Serebruany Victor L, Tomek Ales, Pya Yury, Bekbossynova Makhabbat, Kim Moo Hyun
Johns Hopkins University, Baltimore, MD, USA.
Department of Neurology, 2nd Medical Faculty, Charles University, Prague, Czech Republic.
Int J Cardiol. 2016 Jul 15;215:372-6. doi: 10.1016/j.ijcard.2016.04.125. Epub 2016 Apr 19.
Long-awaiting PHILO trial, conducted in 2011-2012 has been submitted and published late in 2015. In contrast to overall PLATO results, but similar to PLATO-US cohort, PHILO revealed numerical inferiority of ticagrelor with regard to death, myocardial infarction, stroke, and bleeding over clopidogrel. Hence, we comprehend the PHILO results in light of the PLATO-US evidence. To assess the PHILO (n=801) outcomes, applied statistics, and trial conduct, matching them with the PLATO-US (n=1413) patients. The Asian, predominantly Japanese ticagrelor patients had worsened outcomes even when compared to the negative American cohort with regard to death (OR=1.44 (PHILO) vs. 1.17 (PLATO-US); myocardial infarction (OR=1.63 vs. 1.38); and composite primary endpoint (OR=1.60 vs. 1.27); but not for stroke (OR=1.51 vs. 1.75). Moreover, in contrast to the trend in PLATO-US (OR=1.11; CI=0.84-1.48, p=0.46), PHILO revealed significant excess of PLATO-defined composite of major and minor bleeding events (OR=1.83; CI=1.27-2.63,p=0.0014). PLATO-defined "net clinical benefit" in PHILO was also significantly (OR=1.61; CI=1.11-2.34, p=0.0145) inferior for ticagrelor. The "number needed to harm" suggests that for every 29 PHILO patients treated for 12months with ticagrelor instead of clopidogrel, one will suffer an additional major bleeding event. Finally, unexplained premature closure of PHILO just after 200-210days mean drug exposure, and short 240days mean follow-up seems deliberate and concerning with regard to unblinding. Aside from some information censoring, early trial closure, and creative statistics, Asian ticagrelor patients did consistently worse in PHILO, than even in the negative PLATO-US cohort. Especially alarming is a significant bleeding inferiority justifying a necessity for a separate outcome-driven low-dose ticagrelor trial in Asian post-PCI patients. This strategy was successfully implemented with the low-dose prasugrel in Japan. Regulatory authorities in Asia may consider conducting an independent review of PHILO dataset to ensure adequate ticagrelor safety.
期待已久的PHILO试验于2011 - 2012年进行，于2015年末提交并发表。与PLATO总体结果相反，但与PLATO - US队列相似，PHILO显示替格瑞洛在死亡、心肌梗死、中风和出血方面在数值上劣于氯吡格雷。因此，我们根据PLATO - US的证据来理解PHILO的结果。为了评估PHILO（n = 801）的结果、应用的统计方法和试验实施情况，并将其与PLATO - US（n = 1413）的患者进行匹配。亚洲患者（主要是日本的替格瑞洛患者）即使与PLATO - US中结果为阴性的队列相比，在死亡方面（OR = 1.44（PHILO）对1.17（PLATO - US））、心肌梗死方面（OR = 1.63对1.38）以及复合主要终点方面（OR = 1.60对1.27）的结局都更差；但在中风方面并非如此（OR = 1.51对1.75）。此外，与PLATO - US的趋势相反（OR = 1.11；CI = 0.84 - 1.48，p = 0.46），PHILO显示PLATO定义的主要和次要出血事件的复合事件显著过量（OR = 1.83；CI = 1.27 - 2.63，p = 0.0014）。在PHILO中，替格瑞洛的PLATO定义的“净临床获益”也显著更低（OR = 1.61；CI = 1.11 - 2.34，p = 0.0145）。“伤害所需人数”表明，对于每29名接受替格瑞洛而非氯吡格雷治疗12个月的PHILO患者，就会有一人额外发生一次主要出血事件。最后，在平均药物暴露仅200 - 210天后PHILO就无故提前结束，且平均随访时间仅240天，这似乎是有意为之且令人担忧其揭盲情况。除了一些信息审查、试验提前结束和有创造性的统计方法外，亚洲替格瑞洛患者在PHILO中的表现始终比PLATO - US中结果为阴性的队列更差。特别令人担忧的是显著的出血劣势，这证明有必要针对亚洲PCI术后患者开展一项单独的、以结局为导向的低剂量替格瑞洛试验。这种策略在日本使用低剂量普拉格雷时已成功实施。亚洲的监管机构可能会考虑对PHILO数据集进行独立审查，以确保替格瑞洛的安全性。
