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PPIs are Safe! No, PPIs are Dangerous! What to Believe?

PPI confusion continues. One study suggests that PPIs are linked to serious adverse events. Then we are told PPIs are safe! What's going on?

Proton Pump Inhibitors (PPIs) are very popular for relieving symptoms of heartburn. That’s because drugs such as esomeprazole (Nexium), lansoprazole (Prevacid) and omeprazole (Prilosec) are extremely effective at suppressing acid. When acid bubbles up into the esophagus it can be quite uncomfortable. But how long can you take such drugs and how safe are they? The medical literature on PPI adverse reactions is contradictory enough to make your head spin. One study proclaims that PPIs are safe while another insists they are dangerous.

Are PPI Adverse Reactions Real?

Here is a question we recently received:

Q. I have suffered from heartburn for so many years I have lost count. For me, omeprazole works best.

You have written a lot about the side effects of proton pump inhibitors. My doctor says the reports of adverse reactions are unreliable. How do you respond?

A. We understand that GERD (gastroesophageal reflux disease) can be incredibly disruptive. Anyone suffering from chronic heartburn for as long as you have should be seen by a gastroenterologist to rule out serious complications.

A wide range of adverse reactions has been associated with long-term use of PPIs. Reports show that some patients develop deficiencies of vitamin B12, iron, calcium or magnesium. Other complications may include pneumonia, kidney disease or GI infections. Some gastroenterologists contest these side effects, however.

Another reader reported a life-threatening reaction as a result of PPIs:

“My doctors treated my persistent acid reflux for years by prescribing various proton pump inhibitors (PPIs). They diligently tested my calcium levels, but never looked at potassium or magnesium.

“I was admitted to the ER in intense pain, and a surgeon there recognized that I had undetectable levels of those minerals. The hospital gave them intravenously for three weeks, and after I was discharged, the doctor told me I had nearly died.

“During that time, the gastro doctor kept me on a PPI. Once I did my own research, I realized the drug was the cause of the imbalance and stopped taking it. Years later, I learned that my father-in-law nearly died from the same reaction.

“A paper on the FDA website warns about this PPI side effect, but none of my doctors had read it. If people must look out for themselves, there should be warnings on OTC drug packaging to alert them about this problem.”

A. Thank you for sharing this scary experience. Although the prescribing information for PPIs like Nexium or Prilosec warns doctors about dangerously low levels of magnesium and potassium, OTC labels do not mention this problem.

People who would like to learn more about potential side effects of PPIs and alternative approaches to heartburn may be interested in our eGuide to Overcoming Digestive Disorders. This online resource can be found under the Health eGuides tab.

Contradictory Studies:

Prepare for whiplash. A couple of years ago we reported on a large VA study using medical records from 150,000 veterans (BMJ, May 30, 2019).  It showed that people taking proton pump inhibitors to suppress stomach acid were at increased risk of premature death. Complications included kidney disease, cancer, cardiovascular events and infections. You can read the details of the study and our interpretation at this link.

The authors of that study concluded:

“The evidence from all available studies suggests that long term PPI use is associated with serious adverse events, including an increased risk of all cause mortality, and our results specifically suggest an increased mortality due to cardiovascular disease, chronic kidney disease, and upper gastrointestinal cancer. 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.”

But wait! Other studies disagree.

A randomized controlled trial (RCT) involving more than 17,000 participants with heart disease and peripheral artery disease concludes that the PPI pantoprazole is not associated with any adverse events (Gastroenterology, online May 29, 2019).  In other words, PPIs are safe! No worries, mate.

A Possible Exception:

In the conclusions to their paper, the authors state:

“In a large placebo-controlled randomized trial, we found that pantoprazole is not associated with any adverse event when used for 3 years, with the possible exception of an increased risk of enteric [gastrointestinal] infections.”

People taking pantoprazole (Protonix) in this study were 33% more susceptible to gastrointestinal infections.

The authors go on to state:

“To our knowledge, this is the largest PPI trial for any indication and the first prospective randomized trial to evaluate the many long-term safety concerns related to PPI therapy. It is reassuring that there was no evidence for harm for most of these events other than an excess of enteric infections. This is in contrast to systematic reviews of observational studies that report the association of PPI therapy with harms such as pneumonia, fracture and cerebrovascular events.”

Barely Any Adverse Events, So PPIs Are Safe, Right?

The message from this drug company-sponsored trial is pretty clear: PPIs are safe. Full stop! Many of the authors have close contacts with a variety of pharmaceutical companies. That doesn’t mean they are wrong in their enthusiasm for PPIs or their conclusion that PPIs are safe.

Randomized controlled trials (RCTs) are the gold standard for assessing safety and effectiveness of pharmaceuticals. Observational (epidemiological) studies are not as reliable. The authors were quick to note:

“A well-known maxim of epidemiology is that association is not causation and these data suggest that most of these associations relate to residual confounding or biases that are inherent in observational studies.”

