Mahaffey Kenneth W, Pieper Karen S, Lokhnygina Yuliya, Califf Robert M, Antman Elliott M, Kleiman Neal S, Goodman Shaun G, White Harvey D, Rao Sunil V, Hochman Judith S, Cohen Marc, Col Jacques J, Roe Matthew T, Ferguson James J
Division of Cardiology and Duke Clinical Research Institute, Duke University Medical Center, Durham, NC 27715, USA.
Circ Cardiovasc Qual Outcomes. 2011 Mar;4(2):211-9. doi: 10.1161/CIRCOUTCOMES.109.853598. Epub 2011 Feb 8.
In the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) study, patients assigned enoxaparin or unfractionated heparin (UFH) were treated with alternative anticoagulant therapy after randomization at physician discretion, a practice made possible because the trial was open label. Using SYNERGY as an example, we demonstrate the difficulty of evaluating the effect of postrandomization events in clinical trials and discuss possible methodology.
Patients with and without postrandomization crossovers were characterized and event rates analyzed. Statistical modeling was performed using inverse probability weighting and landmark analyses to evaluate the potential impact of postrandomization crossovers on event rates and treatment effect. Of 9978 SYNERGY patients, 9613 (96.3%) received at least 1 dose of randomized therapy and are included in these analyses. Of these, 740 (7.7%; 554 enoxaparin; 186 UFH) had postrandomization crossover. Crossover patients had higher unadjusted rates of 30-day death/myocardial infarction (MI) (18.9% versus 14.0%), thrombolysis in MI (TIMI) bleeding (16.9% versus 7.6%), Global Use of Strategies to Open Occluded Coronary Arteries bleeding (4.5% versus 2.3%), and transfusions (32.3% versus 15.2%). Adjustment for timing of crossover relative to the events attenuated the difference noted in death/MI but accentuated the association with TIMI bleeding. After adjustment using the inverse probability weighting technique, only a modest difference in the absolute treatment effect was observed between enoxaparin and UFH on death/MI (0.6% [unadjusted] versus 0.8% [adjusted]) and TIMI major bleeding (1.5% [unadjusted] versus 1.0% [adjusted]). The landmark analysis indicated a significant association between crossover from enoxaparin to UFH and TIMI bleeding but not in the other direction, and no crossover association was found in death/MI.
Postrandomization events in clinical trials are accompanied by substantial confounders that require careful consideration. In SYNERGY, postrandomization crossovers occurred in nearly 10% of patients, abetted by the open-label trial design. These patients had increased incidence of bleeding and death/MI, but after adjustment using several modeling techniques, only a modest impact of postrandomization crossovers on treatment effect was observed. The usual methods of analyzing end points cannot adequately address biases in changing treatment in these patients. The potential biases of membership in a postrandomization subgroup, as well as the methods used to account for the biases, should be considered when weighing the strength of results. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00043784.
在依诺肝素、血管重建和糖蛋白IIb/IIIa抑制剂新策略的卓越疗效（SYNERGY）研究中，随机分组后，分配至依诺肝素或普通肝素（UFH）组的患者可由医生自行决定采用替代抗凝治疗，由于该试验为开放标签设计，这种做法得以实现。以SYNERGY研究为例，我们展示了在临床试验中评估随机分组后事件的效果的困难，并讨论了可能的方法。
对有和没有随机分组后交叉治疗的患者进行特征描述并分析事件发生率。使用逆概率加权和标志性分析进行统计建模，以评估随机分组后交叉治疗对事件发生率和治疗效果的潜在影响。在9978例SYNERGY研究患者中，9613例（96.3%）接受了至少1剂随机治疗并纳入这些分析。其中，740例（7.7%；554例依诺肝素组；186例UFH组）有随机分组后交叉治疗。交叉治疗患者的30天死亡/心肌梗死（MI）未调整发生率更高（18.9%对14.0%）、MI溶栓（TIMI）出血发生率更高（16.9%对7.6%）、全球应用策略开通闭塞冠状动脉（Global Use of Strategies to Open Occluded Coronary Arteries）出血发生率更高（4.5%对2.3%）以及输血发生率更高（32.3%对15.2%）。对交叉治疗相对于事件的时间进行调整后，死亡/MI中观察到的差异有所减弱，但与TIMI出血的关联则更加明显。使用逆概率加权技术进行调整后，依诺肝素和UFH在死亡/MI（0.6%[未调整]对0.8%[调整]）和TIMI大出血（1.5%[未调整]对1.0%[调整]）方面的绝对治疗效果仅存在适度差异。标志性分析表明，从依诺肝素交叉至UFH与TIMI出血之间存在显著关联，但反之则不然，且在死亡/MI方面未发现交叉关联。
临床试验中的随机分组后事件伴随着大量混杂因素，需要仔细考虑。在SYNERGY研究中，随机分组后交叉治疗发生在近10%的患者中，开放标签试验设计助长了这种情况。这些患者的出血和死亡/MI发生率增加，但在使用几种建模技术进行调整后，仅观察到随机分组后交叉治疗对治疗效果有适度影响。分析终点的常用方法无法充分解决这些患者治疗改变中的偏倚问题。在权衡结果的力度时，应考虑随机分组后亚组成员资格的潜在偏倚以及用于解释偏倚的方法。临床试验注册 - URL：http://www.clinicaltrials.gov。唯一标识符：NCT00043784。
