This finding should offer relief for patients needing long term proton pump inhibitor therapy and is valuable for clinical decision making in healthcare settings, say the researchers.

A fear that proton pump inhibitors could lead to stomach cancer has been ongoing since the 1980s. Recent research has linked their use to around a twofold increased risk, but the literature is hampered by several methodological limitations, making this possible association uncertain.

To help clarify whether long term use of proton pump inhibitors is associated with an increased risk of stomach cancer, researchers designed a study that made extensive efforts to avoid and assess these previous weaknesses.

Their findings are based on healthcare registry data in the five Nordic countries – Denmark, Finland, Iceland, Norway, and Sweden – over a 26-year period from 1994 to 2020.

They identified 17,232 patients with stomach cancer (cases) and randomly matched each one by age, sex, calendar year, and country with 10 healthy participants (controls) from each country’s entire population – a total of 172,297.

They then recorded long term (more than 1 year) use of proton pump inhibitors and histamine-2-receptor antagonists (another class of drugs used to reduce stomach acid) excluding the 12 months before the diagnosis date (cases) or study inclusion date (controls) to prevent the reporting of a potentially false association.

Other factors that may have influenced the results were also accounted for. These included age, sex, Helicobacter pylori eradication treatment (the bacteria implicated in the development of stomach cancer), peptic ulcer disease, smoking and alcohol related diseases, obesity or type 2 diabetes, and use of certain medications.

After adjusting for these factors, the researchers found no remaining association between long term use of proton pump inhibitors or histamine-2-receptor antagonists and increased risk of stomach cancer.

This is an observational study so no firm conclusions can be drawn about cause and effect. And despite extensive efforts, the authors can’t rule out the possibility that unmeasured factors, such as diet and family history of stomach cancer, may have affected the results.

However, they note that this multinational study based on up to 26 years of high quality registry data allowed them to mitigate many of the biases and other problems affecting previous research on this topic.

As such, they conclude: “The results of this study do not support the hypothesis that long term proton pump inhibitor use is associated with an increased risk of gastric adenocarcinoma.”

“This finding should offer relief for patients needing long term proton pump inhibitor therapy and is valuable for healthcare in clinical decision making,” they add.

Led by the University of South Australia (UniSA) and Flinders University, researchers investigated how everyday items such as blood pressure tablets, cholesterol-lowering drugs and heartburn medication may interact with cancer therapies.

They found that proton pump inhibitors (PPIs) used to treat indigestion and heartburn were associated with poorer overall survival for patients with BC, as well as a 36% higher risk of severe, treatment-associated side effects.

It is thought that proton pump inhibitors may interfere with the body’s immune responses or alter how cancer drugs are absorbed and metabolised, although further investigation is needed.

The study, published in Cancer Medicine, also found that beta-blockers, ACE inhibitors, angiotensin receptor blockers and calcium-channel blockers – drugs commonly prescribed for heart disease or hypertension – were linked to higher rates of severe side-effects. However, these medications did not appear to affect overall survival.

Statins and metformin – frequently used to manage high cholesterol and diabetes respectively – showed no significant impact on either survival or adverse events, offering reassurances about their safety.

The data was based on 19 major clinical trials sponsored by pharmaceutical companies including Lilly, Pfizer and Roche, and is believed to be the largest and most comprehensive analysis of its kind in the world.

Lead author Dr Natansh Modi, from UniSA and Flinders University, says the findings reveal a complex relationship between commonly prescribed medications and cancer outcomes.

“Many women with breast cancer are also managing other chronic conditions such as high blood pressure, diabetes or acid reflux, meaning they are often taking multiple drugs at once,” Dr Modi says.

“Our results don’t suggest that people should stop taking their non-cancer medicines, but it underlines how important it is for doctors to regularly review patient medications because people are living longer and managing multiple health issues.”

Corresponding senior author, Flinders University Associate Professor Ashley Hopkins, says the findings show that patients taking PPIs in oncology settings warrant closer attention in particular.

“It doesn’t mean that patients should cease their reflux medication without medical advice, but clinicians should be alert to potential risks and review whether PPIs are genuinely needed,” he says.

The researchers say that the study highlights the need for a more holistic approach to breast cancer management that considers all medications that a patient is taking.

The authors are calling for follow-up studies to explore the biological reasons behind the observed drug interactions and to develop clinical guidelines for the safe co-prescription of these medicines during cancer therapy.

The research was supported by The Hospital Research Foundation, Tour de Cure, Cancer Council SA, the Flinders Foundation, Prostate Cancer Foundation and the National Health and Medical Research Council.

‘Association of Commonly Used Concomitant Medications with Survival and Adverse Event Outcomes in Breast Cancer’ is published in Cancer Medicine. DOI: 10.1002/cam4.71320

Now, a new study published in the BMJ shows the potential promise, and pitfalls, of a massive effort to reduce overuse of a common class of heartburn medications known as proton pump inhibitors or PPIs.

The findings also reveal that some of the feared risks from PPIs may be overblown.

