Veterans AffairsBoston Healthcare System, Brigham and Women's Hospital, Boston, MA 02132, USA.
N Engl J Med. 2010 Nov 11;363(20):1909-17. doi: 10.1056/NEJMoa1007964. Epub 2010 Oct 6.
Gastrointestinal complications are an important problem of antithrombotic therapy. Proton-pump inhibitors (PPIs) are believed to decrease the risk of such complications, though no randomized trial has proved this in patients receiving dual antiplatelet therapy. Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel.
We randomly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo, in addition to aspirin. The primary gastrointestinal end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. The trial was terminated prematurely when the sponsor lost financing.
We planned to enroll about 5000 patients; a total of 3873 were randomly assigned and 3761 were included in analyses. In all, 51 patients had a gastrointestinal event; the event rate was 1.1% with omeprazole and 2.9% with placebo at 180 days (hazard ratio with omeprazole, 0.34, 95% confidence interval [CI], 0.18 to 0.63; P<0.001). The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (hazard ratio, 0.13; 95% CI, 0.03 to 0.56; P = 0.001). A total of 109 patients had a cardiovascular event, with event rates of 4.9% with omeprazole and 5.7% with placebo (hazard ratio with omeprazole, 0.99; 95% CI, 0.68 to 1.44; P = 0.96); high-risk subgroups did not show significant heterogeneity. The two groups did not differ significantly in the rate of serious adverse events, though the risk of diarrhea was increased with omeprazole.
Among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI. (Funded by Cogentus Pharmaceuticals; ClinicalTrials.gov number, NCT00557921.).
胃肠道并发症是抗血栓治疗的一个重要问题。质子泵抑制剂（PPIs）被认为可以降低此类并发症的风险，但尚无随机试验证明在接受双联抗血小板治疗的患者中如此。最近，人们对 PPI 可能会削弱氯吡格雷疗效的问题表示担忧。
我们将有双重抗血小板治疗指征的患者随机分配，接受氯吡格雷联合奥美拉唑或安慰剂加阿司匹林治疗。主要胃肠道终点是显性或隐匿性出血、有症状的胃十二指肠溃疡或糜烂、梗阻或穿孔的复合终点。主要心血管终点是心血管原因死亡、非致死性心肌梗死、血运重建或中风的复合终点。当赞助商失去资金时，试验提前终止。
我们计划招募约 5000 例患者；共随机分配 3873 例患者，3761 例患者纳入分析。共有 51 例患者发生胃肠道事件；奥美拉唑组的事件发生率为 1.1%，安慰剂组为 2.9%，在 180 天时（奥美拉唑组的风险比为 0.34，95%置信区间[CI]为 0.18 至 0.63；P<0.001）。奥美拉唑组与安慰剂组相比，显性上消化道出血的发生率也降低（风险比，0.13；95%CI，0.03 至 0.56；P=0.001）。共有 109 例患者发生心血管事件，奥美拉唑组的事件发生率为 4.9%，安慰剂组为 5.7%（奥美拉唑组的风险比为 0.99；95%CI，0.68 至 1.44；P=0.96）；高危亚组无明显异质性。两组在严重不良事件发生率方面无显著差异，但奥美拉唑组腹泻风险增加。
在接受阿司匹林和氯吡格雷治疗的患者中，预防性使用 PPI 可降低上消化道出血的发生率。氯吡格雷和奥美拉唑之间没有明显的心血管相互作用，但我们的结果不能排除使用 PPI 会导致心血管事件出现有临床意义的差异。（由 Cogentus 制药公司资助；ClinicalTrials.gov 编号，NCT00557921）。
