Long-term use of proton pump inhibitors in patients who have ever had Helicobacter pylori infection more than doubles the risk of developing stomach cancer, new research suggests.

The large population study published online in Gut found a 2.4 fold increased risk in patients who had been treated for H pylori, with dose and duration associated with even higher risk.

Previous research has found an association between PPI use and heightened stomach cancer risk, but did not factor in the potential role of H pylori.

Now researchers from the University of Hong Kong have compared the long-term use of PPIs and H2 blockers in 63,397 adults treated with a triple therapy – a combination of a PPI and two antibiotics – to eradicate H pylori over 7 days between 2003 and 2012.

Patients were monitored for a median follow-up time of 7.6 years.

During this time, 3,271 (5%) people took PPIs for an average of nearly three years and 21,729 took H2 blockers. A total of 153 (0.24%) people developed stomach cancer after triple therapy.

None tested positive for H pylori when diagnosed with cancer, but all had chronic gastritis.

The authors concluded that taking PPIs was associated with a 2.4 fold risk in developing stomach cancer, while H2 blockers were not associated with increased risk.

Daily use was linked to a more than quadrupling in risk (HR 4.55) compared with weekly use (HR 2.4).

Duration of use also increased the risk, which rose to 5-fold after more than a year, to more than 6-fold after two or more years, and to more than 8-fold after three or more years.

This suggests a cause-and-effect relationship, the authors wrote.

Heightened risk is likely related to the profound stomach acid suppression caused by PPIs that worsens atrophic gastritis, particularly when the condition is caused by H pylori, they said.

They concluded “physicians should therefore exercise caution when prescribing long-term PPIs to these patients even after successful eradication of H pylori”.

The research has ”important clinical implications as PPIs, which are among the top 10 selling generic drugs in the US, are commonly prescribed to treat heartburn”, said Associate Professor Richard Ferrero, head of the Gastrointestinal Infection and Inflammation Research Group at the Hudson Institute of Medical Research in Victoria.

Previous research has shown patients taking a PPI with ongoing H pylori infection were at increased risk of developing atrophic gastritis, a precursor condition of stomach cancer.

But this study shows even patients who have successfully eradicated the infection are at risk, he said.

“Interestingly, the authors found no such correlation between gastric cancer risk and long-term treatment with other acid suppressive drugs…suggesting that acid-suppression is not the sole factor.”