Proton Pump Inhibitors: Appropriate Use and Safety Concerns

(Updated August 2022)

Data suggest that only one-third of proton pump inhibitors (PPI) use is appropriate.2-4 Many adverse effects have been associated with chronic PPI therapy; however, cause and effect data are very limited.8 Patients should have a clear and appropriate evidence-based indication for using PPIs and be on the lowest effective dose for the duration most appropriate for the condition being treated. The FAQ below answers common questions about the appropriate use of PPIs and their associated safety concerns.

Question

Answer/Pertinent Information

Which conditions are appropriate for short-term PPI use?

Heartburn/dyspepsia

  • OTC PPIs are indicated for severe or frequent heartburn that occurs at least twice per week.77,78
  • Recommend a 14-day course of therapy with a PPI.77,78
  • Patients who need more than one 14-day course in a four-month period should consult their prescriber.77,78

GERD

  • Recommend an initial eight-week course of a PPI for typical GERD symptoms (heartburn and regurgitation) that occur with sufficient frequency and intensity to impair quality of life.8
  • Consider a switch to a different PPI if patients have adverse effects.8
  • For patients that have symptoms after stopping the eight-week course of PPI; acceptable options include on-demand or intermittent PPI therapy, or step-down to an H2-blocker.8
  • Consider giving the PPI twice daily for 8 to 12 weeks for patients with both extraesophageal (e.g., laryngeal and pulmonary symptoms such as hoarseness, chronic cough, etc) and typical GERD symptoms.8

Gastric and duodenal ulcers

  • Recommend FDA- and Health Canada-approved regimens for ulcer healing, these typically last four to eight weeks.64

H. pylori

Stress ulcer prophylaxis

  • Reserve stress ulcer prophylaxis with PPIs for the most critically ill ICU patients who are at high risk for GI bleeding (e.g., mechanical ventilation with septic shock, acute kidney injury, etc).9,10
  • See our chart, Stress Ulcer Prophylaxis, for more information on which patients should receive PPIs for stress ulcer prophylaxis.
  • Recommend stopping PPI at discharge or transfer to the floor, unless there is another indication for use.11,15

Which conditions may require long-term PPI therapy?

Refractory GERD

  • Consider GERD refractory in patients not responding to twice-daily PPI therapy for 8 to 12 weeks.8
  • Ensure optimized PPI therapy with appropriate dosing, verify adherence, and ensure administration is 30 to 60 minutes prior to first and last meals of the day.8
  • Suggest adding a bedtime dose of an H2-blocker for continuing nighttime symptoms due to histamine-mediated nighttime acid secretion.8

Erosive esophagitis

  • Consider maintenance PPI therapy with continued symptoms after an eight-week trial of PPI.8
  • The dose and length of therapy is determined by the severity of disease and the specific PPI being used.64
  • Recommend using the lowest effective dose, including on-demand or intermittent therapy during maintenance therapy.8

Zollinger-Ellison syndrome

  • Higher doses are often necessary initially, recommend reducing the dose as gastric output decreases.12
  • Suggest using symptom control (e.g., pain, diarrhea) to guide dosage titrations, when gastric output volumes are not an option.12
  • Recommend using the lowest effective dose.12

NSAID-induced ulcers

  • Recommend PPIs for patients using an NSAID who are at moderate risk (one or two risk factors [e.g., age over 65, high-dose NSAID, history of uncomplicated ulcer, or using an antiplatelet]) or high risk (previous complicated ulcer, using a corticosteroid or anticoagulant, or who have more than two of the above risk factors) of a GI bleed.1,13,14 See our FAQ, Managing NSAID Risks, for selection of appropriate NSAID per level of GI risk.

Barrett’s Esophagus

  • Recommend once-daily treatment with a PPI.68
  • Reserve twice-daily dosing for patients with poor control on once-daily PPI therapy.68

Gastroprotection in patients taking antithrombotics

  • Consider a standard-dose PPI for patients with any of the following:13,14,80,81
    • Concomitant steroid or NSAID use
    • Prior GI bleed
    • Use of ≥2 antithrombotics

Should H2-blockers and PPIs be taken together?

Data are lacking on any benefit of administering PPIs and H2-blockers together.

  • There may be a role for the addition of an H2-blocker at bedtime to control nighttime symptoms (e.g., refractory GERD).8,51-53

Is there evidence to support on-demand dosing with PPIs?

