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      The risks of long-term use of proton pump inhibitors: a critical review

      review-article
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      Therapeutic Advances in Drug Safety
      SAGE Publications
      PPIs, proton pump inhibitors, side effects

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          Abstract

          Proton pump inhibitors (PPIs) are among the most frequently prescribed medications. Their use is likely even higher than estimated due to an increase in the number of PPIs available without a prescription. Appropriate indications for PPI use include Helicobacter pylori infection, erosive esophagitis, gastric ulcers, and stress ulcer prevention in high-risk critically ill patients. Unfortunately, PPIs are often used off-label for extended periods of time. This increase in PPI usage over the past two decades has called into question the long-term effects of these medications. The association between PPI use and infection, particularly Clostridium difficile and pneumonia, has been the subject of several studies. It’s proposed that the alteration in gastrointestinal microflora by PPIs produces an environment conducive to development of these types of infections. At least one study has suggested that long-term PPI use increases the risk of dementia. Drug interactions are an important and often overlooked consideration when prescribing any medication. The potential interaction between PPIs and antiplatelet agents has been the subject of multiple studies. One of the more recent concerns with PPI use is their role in the development or progression of chronic kidney disease. There is also some literature suggesting that PPIs contribute to the development of various micronutrient deficiencies. Most of the literature examining the potential adverse effects of PPI use is composed of retrospective, observation studies. There is a need for higher quality studies exploring this relationship.

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          Most cited references41

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          Clopidogrel with or without omeprazole in coronary artery disease.

          Gastrointestinal complications are an important problem of antithrombotic therapy. Proton-pump inhibitors (PPIs) are believed to decrease the risk of such complications, though no randomized trial has proved this in patients receiving dual antiplatelet therapy. Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel. We randomly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo, in addition to aspirin. The primary gastrointestinal end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. The trial was terminated prematurely when the sponsor lost financing. We planned to enroll about 5000 patients; a total of 3873 were randomly assigned and 3761 were included in analyses. In all, 51 patients had a gastrointestinal event; the event rate was 1.1% with omeprazole and 2.9% with placebo at 180 days (hazard ratio with omeprazole, 0.34, 95% confidence interval [CI], 0.18 to 0.63; P<0.001). The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (hazard ratio, 0.13; 95% CI, 0.03 to 0.56; P = 0.001). A total of 109 patients had a cardiovascular event, with event rates of 4.9% with omeprazole and 5.7% with placebo (hazard ratio with omeprazole, 0.99; 95% CI, 0.68 to 1.44; P = 0.96); high-risk subgroups did not show significant heterogeneity. The two groups did not differ significantly in the rate of serious adverse events, though the risk of diarrhea was increased with omeprazole. Among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI. (Funded by Cogentus Pharmaceuticals; ClinicalTrials.gov number, NCT00557921.).
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            Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome.

