Popular Heartburn Drugs May Boost Death Risk: Study

Medically Reviewed by Michael W. Smith, MD on July 03, 2017

July 3, 2017 -- Popular heartburn drugs known as proton pump inhibitors may raise the chance of death, new research shows.

It’s not the first time the drugs, also known as PPIs, have been linked to health dangers. Previous studies have tied the drugs to kidney problems, dementia, and bone fractures, although not all research has agreed.

In the new study, the odds of dying rose the longer people used the drugs, says senior study author Ziyad Al-Aly, MD, director of clinical epidemiology at the VA St. Louis Healthcare System.

For more than 5 years, his team tracked people who took prescription PPIs such as Nexium and Prilosec. He compared them with people who took other drugs that lower stomach acid known as H2 blockers (such as Zantac or Pepcid). The study did not look at the use of PPI drugs that you can buy over the counter.

Compared with the H2 blocker users, "people who take PPIs for about a year have about a 25% higher risk of death," says Al-Aly, who's also an assistant professor of medicine at Washington University School of Medicine in St. Louis.

Because millions of people take PPIs regularly, that 25% chance could translate into thousands of deaths a year, Al-Aly said.

Still, the study is only an association -- it doesn’t prove cause and effect. An industry representative says the drugs are safe when people follow the instructions on the label.

People who take the drugs should not immediately stop doing so, Al-Aly says. "I would say it is a small but significant risk," he says. "It should prompt people to look at whether they should be on PPIs in the first place or not."

PPIs are one of the most widely used types of drugs in the United States, with 15 million monthly prescriptions in 2015 for Nexium alone, according to research firm IMS.

Although the recommended treatment regimen for most PPIs is short -- 2 to 8 weeks for ulcers, for example -- many people end up taking the drugs for months or years. For some patients, doctors could determine the longer use is justified, and the study found the odds of death rose greatly when prescription-strength PPIs were taken for more than a year.

Prescription versions of both PPIs and H2 blockers treat serious conditions such as upper gastrointestinal tract bleeding, gastroesophageal reflux disease (GERD), and ulcers. Lower-dose over-the-counter versions are usually used to treat heartburn and indigestion.

The study received no industry funding. It is published online in BMJ Open.

Study Details

Al-Aly and his colleagues decided to do the new study after recent research suggested the link between PPI use and other health problems. "If there really are all these associations with adverse effects, is it true they could also be associated with a higher risk of death?" he asked.

The researchers examined the medical records of about 275,000 people who used prescription PPIs and nearly 74,000 who took H2 blockers.

The researchers did three analyses, comparing:

  • People who take PPIs with those who take H2 blockers
  • PPI users vs. non-users of PPIs
  • PPI users with those who took neither PPIs nor H2 blockers.

"However we looked at the data, there was a consistent [link] with PPI use and risk of death," Al-Aly says. The longer the use, the higher the risk, he says.

When the researchers factored in how long they took the drugs, the risk rose with length of use. According to the study, the odds of death among people taking PPIs and H2 blocker groups for 30 days was not significantly different. But the odds were nearly 50% higher among people taking the drugs for 1 to 2 years

One limitation of the study, researchers say, is they have no information on the causes of death.

The researchers can't explain the link between use of the drugs and an earlier death with certainty. They speculate the drugs might accelerate aging by shortening the telomeres, the parts of the chromosome that control cellular aging. Or, they may promote harmful stress on cells.

While both PPIs and H2 blockers lower stomach acid, they do so in different ways, Al-Aly says.

The study included the following drugs:


Despite the findings, "there are some patients out there who could benefit from PPIs," Al-Aly says. For instance, someone with a bleeding ulcer, he says.

However, the drugs shouldn't be taken without an appropriate medical reason, and they shouldn’t be taken long term, he says.

For prescription PPIs, doctors should use their judgment to decide how long a patient should take the drugs, he says. "Any use beyond casual use should be under the supervision of a doctor," he says.

"A lot of times people get prescribed PPIs for a good medical reason, but then doctors don't stop it and patients just keep getting refill after refill after refill," Al-Aly said. "There needs to be periodic reassessments 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."

Second Opinions

In a study published in 2016, Matthew Pappas, MD, a research investigator at the Cleveland Clinic Center for Value-Based Care Research, found that the use of PPIs likely leads to more deaths in hospitalized patients not in the ICU. He reviewed the new findings.

"All medications carry benefits and harms," he says.

He urges patients and doctors to be mindful of why they're using a medication. "If there isn't a compelling reason to take a proton pump inhibitor (PPI), it would be worth trying lower-risk strategies instead."

Among them are losing weight and avoiding trigger foods such as alcohol, caffeine, and citrus, says Colin Robinson, MD, an internist at UCLA Health Santa Clarita and an associate professor of medicine at UCLA David Geffen School of Medicine.

Industry Weighs In

In an email, Alexandra Engel, a spokeswoman for AstraZeneca, says: "We are confident in the safety and efficacy of Nexium and Prilosec when used in accordance with the FDA approved label, which has been established through numerous clinical trials.''

In a statement, the Consumer Healthcare Products Association, an industry group for makers of OTC medicines and supplements, notes that the new research did not look at over-the-counter products but only prescription PPIs, ''which are typically used at higher doses and for longer durations."

The group recommended that consumers heed the FDA Drug Facts label to understand safe use. "Lower dose OTC PPIs are approved for short-term use (two-week duration up to three times a year)," the statement adds.

Show Sources


BMJ Open: ''Risk of death among user of Proton Pump Inhibitors: a longitudinal observational cohort study of United States veterans."

Journal of General Internal Medicine: "Defining Appropriate Use of Proton-Pump Inhibitors Among Medical Inpatients."

Statement, Consumer Healthcare Products Association, June 30, 2017.

Andrew Powaleny, spokesman, Pharmaceutical Research and Manufacturers of America.

Ziyad Al-Aly, MD, director of clinical epidemiology, VA St. Louis Healthcare System; assistant professor of medicine, Washington University, St. Louis.

Colin Robinson, MD, internist, UCLA Health Santa Clarita; associate professor of medicine, UCLA David Geffen School of Medicine.

Alexandra Engel, spokeswoman, AstraZeneca.

Matthew Pappas, MD, research investigator, Cleveland Clinic Center for Value-Based Care Research. 

Medscape: “100 Best-Selling, Most Prescribed Branded Drugs Through March, May 6, 2015.

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