Researchers from Washington University in the US examined medical records of about 2,75,000 users of proton pump inhibitors (PPI) and 75,000 people who took another class of drugs - known as H2 blockers - to reduce stomach acid.
"No matter how we sliced and diced the data from this large data set, we saw the same thing: There's an increased risk of death among PPI users," said Ziyad Al-Aly, assistant professor at Washington University.
"People have the idea that PPIs are very safe because they are readily available, but there are real risks to taking these drugs, particularly for long periods of time," Al-Aly said.
Previous studies have linked PPIs to kidney disease and researchers reasoned that since each of the side effects carries a small risk of death, together they may affect the mortality rate of PPI users.
They found a 25 per cent increased risk of death in the PPI group compared with the H2 blocker group.
For every 500 people taking PPIs for a year, there is one extra death that would not have otherwise occurred, researchers said.
They also calculated the risk of death in people who were prescribed PPIs or H2 blockers despite not having the gastrointestinal conditions for which the drugs are recommended.
"A lot of times people get prescribed PPIs for a good medical reason, but then doctors do not stop it and patients just keep getting refill after refill," Al-Aly said.
Both PPIs and H2 blockers are prescribed for serious medical conditions such as upper gastrointestinal tract bleeding, gastroesophageal reflux disease and esophageal cancer. Over-the-counter PPIs are most often used for heartburn and indigestion.
The study was published in the journal BMJ Open.
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