Cinacalcet in patients with chronic kidney disease: a cumulative meta-analysis of randomized controlled trials.
Cinacalcet in patients with chronic kidney disease: a cumulative meta-analysis of randomized controlled trials.
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DOI：
10.1371/journal.pmed.1001436
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发表时间：
2013
期刊：
影响因子：
15.8
通讯作者：
Strippoli GF
中科院分区：
文献类型：
--
作者：
Palmer SC;Nistor I;Craig JC;Pellegrini F;Messa P;Tonelli M;Covic A;Strippoli GF
Giovanni Strippoli及其同事报告了一项系统综述和荟萃分析的结果，该研究检查了成人慢性肾病患者的拟钙化治疗的益处和危害。拟钙化剂可降低慢性肾病（CKD）患者血清甲状旁腺激素水平，但治疗效果对患者相关结局的影响尚不确定。我们进行了一项系统回顾和荟萃分析，总结了模拟钙化治疗在成人CKD患者中的益处和危害，并使用累积荟萃分析来确定在这种临床环境中模拟钙化治疗的证据是如何发展的。通过电子检索Cochrane和Embase数据库（截至2013年2月7日），以确定评估拟钙化治疗对成人CKD患者死亡率和不良事件影响的随机试验。两名独立审稿人确定了试验，提取了数据，并评估了偏倚风险。18项包括7,446名参与者的试验比较了cinacalcet加常规治疗与安慰剂或无治疗加常规治疗对成人CKD的影响。在中度至高质量的证据中（基于分级推荐评估、发展和评估标准），在CKD 5D期成人（透析）中，cinacalcet对全因死亡率的影响很小或没有影响（相对风险为0.97[95%置信区间，0.89-1.05]），对心血管死亡率的影响不精确（0.67[0.16-2.87]），并预防甲状旁腺切除术（0.49[0.40-0.59]）和高钙血症（0.23[0.05-0.97]），但增加低钙血症（6.98[5.10-9.53]）。恶心(2.02[1.45—-2.81]),呕吐(1.97[1.73—-2.24])。成人CKD 3-5期的临床结果数据较少。平均而言，治疗1000名CKD 5D期患者1年对生存率没有影响，并阻止了约3名患者进行甲状旁腺切除术，而60名患者出现了低钙血症，150名患者出现了恶心。由于CKD 3-5期和肾移植受者的数据不足，分析受到限制。Cinacalcet减少了CKD 5D期患者甲状旁腺切除术的需要，但似乎并没有改善全因死亡率或心血管死亡率。CKD 5D期的其他试验不太可能改变我们对cinacalcet在这一人群中的治疗效果的信心。慢性肾脏疾病（CKD）是指肾脏功能随着时间的推移而逐渐丧失，由糖尿病和高血压等几种疾病引起。慢性肾病是一种越来越常见的疾病，仅在美国就有大约2600万成年人受到影响，还有数百万人处于危险之中。与一般人群相比，CKD患者的死亡风险增加，尽管近期护理有所改善，但接受透析治疗的晚期CKD患者的死亡率高达20%。慢性肾病患者还会经历一些生化失衡——比如磷增加（由于滞留），维生素D和钙缺乏（低钙血症），甲状旁腺激素增加——这会导致进一步的健康问题（如骨骼变薄）和疼痛。鉴于这一并发症，目前CKD患者的临床指南建议将血磷和甲状旁腺激素水平维持在一定范围内，以防止需要手术切除腺体（手术甲状旁腺切除术）。有几种医学疗法有助于将磷和甲状旁腺激素的血液水平保持在目标范围内，2004年，药物盐酸昔那卡塞（cinacalcet）在美国被批准用于终末期CKD患者。然而，尽管这种药物的使用和成本不断增加（在美国，cinacalcet已成为透析患者最大的单一药物成本，年支出至少为2.6亿美元，在英国，处方成本从2010年到2011年增加了33%），但这种药物的治疗价值仍然不确定。因此，在本研究中，研究人员系统地回顾了相关已发表的研究，并分析了相关数据，以探讨cinacalcet治疗是否能改善成人CKD患者的临床结局。研究人员通过全面检索电子数据库、试验注册、专业期刊和主要会议记录，确定了在终末期CKD患者中进行的相关随机对照试验。然后，他们根据特定的标准提取数据，并评估偏倚风险。然后，研究人员将证据的质量分为高、中、低和极低质量。使用这些技术，研究人员在他们的分析中纳入了18项试验，涉及7,446名CKD成年患者。所有纳入的试验都评估了cinacalcet（剂量为30毫克至180毫克/天）以及该药物与常规疗法或常规疗法加安慰剂的比较。研究人员发现，与安慰剂或不治疗相比，在高质量证据中，cinacalcet对CKD晚期（5D期）患者的全因死亡率影响很小或没有影响（相对风险[RR]， 0.97），而在低质量证据中，对较轻CKD阶段（3-5期）患者的全因死亡率影响不明确（RR, 0.29）。Cinacalcet对CKD 5D期（RR, 0.67）和CKD 3-5期（RR, 0.29）参与者的心血管死亡率也有不确定的影响，而且它在CKD 5D期患者中预防骨折的作用也不清楚。此外，cinacalcet有明显的副作用，如增加低钙血症（RR, 7.38）、恶心（RR, 2.05）、呕吐（RR, 1.95）和腹泻（RR, 1.15）的风险，但降低高钙血症的风险（RR, 0.23）。研究人员发现，在高质量的证据中，cinacalcet可以预防CKD 5D期患者的甲状旁腺切除术（RR, 0.49）。然而，总的来说，他们还发现，平均而言，用cinacalcet常规治疗1000人一年对死亡率没有影响，可以防止大约3人进行甲状旁腺切除术，并分别导致大约60人和150人出现低钙血症和恶心。这些研究结果表明，对于终末期CKD （5D期）患者，常规cinacalcet （30 ~ 180mg /天）治疗可降低甲状旁腺浓度和高钙血症，并可预防甲状旁腺切除术，但对全因死亡率影响不大或没有影响，对心血管死亡的影响尚不清楚，并且经常伴有低钙血症、恶心、呕吐和腹泻等不良反应，这些不良胃肠道反应可能影响营养和生活质量。尽管CKD 3-5期患者的证据有限且质量一般较低，但该分析表明，尽管cinacalcet的广泛使用和相关的高成本，但该药物几乎没有临床益处。因此，慢性肾病患者常规使用cinacalcet治疗似乎是不合理的；益处可能仅限于对少数手术禁忌的患者预防甲状旁腺切除术。请通过本摘要的在线版本（http://dx.doi.org/10.1371/journal.pmed.1001436）访问这些网站。维基百科上有cinacalcet的药理学信息（请注意，维基百科是一个免费的在线百科全书，任何人都可以编辑），国家肾脏基金会有一些对CKD患者有用的信息，MedlinePlus也是如此
Giovanni Strippoli and colleagues report findings of a systematic review and meta-analysis examining the benefits and harms of calcimimetic therapy in adults with chronic kidney disease. Calcimimetic agents lower serum parathyroid hormone levels in people with chronic kidney disease (CKD), but treatment effects on patient-relevant outcomes are uncertain. We conducted a systematic review and meta-analysis to summarize the benefits and harms of calcimimetic therapy in adults with CKD and used cumulative meta-analysis to identify how evidence for calcimimetic treatment has developed in this clinical setting. Cochrane and Embase databases (through February 7, 2013) were