The People's Perspective on Medicine

PPIs are Safe! New Study Contradicts Prior Research

PPI confusion continues. One week a study suggests that long-term use of PPIs is linked to serious adverse events. Now we are told PPIs are safe! What's up?
People, healthcare and problem concept – unhappy woman suffering from stomach ache over gray background

Prepare for whiplash. Last week 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, cardiovascular events and infections. You can read the details of the study and our interpretation at this link. 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 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:

“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?

The authors of the BMJ article pointed out that:

“…the findings emphasize the need to promote awareness of potential adverse events of long term PPI use…”

“The findings are consistent with emerging evidence suggesting that long term exposure to PPIs increases the risk of gastric malignancy. A recent study by Cheung and colleagues examined the risk of gastric cancer in a cohort of 63,397 patients and reported excess burden among long term users of PPI.

“Wan and colleagues conducted a meta-analysis of 926,f386 patients and found that long term PPI use was associated with a twofold risk of gastric cancer.”

“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.”

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 the epidemiological data.

The authors of the new research 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. Until then, we believe that the authors of the BMJ article offer good advice:

“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.”

One Surprising Disappointment!

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.

What do you think? Share your thoughts in the comment section. 

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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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Digestive Disorders
  • 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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My situation is much like Verne’s – I’m 77, overweight, and have used omeprazole for at least 20 years. No problems yet. My primary physician tests everything twice a year.

If people got lung cancer after smoking cigarettes for three years, the cigarette industry would probably have long been dead. I’m not particularly impressed by a three-year study of the safety of any drug. When any new drug for a chronic condition gets approved, we are all potential guinea pigs as far as the long-term effects of that drug.

In 4/2006 I had an EGD exam and discovered that I had Barretts disease and went on a Rx for Nexium 40mg. I have been on that med ever since until lately when I became aware of the risks. I did reduce taking Nexium from every day to every other day for over a month or so.

I now have switched to Famotidine 10mg daily and as occasionally needed for GERD. I had taken Nexium for 13 years so I feel myself at risk for cancer and organ failure sometime in the future, and to add to that I am 80 years old, which is another risk. I feel I am in a medical vortex where the outcome is grim. Next month I have an appointment with my primary, and I will tell him what I am doing and see what kind of test I need to monitor any cancer and organ failure. I am keeping notes on all of this.

I think PPIs are such big business that all studies will be flawed unless done my independent labs that have no interest in the profits. I have been taking them way too long and have now got 50 polyps in my stomach and scar tissue in my esophagus. I also now have osteoporosis, which no one in my family ever had. My Dad fell out of a tree in his 80s, dusted off his backside and walked around the block. Now when I try to quit the Protonix (generic) I can hardly talk. Safe? NEVER!!!

Drug company sponsored??? Nuff said!!!!

I was diagnosed with Barrett’s esophagus after years of daily PPI use prescribed by my then-gastroenterologist. What I thought was excess stomach acid as the cause for my indigestion, ironically, was low stomach acid caused by, I believe, my hypothyroid condition. My integrative cardiologist subsequently diagnosed that and prescribed Natural Desiccated Thyroid (NDT). My Barrett’s cleared up, and my digestive upsets are controlled with diet, HCI, digestive enzymes, and a commercial antacid, as needed.

It’s so confusing, and one doesn’t know what to believe when we find out that Big Pharmacy are the ones who are doing the studies!!! I have a spasmatic esophagus & Prilosec is the only thing I have found that controls it at all. I’d love to be off of Prilosec, don’t trust the side effect at all!!!

It’s like everything else. Do you blindly trust whatever you are told? Not me.

I took 20mg/day of a PPI for 15 years, and the last 5 years reduced it to 20mg every other day with no serious problems.

I have been taking PPIs for the past 15 years. Topzole gave me terrible diarrhea. I still had GERD attack’s at night. That all changed when I changed to Pariet. Much more expensive but no more GERD, and I must say I feel fine generally.

I can tell you, first hand. PPI’s ARE dangerous. I had a doctor who kept me on Aciphex for 11 years, and it resulted in my now having stage 3 kidney disease!

I took omeprazole for many years. What it did to my body is a sin. Would never touch a PPI again! Thank God I finally got off of these dreadful meds!

I’ve lost all faith in the pharmaceutical companies and the FDA, particularly the former and particularly after the opioid crisis. Seems like the pharmaceuticals are out of control and will do anything for an extra buck.

Short-term study used to claim long-term use is safe? Strong industry ties in researchers? This is unreliable data.

I am 77 yrs old, overweight male, 5’9″ 230 lbs, still working full time yet, play golf regularly, take winters off to AZ and summer in MN. I’ve been taking omeprazole for over 10 years with no known side effects yet. My B/P is good, no diabetes, no stomach or intestinal issues, some mild arthritis. If I try to go off omeprazole I get a bad case of heart burn about midnight which milk and honey have a hard time calming down. My parents both lived into the 90’s so I’m hopeful of making that age also.

My wife of 57 years also has taken omeprazole for over 10 years with no known side effects. She has diabetes, high B/P tendency, arterial schlarosis with calcified mitral valve but no stomach or intestinal issues.

So we are hopeful that taking PPIs for the rest of our lives will not hurt us.

I like to research the FUNDING for these studies. Even studies that are said to be independent/stand alone/ etc/ etc are often funded by the drug companies that make the drugs. It’s a wiggly route. Look at Lipitor. Now, most people get 80mg a day because it is said it reduces LDL as well…??? And ‘that’s just what we prescribe now’. I remember taking 10 mg, and that was enough to lower my cholesterol to under 180. I had to get off of it due to muscle pain and fatigue and now manage my cholesterol via diet and supplements. Research your DRUGS.

My gastroenterologist wants me on PPIs permanently because of GERD and Barrett’s Esophagus. I am currently slowly weaning off them with the help of my gynecologist because of dramatic bone loss over the past 2 years.

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