Commentary
The CHOIR study highlights the importance of randomized controlled trials in determining optimal treatment approaches for patients with CKD. The trial was undertaken with the expectation that the higher hemoglobin target would be associated with better clinical outcomes; however, the opposite effect was found. The Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) trial, results of which were published in the same issue of the New England Journal of Medicine, also compared high (130–150 g/l [13.0–15.0 g/dl]) and low (105–115 g/l [10.5–11.5 g/dl]) hemoglobin targets in patients with stage 3 and 4 CKD. In this trial, the high hemoglobin target was associated with improved QOL, but it did not reduce the risk of a first cardiovascular event or affect left ventricular mass index, and it was associated with a more rapid progression to dialysis. Despite some limitations of the CHOIR and CREATE trials (neither was blinded; the dropout rate was high in CHOIR; and rates of the primary end point components were lower than anticipated in CREATE), their findings are compelling.
The apparently erroneous expectation that a normal hemoglobin target would result in improved clinical outcomes was based on observational cohort studies in both predialysis patients and those on dialysis and perhaps also on the general intuition that 'normal' should be better than 'subnormal'. Like the CHOIR and CREATE studies, earlier randomized controlled trials in patients on hemodialysis and patients with advanced CKD6 found no benefit of high hemoglobin targets. These results have, however, been viewed as either not highly generalizable because enrollment was confined to patients with underlying heart disease,4 or as nondefinitive because sample sizes were small6 or intermediate end points were used. There are multiple possible reasons for discrepant results between observational studies and large randomized trials. Most importantly, observational studies cannot distinguish indicators of risk from causal factors.
Hemoglobin levels in the US end-stage renal disease population have steadily increased since recombinant erythropoietin became available. The mean hemoglobin concentration is currently 120 g/l (12.0 g/dl), and 20% of patients have concentrations greater than 130 g/l (13.0 g/dl).7 The CHOIR and CREATE studies, together with previous randomized controlled trials in patients on dialysis, indicate that we should aim for only partial correction of anemia in patients with CKD, and that 115 g/l (11.5 g/dl) is a reasonable upper limit for a hemoglobin target. It is important to recognize that, because of the difficulty of maintaining hemoglobin concentrations within a narrow window, reducing the upper limits of hemoglobin targets is likely to increase the proportion of patients with hemoglobin concentrations less than 110 g/l (11.0 g/dl), and perhaps even the proportion with levels below 100 g/l (10.0 g/dl). The ongoing Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT), which allows a hemoglobin level as low as 90 g/l (9.0 g/dl) in one treatment arm, should provide important information about acceptable lower limits.
The CHOIR and CREATE trials have received substantial attention from nephrology societies, the Centers for Medicare and Medicaid Services, the US Congress, the pharmaceutical industry, and dialysis providers. It is likely that the hemoglobin targets recommended in clinical practice guidelines will be lowered in response to the findings of these trials, and reimbursement policies for erythropoiesis-stimulating agents might be altered.
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Commentary
评论
The CHOIR study highlights the importance of randomized controlled trials in determining optimal treatment approaches for patients with CKD.
CHOIR研究结果凸显出随机对照临床试验在确定CKD患者最佳治疗手段中的重要性。
The trial was undertaken with the expectation that the higher hemoglobin target would be associated with better clinical outcomes; however, the opposite effect was found.
该试验原本期望达到高血红蛋白靶目标会伴随着更好的临床转归，结果却截然相反。
The Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) trial, results of which were published in the same issue of the New England Journal of Medicine, also compared high (130–150 g/l [13.0–15.0 g/dl]) and low (105–115 g/l [10.5–11.5 g/dl]) hemoglobin targets in patients with stage 3 and 4 CKD.
其结果发表在同一期新英格兰医学杂志上的早期使用依泊丁治疗贫血减少心血管风险试验（CREATE）也对比观察了高血红蛋白靶目标(130–150 g/l [13.0–15.0 g/dl]) 和低血红蛋白靶目标(105–115 g/l [10.5–11.5 g/dl])的3到4期CKD患者
In this trial, the high hemoglobin target was associated with improved QOL, but it did not reduce the risk of a first cardiovascular event or affect left ventricular mass index, and it was associated with a more rapid progression to dialysis.
试验中高血红蛋白靶目标组患者生活质量得以改善，但首次心血管事件的风险并未降低，左心室质量指数也未受影响，患者进展到透析的速度加快。
Despite some limitations of the CHOIR and CREATE trials (neither was blinded; the dropout rate was high in CHOIR; and rates of the primary end point components were lower than anticipated in CREATE), their findings are compelling.
尽管CHOIR和CREATE研究存在某些局限（两者都没有采取盲法，CHOIR研究退出率较高，CREATE研究初级终点发生率低于预期），但其发现却令人关注。
The apparently erroneous expectation that a normal hemoglobin target would result in improved clinical outcomes was based on observational cohort studies in both predialysis patients and those on dialysis and perhaps also on the general intuition that 'normal' should be better than 'subnormal'.