electronically searched to identify randomized trials evaluating effects of calcimimetic therapy on mortality and adverse events in adults with CKD. Two independent reviewers identified trials, extracted data, and assessed risk of bias. Eighteen trials comprising 7,446 participants compared cinacalcet plus conventional therapy with placebo or no treatment plus conventional therapy in adults with CKD. In moderate- to high-quality evidence (based on Grading of Recommendations Assessment, Development, and Evaluation criteria) in adults with CKD stage 5D (dialysis), cinacalcet had little or no effect on all-cause mortality (relative risk, 0.97 [95% confidence interval, 0.89–1.05]), had imprecise effect on cardiovascular mortality (0.67 [0.16–2.87]), and prevented parathyroidectomy (0.49 [0.40–0.59]) and hypercalcemia (0.23 [0.05–0.97]), but increased hypocalcemia (6.98 [5.10–9.53]), nausea (2.02 [1.45–2.81]), and vomiting (1.97 [1.73–2.24]). Data for clinical outcomes were sparse in adults with CKD stages 3–5. On average, treating 1,000 people with CKD stage 5D for 1 y had no effect on survival and prevented about three patients from experiencing parathyroidectomy, whilst 60 experienced hypocalcemia and 150 experienced nausea. Analyses were limited by insufficient data in CKD stages 3–5 and kidney transplant recipients. Cinacalcet reduces the need for parathyroidectomy in patients with CKD stage 5D, but does not appear to improve all-cause or cardiovascular mortality. Additional trials in CKD stage 5D are unlikely to change our confidence in the treatment effects of cinacalcet in this population. Please see later in the article for the Editors' Summary Chronic kidney disease (CKD) refers to a progressive loss in kidney function over time and is caused by several conditions such as diabetes and high blood pressure. CKD is an increasingly common condition, affecting an estimated 26 million adults in the United States alone, with millions more at risk. People with CKD are at increased risk of death compared to the general population, and despite recent improvements in care, people with advanced CKD who are receiving dialysis experience an excess mortality rate of up to 20%. People with CKD also experience several biochemical imbalances—such as increased phosphorus (as a result of retention), low vitamin D and calcium (hypocalcemia), and increased parathyroid hormone—which lead to further health problems (such as a thinning of the bones) and pain. In light of this complication, clinical guidelines for people with CKD currently recommend that the blood levels of phosphorus and parathyroid hormone be maintained in a certain range to prevent the need for surgical removal of the gland (surgical parathyroidectomy). There are several medical therapies that help to keep phosphorus and parathyroid hormone blood levels within the target range, and in 2004, the drug cinacalcet hydrochloride (cinacalcet) was approved in the United States for use in people with end-stage CKD for this purpose. However, despite increasing use and costs of this drug (in the US, cinacalcet has become the largest single drug cost for patients on dialysis, with an annual expenditure of at least US$260 million, and in the UK, prescribing costs increased by up to 33% from 2010 to 2011), the therapeutic value of this drug remains uncertain. So in this study, the researchers systematically reviewed appropriate published studies and analyzed relevant data to investigate whether treatment with cinacalcet improves clinical outcomes in adults with CKD. The researchers identified relevant randomized controlled trials conducted in participants with end-stage CKD by thoroughly searching