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Adverse Effects Associated With Proton Pump Inhibitors

Adverse Effects Associated With Proton Pump Inhibitors Proton pump inhibitors (PPIs) have been among the most widely prescribed medications in the United States for decades. This is largely due to 2 very common uses of PPIs: treatment of dyspepsia and prevention of gastrointestinal bleeding among patients prescribed antiplatelet therapy, coupled with the belief that PPIs have few adverse effects. However, mounting evidence demonstrates that PPIs are associated with a number of adverse effects and are overprescribed. This issue was highlighted in JAMA Internal Medicine’s launch of the Less Is More series in 2010.1,2 Since then, additional evidence of adverse effects of PPIs has accumulated. In this issue of JAMA Internal Medicine, Lazarus et al3 add chronic kidney disease to the list of possible harms of PPIs. To collate data on the adverse effects of PPIs, we surveyed recent studies focusing on systematic reviews. Most of the evidence supporting the adverse effects of PPIs is observational. Thus, it is possible that PPI users are sicker than nonusers, or that adverse effects are caused by other drugs or conditions associated with PPI use. However, some adverse effects have been documented by multiple high-quality observational studies and are likely causal (Table). Herein, we summarize recent data on the adverse effects of PPI use. Table. Evidence Supporting the Potential Adverse Effects of Proton Pump Inhibitor Drugs View LargeDownload Kidney Disease Among 10 439 patients followed for 13.9 years in the Atherosclerosis Risk in Communities study,3 the risk of chronic kidney disease was 50% higher in PPI users compared with nonusers. The findings of this study are strengthened by a thorough assessment of potential confounding using both multivariable and propensity score adjusted analyses, by a dose response with higher risk among patients using twice daily compared with once daily PPI dosing, and by higher risk among PPI users compared with patients using histamine H2 antagonists—a comparison group that should control for potential bias and confounding. Finally, the findings were replicated in a second large cohort using administrative data from patients in the Geisinger Health System.3 Use of PPIs may lead to chronic kidney disease through recurrent acute kidney injury or hypomagnesemia. Although this is a large, high-quality observational study, additional confirmation would be helpful, especially since chronic kidney disease is a common condition. Use of PPIs is also associated with increased risk of acute kidney injury, possibly mediated through acute interstitial nephritis. In a population-based study4 of 290 592 people 66 or older, rates of acute kidney injury and acute interstitial nephritis were 2.5- and 3-fold higher in PPI users compared with nonusers. In a nested case-control study10 of 184 480 patients 18 years or older, renal disease was 2-fold more common in patients who had used PPIs compared with those who had not after controlling for multiple potential confounding variables. Hypomagnesemia Hypomagnesemia has been associated with increased risk of kidney disease and nonrecovery of renal function after acute kidney injury. When severe, hypomagnesemia can lead to muscle weakness, tetany, convulsions, cardiac arrhythmias, and hypotension. Based on case reports, the US Food and Drug Administration (FDA) issued a warning in 2011 that use of PPIs may cause low serum magnesium levels if taken for prolonged periods of time, and noted that magnesium supplementation alone may not correct low serum magnesium levels unless the PPI is discontinued.11 Subsequently, a meta-analysis5 of 9 observational studies including 109 798 participants found that PPI users had a 40% higher risk of hypomagnesemia compared with nonusers. Infections Clostridium difficile Infection Proton pump inhibitors reduce gastric acidity, which may promote bacterial colonization in the gastrointestinal tract, increasing the risk of infection. A meta-analysis6 that included 39 studies showed a 74% higher risk of developing C difficile infection, as well as 2.5-fold higher risk of recurrent C difficile infection among PPI users compared with nonusers. Based on these data, the FDA published a safety alert in 2015 warning of the association of PPIs and C difficile infection.11 Pneumonia Reduced gastric acidity and increased bacterial colonization in the stomach related to PPI use may also lead to increased rates of pneumonia. A meta-analysis7 of 5 observational studies showed that the risk of community-acquired pneumonia was 34% higher among patients using PPIs compared with nonusers, and that the risk was higher with increasing doses of PPIs. Risk for hospital-acquired pneumonia was not increased. A retrospective cohort study using administrative data