PPIs are not approved for on-demand dosing (i.e., prn for symptoms); however, studies have shown this dosing can be effective for patients with non-erosive or other non-complicated GERD.7,8

Systematic reviews have found that on-demand PPIs were more effective than placebo and as effective as continuous PPI therapy for patients with non-erosive GERD and mild erosive esophagitis [Evidence Level A-2].16,76

Consider on-demand dosing for non-erosive GERD and other uncomplicated esophagitis.61-63,76

How should self-medication with OTC PPIs be addressed?
  • PPIs are heavily advertised and readily available OTC.
    • Ensure patients are using PPIs correctly, for example they should take their dose 30 to 60 minutes prior to a meal for optimal acid-lowering.8
  • Remind patients not to exceed 14 days of OTC PPI therapy, used no more than three times per year, unless they have additional guidance from their prescriber.20

What lifestyle measures can be used to manage GERD symptoms?

Encourage the following non-pharmacologic/lifestyle management first-line for GERD symptoms:

  • Elevating the head of the bed six inches.8
  • Avoiding meals two to three hours before bedtime.8
  • Weight loss, if appropriate.8
  • Smoking and alcohol cessation.8
  • Avoiding foods that worsen symptoms (e.g., caffeine, chocolate, spicy foods, acidic foods, high-fat foods).8
  • Stress reduction.70
  • Ensuring adequate sleep (limited data exists).71

How should PPI therapy be handled at transitions of care?

PPIs are commonly used for stress prophylaxis (often inappropriately) in the hospitalized patient.55,56

Recommend re-evaluating PPI indications at transitions of care (e.g., discharge from the ICU or hospital) as an opportunity to eliminate unnecessary therapy.14,54

Do PPIs improve symptoms of asthma?

Asthma and GERD often co-exist.8,19

Randomized controlled trials and a meta-analysis show small, likely clinically insignificant, improvements in asthma (e.g., morning peak expiratory flow [PEF], quality of life, etc) in those using PPIs compared to placebo.8,19,25 However, data from several randomized controlled trials suggest that PPI therapy provides no benefit in managing asthma symptoms.8,18

PPIs are not recommended in patients with asthma unless they have symptoms of GERD, or another appropriate indication.8,19

What are significant drug interactions associated with PPIs?

PPIs can increase concentrations of some medications to toxic levels, by decreasing their metabolism. See our chart, Cytochrome P450 Drug Interactions, for more information.

Different PPIs inhibit CYP2C19 to varying degrees.

  • For example, product labeling recommends avoiding omeprazole and esomeprazole with clopidogrel as its metabolism to its active form is inhibited by strong and moderate CYP2C19 inhibitors (e.g., omeprazole, esomeprazole).22,23 However, the clinical significance of this interaction is unknown.69
    • Other PPIs (e.g., pantoprazole, rabeprazole) are not (or are weak) CYP2C19 inhibitors and may be preferred in patients taking clopidrogrel.22-24

Reduced gastric acidity from PPI therapy may reduce the absorption of calcium, iron, and vitamin B12.8 However, routine monitoring, increased intake, or supplements are not routinely recommended.8

Recommend screening for drug interactions if starting a PPI in a patient taking critical or narrow therapeutic index medication.

  • For example, PPIs can reduce effectiveness of medications requiring an acidic pH for absorption (e.g., iron, ketoconazole, antiretrovirals [contraindicated]).64

Is hypomagnesemia associated with PPI therapy?

PPI therapy has been associated with hypomagnesemia, possibly due to reduced magnesium absorption.28,31

  • Hypomagnesemia has been reported after three months of PPI therapy, but the risk increases after a year.27,28

Data is conflicting on whether PPI therapy causes hypomagnesemia. Two meta-analyses concluded there was an association of PPI therapy with hypomagnesemia; however, two others concluded the risk was unclear due to the heterogenicity of included studies.8

  • National organizations also differ in their recommendations. Recent American Gastroenterology Association best practice recommendations concluded that long-term PPI users do not need to have serum magnesium routinely monitored. The FDA suggests monitoring should be considered before starting PPI therapy and then periodically. The American College of Gastroenterology concludes there is insufficient data to make a meaningful recommendation for monitoring magnesium.8,28

Consider monitoring magnesium in patients also using meds that can lower magnesium levels (e.g., thiazides, loop diuretics) or may be adversely affected by hypomagnesemia (e.g., hypomagnesemia can increase the risk of digoxin toxicity).28,48

Consider checking baseline magnesium levels and then periodically during long-term PPI therapy.28

Does abruptly stopping PPI use cause rebound hypersecretion? 