electronic databases and trial registries, specialist journals, and major conference proceedings. They then extracted data according to specific criteria and assessed the risk of bias. The researchers then graded the quality of evidence into the categories high, moderate, low, and very low quality. Using these techniques, the researchers included 18 trials involving 7,446 adults with CKD in their analysis. All included trials evaluated cinacalcet (at a dose of 30 mg to 180 mg/day) and how this drug compared to conventional therapy or conventional therapy plus placebo. The researchers found that, compared to placebo or no treatment, in high-quality evidence, cinacalcet had little or no effect on all-cause mortality (relative risk [RR], 0.97) for people in the final stage of CKD (stage 5D) and unclear effects on all-cause mortality in low-quality evidence for people in the less severe stages (stages 3–5) of CKD (RR, 0.29). Cinacalcet also had uncertain effects on cardiovascular mortality for participants with CKD stage 5D (RR, 0.67) and CKD stages 3–5 (RR, 0.29), and also its role in fracture prevention was unclear in people with CKD stage 5D. Furthermore, cinacalcet had significant side effects, such as increased risk of hypocalcemia (RR, 7.38), nausea (RR, 2.05), vomiting (RR, 1.95), and diarrhea (RR, 1.15), but reduced the risk of hypercalcemia (RR, 0.23). The researchers found that in high-quality evidence, cinacalcet prevented surgical parathyroidectomy in people with CKD stage 5D (RR, 0.49). However, overall, they also found that, on average, routinely treating 1,000 people with cinacalcet for one year has no effect on mortality, prevents about three people from experiencing surgical parathyroidectomy, and leads to approximately 60 and 150 people experiencing hypocalcemia and nausea, respectively. These findings suggest that routine cinacalcet (30 to 180 mg/day) therapy in people with end-stage CKD (stage 5D) reduces parathyroid concentrations and hypercalcemia, and may prevent surgical parathyroidectomy, but has little or no effect on all-cause mortality, has an unclear effect on cardiovascular death, and is frequently associated with adverse effects such as hypocalcemia, nausea, vomiting, and diarrhea—adverse gastrointestinal effects that may affect nutrition and quality of life. Although the evidence in people with CKD stages 3–5 is limited and generally of low quality, this analysis shows that despite the widespread use of cinacalcet and the associated high costs, this drug provides little clinical benefit. Therefore, routine use of cinacalcet therapy in people with CKD does not appear warranted; benefits may be limited to preventing parathyroidectomy in the small number of patients for whom surgery is contraindicated. Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001436. Wikipedia has information on the pharmacological profile of cinacalcet (note that Wikipedia is a free online encyclopedia that anyone can edit) The National Kidney Foundation has some useful information for patients with CKD, as does MedlinePlus
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影响因子：
13.6
作者：
Goodman, WG;Hladik, GA;Coburn, JW
通讯作者：
Coburn, JW
影响因子：
19.6
作者：
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通讯作者：
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影响因子：
1.9
作者：
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通讯作者：
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影响因子：
2
作者：
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通讯作者：
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影响因子：
158.5
作者：
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通讯作者：
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