#387 Side effects of long-term PPI use: Leaving a bad taste in your mouth?
CLINICAL QUESTION
What are the side effects of long-term proton pump inhibitor (PPI) use?
BOTTOM LINE
Best evidence from large, randomized, placebo-controlled trials suggest PPIs do not increase the risk of cardiovascular disease, fractures, or pneumonia. Observational studies suggest PPIs may be associated with vitamin B12 and magnesium deficiency.
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EVIDENCE
- Focusing on large randomized controlled trials (RCTs) and systematic reviews of observational studies where RCT outcomes not unavailable.
- RCTs:
- 17,598 patients with cardiovascular disease, randomized to pantoprazole or placebo.1 At ~3 years, no statistical difference between PPI or placebo, including:
- All-cause mortality, cardiovascular disease, fractures, pneumonia, clostridium difficile infection, chronic kidney disease, dementia, or gastrointestinal malignancies.
- 3761 patients with cardiovascular disease on aspirin, randomized to clopidogrel plus omeprazole or clopidogrel plus placebo.2 Trial ended prematurely when sponsor declared bankruptcy. Outcomes at 180 days:
- All-cause mortality, cardiovascular events, fractures and pneumonia: No difference.
- Upper gastrointestinal events (examples: bleeding, ulcer): 1.1% omeprazole versus 2.9% placebo, statistically different.
- 17,598 patients with cardiovascular disease, randomized to pantoprazole or placebo.1 At ~3 years, no statistical difference between PPI or placebo, including:
- Observational studies:
- Observational studies of the above outcomes have inconsistent findings.3-6
- Best systematic reviews of observational studies on vitamin B12 and magnesium deficiency (no RCT evidence available):
- Vitamin B12 deficiency: increased risk in case-controlled and cohorts.7
- Largest, high quality North American case-control study:8 Vitamin B12 deficient patients more likely to be on PPIs, Odds Ratio (OR): 1.65, statistically different.
- Hypomagnesiemia: Increased risk, OR: 1.71, statistically different.9
- Vitamin B12 deficiency: increased risk in case-controlled and cohorts.7
- Limitations: Observational studies cannot determine causation. Other patient factors may explain associations.
CONTEXT
- Patients on PPIs should have indication reviewed periodically.10
- Many patients with gastroesophageal reflux disease (GERD) use PPIs, including as needed.11
- Lowering dose or discontinuation could be considered for some; tapering may help.12,13
- Continuing PPIs may be appropriate in patients with:14
- Barrett’s or eosinophilic esophagus,
- Erosive esophagitis or GERD related complications (example: stricture), or
- Previous gastrointestinal bleed or ulcer where gastroprotection is needed.
- All PPIs have similar efficacy: Cost and individual response should guide prescribing.15
- Overall, vitamin B12 deficiency occurs in ~5% of patients >60 years.16
- If PPI association is true, the new risk of vitamin B12 deficiency would be ~8%.
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Complete Activity
consider B12 levels if on PPI long term
Review B 12 levels annually and supplement as necessary.