BARCELONA(EGMN) –Erythropoietin therapy in patients with anemia of heart failure resulted in improved exercise capacity, reduced heart failure symptoms, and decreased hospitalizations, and showed strong trends for reduced rates of MI and all-cause mortality in a meta-analysis of 11 small randomized clinical trials.
Moreover, erythropoietin was not associated with an increased rate of adverse events, as in some clinical trials carried out in the settings of cancer or chronic kidney disease. It may be that erythropoietin’s angiogenesis-promoting effect is therapeutic in the context of heart failure but is the source of side effects in patients with cancer or renal disease, Dr. Dipak Kotecha said at the annual congress of the European Society of Cardiology.
He was quick to offer a caveat, however: “This is all based on a relatively small sample size. Some of these trials were small proof-of-concept trials, others were mechanistic and looked at the effects of different doses. None were individually powered for clinical events. The follow-up was relatively short, at 2-12 months.”
The 11 randomized trials involved 794 patients with mild to moderate anemia and left ventricular systolic heart failure. Nine of the trials were placebo controlled. Mean baseline hemoglobin was 10.1-11.8 g/dL and rose by 2.0 g/dL in response to erythropoietin therapy.
This 2.0-g/dL increase in hemoglobin was associated with a mean 69-meter improvement in 6-minute walk distance compared with controls, a 96-second increase in exercise duration, and an improvement in New York Heart Association functional class equivalent to three-quarters of a class.
“All of these changes were clinically as well as statistically highly significant,” observed Dr. Kotecha of Royal Brompton Hospital, London.
Peak oxygen consumption, or VO2 max, increased by an average of 2.3 mL/kg per min. Left ventricular ejection fraction increased in erythropoietin-treated patients by an absolute 5.8%, compared with controls; that is comparable to the improvement seen in the major clinical trials of beta-blockers. Quality of life scores using the standard Minnesota and Kansas City instruments showed significant gains as well.
Heart failure hospitalizations in erythropoietin-treated patients were significantly reduced by 36%, compared with controls, reflecting an absolute 8% rate difference. “The absolute 8% decrease in hospitalizations for heart failure is very similar to what’s been seen in the major clinical trials of beta-blocker therapy in heart failure,” Dr. Kotecha said.
B-type natriuretic peptide levels fell by an average of 40%, or 237 pg/dL, in response to erythropoietin. Again, that is a magnitude of effect similar to what has been seen in clinical trials of combined beta-blocker and ACE inhibitor or angiotensin receptor blocker therapy, he continued.
The risk of all-cause mortality was reduced by 39% in the erythropoietin treatment group, a strong trend that just missed statistical significance. The 27% relative risk reduction in acute MI also was not quite significant. Definitive answers as to whether erythropoietin therapy has a beneficial effect on these key outcomes are anticipated from the ongoing Amgen-sponsored phase III Reduction of Events With Darbepoetin Alfa in Heart Failure (RED-HF) trial, which is randomizing more than 3,000 patients.
In addition to the question of whether erythropoietin-stimulating agents have a favorable impact on rates of death and acute MI in anemic heart failure patients, other key concerns include the optimal dosage and timing of the therapy and the best target hemoglobin. There are also several ongoing randomized trials looking at whether iron therapy is of value – and if so, in what form – in patients with anemia of heart failure.
Anemia occurs in one-third to one-half of patients with heart failure and has been associated with a markedly worse prognosis. Dr. Kotecha cited as an example a Dutch meta-analysis involving more than 153,000 heart failure patients, 37% of whom were anemic. The mortality after a minimum of 6 months of follow-up was 30% in nonanemic patients and 47% among those with anemia (J. Am. Coll. Cardiol. 2008;52:818-27).
Dr. Kotecha reported having no financial conflicts of interest in connection with the meta-analysis, which was conducted using Cochrane Collaboration methodology and has been submitted to the Cochrane Review for possible publication.