Rebound acid hypersecretion (with increased reflux symptoms) has been demonstrated in healthy controls who discontinued PPI use; however, strong clinical evidence is lacking for an increase in symptoms after abrupt PPI withdrawal.8

  • The clinical significance for patients treated with long-term PPIs remains unclear.47

It is unclear and hard to distinguish if the symptoms reported are related to rebound hypersecretion or to an underlying GI disease.17,47

Symptoms of rebound hypersecretion have been reported to last three months or more and can lead to the inappropriate continued use of PPIs.72

To help patients successfully discontinue their PPI and limit hypersecretion consider tapering off the PPI.46

  • Recommend reducing the dose, if not at the minimum dose per day.
  • Extend the dosing interval to once daily, every other day, and possibly every third day for a week or longer.

Recommend on-demand PPIs, H2-blockers (if appropriate), antacids, and nonpharmacologic measures as needed for breakthrough symptoms after PPI discontinuation.17,46

Is there an association between PPI use and pneumonia?

Suppression of gastric acid can allow ingested pathogens (ordinarily destroyed by acid) to potentially be aspirated and cause pneumonia.8 Even short-term use (less than one week) of PPIs may increase the incidence of infections.32

Ensure PPIs have a clear indication in hospitalized patients, especially those at risk for pneumonia (e.g., elderly, chronic lung disease, patients taking immunosuppressants).32

  • Hospitalized patients on mechanical ventilators while taking a PPI are at greatest risk of developing hospital-acquired gram-negative pneumonia.32
  • One additional case of hospital-acquired pneumonia was seen for every 111 non-ICU patients treated with a PPI for at least three days.33

The evidence (see below) is more conflicting for the association of PPIs with community-acquired pneumonia.58 However, when indicated PPIs should not be withheld due to a potential association with community-acquired pneumonia.8

  • Population-based studies have suggested an association of community-acquired pneumonia in patients on PPIs.34
  • A meta-analysis found that PPIs do not increase the risk of hospitalization for community-acquired pneumonia.44
  • Analysis of pooled patient data from 24 randomized controlled trials concluded that esomeprazole was not associated with a higher risk of community-acquired pneumonia when used for up to 180 days [Evidence Level B-2].45
  • A 2021 meta-analysis of over two million patients in 13 studies concluded that there was an increased incidence of community-acquired pneumonia in patients using PPIs, especially if therapy was for more than 30 days and in patients with stroke [Evidence Level B-2].6
  • A 2016 large cohort study and self-controlled case series concluded that the association between the use of PPIs and the increased risk of community-acquired pneumonia is likely entirely due to confounding factors [Evidence Level B-2].29
    • PPIs may have been prescribed for cough and chest discomfort that were mistakenly attributed to GERD but were actually caused by an unrecognized, early pneumonia.8

Is there an association between PPI use and Clostridioides (Clostridium) difficile infections?

PPI use may be associated with an increase in C. difficile infections and diarrhea.38 The suppression of gastric acid can allow an overgrowth of ingested pathogens (ordinarily destroyed by acid), which may increase the risk of enteric infections.8

  • FDA and Health Canada warnings state that although evidence is limited for a firm cause and effect relationship, the link between PPIs and C. difficile infection cannot be ruled out.36,67
  • A population-based cohort study suggested that PPIs and H2-blockers are associated with an increased risk of
    C. difficile and Campylobacter gastroenteritis in both hospital and the community [Evidence Level B-3].39
  • For every 533 patients receiving a daily PPI in the hospital, at least one will develop C. difficile infection.35
  • A retrospective, cohort study showed PPI use was associated with a 42% increased risk of recurrent C. difficile infection within 90 days.79

Ensure PPIs have a clear indication and use cautiously in patients at risk for C. difficileinfection, (e.g., patients taking antibiotics).8

Consider H2-blockers as alternative to PPIs when appropriate, as risk of C. difficile infection appears to be lower.37

Is there an association between PPI use and fractures?