evaluated the risk of hospitalization for community-acquired pneumonia among more than 4 million patients newly prescribed nonsteroidal anti-inflammatory drugs from 8 regions in Canada, the United States, and the United Kingdom. Among patients who were also started on therapy with a PPI (presumably for prevention of dyspepsia, ulceration, and bleeding), there was no increased risk of hospitalization for community-acquired pneumonia compared with nonusers.8 The results of this study may be more reliable than other observational studies because the study population was restricted to patients without known gastric or esophageal disease, and analyses were adjusted using high-dimensional propensity scores to control for potential confounding. Cardiovascular Events Patients with coronary disease and those who have undergone coronary procedures are generally prescribed antiplatelet therapy to reduce the risk of coronary events. Proton pump inhibitors are often prescribed along with antiplatelet therapy to prevent gastrointestinal bleeding. The commonly used antiplatelet agent, clopidogrel, is metabolized to the active form by liver enzymes that also metabolize PPIs, suggesting that competitive metabolism by PPIs might lead to reduced activation of clopidogrel, reduced antiplatelet effects, and increased cardiovascular events. In fact, pharmacologic studies demonstrate that adding PPIs to clopidogrel results in reduced platelet inhibition, and this finding led the FDA in 2009 to warn against combining clopidogrel and PPIs.11,12 A meta-analysis13 of 31 observational studies found that patients using PPIs with clopidogrel have about a 30% increased risk of cardiovascular events compared with nonusers of PPIs. However, none of the 4 randomized clinical trials identified by this systemic review found an increased risk of coronary events among patients prescribed clopidogrel and treated with omeprazole or esomeprazole.13 It is not clear how to resolve these conflicting findings. The observational studies are much larger than the randomized trials and provide “real-world” experience. However, the observational studies are prone to selection bias and confounding, which are minimized by randomization. In summary, we do not find clear evidence that PPIs increase risk for coronary events in patients on clopidogrel. Fractures Use of PPIs may decrease bone density and increase fracture risk by reducing intestinal calcium absorption. Many observational studies have shown an association between PPI use and increased risk of fractures, prompting the FDA to publish a safety alert in 2010 noting a possible increased risk of fractures among PPI users.11 A recent meta-analysis9 of 18 observational studies that included 244 109 fractures found that compared with nonuse, PPI use was associated with a 26% higher risk of hip fracture, a 58% higher risk of spine fracture, and a 33% higher risk for fracture at any site, even after short-term use of less than 1 year. Conclusions Available evidence suggests that PPI use is associated with an increased risk of both acute and chronic kidney disease, hypomagnesemia, C difficile infection, and osteoporotic fractures. Caution in prescribing PPIs should be used in patients at high risk for any of these conditions. Given the association with kidney disease and low magnesium levels, serum creatinine and magnesium levels should probably be monitored in patients using PPIs, especially those using high doses. Given the evidence that PPI use is linked with a number of adverse outcomes, we recommend that patients and clinicians discuss the potential benefits and risks of PPI treatment, as well as potential alternative regimens such as histamine H2 receptor antagonists or lifestyle changes, before PPIs are prescribed. In patients with symptomatic gastrointestinal reflux, ulcer disease, and severe dyspepsia, the benefits of PPI use likely outweigh its potential harms. However, for less serious symptoms and for prevention of bleeding in low-risk patients, potential harms may outweigh the benefits. A large number of patients are taking PPIs for no clear reason—often remote symptoms of dyspepsia or “heartburn” that have since resolved. In these patients, PPIs should be stopped to determine if symptomatic treatment is needed. Back to top Article Information Corresponding Author: Adam Jacob Schoenfeld, MD, University of California, San Francisco, 3333 California St, Ste 265, PO Box 0936, San Francisco, CA 94118 (Adam.Schoenfeld@ucsf.edu). Published Online: January 11, 2016. doi:10.1001/jamainternmed.2015.7927. Conflict of Interest Disclosures: None reported. References 1. Grady D, Redberg RF. Less is more: how less health care can result in better health . Arch Intern Med. 2010;170(9):749-750.PubMedGoogle ScholarCrossref 2. Katz MH. Failing the acid test: benefits of proton pump inhibitors may not justify the risks for many users . Arch