溃疡出血后停阿司匹林 心血管死亡增5倍

《临床胃肠病学和肝病学》杂志1月刊发的一项研究结果显示，在因消化性溃疡出血住院且正在接受低剂量阿司匹林治疗的患者中，出院后停用阿司匹林的患者在出院后不久发生死亡或心血管(CV)事件的风险，是出院后重新使用阿司匹林的患者的6倍(Clin. Gastroenterol. Hepatol. 2013;11:38-42)。

这项研究由斯德哥尔摩卡罗林斯卡研究所的Maryam Derogar女士及其同事进行，研究对象为2007~2010年间接受治疗的118例上消化道出血成人患者。所有患者存在内镜证实的消化性溃疡，并且在住院时正在接受低剂量阿司匹林治疗(75 mg或160 mg/d)。该研究排除了那些除了消化性溃疡出血之外还存在其他出血源(如食管静脉曲张或血管发育不良)的患者。

Maryam Derogar女士

40%(47例)患者永久停用阿司匹林。40%(48例)在出院后立即再次开始使用阿司匹林，其余20%(23例)患者在出院后2天至2个月(中位值为1周)再次接受阿司匹林治疗。

在中位随访2年期间，37%(44例)患者发生死亡或急性心血管事件。停用阿司匹林患者在随访最初6个月内的死亡或急性CV事件发生率是再次使用阿司匹林患者的6倍，危险比(HR)为6.8。研究者对酒精滥用、慢性缺血性心脏病(心绞痛)、慢性心力衰竭、既往心肌梗死、房颤、既往卒中或TIA、慢性肾功能衰竭、糖尿病、COPD和癌症等潜在混杂因素进行了校正。进一步分析显示，仅原有CV合并症的患者在随访最初6个月内的死亡和急性CV事件发生率增加，而在无CV合并症的患者中未观察到增加的现象。在26例停用阿司匹林的此类患者中，该发生率为31%，而在50例再次使用阿司匹林的患者中，发生率仅为8%。

随访6个月后，停用阿司匹林的患者与再次使用阿司匹林的患者的死亡和急性CV事件发生率无显著差异。6%的患者在随访期间因复发性消化性溃疡出血而再次住院。无患者因再次出血而死亡。

这些结果证实了既往一项随机临床研究的结果，后者显示，永久停用阿司匹林的患者在随访2个月内的死亡率是继续使用阿司匹林的患者的8倍(Ann. Intern. Med. 2010;152:1-9)。

研究者表示，本文研究中的所有死亡或急性CV事件均发生在年龄≥64岁的患者中，因此研究结果可能不完全适用于年龄较小的患者，同时提示老年患者可能更倾向于停止阿司匹林治疗。对于发生消化性溃疡出血且存在CV风险的老年患者，不应永久停用阿司匹林，而应在治疗出血后继续使用阿司匹林。鉴于阿司匹林的致溃疡性，强烈建议联用质子泵抑制剂这样的抑酸剂。
 
Derogar女士声明无经济利益冲突。一位研究者声明从Olle Engkvist Byggmastare基金会获得奖学金。

专家视点：溃疡出血后停用阿司匹林，风险大于获益

威斯康辛大学医学与公共卫生学院的临床内科学教授NIMISH VAKIL表示，在冠状动脉疾病或脑血管疾病患者发生消化道出血并进行内镜治疗时，许多消化科医生面临的问题就是是否应再次使用阿司匹林和(或)氯吡格雷，如果再次使用，应何时使用。这些患者常由于高龄和合并症而具有较高的出血相关并发症风险，并且由于晚期血管疾病，发生心血管或脑血管并发症的风险也较高。临床医生有4种方案可选：永久停用阿司匹林和氯吡格雷；停用阿司匹林，再次使用氯吡格雷；在达到内镜下止血后再次使用这两种抗血小板药物；或在达到内镜下止血后暂停使用抗血小板药7~10天。