These authors are saying that all the prior studies that have linked long-term PPI use to complications were flawed. They clearly disagree with the researchers who wrote in BMJ on May 30, 2019: that there were significant risks:

“Proton pump inhibitors (PPIs) are widely used either as prescription or over-the-counter drugs. Several studies suggest that taking PPIs is associated with a number of serious adverse events including cardiovascular disease, acute kidney injury, chronic kidney disease, dementia, pneumonia, gastric cancer, Clostridium difficile infections, and osteoporotic fractures. Some of these adverse events are associated with an increased risk of death.”

What Are We To Make of This Contradiction?

Since then, there have been many more meta-analyses and systematic reviews of PPIs. In October of 2020 Canadian researchers asked the question:

Do proton pump inhibitors increase mortality? A systematic review and in depth analysis of the evidence

They published the results of their study in Pharmacology Research & Perspectives and concluded:

“Considering the data from the COMPASS RCT together with the pharmaco-epidemiology observational studies leads us to conclude that on balance, it is likely that long-term PPI use increases all-cause mortality in older adults. Given the high prevalence of long-term PPI utilization, this message needs to be conveyed to health professionals and patients.”

What was COMPASS?

The pantoprazole study was part of a much more interesting trial called COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies). Over 27,000 patients with heart disease received either the anticoagulant Xarelto (rivaroxaban) plus aspirin, just Xarelto or just aspirin.

The study was stopped prematurely because the results were so disappointing (New England Journal of Medicine, Oct. 11, 2017):

“Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events.”

A part of the COMPASS trial involved the use of the PPI pantoprazole. The hope was that this acid-suppressing drug would prevent stomach ulcers, upper GI bleeding or perforation of the intestines (Gastroenterology, online, May 2, 2019). Aspirin can be tough on the tummy and an anticoagulant like Xarelto can turn stomach ulcers into dangerous bleeding events.

The results were disappointing to say the least. Of the people who received pantoprazole, 1.2% experienced “significant upper GI events.” Of those who were randomized to placebo, 1.3% developed “significant upper GI events.”

That is a big nothing! The authors report that 1,770 people would need to take pantoprazole to:

“…prevent one overt bleeding gastroduodenal lesion compared to placebo each year.”

In other words, 1,769 got no benefit from taking the PPI. The results of this large study could have ramifications that drug companies might not like. Many gastroenterologists have been encouraged to prescribe PPIs with NSAIDs like aspirin, ibuprofen or naproxen to protect the stomach from damage. This study suggests PPIs may not be as effective for this purpose as once assumed.

The People’s Pharmacy Perspective:

Perhaps you noted the use of the words “long term PPI use.” That could explain the difference between the randomized controlled trial data and epidemiological data.

The authors of the COMPASS trial note that the three-year trial may not have lasted long enough to detect all adverse outcomes:

“Some data suggest adverse events associated with PPI therapy are not seen until after five years of therapy and this trial had a mean follow up of three years and a maximum follow up of 5 years that was achieved in only a small proportion of patients.”

We would suggest that serious complications such as cancer, kidney disease, fractures, dementia or cardiovascular disease might not show up after only three years. These are chronic conditions that often evolve over longer periods of time. This RCT may not have lasted long enough to assess the true long-term risks of PPIs.

We would probably agree with the authors that PPIs are safe for a few months or even a couple of years. After that, however, all bets are off. We will have to await a much longer randomized controlled trial that is not sponsored by a drug company before we give PPIs a clean bill of health. In the meantime, we think everyone should read the label of over-the-counter PPI packages. They come with a clear caution:

“do not take for more than 14 days or more often than every 4 months unless directed by a doctor.”

Gastroenterologists now recognize that these powerful acid-suppressing drugs may be overprescribed in primary care (World Journal of Gastroenterology, June 28, 2022).

You can learn more about the pros and cons of PPIs and ways to control heartburn in our eGuide to Overcoming Digestive Disorders. This online resource may be found under the Health eGuides tab. You will also learn about tricks for treating flatulence, tips to combat constipation, strategies to fight flatulence and ways to deal with diarrhea.

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About the Author
Joe Graedon is a pharmacologist who has dedicated his career to making drug information understandable to consumers. His best-selling book, The People’s Pharmacy, was published in 1976 and led to a syndicated newspaper column, syndicated public radio show and web site. In 2006, Long Island University awarded him an honorary doctorate as “one of the country's leading drug experts for the consumer.”.
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  • Moayyedi, P., et al, "Safety of Proton Pump Inhibitors Based on a Large, Multi-year, Randomized Trial of Patients Receiving Rivaroxaban or Aspirin," Gastroenterology, May 29, 2019, DOI: 10.1053/j.gastro.2019.05.056
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