Still, the study is only an association - it doesn't prove cause and effect.
With so many studies associating PPIs with other health risks, researchers from Washington University School of Medicine in St. Louis wanted to find out if people who took the drugs were at greater risk of dying.
Compared with H2 blocker use, PPI use was associated with a 25% heightened risk of death from all causes.
The results are based on a USA national database of veteran medical records for more than 6 million people who had their health tracked for nearly six years, up to 2013 or death, if that came first.
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If you are self-medicating with an over-the-counter PPI, you should talk with your health care provider about the pros and cons and be sure to follow the label and FDA directions and warning, said Al-Aly.
They found a 25 percent increased risk of death in the patients who took a PPI compared with the people who took H2 blockers - about one extra death for every 500 people taking PPIs for a year.
She said further research on the drugs' possible risks is needed.
They looked at data on 275,933 people who had been prescribed a PPI and 73,355 who'd been prescribed an H2 blocker between October 2006 and September 2008, tracking deaths up to five years.
"There was a relationship between duration of use and risk of death", Al-Aly said. Previous studies have tied the drugs to kidney problems, dementia, and bone fractures, although not all research has agreed.
"This finding is certainly cause for concern and something that should be considered as doctors continue to prescribe PPIs at a high rate and often fail to discontinue these drugs in a timely fashion", said Dr. Louis Cohen. It is these genetic differences that may contribute to earlier deaths.
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While the research was not conclusive, it does support a growing body of evidence showing a "host of adverse events" associated with PPI use.
For instance, they pointed to previous US studies estimate between half to 69 per cent of PPI prescriptions are for "inappropriate indications".
And he advised, "Over-the-counter drugs should be used for a brief period of time".
Choosing Wisely Canada's gastroenterology list of Five Things Physicians and Patients Should Question also includes: "Don't maintain long term Proton Pump Inhibitor (PPI) therapy for gastrointestinal symptoms without an attempt to stop/reduce PPI at least once per year in most patients".
As the majority of subjects were also older white veterans, the findings may not readily apply to other groups. But these differences can not fully account for the increased risk of death since the risk remained even when the researchers statistically controlled for age and illness.
The authors also noted that up to 70 percent of people taking PPI may not need them, especially with links made to increase risks for kidney disease and bacterial infections. "Nevertheless, it is important for patients to regularly review all current medications with the prescribing providers". The Food and Drug Administration recommends taking PPIs no longer than four weeks before consulting a doctor.
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The study was published recently in the Journal of the American Geriatrics Society.