The study tracks the impact of an intervention that imposed limits on PPI prescription size and refills for patients without a documented reason to be on the medication, discontinued old prescriptions, and provided education to patients and clinicians on alternatives.

The effort was carried out in one region of the Veterans Health Administration system, called VISN 17, and involved a quarter of a million patients, making it one of the largest ever studies on deprescribing.

Key findings

In all, the intervention led to a massive reduction in PPI use: a nearly 30% reduction in prescriptions of PPIs compared to other VA regions.

But the drive to reduce potentially unnecessary PPI use had one unintended consequence: a drop in prescribing to veterans who actually have an ongoing need to take PPIs because their other medicines carry a high risk of gastrointestinal bleeding. Strong evidence shows that PPIs are effective for preventing gastrointestinal bleeding and they are recommended in clinical guidelines.

Reassuringly, no matter the reason for taking PPIs, the deprescribing effort didn’t lead to increases in health care visits with gastrointestinal diagnoses. Nor did it lead to increases in gastrointestinal bleeding in patients at high risk, which suggests that the deprescribing initiative itself was safe.

Interestingly, the rate of purported negative PPI effects — such as kidney disease, stroke, heart attack or pneumonia — didn’t go down in VISN17 relative to the other regions. Hip fractures, another risk linked with PPIs in past studies, only went down by a small percentage.

This supports evidence from other high-quality studies that suggest PPIs may be a marker of patients at risk for certain adverse outcomes, but that the drugs are unlikely to be the cause.

For this reason, the main benefits to deprescribing PPIs have more to do with cost and hassle of taking more pills than clinical risk reduction.

More about the study

The new VA-funded study uses data from multiple years before and after VISN 17 implemented its PPI deprescribing program for most veterans living in Texas, and parts of New Mexico and Oklahoma.

It was led by a multi-institutional team that includes investigators from University of Michigan and the VA Center for Clinical Management Research (CCMR) in Ann Arbor; the University of Pennsylvania and the VA Center for Health Equity Research and Promotion (CHERP) in Philadelphia; and the Yale School of Medicine and VA Center for Pain Research, Informatics, Multi-morbidities, and Education (PRIME).

“This intervention worked so well because it was involuntary to some degree — refills could no longer be on autopilot for patients without a clear indication for the medication,” says Jacob Kurlander, M.D., M.S., first author of the study and a gastroenterologist at Michigan Medicine, U-M’s academic medical center, and the Lieutenant Colonel Charles S. Kettles VA Ann Arbor Medical Center. “At the same time, what we saw is that is that patients who benefit from PPIs for bleeding prevention – which is sometimes overlooked by doctors – got swept up in this effort, too.”

This signals that deprescribing efforts need to take even more care to ensure providers don’t allow a patient who has a need for the drug to inadvertently go off it, Kurlander said.

“Our findings also suggest that PPIs may not be as harmful as some have feared,” he adds.

Before the VISN 17 program started, about 26% of veterans across the country who got their primary care from a VA provider were prescribed a PPI in a six-month period.

By the end of the study period in 2019, only about 15% of veterans in VISN 17 had a PPI prescription, compared with about 22% of those in the other regions.

This means PPI prescribing dropped by 30% within VISN 17, and that there was more than a 7% absolute reduction in PPI use between VISN 17 and other regions by the end of the study period.

The researchers even connected veterans’ VA records with their Medicare data in case they received care outside the VA, and also used information from death certificates to look for causes of cardiovascular-related death. There were no differences between VISN 17 and the other regions.

Kurlander is a member of the VA Center for Clinical Management Research, which is directed by co-senior author Sameer Saini, M.D., M.S. Both are members of the U-M Institute for Healthcare Policy and Innovation, and faculty members in the Division of Gastroenterology at the U-M Medical School’s Department of Internal Medicine.

In addition to Kurlander and Saini, the study’s authors are co-senior author Yu-Xiao Yang, M.D., M.S.C.E., of the University of Pennsylvania and the VA CHERP in Philadelphia; VA CCMR researchers Hyungjin Myra Kim, Sc.D., Darcy Saffar, Aimee Myers, Robert Holleman, Yuqing Gao, Jane Forman and Sarah L Krein, Ph.D. as well as Loren Laine, M.D., of the Yale School of Medicine and VA Connecticut; Christopher B Roberts, of CHERP, Michelle Shank, who was the pharmacy executive of VISN 17 during the time covered by the study, Richard Nelson, Ph.D. of the University of Utah and Salt Lake City VA Center for Informatics, Decision Enhancement, & Analytics Sciences (IDEAS); and Christian Helfrich, Ph.D. of the Seattle-Denver Center of Innovation for Veteran-Centered and Value-Driven Care.

The study was funded by the Department of Veterans Affairs Health Services Research and Development Service (HX002693-01). Kurlander’s work is also funded by the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health (DK118179).

Impact of large scale, multicomponent intervention to reduce proton pump inhibitor overuse in integrated healthcare system: difference-in-difference study; BMJ doi:10.1136/bmj‑2023‑076484   http://dx.doi.org/10.1136/bmj‑2023‑076484