Helicobacter pylori Eradication for Primary Prevention of Aspirin-Associated Peptic Ulcer Bleeding
The Lancet: Published on November, 2022
Aspirin is widely recommended for the secondary prevention of
thrombotic vascular disease. Its use is
limited principally by increased risk of bleeding, particularly from the
gastrointestinal tract.
The risks of upper gastrointestinal bleeding can be mitigated
in part by acid suppression with proton pump inhibitors and probably histamine
H2-receptor antagonists.
However, although anti-inflammatory doses of aspirin are
intrinsically ulcerogenic, the much lower doses used for prevention of
thrombosis are less damaging.
There is evidence that Helicobacter pylori might
play a central role in the development of peptic ulceration and ulcer bleeding in patients receiving aspirin. H pylori eradication can prevent acute aspirin-induced
endoscopic injury, but data on secondary prevention of recurrent ulcer bleeding
are contradictory.
Meta-analyses have shown that peptic
ulcers and ulcer bleeding in patients receiving low-dose aspirin (≤325 mg
daily) are strongly associated with Helicobacter pylori. These studies suggest eradication
of H pylori as a therapeutic target to prevent peptic ulceration and
ulcer bleeding
The American College of Gastroenterology guidelines suggests
testing for H pylori when starting prophylactic low-dose aspirin, while
acknowledging that the evidence base for this recommendation is weak.
In view of these uncertainties, authors aimed to investigate whether H pylori eradication
would protect against aspirin-associated ulcer bleeding.
TAKE-HOME MESSAGE
In this double-blind trial included 5357 patients, patients (aged ≥60 years) receiving aspirin (≤325 mg/day) and with a positive breath test for Helicobacter pylori were randomised to receive either combination treatment (lansoprazole 30 mg, clarithromycin 500 mg, and metronidazole 400 mg taken twice daily for 1 week) or placebo to investigate whether H pylori eradication would protect against aspirin-associated ulcer bleeding.
During the first 2.5 years of follow-up, patients who
received H pylori eradication therapy had lower incidence of peptic
ulcer bleeding than those who received placebo. In this large trial of patients
taking low doses of aspirin for several months in the previous year, achieved
high rates of H pylori eradication and showed evidence of benefit,
with a 65% reduction in hospitalisations due to peptic ulcer bleeding over the
first 2·5 years in patients in the active eradication group compared with the
control group.
Interestingly, this advantage was lost with longer follow-up
(>2.5 years), leading to the hypothesis that there is loss of the ability to
prevent ulcers long-term irrespective of H pylori status or the use
of acid suppression.
This trial showed that H pylori eradication can be
reliably achieved in large populations of unselected older patients receiving
aspirin at a dose of 325 mg or less in primary care. H pylori eradication
was associated with a significant reduction in the risk of hospitalisation for
ulcer bleeding, although this benefit was lost over time.
H pylori eradication therapy reduces the incidence of
aspirin-associated peptic ulcer bleeding for 2.5 years but not in the long
term.
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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.
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. Analysis of the primary outcome showed a
significant departure from proportional hazards assumptions, 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 per 1000 person-years vs 17
episodes, rate 2·61 per 1000 person-years. This advantage remained significant
after adjusting for the competing risk of death but was lost with longer
follow-up in the period after the first 2·5 years. 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.
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