Use of proton pump inhibitors – a class of drug taken by millions to treat heartburn and reduce stomach acid – is tied to a higher risk of premature death. So concludes a large study that followed nearly 350,000 United States veterans.

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A team of researchers from Washington University have found that a person’s risk of premature death rises with long-term use of PPIs.

Reporting their findings in the journal BMJ Open, researchers from Washington University School of Medicine in St. Louis explain how they also found that the risk of death rose with longer use of proton pump inhibitors (PPIs).

“No matter how we sliced and diced the data from this large dataset, we saw the same thing: there’s an increased risk of death among PPI users,” says senior author Ziyad Al-Aly, an assistant professor of medicine.

The findings add to a growing list of serious health problems tied to the use of PPIs, some of which include kidney damage, Clostridium difficile infection, bone fractures in people with osteoporosis, and dementia.

Evidence is also emerging, although it is “far from conclusive,” that PPIs may raise the risk of tissue damage resulting from oxidative stress and telomere shortening in cells. Telomeres are protective caps on the ends of chromosomes, which have been likened to the plastic ends on shoelaces that stop them unraveling.

PPIs work by reducing the amount of acid produced by the stomach. They are widely prescribed for the treatment of heartburn, or acid reflux, a condition in which stomach acid is forced back up into the food pipe, or esophagus, causing a burning sensation in the lower chest. If the condition persists, it could be a sign of a more serious problem called gastroesophageal reflux disease (GERD).

In discussing their findings, Prof. Al-Aly and colleagues write that PPIs are “often overprescribed, rarely deprescribed,” and that their use is often “extended for long-term duration without appropriate medical indication.”

National survey results reveal that the proportion of U.S. adults using prescription PPIs nearly doubled in the decade or so leading up to 2012, having risen from 3.9 to 7.8 percent over that period.

The authors also cite estimates from studies that suggest that between half and two thirds of PPI prescriptions are for “inappropriate indications where benefits of PPI use may not justify the risks for many users.”

For their investigation, the team searched through the medical records of millions of U.S. veterans and identified 275,933 who had been prescribed a PPI and 73,355 who had been prescribed an H2 blocker – another class of drug that reduces stomach acid – between October 2006 and September 2008.

From the data, the researchers could also see how many participants in each group died in the following 5 years, although the records did not reveal cause of death.

The team carried out three types of comparison. These were: risk of death in PPI users and users of H2 blockers; risk of death in users and non-users of PPIs; and risk of death in users of PPIs and participants who used neither PPIs nor H2 blockers.

The results showed that compared with use of H2 blockers, use of PPIs was tied to a 25 percent raised risk of death from all causes.

The other analyses showed a similar level of increased risk between users and non-users of PPIs and between participants taking PPIs and those taking neither PPIs nor H2 blockers.

The results also showed that the risk of death went up with longer usage of PPIs. After 30 days of use, the risk of death among PPI users was similar to that of H2 blocker users. But after 1 to 2 years of use, the risk of death among PPI users was nearly 50 percent higher than among H2 blocker users.

The researchers calculated that, for every 500 participants who took PPIs for a year, there was one extra death that would not have occurred without PPI use.

Prof. Al-Aly says that since millions of people take PPIs on a regular basis, this could indicate that thousands of extra deaths each year are linked to PPI use.

He and his colleagues also found that the risk of death was higher among people who were using PPIs even though they appeared to have none of the gastrointestinal conditions that the drugs are recommended for. Here, the results showed that compared with H2 blocker users, PPI users had a 24 percent raised risk of death.

Compared with participants using H2 blockers, the PPI users in the study tended to be older – their average age was 64 compared with 61 in the H2 blocker group – and more likely to have illnesses such as diabetes, high blood pressure, and heart conditions.

However, the researchers say that these differences do not fully explain the higher risk of death in the PPI users, because, when they redid the statistical analysis to take out the effect of age and illness, the result remained the same.

The treatment recommendation for PPIs is that they should not be taken for a long time. In the case of ulcers, for example, the typical recommendation is between 2 and 8 weeks.

However, Prof. Al-Aly and colleagues note that many people can be on the drugs for months or even years.

Prof. Al-Aly also says that it is often the case that doctors have a good medical reason for prescribing PPIs to their patients, but then they do not stop, instead opting to keep refilling the prescription.

He suggests that, “There needs to be periodic re-assessments as to whether people need to be on these. Most of the time, people aren’t going to need to be on PPIs for a year or 2 or 3.” He sums up the implications of the study:

PPIs save lives. If I needed a PPI, I absolutely would take it. But I wouldn’t take it willy-nilly if I didn’t need it. And I would want my doctor to be monitoring me carefully and take me off it the moment it was no longer needed.”

Learn how PPIs may raise the risk of stroke.