阿利吉仑对心力衰竭住院患者无益

3月10日发表于《美国医学会杂志》(JAMA 2013;309: doi10.1001/jama.2013.1954)并同时在美国心脏病学会(ACC)2013年会上公布的ASTRONAUT研究显示，对于心力衰竭住院患者，在标准治疗基础上加用阿利吉仑预防心血管死亡或心力衰竭再入院，并无显著额外益处。在应用阿利吉仑的糖尿病患者中还观察到一些不良影响，包括6个月心血管死亡和心力衰竭再入院风险及1年全因死亡风险显著增加，原因尚不清楚，可能与这种肾素血管紧张素醛固酮系统(RAAS)抑制剂导致低血压、高钾血症和肾功能恶化风险增加有关。

这项随机安慰剂对照研究由美国西北大学的Mihai Gheorghiade博士及其同事进行，目的是在心力衰竭住院患者中比较阿利吉仑/标准治疗与单纯标准治疗的6个月和12个月结局。

共1,639例患者被随机分组，其中1,615例被纳入最终疗效分析。试验组患者在标准治疗基础上加用150 mg阿利吉仑。标准治疗的药物由主管医生决定，可包括利尿剂、地高辛、血管紧张素转换酶(ACE)抑制剂、血管紧张素受体阻滞剂(ARB)和β受体阻滞剂。患者的招募时间为2009~2011年；中位随访时间为11个月。患者的平均年龄为65岁。平均左室射血分数为28%，平均估计肾小球滤过率为67 mL/min·1.73 m²。41%的患者合并糖尿病。入院时，N端脑钠肽前体(NT-proBNP)平均水平为4,239 pg/ml。基线时应用的其他药物包括利尿剂(96%)、β受体阻滞剂(82%)、ACE抑制剂或ARB(84%)，以及盐皮质激素受体拮抗剂 (57%)。

主要疗效终点是6个月内心血管死亡或心力衰竭再入院的复合事件。阿利吉仑组和安慰剂组分别有201例(25%)和214例(26%)患者发生这一复合事件，组间差异不显著。单独分析心血管死亡和心力衰竭再入院，结果显示组间差异也不显著。

次要终点为12个月心血管死亡或心力衰竭再入院的复合事件。虽然阿利吉仑组发生这一复合事件的人数多于安慰剂组(283例 vs. 301例)，但两组的发生率无显著差异(35% vs. 37%)。分析治疗后首次心血管事件的数量发现，阿利吉仑组心肌梗死的发生率显著低于安慰剂组(2% vs. 5%；HR=0.93；P=0.009)。

亚组分析发现，阿利吉仑尤其对糖尿病患者有不良影响。与接受标准治疗的无糖尿病的患者相比，接受阿利吉仑治疗的糖尿病患者的6个月心血管死亡或心力衰竭再入院发生率高出16%，12个月全因死亡率高出64%。

治疗期间，阿利吉仑组糖尿病患者的死亡率为24%，而安慰剂组为17%，组间差异显著。相比之下，阿利吉仑组和安慰剂组无糖尿病史的患者的死亡率分别为15%和20%。

阿利吉仑组以下不良事件的数量显著高于安慰剂组：高钾血症(14% vs. 13%)、重度高钾血症(8% vs. 5%)、高钾血症相关事件(21% vs. 17%)、低血压(17% vs. 13%)、估计肾小球滤过率降低(11% vs. 9%)、肾功能不全相关事件(17% vs. 12%)。

研究者表示，该研究结果不支持在标准治疗基础上常规应用阿利吉仑治疗因慢性心力衰竭恶化住院的患者，并且亚组分析的结果与既往研究结果一致，即对已经在应用RAAS抑制剂的糖尿病患者应用阿利吉仑结局不佳。需开展进一步研究，对肾素抑制剂在糖尿病患者中的应用进行评估。

该研究获诺华公司资助。Gheorghiade博士声明与诺华等32家制药公司存在利益关系。

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By: Michele G. Sullivan, Cardiology News Digital Network

For patients hospitalized with heart failure, aliskiren added no significant benefit to standard therapy in preventing cardiovascular death or heart failure readmission.

