Faculty of Medicine, Department of Pharmacology, UPMC-Univ. Paris 06, Paris, France.
Eur J Heart Fail. 2011 Jul;13(7):765-72. doi: 10.1093/eurjhf/hfr051. Epub 2011 May 6.
Angiotensin-converting enzyme inhibitors (ACE-Is) and beta-blockers are associated with improved outcome in patients with chronic heart failure (CHF). In this post hoc analysis of the CIBIS III trial, we examined the influence of the order of drug administration on clinical events and achieved dose. We also assessed the relations between dose levels and baseline variables or adverse events.
In the CIBIS III trial, 1010 patients (mean age: 72.4 years; mean ejection fraction: 28.8%; male: 68.2%) with stable CHF were randomized to up-titration of monotherapy with either bisoprolol (target dose 10 mg o.d.) or enalapril (target dose 10 mg b.i.d.) for 6 months, followed by their combination for 6-24 months. Endpoints were mortality or all-cause hospitalization, mortality alone and mortality or cardiovascular hospitalization. The study drug (ACE-I or beta-blocker) was last prescribed at ≥50% of target dose to significantly more patients for the first initiated drug in both treatment groups (both P< 0.001). Sixty per cent of endpoints were reached during the monotherapy phase and randomized treatment during monotherapy was not a predictor of the three assessed outcomes. Monotherapy phase was the strongest independent predictor of outcome (P< 0.0001 for all endpoints). Older age, NYHA class III, impaired renal function, lower body weight and blood pressure at baseline, and hypotension, bradycardia and heart failure during treatment were associated with the inability to reach high dose of both study drugs.
The order of drug administration plays an important role in whether CHF patients reach target doses of bisoprolol and enalapril. For both study drugs, the dose level reached was associated with baseline characteristics and adverse events. In CHF patients not treated with an ACE-I or a beta-blocker, the duration of monotherapy with either type of drug should be shorter than 6 months.
血管紧张素转换酶抑制剂（ACE-Is）和β受体阻滞剂可改善慢性心力衰竭（CHF）患者的预后。在 CIBIS III 试验的事后分析中，我们研究了药物给药顺序对临床事件和达到剂量的影响。我们还评估了剂量水平与基线变量或不良事件之间的关系。
在 CIBIS III 试验中，1010 例（平均年龄：72.4 岁；平均射血分数：28.8%；男性：68.2%）稳定的 CHF 患者被随机分为两组，分别接受比索洛尔（目标剂量 10mg 每天一次）或依那普利（目标剂量 10mg 每天两次）单药滴定治疗 6 个月，随后联合治疗 6-24 个月。终点为死亡率或全因住院率、死亡率和死亡率或心血管住院率。在两个治疗组中，首次起始药物达到≥50%目标剂量的患者中，最后开出处方的研究药物（ACE-I 或β受体阻滞剂）显著更多（两组均 P<0.001）。60%的终点发生在单药治疗阶段，单药治疗期间的随机治疗不是三个评估结局的预测因素。单药治疗阶段是结局的最强独立预测因素（所有终点均 P<0.0001）。年龄较大、NYHA 心功能分级 III 级、肾功能受损、基线时体重和血压较低，以及治疗期间出现低血压、心动过缓和心力衰竭与无法达到两种研究药物的高剂量相关。
药物给药顺序对 CHF 患者是否达到比索洛尔和依那普利的目标剂量起着重要作用。对于两种研究药物，达到的剂量水平与基线特征和不良事件相关。在未接受 ACE-I 或β受体阻滞剂治疗的 CHF 患者中，应将两种药物中任何一种的单药治疗时间缩短至 6 个月以下。
