NPC Archive Item: Increased risk of C difficile infections and of fractures: two more good reasons to review PPI prescribing

NOTE – This is an archive post from the NPC and has not been updated since first publication. Therefore, some hyperlinks may no longer be working.
MeReC Rapid Review NPC Logo

3 June 2010

A group of US studies published under the theme ‘less is more’ adds to earlier evidence around two potential harms associated with proton pump inhibitor (PPI) use. A large observational study found that hospital inpatients taking daily PPIs were over 70% more likely to develop Clostridium difficile infection than non-users. A second US study found that people who already have C difficile infection and are treated with PPIs had a more than 40% increased relative risk of recurrence of infection. A third study alongside earlier evidence, has prompted the FDA to update PPI product information to warn of a possible increased risk of hip, wrist and spine fractures, especially in long term users of PPIs and when used at high doses.

Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.

Health professionals should carefully review PPI prescribing and make sure it is in line with NICE guidance. PPIs have several important places in therapy. Nevertheless, in hospital practice PPIs should not be initiated lightly; in primary care, PPIs should not be continued after discharge routinely, nor should they be prescribed long term or in high doses in primary care without careful thought.

What is the background to this?
PPIs are highly effective at suppressing gastric acid production. They have undoubted benefits in certain conditions such as gastrointestinal (GI) ulcers, gastro-oesophageal reflux disease (GORD), etc, and as prophylaxis against GI damage in many obligate long term NSAID users. However, gastric acid suppression has been suggested as a risk factor for C difficile infection since more-acidic gastric juices are more effective at killing the bacterium and neutralising its toxin than less-acidic juices. Some, but not all, studies had previously suggested a link between PPI use and C difficile infection.

The authors of the first paper analysed data collected as part of usual care at a large hospital in Boston, Massachusetts.  They looked at data for more than 100,000 patients aged 18 years and older who had a hospital stay of at least three days, over a five year period. Only the first episode of C difficile infection in a particular patient was considered.

What does this study claim?
The incidence of C difficile infection in people not receiving acid suppression therapy was 0.3%.  After adjustment for comorbid conditions, age, antibiotic use and propensity-score-based likelihood of acid suppression therapy (to reduce bias due to inherent differences between patients) the risk of having C difficile infection in various group of acid-suppression users was compared with non-use. The odds ratio (OR) of C difficile infection was 1.53 (95% confidence interval [CI] 1.12 to 2.10, P=0.08) in those taking histamine H2 receptor antagonists (H2RAs), 1.74 (95%CI 2.39 to 2.18, P<0.001) in those taking daily PPIs and 2.36 (95%CI 1.79 to 3.11, P<0.001) in those taking PPIs more than once daily.

How does this relate to other studies?
A second observational study in US veterans in New England looked at the risk of recurrence of C difficile infection. This was defined as a positive finding for C difficile toxin 15 to 90 days after the date of diagnosis of the incident infection. This involved 527 patients prescribed PPIs during the 14 days after the incident infection, compared with 639 patients who were not prescribed PPIs. After adjusting for numerous factors including patient age, comorbidities, antibiotic exposure, etc, the hazard ratio (HR) for recurrence in PPI users compared to non-users was 1.42 (95%CI 1.10 to 1.83, P=0.008).

A previous study based on the UK GPRD, had looked at 1,672 patients identified as cases of C difficile between 1994 and 2004, of whom 1,233 (74%) had not been hospitalised in the year prior to diagnosis and were considered community-acquired. After controlling for many covariates including antibiotic exposure, the adjusted relative risk (RR) for PPI prescription in the previous 90 days was 2.9 (95%CI 2.4 to 3.4). That is, people with community-acquired C difficile infection were about three times more likely to have been prescribed a PPI in the previous 90 days than people who did not have the infection. The adjusted RR for H2RAs was 2.0 (95%CI 1.6 to 2.7).