The drug did, however, have some problematic effects on patients with diabetes, including significant increases in the risk of cardiovascular death and heart failure readmission at 6 months and all-cause death at 1 year.

The negative interaction between diabetes and aliskiren – an inhibitor of the angiotensin-renin-aldosterone system (RAAS) – is unclear, according to Dr. Mihai Gheorghiade and colleagues.

"[The issue] may be related to the increased risk of hypotension, hyperkalemia, and worsening renal function with the study drug," wrote Dr. Gheorghiade of Northwestern University, St. Louis, Mo., and his colleagues. The conclusions were published in the March 10 issue of JAMA and simultaneously presented at the annual meeting of the American College of Cardiology in San Francisco (JAMA 2013;309: doi10.1001/jama.2013.1954).

The randomized, placebo-controlled ASTRONAUT trial compared 6-and 12-month outcomes of aliskiren plus standard therapy to standard therapy alone in patients hospitalized with heart failure. 

The study randomized 1,639 patients; 1,615 were included in the final efficacy analysis. Patients in the investigational arm received 150 mg aliskiren daily in addition to standard treatment. Standard treatment was at the treating physician’s discretion, and could include, among others, diuretics, digoxin, ACE inhibitors, angiotensin receptor blockers, and beta-blockers. The study enrolled patients from 2009-2011; the median follow-up was 11 months

The patients were a mean of 65 years old. Their mean left ventricular ejection fraction was 28%, and mean estimated glomeular filtration rate was 67 mL/min/1.73 m3.  Nearly half (41%) had diabetes.

At admission, the mean N-terminal pro–brain natriuretic peptide (NT-proBNP) level was 4,239 pg/mL. Other drugs taken at baseline included diuretics (96%), beta-blockers (82%), ACE inhibitors or ARBs (84%), and mineralocorticoid antagonists (57%).

The primary efficacy endpoint was a combination of cardiovascular death or heart failure readmission within 6 months. This occurred in 201 (25%) of the aliskiren group and 214 (26%) of the placebo group – a nonsignificant difference. Nor were there significant differences when CV death and readmission were examined separately.

The main secondary endpoint was the composite of cardiovascular death or heart failure readmission at 12 months; again, there was no significant between-group difference (35% vs. 37%), although the events were numerically less in the aliskiren group than the control group (283 vs. 301). Parsing down the number of first cardiovascular events after treatment, the investigators did find that myocardial infarction was significantly less common in the aliskiren group (2% vs. 5%; HR 0.93; P = 0.009).

A subgroup analysis found that the drug was especially problematic for patients with diabetes. Compared to patients without the disorder who had standard treatment, diabetic patients who took aliskiren were 16% more likely to experience cardiovascular death or heart failure readmission by 6 months, and 64% more likely to experience all-cause death by 12 months.

During the treatment period, death occurred in 24% of patients with diabetes who took aliskiren, compared with 17% who took placebo – also a significant difference.

"In contrast, the rates of death among patients without a history [of diabetes] were 15% and 20% in the aliskiren and placebo groups, respectively," the authors wrote.

A number of adverse events were significantly higher in the aliskiren group, including hyperkalemia (14% vs. 13%) and severe hyperkalemia (8% vs. 5%). Hyperkalemia-related events occurred in 21% of the aliskiren group and 17% of the control group. Hypotension was also more common in the aliskiren group (17% vs. 13%). Decreased eGFR was significantly more common among those taking the study drug (11% vs. 9%), as were events potentially related to renal dysfunction (17% vs. 12%).

"The results of the ASTRONAUT study do not support the routine administration of aliskiren in addition to standard therapy, to patients hospitalized for worsening chronic heart failure," the investigators concluded, adding that the subgroup analysis was "consistent with previous reports of poor outcomes  with the use of aliskiren in patients with diabetes already taking RAAS inhibitors."

Further studies will be necessary to evaluate rennin inhibiting drugs in patients with diabetes, they added.

Dr. Gheorghiade reported financial relationships with 32 pharmaceutical companies, including Novartis Pharma AG, the study sponsor.