3. 统计学分析

基于安慰剂对照组2.25年时主要复合终点的发生率为11%的假设^[19-21]，计算需要950次主要终点事件，样本量应该为9650例，伊伐布雷定组和安慰剂组之间存在显著性差异的效能达到90%，同时RR下降5%（双侧1型错误为5%）。最初设计了一项事件驱动试验，并且计划在出现950次主要终点事件时终止试验。然而主要终点发生率高于预期，可能由于入组患者的基线特征风险较高（如NYHAⅠ级比例较低，而糖尿病和高血压的比例较高）。经­计算当发生950次主要终点事件时，多数患者可能只治疗了3个月。因此，在2007年1月，执行委员会决定改变研究方案，由原­来的事件驱动改为时间驱动，并继续试验直至最后入组的患者被随访12个月。这种改变不影响预定的为期3年的研究计划。

采用Kaplan-Meier方法计算了时间–事件曲线。研究期间已经­发表的其他结果显示，心率只有在70～75次/min以上时才是预后的预测因子^[9-10]。因此，预定分析伊伐布雷定在心率≥70次/min患者亚组中的作用，估计在这一亚组中有足够的终点事件可确保充分的效能。

采用对数秩检验评价伊伐布雷定对主要复合终点的效应，并按患者入组时是否使用β受体阻断剂分层。随访确认每例受试者的研究终止日期、知情同意书撤销日期及最近的随访日期（仅针对失访的患者）。采用意向治疗分析，以既往使用β受体阻断剂作为协­变量对Cox比例风险模型进行校正以估计HR。根据统计学分析计划，分析基线心率≥70次/min亚组的结果。独立的数据监测委员会进行了了两次期中有效性分析，而且根据Haybittle-Peto法则，每次期中分析的Ⅰ类错误率均为0.1%，对最终分析的总体Ⅰ类错误率没有显著影响^[22]。在每个时间点评价时，均计算了各组中所记录受试者的平均静息心率，因此未遗漏信息。

同时分析了各预设亚组的主要结局，以既往使用β受体阻断剂作为协­变量对Cox比例风险模型进行校正以计算各亚组治疗效应的HR。以包括随机治疗组、亚组状态和相互作用的Cox比例风险模型分析治疗组和亚组间状态的相互作用。本研究在ClinicalTrials.gov上注册编号为NCT00143507。

4. 研究基金赞助者的角色

赞助方的代表是研究执行委员会中的非投票委员，在研究设计、数据解释和试验报告撰写时参加执行委员会。通信作者有权使用所有数据并最终负责论文的提交与发表。

讨 论

除外安慰剂效应，伊伐布雷定治疗可以在12个月时使心率降低6次/min，在24个月时降低5次/min。伊伐布雷定不影响任何一个亚组的主要复合终点即心血管死亡、急性心肌梗死入院、新发或加重的心力衰竭入院（图4）。多数患者接受了指南推荐的治疗，应用的比例与血运重建和强化药物治疗对稳定型冠心病临床结局的评价（COURAGE）试验一致^[23]，比欧洲心力衰竭调查^[24]中的心力衰竭患者用药的比例高。尽管如此，事件发生率仍然很高，每年发生大约10%的主要终点事件，其中半数为致死性事件。伊伐布雷定耐受性良好，除了心动过缓外（多数无症状），其他不良反应很少。87%的患者应用研究药物的同时还应用β受体阻断剂，没有安全性方面的问题。

应用伊伐布雷定治疗未出现临床结局改善的原­因可能是因为心率下降不够或基线心率过低。对基线心率≥70次/min亚组患者的分析证明了基线心率确实太低。在这一亚组中，伊伐布雷定对主要复合终点，或心血管死亡或需要入院的心力衰竭没有作用。然而，伊伐布雷定确实减少了与冠状动脉疾病（因致死性或非致死性急性心肌梗死入院）相关的终点事件发生率（相对下降36%，P = 0.001）。这些结果与那些主张心率只有≥75次/min时才有决定意义的报道^[9-10]一致。这些发现提示，对冠心病患者而言，降低心率对冠状动脉终点事件最有效，而且对那些基线心率高的患者效果好。

