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Giovanna Liuzzo, Carlo Patrono, Helicobacter pylori eradication as a gastroprotective strategy in elderly aspirin-treated subjects: established facts and unanswered questions, European Heart Journal, Volume 44, Issue 9, 1 March 2023, Pages 711–712, https://doi.org/10.1093/eurheartj/ehac808
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Comment on the article ‘Helicobacter pylori eradication for primary prevention of peptic ulcer bleeding in older patients prescribed aspirin in primary care (HEAT): a randomised, double-blind, placebo-controlled trial’, which was published in The Lancet, https://doi.org/10.1016/S0140-6736(22)01843-8.
The Helicobacter Eradication Aspirin Trial was a randomized, double-blind, placebo-controlled trial to investigate whether Helicobacter pylori (HP) eradication would protect against aspirin-associated ulcer bleeding, using routinely collected clinical data and a novel real-world methodology.1 Patients aged ≥60 years, who were receiving a daily aspirin dose of ≤325 mg, and who had a positive urea breath test for HP at screening were eligible.
Out of 30 166 patients, 5367 (18%) tested positive for HP, and 5352 were randomly assigned (1:1) to receive either HP eradication medication—a combination of oral clarithromycin 500 mg, metronidazole 400 mg, and lansoprazole 30 mg (2677 participants)—or placebo (2675 participants), twice daily for 1 week. The primary outcome was time to hospitalization or death due to definite or probable peptic ulcer bleeding and was analysed by the Cox proportional hazards method in the intention-to-treat population.
Mean age at randomization was 74 ± 7 years; 73% of participants were male; median duration of previous aspirin use was 2.3 years. Coronary heart disease was the most common indication to aspirin use (approximately 50%), followed by diabetes (22%) and a history of stroke or transient ischaemic attack (13%). A random 10% of patients were retested for HP at a median of 4 years, and 91% in the active eradication group had a negative breath test vs. 24% in the control group (P < 0.0001). During 26 668 person-years of follow-up (median, 5.0 years), 141 episodes of clinically significant gastrointestinal bleeding were identified and 44 were adjudicated as definite or probable peptic ulcer bleeds, 18 in the active eradication group and 26 in the control group.
The Cox proportional hazards assumption was not met, due to a marked difference between the treatment groups early in the study, which was attenuated over time. Therefore, the primary outcome was analysed in two periods of 2.5 years each, and this analysis showed a significant reduction in incidence of the primary outcome in the active eradication group compared with the control group during the first 2.5 years [6 episodes of 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]. The number needed to treat was 238 patients (95% CI 184–1661). This advantage remained significant after adjusting for the competing risk of death (P = 0.028) and gastroprotective or ulcerogenic drug use after randomization. However, the benefit of HP eradication was lost (HR, 1.31; 95% CI, 0.55–3.11; P = 0.54) in the period after the first 2.5 years. Overall, 657 patients died during follow-up (306 in the active eradication group and 351 in the control group). Only 2 of the 657 deaths were recorded as due to peptic ulcer (one due to bleeding).
Comment
Aspirin is widely used for the prevention of cardiovascular disease (CVD) but is associated with a substantial increase in the risk of bleeding, especially of gastrointestinal (GI) origin. This is particularly relevant in primary CVD prevention, where the net benefit is being questioned,2 particularly in the elderly. An analysis of ASPirin in Reducing Events in the Elderly, a primary prevention trial in 19 114 community-dwelling persons aged ≥70 years, found that low-dose aspirin increases the risk of significant GI bleeding by 60% [hazard ratio (HR) 1.61, 95% CI, 1.26–2.08; P = 0.002].3 A meta-analysis of 13 trials of aspirin for primary prevention in somewhat younger populations found a similar risk for serious GI bleeding (HR 1.56; 95% CI, 1.38–1.78).4
Helicobacter pylori (HP) infection is considered a risk factor for peptic ulcer bleeding in people taking aspirin;5,6 this is compatible with the hypothesis that low-dose aspirin acts to enhance bleeding from ulcers caused by HP through its anti-haemostatic activity. The American College of Gastroenterology guidelines suggest testing for HP when starting prophylactic low-dose aspirin,7 while acknowledging that the evidence for this recommendation is weak, observational, and based on indirect extrapolation.
The Helicobacter Eradication Aspirin Trial (HEAT) trial showed the feasibility of achieving high rates of HP eradication and provided evidence of benefit, with a 65% reduction in hospitalizations due to peptic ulcer bleeding over the first 2.5 years, largely attributable to differences in gastric and duodenal ulcer bleeding. However, this advantage appeared to be lost subsequently with longer follow-up.1
The trial has several limitations. The number of bleeding events in the study was considerably lower than expected (2.7 events per 1000 person-years in the control group in the first 2.5 years vs. 8 expected); thus, follow-up had to be prolonged for a median of 5 years, and the study was terminated before the planned number of primary outcome events had occurred.
The pragmatic nature of the study, allowing changes in aspirin, non-steroidal anti-inflammatory drugs, proton pump inhibitors (PPIs), or antibiotic use over time, although accounted for in the statistical analysis, may have resulted in a potential loss of precision. Furthermore, re-testing for HP eradication was performed in only a small percentage of patients.
The progressive loss of protection from ulcer bleeding after HP eradication is difficult to interpret and cannot be explained by time-related changes in the bleeding event rate. Possible explanations suggested by the authors could be enhanced acid secretion or reduced release of protective prostaglandins following HP eradication or idiopathic ulcers with a high relapse rate. Because the trial did not include aspirin-naive patients, it may have selected a population at low bleeding risk, who had tolerated aspirin intake for 1–4 years prior to randomization. In this regard, whether HP eradication might have a larger absolute benefit in patients at the time of first aspirin prescription, when there is an increased risk of GI bleeding,8 is an open question not addressed by the HEAT trial that may deserve further investigation.
In conclusion, the very low rate of ulcer bleeding events, in patients with confirmed HP infection, together with the time-dependent loss of efficacy of HP eradication, questions the need for a HP test-and-treat strategy for all patients taking aspirin for CVD prevention. Current European clinical practice guidelines, which recommend HP eradication only in patients taking aspirin at high risk of bleeding,9 are unlikely to change. On the other hand, the recorded low rate of ulcer bleeding and related mortality in a contemporary trial, coupled with the availability of two effective preventive strategies, i.e. HP eradication and PPI prophylaxis, should also reframe the benefit-risk profile of low-dose aspirin in primary prevention and encourage considering its prescription.2,10
Data Availability
No new data were generated or analysed in support of this research.
Funding
All authors declare no funding for this contribution.
References
Author notes
Conflict of interest: G.L. received grant support (to the Institution) for investigator-initiated research from American Heart Association, Italian National Health Service, and Italian Minister of Education, University and Research. She is currently involved in the Research Programs of the Italian Cardiovascular Network. She received personal fees from Astra Zeneca, Boehringer Ingelheim, Novo Nordisk, Daiichi Sankyo, Sanofi, and Novartis. C.P. received consultant and speaker fees from Acticor Biotech, Amgen, Bayer, GlaxoSmithKline, Tremeau, Zambon, and grant support (to the Institution) for investigator-initiated research from AIFA (Italian Drug Agency), Bayer, Cancer Research UK and European Commission; he chairs the Scientific Advisory Board of the International Aspirin Foundation.