这一明显错误的期望—即达到正常血红蛋白水平会带来临床转归的改善，建立在对透析前和透析患者所作的观察性队列研究结果之上，也许还受了“正常”总比“低于正常”好这一直觉的影响。
Like the CHOIR and CREATE studies, earlier randomized controlled trials in patients on hemodialysis and patients with advanced CKD6 found no benefit of high hemoglobin targets.
与这两个研究相仿，早期在血透患者和进展性CKD6期患者所作的随机对照临床试验也未发现高血红蛋白的益处。
These results have, however, been viewed as either not highly generalizable because enrollment was confined to patients with underlying heart disease, or as nondefinitive because sample sizes were small or intermediate end points were used.
然而这些研究要么被认为不具普遍性（因为入选标准限定在伴有基础心脏疾病的患者），要么被认为不具权威性（因为样本数小或使用了中间性终点）。
There are multiple possible reasons for discrepant results between observational studies and large randomized trials.
导致观察性研究和大规模随机临床试验结果之间不一致的可能原因有多种。
Most importantly, observational studies cannot distinguish indicators of risk from causal factors.
最为重要的是观察性研究无法区分风险指标和偶然因素。
emoglobin levels in the US end-stage renal disease population have steadily increased since recombinant erythropoietin became available.
自从重组促红细胞生成素应用以来，美国终末期肾脏疾病患者的血红蛋白水平稳步上升。
The mean hemoglobin concentration is currently 120 g/l (12.0 g/dl), and 20% of patients have concentrations greater than 130 g/l (13.0 g/dl).
目前平均血红蛋白水平为120 g/l (12.0 g/dl)，其中20%高于130 g/l (13.0 g/dl)。
The CHOIR and CREATE studies, together with previous randomized controlled trials in patients on dialysis, indicate that we should aim for only partial correction of anemia in patients with CKD, and that 115 g/l (11.5 g/dl) is a reasonable upper limit for a hemoglobin target.
CHOIR、CREATE、连同以前的透析患者随机对照临床试验结果表明：我们纠正CKD患者贫血的目标应当只是部分改善，而115 g/l (11.5 g/dl)是一个合理的血红蛋白靶目标的上限。
It is important to recognize that, because of the difficulty of maintaining hemoglobin concentrations within a narrow window, reducing the upper limits of hemoglobin targets is likely to increase the proportion of patients with hemoglobin concentrations less than 110 g/l (11.0 g/dl), and perhaps even the proportion with levels below 100 g/l (10.0 g/dl).
因为将血红蛋白水平维持在一个狭窄的范围内非常困难，所以必须认识到降低血红蛋白靶目标上限有可能使血红蛋白低于11.0 g/dl甚至10.0 g/dl患者的比例有所增加。
The ongoing Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT), which allows a hemoglobin level as low as 90 g/l (9.0 g/dl) in one treatment arm, should provide important information about acceptable lower limits.
正在进行的使用Aranesp减少心血管事件研究（TREAT，其中一组允许的血红蛋白值低至9.0 g/dl）应当会提供关于可接受的血红蛋白低限方面重要的信息。
The CHOIR and CREATE trials have received substantial attention from nephrology societies, the Centers for Medicare and Medicaid Services, the US Congress, the pharmaceutical industry, and dialysis providers.
CHOIR和CREATE研究已经引起了肾脏病学界、美国医疗保险和医疗补助服务中心、美国议会、制药企业和透析提供商的强烈关注。
It is likely that the hemoglobin targets recommended in clinical practice guidelines will be lowered in response to the findings of these trials, and reimbursement policies for erythropoiesis-stimulating agents might be altered.
