Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
Sydney School of Public Health, The University of Sydney, Sydney, Australia.
Cochrane Database Syst Rev. 2022 Aug 25;8(8):CD013751. doi: 10.1002/14651858.CD013751.pub2.
Anaemia occurs in chronic kidney disease (CKD) and is more prevalent with lower levels of kidney function. Anaemia in CKD is associated with death related to cardiovascular (CV) disease and infection. Established treatments include erythropoiesis-stimulating agents (ESAs), iron supplementation and blood transfusions. Oral hypoxia-inducible factors (HIF) stabilisers are now available to manage anaemia in people with CKD.
We aimed to assess the benefits and potential harms of HIF stabilisers for the management of anaemia in people with CKD.
We searched the Cochrane Kidney and Transplant Register of Studies up to 22 November 2021 through contact with the Information Specialist using search terms relevant to our review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov.
Randomised and quasi-randomised studies evaluating hypoxia-inducible factors stabilisers compared to placebo, standard care, ESAs or iron supplementation in people with CKD were included.
Five authors independently extracted data and assessed the risk of bias. Treatment estimates were summarised using random effects pair-wise meta-analysis and expressed as a relative risk (RR) or mean difference (MD), with a corresponding 95% confidence interval (CI). Evidence certainty was assessed using GRADE.
We included 51 studies randomising 30,994 adults. These studies compared HIF stabilisers to either placebo or an ESA. Compared to placebo, HIF stabiliser therapy had uncertain effects on CV death (10 studies, 1114 participants): RR 3.68, 95% CI 0.19 to 70.21; very low certainty evidence), and nonfatal myocardial infarction (MI) (3 studies, 822 participants): RR 1.29, 95% CI 0.31 to 5.36; I² = 0%; very low certainty evidence), probably decreases the proportion of patients requiring blood transfusion (8 studies, 4329 participants): RR 0.51, 95% CI 0.44 to 0.60; I² = 0%; moderate certainty evidence), and increases the proportion of patients reaching the target haemoglobin (Hb) (10 studies, 5102 participants): RR 8.36, 95% CI 6.42 to 10.89; I² = 37%; moderate certainty evidence). Compared to ESAs, HIF stabiliser therapy may make little or no difference to CV death (17 studies, 10,340 participants): RR 1.05, 95% CI 0.88 to 1.26; I² = 0%; low certainty evidence), nonfatal MI (7 studies, 7765 participants): RR 0.91, 95% CI 0.76 to 1.10; I² = 0%; low certainty evidence), and nonfatal stroke (5 studies, 7285 participants): RR 1.06, 95% CI 0.71 to 1.56; I² = 8%; low certainty evidence), and had uncertain effects on fatigue (2 studies, 3471 participants): RR 0.80, 95% CI 0.56 to 1.16; I² = 0%; very low certainty evidence). HIF stabiliser therapy probably decreased the proportion of patients requiring blood transfusion (11 studies, 10,786 participants): RR 0.87, 95% CI 0.76 to 1.00; I² = 25%; moderate certainty evidence), but may make little or no difference on the proportion of patients reaching the target Hb (14 studies, 4601 participants): RR 1.00, 95% CI 0.93 to 1.07; I² = 70%; low certainty evidence), compared to ESA. The effect of HIF stabilisers on hospitalisation for heart failure, peripheral arterial events, loss of unassisted dialysis vascular access patency, access intervention, cancer, infection, pulmonary hypertension and diabetic nephropathy was uncertain. None of the included studies reported life participation. Adverse events were rarely and inconsistently reported.
AUTHORS' CONCLUSIONS: HIF stabiliser management of anaemia had uncertain effects on CV death, fatigue, death (any cause), CV outcomes, and kidney failure compared to placebo or ESAs. Compared to placebo or ESAs, HIF stabiliser management of anaemia probably decreased the proportion of patients requiring blood transfusions, and probably increased the proportion of patients reaching the target Hb when compared to placebo.
