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.