PPIs in older people — do you know the risks?
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Proton pump inhibitors (PPIs) are widely prescribed, effective and generally safe for the management of acid-related gastrointestinal disorders. However, there are risks that may be elevated for some older people when PPIs are used regularly and long term, including fractures, enteric infection and community-acquired pneumonia.
The goal of treatment is to control symptoms at the lowest dose and for the shortest possible duration. Some patients require long-term treatment, so consider step-down or symptom-driven dosing and regularly review the need for treatment.
Establish whether PPI therapy is necessary in your older patient.
- Consider stopping PPI treatment after an initial course as some people will not relapse. Monitor symptoms closely after stopping. For relapses, trial a repeat 4–8 week course, then step-down to discontinuation or a reduced dose.1,3
- If the initial attempt to step-down or discontinue PPI therapy is unsuccessful, a further attempt to reduce the dose or cease treatment can be made after a few weeks.3
Advise people to avoid smoking and dietary components such as fat, chocolate, caffeine and alcohol, that may aggravate symptoms.4
- Regular, long-term treatment may be required for some people with known oesophagitis or some complicated upper gastrointestinal diseases. Seek specialist advice.1
As a class, PPIs are consistently among the 10 most commonly used drugs in Australia (based on defined daily dose, prescription count and cost to the Government).5 In older people, PPIs are widely used to treat gastroesophageal reflux, dyspepsia and peptic ulcer. While these drugs are effective for reducing symptoms and may have a favourable safety profile overall, there is increasing awareness of rare but serious adverse drug reactions, particularly with high dose and long-term use.6
The absolute risk of adverse outcomes from long-term use is very low (at least for extended use up to 20 years),7 and, for most patients, the benefits of PPIs outweigh the potential risks.2 However, PPIs are increasingly used long term and often without a proper indication.2 Evaluate the indication for PPI treatment and consider the risk of harm from long-term use in older people, those malnourished and those with significant comorbidity.2
Consider the risk of fractures
In recent years, the FDA and the EMA have issued safety warnings about the risk of fractures of the hip, wrist and spine associated with use of PPIs.8,9 As with many rare adverse effects, the risk was not recognised in RCTs prior to post-marketing epidemiological studies. Both regulators reported there was a possible increase in fracture risk particularly if PPIs are used in high dose and over prolonged periods (> 1 year).
The most recent meta-analysis of observational studies (mostly conducted in postmenopausal women and older men), found the risk of hip fracture was modestly increased in those taking PPIs by about 10% to 50% and by 30% to 80% for spine fractures, although heterogeneity was seen in the data leading to wide confidence intervals.8,10,11 The elevated risk remained when the data were stratified according to duration of use, with either short- (<1 year) or longer-term use (>1 year).12
The mechanism for the increase in fracture risk does not appear to be associated with either the presence of osteoporosis or accelerated bone mineral density loss but remains largely unexplained.13 Although the risk is only marginally higher than that in control populations matched for age,6 consider the presence of additional risk factors such as steroid use or pre-existing osteoporosis before prescribing.14
Increased susceptibility to enteric infection
The reduction in gastric acidity due to PPI treatment is associated with increased risk of both enteric and systemic infections including C. difficile-associated diarrhoea (CDAD). A recent pooled analysis reported a 65% increase in the incidence of CDAD among PPI users.15 This confirmed earlier findings of a near-doubled risk of enteric infections associated with using PPIs.16
The risk may be higher for people using PPIs more frequently, which supports a dose-response effect.17 However, another more recent meta-analysis found only a weak association with a number needed to harm (NNH) of 3925 at 1 year with the highest risk in hospitalised patients receiving antibiotics, which has an estimated NNH of 50 at 2 weeks.18 The risk may be greater in patients with chronic renal failure and in patients exposed to settings that increase the risk of infection (e.g. hospitals or aged-care facilities).6
The risk of pneumonia is highest soon after starting a high-dose PPI
Several observational studies and meta-analyses have investigated the risk of pneumonia associated with PPIs with somewhat mixed results. The latest evidence seems to support a stronger association. A study of the risk of community-acquired pneumonia in American veterans (mean age ~65 years) found a modest increase in risk of ~30%,19 while some have reported as much as a doubling in the risk of pneumonia associated with use of PPIs.7,20 A recent meta-analysis found a higher dose and shorter duration of PPI use was associated with the development of community-acquired pneumonia.21 This was confirmed in another meta-analysis, which reported the risk of pneumonia was highest for higher doses and decreased with longer duration of PPI therapy.22
Reduced antiplatelet effect when coadministered with clopidogrel
In recent years, the FDA and EMA released safety advice regarding the risk of interactions between PPIs and clopidogrel.23,24 Observational studies suggest that PPIs may reduce the antiplatelet effect of clopidogrel when taken concurrently, predominantly by competition for the cytochrome P 450 (CYP450) 2C19 enzyme system.6
Consequently, guidelines recommend that a PPI only be prescribed with clopidogrel for prophylaxis if there is a significant risk of upper gastrointestinal bleeding, or if it is required to treat another condition such as gastroesophageal reflux.7
Whether or not this effect on platelet activation influences the risk of myocardial infarction or other thrombotic risks is unclear.6 A recent meta-analysis reported no statistically significant association with overall mortality but the data were conflicting and inconsistent.25 Weigh the relative risks to the patient of ulcers versus haemorrhage when deciding whether to prescribe PPIs in people taking clopidogrel.25
Although the absolute risk for the adverse outcomes listed above is low, using PPIs is not without risk and requires careful consideration. By stopping treatment when appropriate, the benefit can be preserved and the risk of serious adverse effects is reduced.
