Scientists in the U.S. have linked long term use of a common class of heartburn drug with fatal cases of cardiovascular disease, chronic kidney disease, and upper gastrointestinal cancer. Proton pump inhibitor (PPI) drugs suppress the production of gastric acid, and are routinely prescribed to treat heartburn, ulcers, and acid reflux. Prior research has suggested that prolonged use of these drugs has adverse health effects and may increase the risk of death. Results from the new study, involving more than 210,000 U.S. veterans, has clarified which causes of death are linked with taking PPIs for prolonged periods, and highlight the need to increase awareness of the potential risks, and to reduce unnecessary use of these drugs. The findings are reported by researchers at Washington University School of Medicine in St. Louis and Veterans Affairs St. Louis Health Care System, in a paper published in BMJ.

“Taking PPIs over many months or years is not safe, and now we have a clearer picture of the health conditions associated with long-term PPI use,” said senior author Ziyad Al-Aly, MD, an assistant professor of medicine at the Washington University School of Medicine. Al-Aly and colleagues’ published paper is titled “Estimates of all cause mortality and cause specific mortality associated with proton pump inhibitors among US veterans: cohort study.”

PPIs are prescribed to more than 15 million people in the U.S., and millions more purchase PPIs over-the-counter and continue to take the gastric acid-suppressing drugs over the long term without any medical supervision. Multiple studies have linked PPI use with serious adverse events spanning cardiovascular and kidney diseases, dementia, pneumonia, and osteoporosis. Prior research by Al-Aly’s group has found PPI users are at an increased risk of all-cause mortality. What hasn’t been understood is which specific causes of death might be associated with taking PPIs. “… a detailed quantitative analysis of the cause specific mortality that is attributable to taking PPIs is not available,” the authors wrote.

To look at this in more detail the team turned to medical records held in the U.S. Department of Veterans Affairs databases, and looked at data acquired between July 2002 and June 2004. They identified 157,625 people, primarily Caucasian men aged 65 years and older, who had been newly prescribed PPIs, and another 56,842 who had been newly prescribed a different type of acid-suppressing drug known as an H2 blocker. All 214,467 patients were then followed for up to 10 years.

After controlling for potentially confounding factors, the researchers found a 17% increased risk of death in the PPI group, when compared with the H2 blocker group. Death rates for PPIs were 387 per 1,000 people, and death rates for H2 blockers were 342 per 1,000. This equated to an extra 45 deaths attributable to long-term PPI use, per 1,000 people. “Given the millions of people who take PPIs regularly, this translates into thousands of excess deaths every year,” said Al-Aly, who is a nephrologist and clinical epidemiologist.

When the researchers looked at specific causes of death, they found that PPI use was linked with deaths caused by cardiovascular disease, chronic kidney disease, and upper gastrointestinal cancer. More specifically 15 per 1,000 of the PPI group died from heart disease; 4 per 1,000 from chronic kidney disease, and 2 per 1,000 from stomach cancer. Death rates due to cardiovascular disease were 88/1000 among PPI users, and 73/1000 among individuals prescribed H2 blockers. For the PPI and H2 blocker groups, respectively, the death rates due to chronic kidney disease were 8/1000 and 4/1000, and deaths due to stomach cancer were 6/1000 and 4/1000, respectively.

The study also found that more than half of people in the PPI group were prescribed the drugs without any documented gastrointestinal indication that would suggest the drugs were medically required. Among this group of individuals, PPI-related death rates were even higher, with 23/1000 dying from heart disease, nearly 5/1000 from chronic kidney disease, and 3/1000 from stomach cancer. “Most alarming to me is that serious harm may be experienced by people who are on PPIs but may not need them,” Al-Aly said. “Overuse is not devoid of harm.”

Notably, more than 80% of individuals in the PPI group were prescribed doses equivalent to those found in over-the-counter preparations. “This suggests the risk may not be limited to prescription PPIs, but it also may occur at over-the-counter doses,” Al-Aly added. The finding that prolonged use of even these low doses increases the risk of death suggests that any prescription of PPIs should be limited to patients for whom the benefits will outweigh the risks, and for as short a treatment period as possible. There should also be more effort to make people more aware of the potential dangers of using PPIs over the long term. “Efforts to target and reduce prolonged use of prescription PPIs without indications and to curtail extended use of over-the-counter PPIs might be a good approach,” the authors stated.

“PPIs sold over the counter should have a clearer warning about the potential for significant health risks, as well as a clearer warning about the need to limit length of use, generally not to exceed 14 days,” Al-Aly noted. “People who feel the need to take over-the-counter PPIs longer than this need to see their doctors.”

The researchers aim to continue studying adverse health effects related to PPIs. “A lot of people may be taking PPIs unnecessarily,” Al-Aly added. “These people may be exposed to potential harm when it is unlikely the drugs are benefiting their health. Our study suggests the need to avoid PPIs when not medically necessary. For those who have a medical need, PPI use should be limited to the lowest effective dose and shortest duration possible.”

It will also be important to find out which patients taking PPIs are most likely to suffer PPI-related adverse effects. “Identification of those at high risk of adverse events attributable to taking PPIs is an important knowledge gap and could inform risk stratification and risk mitigation strategies,” the authors concluded. “Future research should also investigate the best way to implement deprescription programs to reduce the unnecessary or un-indicated use of PPIs … Because of the high prevalence of PPI use, the findings have public health implications and underscore the important message that PPIs should be used only when medically indicated and for the minimum duration necessary.”

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