heart disease (PH-LHD). The quality of data were low due to imprecision and inconsistency across trials. In those with PH-LHD there were reduced odds of an improvement in WHO functional class using PDE5 inhibitors compared to placebo (OR 0.53, 95% CI 0.32 to 0.87; 3 trials, 285 participants), and those using PDE5 inhibitors walked 34 metres further compared to placebo (95% CI 23 to 46; 3 trials, 284 participants). There was no evidence of a difference in mortality. Five trials compared PDE5 inhibitors to placebo in PH secondary to lung disease/hypoxia, mostly in COPD. Data were of low quality due to imprecision of effect and inconsistency across trials. There was a small improvement of 27 metres in 6MWD using PDE5 inhibitors compared to placebo in those with PH due to lung disease. There was no evidence of worsening hypoxia using PDE5 inhibitors, although data were limited. Three studies compared PDE5 inhibitors to placebo or other PAH-specific therapy in chronic thromboembolic disease. There was no significant difference in any outcomes. Data quality was low due to imprecision of effect and heterogeneity across trials.
AUTHORS' CONCLUSIONS: PDE5 inhibitors appear to have clear beneficial effects in group 1 PAH. Sildenafil, tadalafil and vardenafil are all efficacious in this clinical setting, and clinicians should consider the side-effect profile for each individual when choosing which PDE5 inhibitor to prescribe.While there appears to be some benefit for the use of PDE5 inhibitors in PH-left-heart disease, it is not clear based on the mostly small, short-term studies, which type of left-heart disease stands to benefit. These data suggest possible harm in valvular heart disease. There is no clear benefit for PDE5 inhibitors in pulmonary hypertension secondary to lung disease or chronic thromboembolic disease. Further research is required into the mechanisms of pulmonary hypertension secondary to left-heart disease, and cautious consideration of which subset of these patients may benefit from PDE5 inhibitors. Future trials in PH-LHD should be sufficiently powered, with long-term follow-up, and should include invasive haemodynamic data, WHO functional class, six-minute walk distance, and clinical worsening.
肺动脉高压（PH）是一组复杂的异质性疾病，其特征为肺动脉压力升高，若不治疗会导致右心衰竭和死亡。PH包括世界卫生组织（WHO）1组肺动脉高压（PAH）；2组为左心疾病所致的PH（PH-LHD）；3组由肺部疾病或缺氧或两者共同导致的PH组成；4组包括慢性血栓栓塞性肺血管闭塞（CTEPH）所致的PH，5组为由不明和/或多因素机制引起的PH病例，包括血液学、全身性或代谢性疾病。5型磷酸二酯酶（PDE5）抑制剂可增加血管舒张并抑制增殖。
确定PDE5抑制剂对成人和儿童肺动脉高压的疗效。
我们检索了截至2018年9月26日的CENTRAL、MEDLINE、Embase、CINAHL和Web of Science。我们手工检索了综述文章、临床试验注册库以及检索到文章的参考文献列表。
我们纳入了比较任何PDE5抑制剂与安慰剂或任何其他PAH疾病特异性疗法至少12周的随机对照试验。我们对每个PH组进行单独分析。
我们将检索到的研究导入参考文献管理数据库。我们获取了相关研究的全文版本，两位综述作者独立提取数据。主要结局为：WHO功能分级的变化、六分钟步行距离（6MWD）和死亡率。次要结局为血流动力学参数、生活质量/健康状况、呼吸困难、临床恶化（住院/干预）和不良事件。在适当情况下，我们按肺功能严重程度、结缔组织病诊断和纤维化放射学模式进行荟萃分析和亚组分析。我们使用GRADE方法评估证据并创建“结果总结”表。
我们在最终综述中纳入了36项研究，共2999名参与者（各种原因导致的肺动脉高压）。试验平均进行14周，有些长达12个月。两项试验专门纳入了儿童。19项试验纳入了1组PAH参与者。与安慰剂相比，接受PDE5抑制剂治疗的PAH参与者更有可能改善其WHO功能分级（优势比（OR）8.59，95%置信区间（CI）3.95至18.72；4项试验，282名参与者），在6MWD中多走48米（95%CI 40至56；8项试验，880名参与者），并且在平均14周的时间内死亡可能性降低22%（95%CI 0.07至0.68；8项试验，1119名参与者）（高确定性证据）。预防一例额外死亡所需治疗的人数为32名参与者。PDE5抑制剂会增加不良事件的风险，尤其是头痛（OR 1.97，95%CI 1.33至2.92；5项试验，848名参与者）、胃肠道不适（OR 1.63，95%CI 1.07至2.48；5项试验，848名参与者）、潮红（OR 4.12，95%CI 1.83至9.26；3项试验，748名参与者）以及肌肉酸痛和关节疼痛（OR 2.52，95%CI 1.59至3.99；4项试验，792名参与者）。在其他PAH特异性治疗期间将PDE5抑制剂与安慰剂进行比较的数据，因纳入试验数量少而受到限制。与安慰剂相比，接受PDE5抑制剂加联合治疗的PAH参与者在六分钟内多走19.66米（95%CI 9至30；4项试验，509名参与者）（中等确定性证据）。将PDE5抑制剂与其他PAH特异性治疗（内皮素受体拮抗剂（ERA））直接比较的试验有限。接受PDE5抑制剂治疗的参与者比接受ERA治疗的参与者多走49米（95%CI 4至95；2项试验，36名参与者）（低确定性证据）。两种治疗在WHO功能分级或死亡率方面均无差异的证据。五项试验在左心疾病所致的PH（PH-LHD）中将PDE5抑制剂与安慰剂进行比较。由于试验间的不精确性和不一致性，数据质量较低。在PH-LHD患者中，与安慰剂相比，使用PDE5抑制剂改善WHO功能分级的可能性降低（OR 0.53，95%CI 0.32至0.87；3项试验，285名参与者），使用PDE5抑制剂的参与者比安慰剂组多走34米（95%CI 23至46；3项试验，284名参与者）。在死亡率方面无差异的证据。五项试验在肺部疾病/缺氧所致的PH（主要为慢性阻塞性肺疾病（COPD））中将PDE5抑制剂与安慰剂进行比较。由于效应的不精确性和试验间的不一致性，数据质量较低。在肺部疾病所致的PH患者中，与安慰剂相比，使用PDE5抑制剂在6MWD中有27米的小幅改善。尽管数据有限，但没有证据表明使用PDE5抑制剂会使缺氧情况恶化。三项研究在慢性血栓栓塞性疾病中将PDE5抑制剂与安慰剂或其他PAH特异性治疗进行比较。在任何结局方面均无显著差异。由于效应的不精确性和试验间的异质性，数据质量较低。
PDE5抑制剂在1组PAH中似乎具有明确的有益作用。西地那非、他达拉非和伐地那非在此临床环境中均有效，临床医生在选择开具哪种PDE5抑制剂时应考虑每个患者的副作用情况。虽然在PH-左心疾病中使用PDE5抑制剂似乎有一些益处，但基于大多数小规模、短期研究尚不清楚哪种类型的左心疾病会从中受益。这些数据提示在瓣膜性心脏病中可能有害。PDE5抑制剂在肺部疾病或慢性血栓栓塞性疾病所致的肺动脉高压中没有明确益处。需要进一步研究左心疾病所致肺动脉高压的机制，并谨慎考虑这些患者中的哪些亚组可能从PDE5抑制剂中受益。未来在PH-LHD中的试验应有足够的样本量，进行长期随访，并应包括有创血流动力学数据、WHO功能分级、六分钟步行距离和临床恶化情况。