- Rossi SE. Australian Medicines Handbook Aged Care Companion. Australian Medicines Handbook Pty Ltd, 2013. [Online] (accessed 18 December 2013).
- Reimer C. Safety of long-term PPI therapy. Best Pract Res Clin Gastroenterol 2013;27:443-54. [PubMed]
- Zarowitz BJ. The challenge of discontinuing proton pump inhibitors. Geriatr Nurs 2011;32:276-8. [PubMed]
- Gastroenterological Society of Australia. Gastro-oesophageal reflux disease in adults. 2011. [Online] (accessed 18 December 2013).
- Australian Prescriber. Top 10 Drugs. Australian Prescriber 2013;36:211. [Full text]
- McCarthy DM. Adverse effects of proton pump inhibitor drugs: clues and conclusions. Curr Opin Gastroenterol 2010;26:624-31. [PubMed]
- Therapeutic Guidelines Limited. eTG Complete. Proton pump inhibitors 2013. [Online] (accessed 21 November 2013).
- European Medicines Agency. Proton-pump inhibitors - risk of bone fracture. Pharmacovigilance Working Party (PHVWP) Monthly report on safety concerns, guidelines and general matters 2012. [Online] (accessed 22 November 2013).
- Food and Drug Administration. FDA Drug Safety Communication: Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors. 2010. [Online] (accessed 21 November 2013).
- Eom CS, Park SM, Myung SK, et al. Use of acid-suppressive drugs and risk of fracture: a meta-analysis of observational studies. Ann Fam Med 2011;9:257-67. [PubMed]
- Kwok CS, Yeong JK, Loke YK. Meta-analysis: risk of fractures with acid-suppressing medication. Bone 2011;48:768-76. [PubMed]
- Yu EW, Bauer SR, Bain PA, et al. Proton pump inhibitors and risk of fractures: a meta-analysis of 11 international studies. Am J Med 2011;124:519-26. [PubMed]
- Targownik LE, Lix LM, Leung S, et al. Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss. Gastroenterology 2010;138:896-904. [PubMed]
- Corley DA, Kubo A, Zhao W, et al. Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients. Gastroenterology 2010;139:93-101. [PubMed]
- Janarthanan S, Ditah I, Adler DG, et al. Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis. Am J Gastroenterol 2012;107:1001-10. [PubMed]
- Leonard J, Marshall JK, Moayyedi P. Systematic review of the risk of enteric infection in patients taking acid suppression. Am J Gastroenterol 2007;102:2047-56; quiz 57. [PubMed]
- Howell MD, Novack V, Grgurich P, et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med 2010;170:784-90. [PubMed]
- Tleyjeh IM, Bin Abdulhak AA, Riaz M, et al. Association between proton pump inhibitor therapy and clostridium difficile infection: a contemporary systematic review and meta-analysis. PLoS One 2012;7:e50836. [PubMed]
- Hermos JA, Young MM, Fonda JR, et al. Risk of community-acquired pneumonia in veteran patients to whom proton pump inhibitors were dispensed. Clin Infect Dis 2012;54:33-42. [PubMed]
- de Jager CP, Wever PC, Gemen EF, et al. Proton pump inhibitor therapy predisposes to community-acquired Streptococcus pneumoniae pneumonia. Aliment Pharmacol Ther 2012;36:941-9. [PubMed]
- Giuliano C, Wilhelm SM, Kale-Pradhan PB. Are proton pump inhibitors associated with the development of community-acquired pneumonia? A meta-analysis. Expert Rev Clin Pharmacol 2012;5:337-44. [PubMed]
- Eom CS, Jeon CY, Lim JW, et al. Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis. CMAJ 2011;183:310-9. [PubMed]
- Food and Drug Administration. Warnings and precautions - Diminished antiplatelet activity due to impaired CYP2C19 function. 2010. [Online] (accessed 19 December 2013).
- European Medicines Agency. Interction between clopidogrel and proton-pump inhibitors. 2010. [Online] (accessed 18 December 2013).
- Kwok CS, Loke YK. Meta-analysis: the effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel. Aliment Pharmacol Ther 2010;31:810-23. [PubMed]