Does taking proton pump inhibitors increase the risk of death?

A recently published study has investigated whether there is an increased risk of death for people who take proton pump inhibitors (PPIs) (Risk of death among users of Proton Pump Inhibitors: a longitudinal observational cohort study of United States veterans).¹

The study compared death from any cause for people prescribed a proton pump inhibitor, people prescribed a histamine H₂-receptor antagonists (H₂ blockers) and people prescribed neither medicine.

The results suggested an increased risk of death among PPI users compared with those prescribed H₂ blockers and those prescribed no acid suppression therapy, and that this risk increased with duration of use.

However, the added risk of dying was small (an extra 14 deaths per 1000 people) and the study could not specifically account for how this might have happened.

The findings show that, like other medicines, PPIs are not free from side effects, but that the change in absolute risk (your background risk) is small. For the vast majority of people prescribed PPIs the benefits of treatment far outweigh the risk of taking them.

If you have any concerns about the prescription or non-prescription medicines you are taking, including PPIs, please speak with a doctor, nurse or pharmacist and do not stop any of your medicines unless they advise you to. 

Proton pump inhibitors (PPIs) are medicines that reduce stomach acid production. They have greatly improved how a number of common upper gastrointestinal (GI) conditions are managed. This includes conditions like gastro-oesophageal reflux disease (also known as GORD), peptic ulcer disease, and functional dyspepsia.

PPIs are also used in short courses to help eradicate Helicobacter pylori (the bacterium that can cause stomach ulcers), and to help counter the side effects of non-steroidal anti-inflammatory medicines (such as aspirin and ibuprofen) on the GI tract, in some people.²

Correct use of PPIs is generally safe, although some studies have linked the long-term use of PPIs to a small increase in the risk of adverse outcomes, such as osteoporosis-related fractures, infections of the lungs and gut, cardiovascular events and a rare complication called acute interstitial nephritis (a type of kidney disease).^3,4

However, there is no firm evidence to suggest that PPIs are the direct cause of these outcomes, as most of the findings come from observational studies and not higher-quality evidence. A recent trial of long-term use of PPIs for chronic GORD found no major safety concerns after 5–12 years of continuous PPI therapy.⁴

There is some concern about the overuse of PPIs – in Australia, the use of PPIs has risen dramatically, particularly for minor symptoms of indigestion which might be easily treated using other medicines that work just as well, have fewer side effects and are less expensive.⁵

An H₂ blocker is another type of medicine that works by blocking and decreasing the production of stomach acid, but PPIs are considered to have a stronger effect.

This large ‘cohort’ study looked at whether PPIs or H₂ blockers were associated with risk of ‘all-cause mortality’, which means dying for any reason. In cohort studies, groups of people are monitored (observed) over time to see what happens if they are exposed to something such as a particular medicine.

These types of studies look for an association between an exposure and an outcome. That means the authors can only conclude whether or not something may be linked to an outcome, not whether the exposure caused the outcome.

This is an important distinction – this type of study design can only establish that more deaths occurred in people who take long-term PPIs compared with those who take H₂ blockers. It does not establish that taking long-term PPI use is the main cause of death.

In this case, researchers identified 349,312 people (average age 61, 94% male) from the US Department of Veterans Affairs national databases who'd been prescribed PPIs or H₂ blockers between 2006 and 2008. They were then followed (via their medical records) for an average of 5.71 years.

In their analysis the researchers took into consideration things that could have influenced the results, such as the number of times a person had been hospitalised during the follow-up period, their age, and kidney function. They took into account whether a person had experienced an illness such as diabetes, stroke, cancer or cardiovascular disease, and also used a number of different statistical methods to improve the validity of their findings. 

The researchers found:

• there were 47 deaths annually per 1000 veterans taking PPIs, compared with 33 deaths per 1000 in veterans taking H₂ blockers – an excess annual mortality of 14 people in the PPI group
  
• risk of dying was increased in veterans with no recorded GI problems who had taken PPIs, compared with those who had taken H₂ blockers or neither medicine
  
• the longer a veteran took PPIs, the greater their risk of death.
  

If you have been prescribed a PPI, you should keep taking it as directed by your doctor or speak with your pharmacist for advice. If you have been taking a PPI on a regular basis, stopping immediately may lead to an increase in or worsening of your symptoms. Symptoms can be mild, such as rebound acidity, or can be very serious and potentially life-threatening, such as a bleeding stomach ulcer.

This recent study was observational – it doesn’t prove that taking a PPI directly causes death, it can only show there is an association. The increased risk of death may be real, or may be due to chance – observational studies can’t account for any number of unmeasured factors that might influence the outcome. It is possible that other health, socio-demographic or lifestyle factors, such as poor diet, contributed to the higher risk of death.

The authors did not discuss the possible variation in dosages used. As with many medicines, adverse effects for PPIs are dose related. That is, the higher the dose, the greater the chance of a side effect occurring.

The authors noted in their discussion that although they had done their best to account for what is called ‘indication bias’, they could not rule it out. This occurs when a medicine is more likely to be prescribed in patients who appear to have a more severe form of a condition, or are sicker. This raises the question of whether those who were prescribed PPIs generally had worse overall health and were more likely to develop adverse outcomes than those who were given H₂ blockers.

No information was included on cause of death. Several deaths occurred in the first year of the study, and could be due to underlying illnesses or other causes.

The people in the study were mostly older, white, male veterans living in the US, which may limit how results can be generalised to the Australian population. The analysis was based on the number of prescriptions issued, but we do not know how many of them were filled, which PPI brands were prescribed, or what the doses were.

The authors of the study noted that PPI use should be limited to cases and durations for which they are medically indicated (that is, when there is good evidence for their use).

In people who respond well to initial full-dose therapy it may be appropriate to reduce PPIs using a ‘step down’ or gradual approach after their problem is resolved.

Long-term use may be needed to help treat some conditions, and in these cases the benefits outweigh the harms for most patients.

Make sure to keep your doctor, nurse or pharmacist informed if you are taking an over-the-counter acid-suppressing medicine, or any other medicine or supplement that may affect the treatment of your condition.

If you have any concerns about a medicine you have been prescribed, talk with your health care professional about treatment options.

• Consumer Medicine Information is available for PPIs approved for use in Australia.
  
• NPS MedicineWise has information for consumers on finding the active ingredient.
  
• Call 1300 MEDICINE (1300 633 424) from anywhere in Australia.