治疗贫血对心力衰竭患者无益

旧金山——美国心脏病学会(ACC)2013年会上报告的一项随机、多中心试验显示，采用促红细胞生成素α治疗贫血性心力衰竭患者，未能产生任何有临床意义的改善，反而显著增加缺血性卒中和血栓事件的发生率。

Karl Swedberg博士

主要研究者、瑞典哥德堡大学的Karl Swedberg博士指出，这一结果“不支持对收缩性心力衰竭合并轻至中度贫血患者使用促红细胞生成素α”。这项研究同期发表在《新英格兰医学杂志》上(N. Engl. J. Med. 2013; 368: doi:10.1056/NEJMoa1214865)。

心力衰竭患者常合并贫血，既往小规模研究提示升高患者的血红蛋白水平可改善其功能。而且，来自观察性研究的结果也显示，血红蛋白水平低于12.0 g/dl的心力衰竭患者结局更差，血红蛋白水平每改变1.0 g/dl，全因死亡率随之发生15%~20%的变化。但本次报告的研究结果却对贫血在不良结局中扮演主要角色的观点提出了质疑。“我们的发现提示，血红蛋白水平与其他替代指标一样，只是心力衰竭不良预后的一个标志物，而不是治疗对象。”

“促红细胞生成素α用于减少心力衰竭患者的事件”(RED-HF)试验于2006年6月~2012年5月期间从33个国家的453家医院招募了2,278例患者，纽约心脏协会Ⅱ~Ⅳ级心力衰竭，血红蛋白水平介于9.0~12.0 g/dl。该研究排除了缺铁(转铁蛋白饱和度低于15%)、因出血或其他原因导致贫血，以及血清肌酐水平高或血压超过160/100 mmHg的患者。受试者的中位年龄为72岁，65%为Ⅲ~Ⅳ级心力衰竭，中位射血分数为31%。入组时的中位血红蛋白水平为11.2 g/dl。

被分入促红细胞生成素注射组的1,136例患者，起始剂量为0.75 mcg/kg体重，每2周注射1次；一旦血红蛋白水平达到13.0 g/dl，注射频率就降至每月1次，持续治疗以便将血红蛋白水平维持在13.0~14.5 g/dl范围内。该组患者与安慰剂对照组1,142例患者在血红蛋白水平上的差异，在1个月后达到了统计学显著性，并且保持显著性直至研究结束，中位随访时间为28个月。受试者使用促红细胞生成素的中位剂量为每月167 mcg。当患者的转铁蛋白饱和度低于20%时即给予铁剂治疗。

该研究的主要终点是全因死亡+因心力衰竭加重而住院的复合发生率。结果促红细胞生成素α组和安慰剂对照组分别有51%和50%的患者达到这一终点，差异不显著。各个亚组的分析结果均与总体结果一致，而且不受基线时组间差异校正的影响。两组患者的总死亡率也相似，分别为42%和40%。

两组分别有572例和695例患者因心力衰竭而住院，组间差异差一点达到统计学显著性(P=0.06)。

在生活质量方面，促红细胞生成素α组和安慰剂对照组的堪萨斯城心肌病问卷总分分别为6.68分和4.48分，平均相差2.2分，具有统计学意义。但与基线相比评分增加至少5分(具有临床意义的增加幅度)的患者比例，两组分别为53%和48%，差异不具有统计学意义(P=0.06)。

两组因不良事件而停药的患者比例相似。任何血栓和栓塞事件的发生率分别为14%和10%，差异有统计学意义。缺血性脑血管事件的发生率分别为5%和3%，也有统计学差异，不过两组的总体脑血管疾病(缺血性或出血性)发生率相似。促红细胞生成素α组的脓毒症休克发生率也明显更高。

RED-HF研究由安进公司资助，后者是促红细胞生成素α(Aranesp)的销售商。Swedberg博士报告称，担任了安进、诺华和施维雅的顾问和讲者。

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By: Mitchel L. Zoler, Cardiology News Digital Network

SAN FRANCISCO – Treatment of anemic heart failure patients with the erythropoiesis-stimulating agent darbepoetin alfa failed to produce any clinically meaningful improvements and significantly raised the incidence of ischemic stroke and thrombotic events in a randomized, multicenter trial with more than 2,200 patients.