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巴塞罗那(EGMN)——一份对11项小型随机临床试验的荟萃分析显示：促红细胞生成素治疗心力衰竭合并贫血患者，可改善运动能力、减少心力衰竭症状、降低入院率，并可显著减少心肌梗死的发生率及各种原因导致的死亡率。
Dipak Kotecha博士在欧洲心脏病学会年会上说道，此外，促红细胞生成素与不良事件发生率的增加无关，而在部分癌症或慢性肾病临床试验中却存在相关性。这可能是由于促红细胞生成素的促血管生成效应具有治疗心力衰竭的作用，但同时也可引发癌症或肾病患者的副作用。
但他马上做出说明以防止被误解。“这些研究都是以相对较小的样本量为基础的。部分研究是小型验证性试验，其他的则为机制研究以及不同剂量疗效的观察研究。但没有一项是单独的临床事件研究。随访时间在2~12个月不等，相对较短。”
这11项随机试验共纳入794例轻至中度贫血合并左室收缩性心力衰竭患者。其中9项试验为安慰剂对照研究。血红蛋白的平均基线值为10.1~11.8 g/dl，促红细胞生成素治疗后平均升高2.0 g/dl。
与对照组相比，血红蛋白上升2.0 g/dl与6 min步行距离平均增加69 m、运动持续时间提高96 s以及纽约心脏病协会(NYHA)心功能分级改善3/4级相关。
英国伦敦皇家布朗普顿医院的Kotecha博士评论说：“上述所有这些变化均具有临床及统计学上的显著差异。”
峰值耗氧量(亦称最大摄氧量)每分钟平均增加2.3 ml/kg。与对照组相比，促红细胞生成素治疗患者左心室射血分数绝对值增加5.8%，与主要的β受体阻滞剂临床试验中受试者的改善程度类似。采用明尼苏达州(MLHFQ)和堪萨斯城(KCCQ)标准的生活质量评分，治疗组生活质量得到显著改善。
与对照组相比，促红细胞生成素治疗组中因心力衰竭住院者明显减少了36%，在绝对值上则有8%的差异。Kotecha博士说：“心力衰竭住院率绝对值下降8%与β受体阻滞剂治疗心力衰竭主要临床试验中的情况十分相似。”
促红细胞生成素治疗患者的B型利钠肽水平平均下降了40%(下降237 pg/dl)。这同样与β受体阻滞剂联合血管紧张素转换酶抑制剂(ACEI)或血管紧张素受体阻滞剂治疗后的改善效果类似，他继续说道。
促红细胞生成素治疗组所有原因导致的死亡风险下降39%，趋势明显，几乎达到统计学差异。急性心肌梗塞的相对危险性27%的下降值也不具备显著差异。促红细胞生成素治疗对这些关键的临床预后是否具有改善作用，由安进公司资助、正在进行当中的“阿法达贝泊汀(Darbepoetin Alfa)减少心力衰竭不良事件”(RED-HF) III期随机临床试验预计将给出明确的答案，该试验共纳入3,000多例患者。
除了关心促红细胞生成素刺激因子(ESA)是否对心力衰竭合并贫血患者的死亡率和急性心肌梗死率产生影响以外，其他需重点关注的还包括最佳剂量、治疗时间选择以及最佳靶向血红蛋白。此外，还有几个正在进行当中的随机临床试验，观察铁剂是否具有治疗价值。如果有的话，那么，心力衰竭合并贫血患者可从何种类型的铁剂中获益。
心力衰竭患者有1/3~1/2合并有贫血，已经证实与显著的预后不良相关。Kotecha博士以荷兰的一份荟萃分析为例，该研究共纳入超过15.3万例心力衰竭患者，其中37%合并有贫血。在为期最短为6个月的随访中，非贫血患者的死亡率为30%，而贫血患者的死亡率达47% (J. Am. Coll. Cardiol. 2008;52:818-27) 。
该荟萃分析采用Cochrane协作网提供的方法进行，并已投稿至《Cochrane综述》(Cochrane Review)以供发表。Kotecha 博士报告称研究无相关的财务利益冲突。
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