Taking long-term and/or high doses of PPIs has been reported to increase the incidence of hip, wrist, or spine fractures; however, some results have been conflicting.5,43,73,74

  • A large prospective analysis of postmenopausal women in the Women’s Health Initiative Observational Study and Clinical Trails found PPI use was associated with a 25% increase in overall fractures, a 47% increase in spinal fractures, but no increase in hip fractures [Evidence level B-3].5
  • A meta-analysis of 24 studies with over 2 million patients suggested an increased risk of hip fracture of 20% in patients taking PPIs compared to non-PPI users [Evidence Level B-2].73
  • Approximately 2,000 Canadian females would need to be treated with a PPI for one year to cause one additional fracture.65

PPIs probably don’t increase fracture risk when used short term in low doses.20

Data suggest that PPIs do not increase the risk of osteoporosis and that the risk of hip fracture is only increased in patients with at least one other risk factor for hip fracture.8

Long-term PPI therapy should be considered with caution in patients with risk factors for fractures.73

Per the FDA and Health Canada, use the lowest effective PPI dose, for the shortest amount of time to minimize any possible increased risk of fracture.20,66

Encourage calcium citrate and vitamin D supplementation in patients taking PPIs who have risk factors for osteoporosis.8,20

Is there an association between PPI use and cancer?

Reduced gastric acidity can increase serum levels of gastrin, a growth factor with pro-proliferative effects that theoretically might predispose patients to cancer.8

Three large case-control studies in long-term PPI users have shown no association between the use of PPIs and colon cancer.75

There is no clear evidence to support an increased incidence of gastric cancer in patients on PPIs.21,75

Some adverse effect data from observational studies may be confounded by the PPI indication:8

  • There is a strong association between PPIs and esophageal adenocarcinoma; however, this association is likely confounded by the PPI indication (i.e., GERD is a known risk factor for adenocarcinoma).

Is there an association between PPI use and cardiovascular (CV) events?

In 2015, a data-mining study found a possible association of PPI exposure with risk for MI in the general population.41

  • Proposed mechanisms include increased plasma levels of ADMA and decreased levels of nitrous oxide. Elevated ADMA is associated with an increased risk of CV disease.40

Randomized controlled trials do NOT show an increased risk for major adverse cardiovascular and cerebrovascular events (MACCE), including risk for MI with PPI use.42,75,81

Is there an association between PPI use and dementia?

Limited and conflicting evidence (mainly from large observational studies) has suggested an association with PPI use and an increased risk of dementia [Evidence level B-3].26,47,59,60 Proposed mechanisms include effects on amyloid or neurologic damage secondary to vitamin B12 deficiency.59,60

  • Recently, a meta-analysis of 17 studies with over 1.2 million patients concluded that PPIs and H2-blockers do not increase the risk of dementia [Evidence Level B-2].30

When indicated, PPI therapy should not be withheld due to concerns of a potential increased risk of dementia.

Is there an association between PPIs and kidney disease?

PPI use may be associated with a slight increased risk of acute kidney injury (AKI) and/or chronic kidney disease (CKD) [Evidence Level B-2].47,57 The mechanism is hypothesized to be due to acute interstitial nephritis.47,57

If appropriate, recommend H2-blockers over PPIs in patients with kidney impairment, as these have not been associated with CKD.57

  • If PPIs are required, closely monitor and consider consult with a nephrologist.8

Abbreviations: ADMA = asymmetric dimethylarginine; BID = twice daily; BMD = bone mineral density; COX-2 = cyclooxygenase-2; CKD = chronic kidney disease; CV = cardiovascular; GERD = gastroesophageal reflux disease; GI = gastrointestinal; ICU = intensive care unit; INR = international normalized ratio; MI = myocardial infarction; NSAID = non-steroidal anti-inflammatory drug; OTC = over-the-counter; PPI = proton pump inhibitor; TID = three times daily.

Levels of Evidence

In accordance with our goal of providing Evidence-Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish.

Level

Definition

Study Quality

A

Good-quality patient-oriented evidence.*
  1. High-quality randomized controlled trial (RCT)
  2. Systematic review (SR)/Meta-analysis of RCTs with consistent findings
  3. All-or-none study

B

Inconsistent or limited-quality patient-oriented evidence.*
  1. Lower-quality RCT
  2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings
  3. Cohort study
  4. Case control study

C

Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening.

*Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life).

[Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56. https://www.aafp.org/afp/2004/0201/p548.pdf.]

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Cite this document as follows: Clinical Resource, Proton Pump Inhibitors: Appropriate Use and Safety Concerns. Pharmacist’s Letter/Prescriber’s Letter. February 2022. [380205]



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