The findings "do not support the use of darbepoetin alfa in patients with systolic heart failure and mild to moderate anemia," concluded Dr. Karl Swedberg, who presented the results in a report on March 10 at the annual meeting of the American College of Cardiology, and his associates.
     
Patients with heart failure also often have anemia, and results from small studies had suggested that increasing patients’ hemoglobin levels could improve their functional capacity. In addition, results from observational studies had shown worse outcomes in heart failure patients with hemoglobin levels less than 12.0 g/dL, and that a 1.0 g/dL change in hemoglobin level linked with a difference of 15-20 percentage points in all-cause mortality.

But the results of the current study called into question whether anemia plays any primary role in worsened outcomes.

"Our findings suggest that the hemoglobin level, like other surrogates, is simply a marker of poor prognosis in heart failure rather than a therapeutic target," said Dr. Swedberg, professor of medicine at the University of Gothenburg, Sweden, and his associates in their report, which was published concurrent with Dr. Swedberg’s presentation at the meeting (N. Engl. J. Med. 2013; 368: doi:10.1056/NEJMoa1214865).

The Reduction of Events by Darbepoetin Alfa in Heart Failure (RED-HF) trial enrolled 2,278 patients with New York Heart Association class II-IV heart failure and a hemoglobin level of 9.0-12.0 g/dL at 453 sites in 33 countries during June 2006–May 2012. All patients also had a left ventricular ejection fraction of 40% or less. The study excluded patients with iron deficiency (transferrin saturation of less than 15%), evidence or bleeding or other causes of anemia, and patients with a high serum creatinine level or blood pressure above 160/100 mm Hg. The median age of the enrolled patients was 72 years, 65% had class III or IV heart failure, and their median ejection fraction was 31%. Median hemoglobin at entry was 11.2 g/dL.

The 1,136 patients assigned to receive darbepoetin injections began at a dose of 0.75 mcg/kg body weight once every 2 weeks; once they achieved a hemoglobin level of 13.0 g/dL treatment scaled back to once monthly, and treatment was continued to maintain a hemoglobin level of 13.0-14.5 g/dL. The difference in hemoglobin levels between these patients and the 1,142 randomized to the placebo control group became statistically significant after 1 month and remained significant through the study, which had a median follow-up of 28 months. The median monthly darbepoetin dosage was 167 mcg. When patients’ transferrin saturation fell below 20% they received supplemental iron.

The study’s primary endpoint was the combined rate of all-cause death and hospitalization for worsening heart failure. This occurred in 51% of the patients treated with darbepoetin alfa and 50% of those who received placebo, a difference that was not statistically significant. The result was consistent across all subgroups examined, and was not affected by adjustment for baseline differences between the two treatment arms. Total mortality was also similar between the two groups, 42% in the darbepoetin-treated patients and 40% in the controls.

The total number of hospitalizations for heart failure was 572 in the darbepoetin arm and 695 among the placebo patients, a difference that just missed being statistically significant (P = 0.06).

The overall Summary Score of the Kansas City Cardiomyopathy Questionnaire, a measure of quality of life in heart failure patients, was 6.68 in the darbepoetin-treated patients and 4.48 in the placebo patients, an average 2.2 point difference that was statistically significant. But the percent of patients with at least a 5-point increase in their score over baseline – a clinically meaningful increase – was 53% in the darbepoetin group and 48% in the placebo arm, a difference that fell short of statistical significant (P = 0.06).

The rate of study drug discontinuations due to adverse events was similar in the two arms. The rate of any embolic and thrombotic event was 14% in the darbepoetin patients and 10% in the placebo patients, a statistically significant difference. The rate of ischemic cerebrovascular events was 5% in the darbepoetin arm and 3% in the placebo arm, a statistically significant difference, although the overall rate of all cerebrovascular disorders – ischemic or hemorrhagic – was not significantly different between the two treatment groups. Episodes of septic shock were also significantly more frequent in the darbepoetin-treatment patients.

The RED-HF study was sponsored by Amgen, the company that market darbepoetin alfa (Aranesp). Dr. Swedberg said that he has been a consultant to and lecturer on behalf of Amgen as well as Novartis and Servier.