Background

Peptic ulcers in patients receiving aspirin are associated with Helicobacter pylori infection. We aimed to investigate whether H pylori eradication would protect against aspirin-associated ulcer bleeding.

Methods

We conducted a randomised, double-blind, placebo-controlled trial (Helicobacter Eradication Aspirin Trial [HEAT]) at 1208 primary care centres in the UK, using routinely collected clinical data. Eligible patients were aged 60 years or older who were receiving aspirin at a daily dose of 325 mg or less (with four or more 28-day prescriptions in the past year) and had a positive C13 urea breath test for H pylori at screening. Patients receiving ulcerogenic or gastroprotective medication were excluded. Participants were randomly assigned (1:1) to receive either a combination of oral clarithromycin 500 mg, metronidazole 400 mg, and lansoprazole 30 mg (active eradication), or oral placebo (control), twice daily for 1 week. Participants, their general practitioners and health-care providers, and the research nurses, trial team, adjudication committee, and analysis team were all masked to group allocation throughout the trial. Follow-up was by scrutiny of electronic data in primary and secondary care. The primary outcome was time to hospitalisation or death due to definite or probable peptic ulcer bleeding, and was analysed by Cox proportional hazards methods in the intention-to-treat population. This trial is registered with EudraCT, 2011-003425-96.

Findings

Between Sept 14, 2012, and Nov 22, 2017, 30 166 patients had breath testing for H pylori, 5367 had a positive result, and 5352 were randomly assigned to receive active eradication (n=2677) or placebo (n=2675) and were followed up for a median of 5·0 years (IQR 3·9–6·4). Analysis of the primary outcome showed a significant departure from proportional hazards assumptions (p=0·0068), requiring analysis over separate time periods. There was a significant reduction in incidence of the primary outcome in the active eradication group in the first 2·5 years of follow-up compared with the control group (six episodes adjudicated as definite or probable peptic ulcer bleeds, rate 0·92 [95% CI 0·41–2·04] per 1000 person-years vs 17 episodes, rate 2·61 [1·62–4·19] per 1000 person-years; hazard ratio [HR] 0·35 [95% CI 0·14–0·89]; p=0·028). This advantage remained significant after adjusting for the competing risk of death (p=0·028) but was lost with longer follow-up (HR 1·31 [95% CI 0·55–3·11] in the period after the first 2·5 years; p=0·54). Reports of adverse events were actively solicited; taste disturbance was the most common event (787 patients).

Interpretation

H pylori eradication protects against aspirin-associated peptic ulcer bleeding, but this might not be sustained in the long term.

Funding

National Institute for Health and Care Research Health Technology Assessment.

中文翻译：

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在初级保健中服用阿司匹林的老年患者根除幽门螺杆菌以一级预防消化性溃疡出血 (HEAT)：一项随机、双盲、安慰剂对照试验

背景

接受阿司匹林治疗的患者的消化性溃疡与幽门螺杆菌感染有关。我们的目的是调查根除幽门螺杆菌是否会预防阿司匹林相关的溃疡出血。

方法

我们使用常规收集的临床数据，在英国 1208 个初级保健中心开展了一项随机、双盲、安慰剂对照试验（幽门螺杆菌根除阿司匹林试验 [HEAT]）。符合条件的患者年龄在 60 岁或以上，每天服用阿司匹林的剂量为 325 毫克或更少（过去一年有四次或更多的 28 天处方）并且幽门螺杆菌 C13 尿素呼气试验呈阳性在放映时。接受溃疡病或胃保护药物的患者被排除在外。参与者被随机分配 (1:1) 接受口服克拉霉素 500 mg、甲硝唑 400 mg 和兰索拉唑 30 mg（主动根除）或口服安慰剂（对照）的组合，每天两次，持续 1 周。在整个试验过程中，参与者、他们的全科医生和医疗保健提供者以及研究护士、试验团队、裁决委员会和分析团队都不知道分组情况。后续行动是通过审查初级和二级保健中的电子数据进行的。主要结果是住院时间或因明确或可能的消化性溃疡出血而死亡，并在意向治疗人群中通过 Cox 比例风险方法进行分析。该试验在 EudraCT 注册，2011-003425-96。

发现

2012 年 9 月 14 日至 2017 年 11 月 22 日期间，30166 名患者进行了幽门螺杆菌呼气测试， 5367 名患者结果呈阳性，5352 名患者被随机分配接受主动根除治疗 (n=2677) 或安慰剂 (n=2675) 和中位随访时间为 5·0 年 (IQR 3·9–6·4)。对主要结果的分析表明与比例风险假设存在显着差异 (p=0·0068)，需要在不同的时间段进行分析。与对照组相比，主动根除组在最初 2·5 年的随访中主要结局的发生率显着降低（6 次事件被判定为明确或可能的消化性溃疡出血，发生率为 0·92 [95 % CI 0·41–2·04] 每 1000 人年与17 次，发生率为 2·61 [1·62–4·19]/1000 人年；风险比 [HR] 0·35 [95% CI 0·14–0·89]；p=0·028）。在调整了死亡的竞争风险后，这一优势仍然显着 (p=0·028)，但随着随访时间的延长，该优势消失了（HR 1·31 [95% CI 0·55–3·11] 2·5 年；p=0·54)。积极征求不良事件报告；味觉障碍是最常见的事件（787 名患者）。

解释

根除幽门螺杆菌可以防止阿司匹林相关的消化性溃疡出血，但这可能无法长期持续。

资金

国家卫生保健研究所卫生技术评估。