Tanaka Yukari, Matsuyama Yutaka, Ohashi Yasuo
Department of Biostatistics/Epidemiology and Preventive Health Sciences, School of Health Sciences and Nursing, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Stat Med. 2008 May 10;27(10):1718-33. doi: 10.1002/sim.3065.
The MEGA study was a prospective, randomized, open-labeled, blinded-endpoints study conducted in Japan to evaluate the primary preventive effect of pravastatin against coronary heart disease (CHD), in which 8214 subjects were randomized to diet or diet plus pravastatin. The intention-to-treat (ITT) analysis showed that pravastatin reduced the incidence of CHD (hazard ratio=0.67; 95 per cent confidence interval (CI): 0.49-0.91) and of stroke events, which was the secondary endpoint in the MEGA study (hazard ratio=0.83; 95 per cent CI: 0.57-1.21). Owing to considerable treatment changes, it is also of interest to estimate the causal effect of treatment that would have been observed had all patients complied with the treatment to which they were assigned. In this paper, we present an intensity score method developed for clinical trials with time-to-event outcomes that correct for treatment changes during follow-up. The proposed method can be easily extended to the estimation of time-dependent treatment effects, where the technique of g-estimation has been difficult to apply in practice. We compared the performances of the proposed method with other methods (as-treated, ITT, and g-estimation analysis) through simulation studies, which showed that the intensity score estimator was unbiased and more efficient. Applying the proposed method to the MEGA study data, several prognostic factors were associated with the process of treatment changes, and after adjusting for these treatment changes, larger treatment effects for pravastatin were observed for both CHD and stroke events. The proposed method provides a valuable and flexible approach for estimating treatment effect adjusting for non-random non-compliance.
MEGA研究是一项在日本进行的前瞻性、随机、开放标签、终点设盲的研究,旨在评估普伐他汀对冠心病(CHD)的一级预防效果,该研究中8214名受试者被随机分为饮食组或饮食加普伐他汀组。意向性分析(ITT)表明,普伐他汀降低了冠心病的发病率(风险比=0.67;95%置信区间(CI):0.49 - 0.91)以及中风事件的发病率,中风事件是MEGA研究中的次要终点(风险比= 0.83;95%CI:0.57 - 1.21)。由于治疗方案有相当大的改变,估计在所有患者都依从其分配的治疗方案的情况下所观察到的治疗因果效应也很有意义。在本文中,我们提出了一种为具有事件发生时间结局的临床试验开发的强度评分方法,该方法可校正随访期间的治疗改变。所提出的方法可以很容易地扩展到时间依赖性治疗效果的估计,而g估计技术在实际应用中一直难以应用。我们通过模拟研究比较了所提出的方法与其他方法(实际治疗、ITT和g估计分析)的性能,结果表明强度评分估计量是无偏且更有效的。将所提出的方法应用于MEGA研究数据,发现几个预后因素与治疗方案改变的过程相关,在调整这些治疗改变后,观察到普伐他汀对冠心病和中风事件都有更大的治疗效果。所提出的方法为估计调整非随机不依从后的治疗效果提供了一种有价值且灵活的方法。