尽管目前尚无完整且有效的证据基础来指导当前临床实践，但根据近期研究可归纳出重要的几点。上述研究显示，完全停用阿司匹林与死亡或CV并发症高发生率相关，而另一方面，在继续使用阿司匹林的患者中再出血较罕见。近期一项纳入接受低剂量阿司匹林治疗的消化道出血患者的随机对照研究显示，内镜下止血后继续使用阿司匹林的患者组的30天内复发性溃疡出血发生率为10.3%，而内镜下止血后停用阿司匹林的安慰剂组的该发生率为5.4%。阿司匹林组的全因死亡率低于安慰剂组(1.3% vs. 12.9%)(Ann. Intern. Med. 2010;152:1-9)。其他研究显示，再次使用阿司匹林及合用质子泵抑制剂的效果优于单用氯吡格雷。

至于内镜下止血后是应该立即再次使用还是暂停使用阿司匹林或氯吡格雷一段时间，目前尚缺乏指导依据。具体的治疗决定可能应取决于出血的程度、基础CV和脑血管疾病及合并症的严重程度。现有证据表明，在使用阿司匹林治疗CV或脑血管疾病的患者中，停用阿司匹林是不明智的，会增加不良结局的发生率。

VAKIL博士是阿斯利康等多家公司的顾问，并持有Orexo和Meridian Bioscience公司的股票期权。

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By: By MARY ANN MOON, Cardiology News Digital Network

Aspirin therapy should be continued at the time of hospital discharge in patients with cardiovascular comorbidities treated for peptic ulcer bleeding, researchers say.

Among patients taking low-dose aspirin therapy who were hospitalized for bleeding of peptic ulcers, those who stopped aspirin altogether were more than six times as likely to die or have a cardiovascular event in the near future as were patients who resumed aspirin therapy after discharge, according to a database analysis. Researcher Maryam Derogar of the Karolinska Institute, Stockholm, and her associates reported their findings in the January issue of Clinical Gastroenterology and Hepatology.
 
"Balancing between the cardioprotective effect of aspirin and the increased risk of rebleeding associated with aspirin use requires a careful clinical tradeoff," the investigators wrote (Clin. Gastroenterol. Hepatol. 2013;11:38-42).

They noted that all deaths or acute CV events in the study were among patients at least 64 years old. The study findings indicate that aspirin therapy should not be permanently discontinued in older patients at cardiovascular risk who develop bleeding peptic ulcer, but should resume after the bleeding episode is treated, they wrote.

Given the ulcerogenic properties of aspirin, "concomitant prescription of acid suppressants in the form of proton pump inhibitors is highly recommended," the researchers added.

Only one randomized clinical trial has examined the consequences of discontinuing aspirin therapy in this patient population, and it found a substantially higher risk of short-term mortality in patients who didn’t resume taking aspirin after treatment of the bleeding ulcer (Ann. Intern. Med. 2010;152:1-9). However, that trial had methodological flaws and a short follow-up of only 8 weeks, the investigators said.

They used an administrative database at their hospital to examine this issue, reviewing the medical records of 118 adults treated in 2007-2010 for upper GI bleeding. All the study subjects had endoscopically verified peptic ulcer and were taking low-dose aspirin therapy (75 mg or 160 mg daily) at the time of hospitalization.

Patients who had bleeding from sources other than peptic ulcer, such as esophageal varices or angiodysplasia, were excluded from the study.

Aspirin therapy was permanently discontinued in 40% (47) of the study subjects. Forty percent of patients (48) restarted aspirin therapy immediately after hospital discharge, and the remaining 20% (23) restarted aspirin therapy a median of 1 week later (range, 2 days to 2 months).

During a median follow-up of 2 years, 37% (44) of study subjects either died or had acute cardiovascular events.