心率过快增加了冠心病患者的心脏负荷和心肌耗氧量，并且减少了舒张期心肌灌注时间，从而导致心肌需氧和供氧的失衡，引起心肌缺血^[6]。较快的心率也可以加速冠状动脉粥样硬化进程^[25]，并且可引起狭窄­的冠状动脉上动脉粥样硬化斑块破裂^[26]。

伊伐布雷定还可以减少这一亚组中冠状动脉血运重建达30%（P = 0.016）。这种血运重建的减少与伊伐布雷定降低心率缓解心绞痛的报道^[15-16]一致。在本研究中，可以看到在应用β受体阻断剂的基础上伊伐布雷定可以进一步减少冠状动脉血运重建。

由于在先前的观察中^[27-29]，心力衰竭患者应用β受体阻断剂可以改善预后，因此我们期望伊伐布雷定可以影响心力衰竭终点。对这种作用消失的原­因的一种解释是，潜在疾病不同，对心率降低的要求也不同。如果心率是对某种疾病的生理性反应（如心力衰竭），那么心率应该降到较低水平；相比而言，当心率直接影响疾病时（如心肌缺血或心绞痛）心率要相对高。

本研究结果提示，伊伐布雷定可安全用于冠心病合并左室收缩功能障碍­的患者，并且可以与β受体阻断剂同时使用。此外，伊伐布雷定与β受体阻断剂联用不仅安全，而且可改善心率≥70次/min冠心病患者的结局。这个结论尚需要前瞻性研究予以证实。

Lancet 2008; 372: 807–16

（徐绍鹏  译）

Royal Brompton Hospital, London, UK (Prof K Fox MD); Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK (Prof I Ford PhD); Hôpital Bichat-Claude Bernard, Paris, France (Prof P G Steg MD); Medical University of Silesia, Katowice, Poland (Prof M Tendera MD); and S Maugeri Foundation, University of Ferrara, Ferrara, Italy (Prof R Ferrari MD)

BEAUTIFUL Trial Investigators

Executive Committee: K Fox (Chair), R Ferrari, I Ford, P G Steg, M Tendera. Steering Committee: R Ferrari (Chair), H Grancelli (Argentina), B Freedman (Australia), B Eber (Austria), J L Vanoverschelde (Belgium), B Finkov, Y Yotov (Bulgaria), J C Tardif (Canada), D Hu (China), C Lau (Hong Kong), J Hradec (Czech Republic), P Hildebrandt (Denmark), J Eha (Estonia), K Peuhkurinen (Finland), N Danchin, P G Steg (France), T Meinertz (Germany), P Vardas (Greece), J Borbola (Hungary), D Mulcahy (Ireland), A Maggioni (Italy), A Erglis, J Jirgensons,† U Kalnins† (Latvia), A Laucevicius (Lithuania), K Dickstein (Norway), W Ruzyllo, M Tendera (Poland), R Seabra-Gomes (Portugal), R Capalneanu (Romania), Y Belenkov, Y Mareev (Russia), J Murin (Slovakia), P Rakovec (Slovenia), C Macaya (Spain), M Dellborg (Sweden), T U Lüscher (Switzerland), W van Gilst (Netherlands), A Oto (Turkey), I Ford, K Fox, A Hall (UK),

A Parkhomenko (Ukraine)

†These members have died.

Independent Statistical Centre: I Ford, M Robertson, C Weir, J Aziz, S Kean, R Wilson (Robertson Centre for Biostatistics, University of Glasgow, UK)

Endpoint Validation Committee: K Thygesen (Chair), M Frenneaux, G Jondeau

Data Monitoring Committee: A J Camm (Chair), H Dargie, J Kjekshus, G Murray

Correspondence to: Prof Kim Fox, RoyalBromptonHospital, Sydney Street, LondonSW3 6NP, UK (e-mail:k.fox@rbht.nhs.uk)

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