与这些试验结果相呼应，临床实践指南中所推荐的血红蛋白靶目标可能会调低，对刺激红细胞生成药物的补偿政策也能也会改变。
述评；
CHOIR研究结果凸显出随机对照临床试验在确定CKD患者最佳治疗手段中的重要性。该试验原本期望达到高血红蛋白靶目标会伴随着更好的临床转归，结果却截然相反。其结果发表在同一期新英格兰医学杂志上的早期使用依泊丁治疗贫血减少心血管风险试验（CREATE）也对比观察了高血红蛋白靶目标(130–150 g/l [13.0–15.0 g/dl]) 和低血红蛋白靶目标(105–115 g/l [10.5–11.5 g/dl])的3到4期CKD患者。试验中高血红蛋白靶目标组患者生活质量得以改善，但首次心血管事件的风险并未降低，左心室质量指数也未受影响，患者进展到透析的速度加快。
尽管CHOIR和CREATE研究存在某些局限（两者都没有采取盲法，CHOIR研究退出率较高，CREATE研究初级终点发生率低于预期），但其发现却令人关注。
这一明显错误的期望—即达到正常血红蛋白水平会带来临床转归的改善，建立在对透析前和透析患者所作的观察性队列研究结果之上，也许还受了“正常”总比“低于正常”好这一直觉的影响。
与这两个研究相仿，早期在血透患者和进展性CKD6期患者所作的随机对照临床试验也未发现高血红蛋白的益处。然而这些研究要么被认为不具普遍性（因为入选标准限定在伴有基础心脏疾病的患者），要么被认为不具权威性（因为样本数小或使用了中间性终点）。
导致观察性研究和大规模随机临床试验结果之间不一致的可能原因有多种。最为重要的是观察性研究无法区分风险指标和偶然因素。
自从重组促红细胞生成素应用以来，美国终末期肾脏疾病患者的血红蛋白水平稳步上升。目前平均血红蛋白水平为120 g/l (12.0 g/dl)，其中20%高于130 g/l (13.0 g/dl)。
CHOIR、CREATE、连同以前的透析患者随机对照临床试验结果表明：我们纠正CKD患者贫血的目标应当只是部分改善，而115 g/l (11.5 g/dl)是一个合理的血红蛋白靶目标的上限。因为将血红蛋白水平维持在一个狭窄的范围内非常困难，所以必须认识到降低血红蛋白靶目标上限有可能使血红蛋白低于11.0 g/dl甚至10.0 g/dl患者的比例有所增加。正在进行的使用Aranesp减少心血管事件研究（TREAT，其中一组允许的血红蛋白值低至9.0 g/dl）应当会提供关于可接受的血红蛋白低限方面重要的信息。
CHOIR和CREATE研究已经引起了肾脏病学界、美国医疗保险和医疗补助服务中心、美国议会、制药企业和透析提供商的强烈关注。与这些试验结果相呼应，临床实践指南中所建议的血红蛋白靶目标可能会调低，对刺激红细胞生成药物的补偿政策也能也会改变。
编译稿
2006年11月新英格兰医学杂志发表的两项大规模研究CHORI(Correction of Hemoglobin and Outcomes in Renal Insufficiency, 纠正血红蛋白与肾功能不全临床转归)和CREATE（The Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta， 早期使用依泊丁治疗贫血减少心血管风险试验）结果引起了肾脏病学界、政府部门、医疗设备和制药企业的广泛关注。
CHORI研究共纳入1432名伴有有贫血（血红蛋白低于110g/L）的慢性肾脏病(肾小球滤过率在15-50ml/min/1.73m2)患者。参与试验者皮下注射足量重组α促红细胞生成素以达到13.5g/dL或11.3g/L血红蛋白。以死亡，心肌梗死，中风，因充血性心力衰竭住院治疗（未进行肾脏替代疗法）为主要观察终点。生活质量为次要观察终点。结果：较高血红蛋白目标组主要终点事件发生率明显高于较低目标组（P = 0.03）。通过LASA, KDQ和SF-36评分来评价生活质量改善，两组基本相似。研究结论：慢性肾脏病贫血患者以13.5 g/dl作为血红蛋白治疗目标较11.3 g/dl死亡或心血管事件风险明显增加。
CREATE研究将603例肾小球滤过率为15.0至35.0ml每分/1.73m2体表面积并轻到中度贫血症（血红蛋白水平：11.0~12.5 g/dL）的慢性肾脏病患者随机分配到正常血红蛋白靶目标组（目标血红蛋白水平11.0~12.5 g/dL，组1）和低于正常血红蛋白靶目标组（目标血红蛋白水平10.5~ 11.5 g/dL，组2）。初级终点由八项心血管事件组成评估，次级终点包括评估左心室体积指数，生命质量评分以及慢性肾脏疾病的进展程度。结果显示在3年的研究中，完全纠正贫血并不影响首次心血管事件发生的风险(组1 ：58例，组2：47例，危害比：0.78；95%可信区间为0.53到1.14；P=0.20)。两组左心室体积指数保持稳定。组1 中需要透析的患者多于组2（127对111，P=0.03)。与组2相比，组1总体健康及躯体功能有显著改善(P <0.001)。两组之间不良反应事件发生率无明显统计学差异，但组1更易出现高血压和头痛。研究结论：早期完全纠正慢性肾脏疾病患者贫血并不能减少心血管事件发生的风险性。
“尽管CHOIR和CREATE研究存在某些局限（两者都没有采取盲法，CHOIR研究退出率较高，CREATE研究初级终点发生率低于预期），但其发现却令人关注”。 美国波士顿大学肾病科Laura M Dember博士评论说。
“CHOIR、CREATE、连同以前的透析患者随机对照临床试验结果表明：我们纠正CKD患者贫血的目标应当只是部分改善，而115 g/l (11.5 g/dl)是一个合理的血红蛋白靶目标的上限。因为将血红蛋白水平维持在一个狭窄的范围内非常困难，所以必须认识到降低血红蛋白靶目标上限有可能使血红蛋白低于11.0 g/dl甚至10.0 g/dl患者的比例有所增加。正在进行的使用Aranesp减少心血管事件研究（TREAT，其中一组允许的血红蛋白值低至9.0 g/dl）应当会提供关于我们所能接受的最低血红蛋白值方面重要的信息。”
Laura M Dember博士还补充说“与这些试验结果相呼应，临床实践指南中所建议的血红蛋白靶目标可能会调低，对刺激红细胞生成药物的补偿政策也可能会改变。”
（丁香）