The rate of death or acute CV events during the first 6 months of follow-up was more than sixfold higher in patients who discontinued aspirin therapy than in those who resumed aspirin therapy, with a hazard ratio of 6.8, the investigators said. The investigators adjusted the comparison to account for numerous potential confounders, such as alcohol abuse, chronic ischemic heart disease (angina), chronic heart failure, previous MI, atrial fibrillation, previous stroke or TIA, chronic renal failure, diabetes, COPD, and cancer.

Further analysis showed that the rate of mortality and acute CV events during the first 6 months of follow-up rose only in study subjects who had existing cardiovascular comorbidities at hospitalization, and did not rise in those who had no CV comorbidities. This rate was 31% in the 26 such patients who stopped aspirin therapy, compared with only 8% in the 50 who resumed aspirin therapy.

After 6 months of follow-up, the rate of mortality and acute CV events was not significantly different between patients who stopped and patients who resumed aspirin therapy.

Six percent of patients required rehospitalization for recurrent peptic ulcer bleeding during follow-up. No patients died from such rebleeding.

These findings confirm and extend those of the previous randomized clinical trial, which reported an eightfold increase in mortality during 2 months of follow-up for patients who permanently discontinued aspirin therapy, Ms. Derogar and her colleagues said.

No patients in their study who were under age 64 died or developed an acute CV event. "The results are therefore not fully applicable to younger patients and might imply that the elderly are more susceptible to discontinuation of aspirin therapy," they wrote.

Ms. Derogar reported no potential financial conflicts of interest. One of her associates reported receiving a scholarship from the Olle Engkvist Byggmastare Foundation.

Stopping aspirin after ulcer bleeding: More risk than benefit

When patients with coronary artery disease or cerebrovascular disease develop GI bleeding and undergo endoscopic therapy, a question that most gastroenterologists face is whether aspirin, clopidogrel, or both should be restarted, and if so, when. Many of these patients are at high risk for bleeding-related complications due to advanced age and comorbidities and are also at increased risk for cardiovascular or cerebrovascular complications due to advanced vascular disease.

There are four possible courses of action for the practitioner: Discontinue the aspirin and clopidogrel with no intent to resume them, discontinue aspirin and resume clopidogrel, resume both antiplatelet drugs after endoscopic hemostasis is achieved, or withhold antiplatelet drugs for 7-10 days after endoscopic hemostasis has been achieved.

Although we do not have a complete and valid evidence base to guide our current practice, several important points can be made from recent studies. Ms. Derogar and her colleagues show us that discontinuing aspirin completely is associated with a high rate of death or cardiovascular complications. Rebleeding, on the other hand, was rare patients in whom aspirin was continued. In a recent randomized controlled trial, patients on low-dose aspirin who developed a GI bleed were randomized to continued aspirin or no aspirin after endoscopic hemostasis (Ann. Intern. Med. 2010;152:1-9). Recurrent ulcer bleeding within 30 days was 10.3% in the aspirin group and 5.4% in the placebo group. Patients who received aspirin had lower all-cause mortality rates than patients who received placebo (1.3% vs. 12.9%). Other studies have shown that resuming aspirin with a proton pump inhibitor is superior to administering clopidogrel alone.

There is little evidence to guide us as to whether aspirin or clopidogrel should be held for a short period of time or resumed immediately after endoscopic hemostasis is achieved. This decision should probably be individualized based on the magnitude of the bleeding, the severity of the underlying cardiovascular and cerebrovascular disease, and concurrent comorbid illnesses. The available evidence is clear that it is unwise to discontinue aspirin in patients receiving this agent for cardiovascular or cerebrovascular disease due to the high rate of adverse outcomes.

NIMISH VAKIL, M.D., AGAF, is a clinical professor of medicine at the University of Wisconsin School of Medicine and Public Health, Madison. He is a consultant to AstraZeneca, Takeda, Otsuka, Xenoport, Orexo, Ironwood, and Restech, and has stock options in Orexo and Meridian Bioscience.