American Journal of Medicine, internal medicine, medicine, health, healthy lifestyles, cancer, heart disease, drugs

Appropriate Use of Proton Pump Inhibitors: A Double-Edged Sword

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We read with great interest the article published by Wombell et al in the current issue of The American Journal of Medicine. The authors summarize the evidence linking proton pump inhibitors (PPIs) to hospital-acquired Clostridium difficile infection.1 They also provide a description of the possible mechanisms responsible for this association. We commend the authors for their timely contribution to the literature and wish to express our additional thoughts. While the evidence about PPI-associated hospital-acquired C. difficile infection continues to grow, there are additional complications associated with PPIs that also warrant provider discretion when prescribing. In addition to the risk of opportunistic gastrointestinal infections, including hospital-acquired C. difficileinfection, recent studies have also linked PPI use to dementia, community-acquired pneumonia myocardial infarction, renal complications, osteoporosis-related fractures, and vitamin and mineral deficiencies.2 Given the significant risks associated with PPIs, their use should be guided strictly by appropriate indications. Unfortunately, PPIs remain the most frequently prescribed medications globally and are prescribed without an appropriate indication in up to 70% of cases.3 In fact, in a recent retrospective study, 31% of patients who developed hospital-acquired C. difficile infection were on a PPI without an appropriate indication.4

However, not all PPI-associated risk is avoidable, as PPIs still play an important role in acid hypersecretion and the prevention of stress ulcer prophylaxis in the intensive care unit (ICU). Early studies cite the incidence of stress-related gastrointestinal bleeding to be as high as 17% in the critically ill patients without gastrointestinal prophylaxis.56 In a large, multicenter, prospective trial, the risk of mortality increased significantly in patients who developed stress-related gastrointestinal bleeding compared with patients without bleeding (49% vs 9%, P < .001).7 Using multiple regression, the trial identified 2 major risk factors that contributed to the development of stress-related gastrointestinal bleeding: mechanical ventilation (odds ratio 15.6; P < .001) and coagulopathy (odds ratio 4.3; P < .001).7 Based on this risk, the American Society of Health-System Pharmacists stress ulcer prophylaxis guidelines define appropriate use to include admission to the intensive care unit and either mechanical ventilation for >48 hours or coagulopathy.8

Upper gastrointestinal bleeds remain a significant source of morbidity, mortality, and health care expenditure, accounting for more than 300,000 hospitalizations and more than $2.5 billion health care dollars annually.9Mortality has been reported as high as 11% for patients presenting to the emergency department with an upper gastrointestinal bleed, and 33% for patients who develop an upper gastrointestinal bleed during their hospitalization.10 PPIs remain the treatment of choice for gastric and duodenal ulcers, pathological hypersecretory disorders, erosive esophagitis, and Helicobacter pylori eradication therapy. PPIs are also appropriate for the treatment of gastroesophageal reflux disease and severe indigestion not responsive to less aggressive treatment and nonpharmacologic strategies.111213 Other potential high-risk patient populations include those on dual antiplatelet therapy, antiplatelet plus anticoagulant therapy, antiplatelet or anticoagulant therapy with a history of a complicated ulcer, and chronic antiplatelet therapy or nonsteroidal anti-inflammatory drug therapy with other risk factors for bleeding. Additional risk factors for upper gastrointestinal bleeds include concomitant high-dose corticosteroids, age >60 years, and previous uncomplicated ulcer.14

PPIs are true pharmacologic double-edged swords. When used appropriately, they promote gastric mucosal healing and treat gastrointestinal diseases such as H. pylori, peptic ulcer disease, and hypersecretory conditions, as well as prevent stress-related gastrointestinal bleeding in the critically ill patient. However, when overprescribed, chronic gastric acid suppression causes significant collateral damage. Clinician decision-making support is paramount to ensure appropriate and judicious use of PPIs. For mild or moderate nonerosive conditions, less aggressive acid-suppressing therapies such as histamine blockers or antacids or nonpharmacologic interventions are an appropriate first step with close follow-up to assess for clinical response. If a patient’s response is deemed inadequate, then he/she can be “stepped up” to a PPI. In severe conditions, when the risk of therapy failure outweighs the risk of the PPI (eg, upper gastrointestinal bleeds, H. pylori eradication), aggressive acid suppression therapy is warranted. Notably, antihistamines are noninferior to PPIs for prevention of stress-related gastrointestinal bleeding; thus, we do not believe PPIs should be empirically used for this indication.15

The final challenge with PPIs is the notion of de-prescribing. Given the significant overuse of PPIs, hundreds of thousands of patients are on these medications without a clear indication. There is significant risk for acid hypersecretion upon abrupt discontinuation of a long-term PPI. As such, clinicians need decision-making support with evaluating the need for continued acid suppression therapy and, if therapy is deemed unnecessary, effectively tapering these medications. For patients in which there is no clear indication for long-term acid suppression therapy (eg, mild to moderate esophagitis, treated gastroesophageal reflux disease, ICU stress ulcer prophylaxis beyond ICU admission) and who have been on PPI therapy for longer than 8 weeks, PPIs should be either decreased to a lower dose or changed to an as-needed basis. During this tapering period, patients may need symptomatic control with an antihistamine, antacid, and nonpharmacologic interventions. In patients on PPI therapy for <8 weeks, PPIs may be abruptly discontinued, but follow-up is necessary to assess for rebound hypersecretion.1617

The crucial step to deciding the most appropriate therapy in any setting is a risk-benefit analysis. The recent negative findings about PPIs certainly bring to light that these are not “no risk” medications. As such, it is imperative that providers be well-informed on the negative consequences of PPIs as well as their appropriate indications when deciding to prescribe these agents. Additionally, pharmacists are uniquely equipped to assess the continued appropriateness of PPI therapy and can have a significant impact on PPI over-utilization.

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-Paul O. Lewis, PharmD, BCPS (AQ-ID), Kelly L. Covert, PharmD, BCPS

This article originally appeared in the March issue of The American Journal of Medicine.

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