Intern Med. 2010;170(9):747-748.PubMedGoogle ScholarCrossref 3. Lazarus B, Yuan C, Wilson FP, et al. Proton pump inhibitor use and the risk of chronic kidney disease [published online January 11, 2016]. JAMA Intern Med. doi:10.1001/jamainternmed.2015.7193.Google Scholar 4. Antoniou T, Macdonald EM, Hollands S, et al. Proton pump inhibitors and the risk of acute kidney injury in older patients: a population-based cohort study . CMAJ Open. 2015;3(2):E166-E171.PubMedGoogle ScholarCrossref 5. Cheungpasitporn W, Thongprayoon C, Kittanamongkolchai W, et al. Proton pump inhibitors linked to hypomagnesemia: a systematic review and meta-analysis of observational studies . Ren Fail. 2015;37(7):1237-1241.PubMedGoogle ScholarCrossref 6. Kwok CS, Arthur AK, Anibueze CI, Singh S, Cavallazzi R, Loke YK. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis . Am J Gastroenterol. 2012;107(7):1011-1019.PubMedGoogle ScholarCrossref 7. Eom CS, Jeon CY, Lim JW, Cho EG, Park SM, Lee KS. Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis . CMAJ. 2011;183(3):310-319.PubMedGoogle ScholarCrossref 8. Filion KB, Chateau D, Targownik LE, et al; CNODES Investigators. Proton pump inhibitors and the risk of hospitalisation for community-acquired pneumonia: replicated cohort studies with meta-analysis . Gut. 2014;63(4):552-558.PubMedGoogle ScholarCrossref 9. Zhou B, Huang Y, Li H, Sun W, Liu J. Proton-pump inhibitors and risk of fractures: an update meta-analysis [published online October 13, 2015] . Osteoporos Int. doi:10.1007/s00198-015-3365-x.PubMedGoogle Scholar 10. Klepser DG, Collier DS, Cochran GL. Proton pump inhibitors and acute kidney injury: a nested case-control study . BMC Nephrol. 2013;14:150.PubMedGoogle ScholarCrossref 11. Proton Pump Inhibitors Information. 2015; http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm213259.htm. Accessed November 12, 2015. 12. Focks JJ, Brouwer MA, van Oijen MG, Lanas A, Bhatt DL, Verheugt FW. Concomitant use of clopidogrel and proton pump inhibitors: impact on platelet function and clinical outcome: a systematic review . Heart. 2013;99(8):520-527.PubMedGoogle ScholarCrossref 13. Melloni C, Washam JB, Jones WS, et al. Conflicting results between randomized trials and observational studies on the impact of proton pump inhibitors on cardiovascular events when coadministered with dual antiplatelet therapy: systematic review . Circ Cardiovasc Qual Outcomes. 2015;8(1):47-55.PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Internal Medicine American Medical Association

Adverse Effects Associated With Proton Pump Inhibitors

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American Medical Association
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Copyright © 2016 American Medical Association. All Rights Reserved.
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2168-6106
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2168-6114
DOI
10.1001/jamainternmed.2015.7927
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Abstract

Proton pump inhibitors (PPIs) have been among the most widely prescribed medications in the United States for decades. This is largely due to 2 very common uses of PPIs: treatment of dyspepsia and prevention of gastrointestinal bleeding among patients prescribed antiplatelet therapy, coupled with the belief that PPIs have few adverse effects. However, mounting evidence demonstrates that PPIs are associated with a number of adverse effects and are overprescribed. This issue was highlighted in JAMA Internal Medicine’s launch of the Less Is More series in 2010.1,2 Since then, additional evidence of adverse effects of PPIs has accumulated. In this issue of JAMA Internal Medicine, Lazarus et al3 add chronic kidney disease to the list of possible harms of PPIs. To collate data on the adverse effects of PPIs, we surveyed recent studies focusing on systematic reviews. Most of the evidence supporting the adverse effects of PPIs is observational. Thus, it is possible that PPI users are sicker than nonusers, or that adverse effects are caused by other drugs or conditions associated with PPI use. However, some adverse effects have been documented by multiple high-quality observational studies and are likely causal (Table). Herein, we summarize recent data on the adverse effects of PPI use. Table. Evidence Supporting the Potential Adverse Effects of Proton Pump Inhibitor Drugs View LargeDownload Kidney Disease Among 10 439 patients followed for 13.9 years in the Atherosclerosis Risk in Communities study,3 the risk of chronic kidney disease was 50% higher in PPI users compared with nonusers. The findings of this study are strengthened by a thorough assessment of potential confounding using both multivariable and propensity score adjusted analyses, by a dose response with higher risk among patients using twice daily compared with once daily PPI dosing, and by higher risk among PPI