            Prior mechanistic studies reported that omeprazole decreases the platelet inhibitory effects of clopidogrel, yet the clinical significance of these findings is not clear. To assess outcomes of patients taking clopidogrel with or without a proton pump inhibitor (PPI) after hospitalization for acute coronary syndrome (ACS). Retrospective cohort study of 8205 patients with ACS taking clopidogrel after discharge from 127 Veterans Affairs hospitals between October 1, 2003, and January 31, 2006. Vital status information was available for all patients through September 30, 2006. All-cause mortality or rehospitalization for ACS. Of 8205 patients taking clopidogrel after discharge, 63.9% (n = 5244) were prescribed PPI at discharge, during follow-up, or both and 36.1% (n = 2961) were not prescribed PPI. Death or rehospitalization for ACS occurred in 20.8% (n = 615) of patients taking clopidogrel without PPI and 29.8% (n = 1561) of patients taking clopidogrel plus PPI. In multivariable analyses, use of clopidogrel plus PPI was associated with an increased risk of death or rehospitalization for ACS compared with use of clopidogrel without PPI (adjusted odds ratio [AOR], 1.25; 95% confidence interval [CI], 1.11-1.41). Among patients taking clopidogrel after hospital discharge and prescribed PPI at any point during follow-up (n = 5244), periods of use of clopidogrel plus PPI (compared with periods of use of clopidogrel without PPI) were associated with a higher risk of death or rehospitalization for ACS (adjusted hazard ratio, 1.27; 95% CI, 1.10-1.46). In analyses of secondary outcomes, patients taking clopidogrel plus PPI had a higher risk of hospitalizations for recurrent ACS compared with patients taking clopidogrel without PPI (14.6% vs 6.9%; AOR, 1.86 [95% CI, 1.57-2.20]) and revascularization procedures (15.5% vs 11.9%; AOR, 1.49 [95% CI, 1.30-1.71]), but not for all-cause mortality (19.9% vs 16.6%; AOR, 0.91 [95% CI, 0.80-1.05]). The association between use of clopidogrel plus PPI and increased risk of adverse outcomes also was consistent using a nested case-control study design (AOR, 1.32; 95% CI, 1.14-1.54). In addition, use of PPI without clopidogrel was not associated with death or rehospitalization for ACS among patients not taking clopidogrel after hospital discharge (n = 6450) (AOR, 0.98; 95% CI, 0.85-1.13). Concomitant use of clopidogrel and PPI after hospital discharge for ACS was associated with an increased risk of adverse outcomes than use of clopidogrel without PPI, suggesting that use of PPI may be associated with attenuation of benefits of clopidogrel after ACS.
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              Complications of Proton Pump Inhibitor Therapy.

              Safety issues associated with proton pump inhibitors (PPIs) have recently attracted widespread media and lay attention. Gastroenterologists are frequently asked about the appropriateness of PPI therapy for specific patients. Furthermore, some patients may have had PPI therapy discontinued abruptly or inappropriately due to safety concerns. Faced with such a wide variety of potentially serious adverse consequences, prescribers need to evaluate the evidence objectively to discern the likelihood that any reported association might actually be causal. Here, we review many of the proposed adverse consequences of PPI therapy and apply established criteria for the determination of causation. We also consider the potential contribution of residual confounding in many of the reported studies. Evidence is inadequate to establish causal relationships between PPI therapy and many of the proposed associations. Residual confounding related to study design and the over-extrapolation of quantitatively small estimates of effect size have probably led to much of the current controversy about PPI safety. In turn, this has caused unnecessary concern among patients and prescribers. The benefits of PPI therapy for appropriate indications need to be considered along with the likelihood of the proposed risks. Patients with a proven indication for a PPI should continue to receive it in the lowest effective dose. PPI dose escalation and continued chronic therapy in those unresponsive to initial empiric therapy is discouraged.
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                Author and article information

                Contributors
                Journal
                Ther Adv Drug Saf
                Ther Adv Drug Saf
                TAW
                sptaw
                Therapeutic Advances in Drug Safety
                SAGE Publications (Sage UK: London, England )
                2042-0986
                2042-0994
                19 November 2018
                2019
                : 10
                : 2042098618809927
                Affiliations
                [1-2042098618809927]Division of Critical Care, Department of Pharmacy, Vanderbilt University Medical Center, Nashville, TN, USA
                [2-2042098618809927]Division of Critical Care, Department of Anesthesiology, Vanderbilt University, Nashville, TN 37212, USA
                Author notes
                Article
                10.1177_2042098618809927
                10.1177/2042098618809927
                6463334
                31019676
                c4b8077a-d607-4bdc-8ca4-9fdaa72704b4
                © The Author(s), 2019

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 23 July 2018
                : 28 September 2018
                Categories
                Review
                Custom metadata
                January-December 2019

                ppis,proton pump inhibitors,side effects
                ppis, proton pump inhibitors, side effects

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