贫血发生在慢性肾脏病（CKD）中，并且随着肾功能水平的降低而更为普遍。CKD 中的贫血与心血管（CV）疾病和感染相关的死亡有关。既定的治疗方法包括促红细胞生成素刺激剂（ESA）、铁补充剂和输血。口服低氧诱导因子（HIF）稳定剂现在可用于治疗 CKD 患者的贫血。
我们旨在评估 HIF 稳定剂在管理 CKD 患者贫血方面的益处和潜在危害。
我们通过与信息专家联系，使用与我们的综述相关的检索词，对截至 2021 年 11 月 22 日的 Cochrane 肾脏和移植登记册中的研究进行了检索。通过对 CENTRAL、MEDLINE、EMBASE、会议记录、国际临床试验注册平台（ICTRP）搜索门户和 ClinicalTrials.gov 的搜索，确定了登记册中的研究。
纳入了随机和准随机研究，评估了 HIF 稳定剂与安慰剂、标准护理、ESA 或铁补充剂在 CKD 患者中的比较。
五位作者独立提取数据并评估了偏倚风险。使用随机效应成对荟萃分析汇总治疗估计值，并表示为相对风险（RR）或均数差（MD），并附有相应的 95%置信区间（CI）。使用 GRADE 评估证据确定性。
我们纳入了 51 项研究，共纳入 30994 名成年人。这些研究将 HIF 稳定剂与安慰剂或 ESA 进行了比较。与安慰剂相比，HIF 稳定剂治疗对心血管死亡（10 项研究，1114 名参与者）的影响不确定：RR 3.68，95%CI 0.19 至 70.21；极低确定性证据），非致命性心肌梗死（MI）（3 项研究，822 名参与者）：RR 1.29，95%CI 0.31 至 5.36；I² = 0%；极低确定性证据），可能减少需要输血的患者比例（8 项研究，4329 名参与者）：RR 0.51，95%CI 0.44 至 0.60；I² = 0%；中等确定性证据），并增加达到目标血红蛋白（Hb）的患者比例（10 项研究，5102 名参与者）：RR 8.36，95%CI 6.42 至 10.89；I² = 37%；中等确定性证据）。与 ESA 相比，HIF 稳定剂治疗对心血管死亡（17 项研究，10340 名参与者）的影响可能不大或没有：RR 1.05，95%CI 0.88 至 1.26；I² = 0%；低确定性证据），非致命性 MI（7 项研究，7765 名参与者）：RR 0.91，95%CI 0.76 至 1.10；I² = 0%；低确定性证据），非致命性卒中（5 项研究，7285 名参与者）：RR 1.06，95%CI 0.71 至 1.56；I² = 8%；低确定性证据），以及疲劳（2 项研究，3471 名参与者）的影响不确定：RR 0.80，95%CI 0.56 至 1.16；I² = 0%；极低确定性证据）。HIF 稳定剂治疗可能减少需要输血的患者比例（11 项研究，10786 名参与者）：RR 0.87，95%CI 0.76 至 1.00；I² = 25%；中等确定性证据），但可能对达到目标 Hb 的患者比例（14 项研究，4601 名参与者）的影响不大或没有：RR 1.00，95%CI 0.93 至 1.07；I² = 70%；低确定性证据），与 ESA 相比。HIF 稳定剂对心力衰竭住院、外周动脉事件、未辅助透析血管通路通畅性丧失、通路干预、癌症、感染、肺动脉高压和糖尿病肾病的影响不确定。纳入的研究均未报告生活参与情况。不良事件很少且不一致地报告。
与安慰剂或 ESA 相比，HIF 稳定剂治疗贫血对心血管死亡、疲劳、任何原因导致的死亡、心血管结局和肾功能的影响不确定。与安慰剂或 ESA 相比，HIF 稳定剂治疗贫血可能减少需要输血的患者比例，并且可能增加达到目标 Hb 的患者比例。