users compared with patients using histamine H2 antagonists—a comparison group that should control for potential bias and confounding. Finally, the findings were replicated in a second large cohort using administrative data from patients in the Geisinger Health System.3 Use of PPIs may lead to chronic kidney disease through recurrent acute kidney injury or hypomagnesemia. Although this is a large, high-quality observational study, additional confirmation would be helpful, especially since chronic kidney disease is a common condition. Use of PPIs is also associated with increased risk of acute kidney injury, possibly mediated through acute interstitial nephritis. In a population-based study4 of 290 592 people 66 or older, rates of acute kidney injury and acute interstitial nephritis were 2.5- and 3-fold higher in PPI users compared with nonusers. In a nested case-control study10 of 184 480 patients 18 years or older, renal disease was 2-fold more common in patients who had used PPIs compared with those who had not after controlling for multiple potential confounding variables. Hypomagnesemia Hypomagnesemia has been associated with increased risk of kidney disease and nonrecovery of renal function after acute kidney injury. When severe, hypomagnesemia can lead to muscle weakness, tetany, convulsions, cardiac arrhythmias, and hypotension. Based on case reports, the US Food and Drug Administration (FDA) issued a warning in 2011 that use of PPIs may cause low serum magnesium levels if taken for prolonged periods of time, and noted that magnesium supplementation alone may not correct low serum magnesium levels unless the PPI is discontinued.11 Subsequently, a meta-analysis5 of 9 observational studies including 109 798 participants found that PPI users had a 40% higher risk of hypomagnesemia compared with nonusers. Infections Clostridium difficile Infection Proton pump inhibitors reduce gastric acidity, which may promote bacterial colonization in the gastrointestinal tract, increasing the risk of infection. A meta-analysis6 that included 39 studies showed a 74% higher risk of developing C difficile infection, as well as 2.5-fold higher risk of recurrent C difficile infection among PPI users compared with nonusers. Based on these data, the FDA published a safety alert in 2015 warning of the association of PPIs and C difficile infection.11 Pneumonia Reduced gastric acidity and increased bacterial colonization in the stomach related to PPI use may also lead to increased rates of pneumonia. A meta-analysis7 of 5 observational studies showed that the risk of community-acquired pneumonia was 34% higher among patients using PPIs compared with nonusers, and that the risk was higher with increasing doses of PPIs. Risk for hospital-acquired pneumonia was not increased. A retrospective cohort study using administrative data evaluated the risk of hospitalization for community-acquired pneumonia among more than 4 million patients newly prescribed nonsteroidal anti-inflammatory drugs from 8 regions in Canada, the United States, and the United Kingdom. Among patients who were also started on therapy with a PPI (presumably for prevention of dyspepsia, ulceration, and bleeding), there was no increased risk of hospitalization for community-acquired pneumonia compared with nonusers.8 The results of this study may be more reliable than other observational studies because the study population was restricted to patients without known gastric or esophageal disease, and analyses were adjusted using high-dimensional propensity scores to control for potential confounding. Cardiovascular Events Patients with coronary disease and those who have undergone coronary procedures are generally prescribed antiplatelet therapy to reduce the risk of coronary events. Proton pump inhibitors are often prescribed along with antiplatelet therapy to prevent gastrointestinal bleeding. The commonly used antiplatelet agent, clopidogrel, is metabolized to the active form by liver enzymes that also metabolize PPIs, suggesting that competitive metabolism by PPIs might lead to reduced activation of clopidogrel, reduced antiplatelet effects, and increased cardiovascular events. In fact, pharmacologic studies demonstrate that adding PPIs to clopidogrel results in reduced platelet inhibition, and this finding led the FDA in 2009 to warn against combining clopidogrel and PPIs.11,12 A meta-analysis13 of 31 observational studies found that patients using PPIs with clopidogrel have about a 30% increased risk of cardiovascular events compared with nonusers of PPIs. However, none of the 4 randomized clinical trials identified by this systemic review found an increased risk of coronary events among patients prescribed clopidogrel and treated with omeprazole or esomeprazole.13 It is not clear how to resolve these conflicting findings. The observational studies are much larger than the randomized trials