What about the risk of fractures with PPIs?
The FDA has announced that it is revising product information for PPIs to include new safety information about a possible increased risk of fractures of the hip, wrist, and spine. This is based on the FDA’s review of several epidemiological studies. Some studies found that those at greatest risk for these fractures received high doses of proton pump inhibitors or used them for one year or more (see the FDA’s data summary).The majority of the studies evaluated individuals 50 years of age or older and the increased risk of fracture primarily was observed in this age group. RCTs of PPIs have not shown an increased risk of fractures but these trials have generally lasted only 6 months.

So what?
As the related editorial comments, even modest increases in risks of adverse events add up to a substantial amount of patient harm at a population level when the risk factor (e.g. PPI exposure) is widely experienced. Some 9.5million prescriptions for PPIs were dispensed in England during the last quarter for which data are available (October to December 2009: personal communication, NHSBSA PPD). In 2008/9 (the last year for which data are available), there were more than 11million admissions to English NHS hospitals, which were not day cases (HESonline). It is not known how many people admitted to hospital receive PPIs.

NICE guidance recommends that patients presenting in primary care with dyspepsia in whom urgent referral for endoscopy is not indicated should initially have their medication reviewed and be offered lifestyle advice. If this is not successful, they should be offered either one month of full dose PPI, or testing for H pylori infection and eradication treatment. If the option tried is not successful, the alternative should be offered. If patients still experience symptoms, NICE advises health professionals to offer low-dose treatment with a limited number of repeat prescriptions. They should discuss the use of treatment on an as-required basis to help patients manage their own symptoms. Similarly, after initial treatment, patients with endoscopically-determined GORD or peptic ulceration should continue on low dose treatment, as required, only if necessary and with a limited number of repeat prescriptions. Patients should be reviewed at least annually.

NICE guidance on osteoarthritis and rheumatoid arthritis advise that in these conditions, NSAIDs should be co-prescribed with a PPI.

PPI use is a Better Care, Better Value indicator. Current expenditure on PPIs in primary care is around £150million a year. A monthly course of a branded PPI is on average about 5 times more costly than an appropriate generic PPI. If PCTs with below 92% use of lower cost PPIs (achieved by the top quartile of trusts) increased this to over 92%, £22m would be saved in a year (based on quarter 1, 2009/10). The data discussed above suggest that, not only the choice of PPI (lower cost versus higher cost) but also the use of PPIs at all in individual patients should be carefully reviewed. As the related editorial comments, the benefits of PPIs may not justify the risks for many users.
Study details
Howell M D et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med 2010;170:784–90

Design Pharmacoepidemiological cohort study

Patients Patients who were at least 18 years old and had a length of stay of 3 or more days between January 1, 2004, and January 31, 2008, at the Beth Israel Deaconess Medical Center, Boston, and who had a newly positive C difficile toxin assay result on or after the third hospital day. Only a first diagnosis of C difficile was included; subsequent admissions of patients with index C difficile infection were excluded.

Primary exposure of interest Receipt of acid suppression therapy. Exposure was classified by the most intense acid suppression therapy received before a positive C difficile test result or hospital discharge, whichever was earlier. The acid suppression groups were no acid suppression therapy, H2RA therapy, daily PPI, and PPI more frequently than daily.

Outcomes and results After adjustment for comorbid conditions, age, antibiotic use and propensity-score-based likelihood of acid suppression therapy (to reduce bias due to inherent differences between patients) and compared to non-exposed patients, the OR of C difficile infection in those taking H2RA was 1.53 (95%CI 1.12 to 2.10, P=0.08), 1.74 (95%CI 2.39 to 2.18, P<0.001) in those taking daily PPIs and 2.36 (95%CI 1.79 to 3.11, P<0.001) in those taking PPIs more than once daily.

Sponsorship none stated

More information on use of PPIs can be found on the dyspepsia section of NPC

Please comment on this blog in the NPC discussion rooms, or using our feedback form.

Make sure you are signed up to NPC Email updates — the free email alerting system that keeps you up to date with the NPC news and outputs relevant to you