Adding a proton pump inhibitor to dual antiplatelet therapy significantly reduced the risk of gastrointestinal bleeding without raising the risk of cardiovascular events, according to a report published online Oct. 6 in the New England Journal of Medicine.

The finding that PPIs don’t appear to blunt the effect of antiplatelets is reassuring in view of the results of several previous studies that found a possible adverse drug interaction, said Dr. Deepak L. Bhatt of Harvard Medical School and the Veterans Affairs Boston Healthcare System, and his associates in the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT).

“Our trial, in which the study population was at least 10 times as large as those in previous randomized studies and was not selected to represent high-risk patients, showed a significant reduction in clinically manifested gastrointestinal bleeding events, including overt bleeding, with a PPI as compared with placebo,” they noted.

COGENT, an international, randomized, double-blind phase III study, assessed the safety and efficacy of omeprazole in 3,761 patients with coronary heart disease who were already taking clopidogrel plus aspirin. The study subjects were enrolled at 393 sites in 15 countries, randomly assigned to add either omeprazole 20 mg (1,876 patients) or placebo (1,885 patients) to their treatment regimen, and followed for a median of 106 days (341 days maximum). The median age was 69 years in both groups; 67% and 70% of patients were male in the omeprazole and placebo groups, respectively.

The study was halted prematurely when the sponsor, Cogentus Pharmaceuticals, suddenly lost its financial backing; the company has since become defunct. The study’s statistical power is limited because the number of adverse events that developed was smaller than had been anticipated when it was designed.

At 180 days, there were 55 gastrointestinal bleeding events, with 47 patients having 1 such event and 4 patients having 2 events. The GI bleeding event rate was 1.1% with omeprazole, significantly lower than the 2.9% rate with placebo. Similarly, the rates of overt gastroduodenal bleeding, overt upper GI bleeding of unknown origin, and a composite of all overt and occult GI bleeding events also were significantly lower with the active drug.

“The number of patients who would need to be treated for 6 months to prevent one occurrence of an event that was part of the primary gastrointestinal end point was 55, and the number needed to treat to prevent one occurrence of overt GI bleeding was 98,” Dr. Bhatt and his colleagues said (N. Engl. J. Med. 2010 Oct. 6 [doi 10.1056/NEJMoa1007964]).

In addition, at 180 days the percentage of participants with symptoms of gastroesophageal reflux disease was only 0.2% in the omeprazole group, compared with 1.2% in the placebo group.

There were 109 cardiovascular adverse events (55 in the omeprazole group and 54 in the placebo group). The two groups were not significantly different in their rates of the primary cardiovascular end point, a composite of death from CV causes, nonfatal MI, coronary revascularization, or ischemic stroke.

“Although previous observational studies have yielded conflicting results in this regard, [our] study reveals no signal of harm from concomitant clopidogrel and PPI use,” the investigators said.

The rates of serious adverse events did not differ significantly between the two study groups (10% with omeprazole and 9% with placebo). Similarly, the rates of overall diverse events did not differ significantly (41% and 43%, respectively). None of the patients had diarrhea due to Clostridium difficile infection.

This study was supported by Cogentus Pharmaceuticals, which is now defunct. Dr. Bhatt reported receiving grants from AstraZeneca, Bristol-Myers Squibb, Eisai, Sanofi Aventis, and the Medicines Company, and his associates reported ties to numerous drug and device manufacturers.

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

10月6日在线发表于《新英格兰医学杂志》(New England Journal of Medicine)的一项研究显示，在双联抗血小板治疗基础上加用质子泵抑制剂奥美拉唑可显著降低胃肠道出血风险而又不增加心血管事件风险。

 

这项国际随机双盲Ⅲ期氯吡格雷与胃肠道事件优化研究(COGENT)的目的是在正服用氯吡格雷和阿司匹林的3,761例冠心病患者中评价奥美拉唑的安全性和疗效。 受试者来自15个国家的393个研究中心，在已有治疗方案上随机加用奥美拉唑20 mg(1,876例)或安慰剂(1,885例)，中位随访时间为106天(最长341天)。两组的中位年龄为69岁；奥美拉唑组与安慰剂组的男患者比例分别为67%和70%。

 

结果发现，180天时，共发生55起胃肠道出血事件，其中有47例发生1起此类事件，有4例发生2起事件。奥美拉唑组胃肠道出血发生率为1.1%，显著低于安慰剂组的2.9%。同样，奥美拉唑组的显性胃十二指肠出血发生率、不明原因显性上消化道出血发生率以及所有显性和隐性胃肠道出血事件复合发生率也均显著低于安慰剂组。为防止发生1起主要胃肠道终点事件而需治疗6个月的患者数为55例，为了防止发生1起显性胃肠道出血事件而需治疗的患者数为98例(N. Engl. J. Med. 2010 Oct. 6 [doi 10.1056/NEJMoa1007964])。

 

此外，180天时，奥美拉唑组具有胃食管反流病症状的患者比例仅为0.2%，而安慰剂组为1.2%。共发生109起心血管不良事件，其中奥美拉唑组55起，安慰剂组54起。主要心血管复合终点(包括心血管原因死亡、非致死性心肌梗死、冠状动脉血运重建或缺血性脑卒中)发生率的组间差异不显著。奥美拉唑组和安慰剂组的严重不良事件发生率分别为10%和9%，所有事件发生率分别为41%和43%。没有患者发生因艰难梭菌感染引起的腹泻。

 

本研究因申办者Cogentus制药公司突然失去资金支持而提前停止。 鉴于所发生的不良事件数少于设计时的预期数，故本研究的统计学效能有限。

 

本研究获现已破产的Cogentus制药公司支持。研究者称获多家医药公司经济资助。

 

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