A new study shows that long-time use of heartburn drugs called proton pump inhibitors is associated with an increased risk of death.
Past studies have linked PPIs to several health problems, including serious kidney damage, bone fractures, and dementia.
Millions of US residents take proton pump inhibitors to treat heartburn, ulcers, and other gastrointestinal problems. The drugs also are available over the counter under brand names that include Prevacid, Prilosec, and Nexium.
Researchers examined medical records of some 275,000 users of PPIs and nearly 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,” says Ziyad Al-Aly, an assistant professor of medicine at Washington University in St. Louis and senior author of the study in BMJ Open.
“For example, when we compared patients taking H2 blockers with those taking PPIs for one to two years, we found those on PPIs had a 50 percent increased risk of dying over the next five years. 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.”
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 and have become one of the most commonly used classes of drugs in the United States with 15 million monthly prescriptions in 2015 for Nexium alone.
Al-Aly has previously published studies linking PPIs to kidney disease, and other researchers have shown an association with other health problems, so Al-Aly and colleagues reasoned that since each of these side effects carries a small risk of death, together they may affect the mortality rate of PPI users.
“If I needed a PPI, I absolutely would take it. But I wouldn’t take it willy-nilly if I didn’t need it.”
They sifted through millions of de-identified veterans’ medical records in a database maintained by the US Department of Veterans Affairs and identified 275,933 people who had been prescribed a PPI and 73,355 people prescribed an H2 blocker between October 2006 and September 2008, and noted how many died and when over the following five years. The database did not include information on cause of death.
The findings show a 25 percent increased risk of death in the PPI group compared with the H2 blocker group. The researchers calculate that for every 500 people taking PPIs for a year, there is one extra death that would not have otherwise occurred. Given the millions of people who take PPIs regularly, this could translate into thousands of excess deaths every year, Al-Aly says.
The researchers 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. These people had a 24 percent increased risk of death compared with people taking H2 blockers.
Further, the risk rose steadily the longer people used the drugs. After 30 days, the risk of death in the PPI and H2 blocker groups was not significantly different, but among people taking the drugs for one to two years, the risk to PPI users was nearly 50 percent higher than that of H2 blocker users.
Although the recommended treatment regimen for most PPIs is short—two to eight weeks for ulcers, for example—many people end up taking the drugs for months or years.
“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 says. “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 two or three.”
As compared with the H2 blocker group, people in the PPI group were older (64 years old, on average, versus 61) and also somewhat sicker, with higher rates of diabetes, hypertension, and cardiovascular disease. But these differences cannot fully account for the increased risk of death since the risk remained even when the researchers statistically controlled for age and illness.
Over-the-counter PPIs contain the same chemical compounds as in prescription PPIs, just at lower doses, and there is no way to know how long people stay on them. The Food and Drug Administration recommends taking PPIs no longer than four weeks before consulting a doctor.
Deciding whether to take a PPI requires a risk-benefit calculation, Al-Aly says.
“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.”
Data scientist Yan Xie is the study’s first author. The United States Department of Veterans Affairs funded the work.