and provide “real-world” experience. However, the observational studies are prone to selection bias and confounding, which are minimized by randomization. In summary, we do not find clear evidence that PPIs increase risk for coronary events in patients on clopidogrel. Fractures Use of PPIs may decrease bone density and increase fracture risk by reducing intestinal calcium absorption. Many observational studies have shown an association between PPI use and increased risk of fractures, prompting the FDA to publish a safety alert in 2010 noting a possible increased risk of fractures among PPI users.11 A recent meta-analysis9 of 18 observational studies that included 244 109 fractures found that compared with nonuse, PPI use was associated with a 26% higher risk of hip fracture, a 58% higher risk of spine fracture, and a 33% higher risk for fracture at any site, even after short-term use of less than 1 year. Conclusions Available evidence suggests that PPI use is associated with an increased risk of both acute and chronic kidney disease, hypomagnesemia, C difficile infection, and osteoporotic fractures. Caution in prescribing PPIs should be used in patients at high risk for any of these conditions. Given the association with kidney disease and low magnesium levels, serum creatinine and magnesium levels should probably be monitored in patients using PPIs, especially those using high doses. Given the evidence that PPI use is linked with a number of adverse outcomes, we recommend that patients and clinicians discuss the potential benefits and risks of PPI treatment, as well as potential alternative regimens such as histamine H2 receptor antagonists or lifestyle changes, before PPIs are prescribed. In patients with symptomatic gastrointestinal reflux, ulcer disease, and severe dyspepsia, the benefits of PPI use likely outweigh its potential harms. However, for less serious symptoms and for prevention of bleeding in low-risk patients, potential harms may outweigh the benefits. A large number of patients are taking PPIs for no clear reason—often remote symptoms of dyspepsia or “heartburn” that have since resolved. In these patients, PPIs should be stopped to determine if symptomatic treatment is needed. Back to top Article Information Corresponding Author: Adam Jacob Schoenfeld, MD, University of California, San Francisco, 3333 California St, Ste 265, PO Box 0936, San Francisco, CA 94118 (Adam.Schoenfeld@ucsf.edu). Published Online: January 11, 2016. doi:10.1001/jamainternmed.2015.7927. Conflict of Interest Disclosures: None reported. References 1. Grady D, Redberg RF. Less is more: how less health care can result in better health . Arch Intern Med. 2010;170(9):749-750.PubMedGoogle ScholarCrossref 2. Katz MH. Failing the acid test: benefits of proton pump inhibitors may not justify the risks for many users . Arch Intern Med. 2010;170(9):747-748.PubMedGoogle ScholarCrossref 3. Lazarus B, Yuan C, Wilson FP, et al. Proton pump inhibitor use and the risk of chronic kidney disease [published online January 11, 2016]. JAMA Intern Med. doi:10.1001/jamainternmed.2015.7193.Google Scholar 4. Antoniou T, Macdonald EM, Hollands S, et al. Proton pump inhibitors and the risk of acute kidney injury in older patients: a population-based cohort study . CMAJ Open. 2015;3(2):E166-E171.PubMedGoogle ScholarCrossref 5. Cheungpasitporn W, Thongprayoon C, Kittanamongkolchai W, et al. Proton pump inhibitors linked to hypomagnesemia: a systematic review and meta-analysis of observational studies . Ren Fail. 2015;37(7):1237-1241.PubMedGoogle ScholarCrossref 6. Kwok CS, Arthur AK, Anibueze CI, Singh S, Cavallazzi R, Loke YK. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis . Am J Gastroenterol. 2012;107(7):1011-1019.PubMedGoogle ScholarCrossref 7. Eom CS, Jeon CY, Lim JW, Cho EG, Park SM, Lee KS. Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis . CMAJ. 2011;183(3):310-319.PubMedGoogle ScholarCrossref 8. Filion KB, Chateau D, Targownik LE, et al; CNODES Investigators. Proton pump inhibitors and the risk of hospitalisation for community-acquired pneumonia: replicated cohort studies with meta-analysis . Gut. 2014;63(4):552-558.PubMedGoogle ScholarCrossref 9. Zhou B, Huang Y, Li H, Sun W, Liu J. Proton-pump inhibitors and risk of fractures: an update meta-analysis [published online October 13, 2015] . Osteoporos Int. doi:10.1007/s00198-015-3365-x.PubMedGoogle Scholar 10. Klepser DG, Collier DS, Cochran GL. Proton pump inhibitors and acute kidney injury: a nested case-control study . BMC Nephrol. 2013;14:150.PubMedGoogle ScholarCrossref 11. Proton Pump Inhibitors Information. 2015; http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm213259.htm. Accessed November 12, 2015. 12. Focks JJ, Brouwer MA, van Oijen MG, Lanas A, Bhatt DL, Verheugt FW. Concomitant use of clopidogrel and proton pump inhibitors: impact on platelet function and clinical outcome: a systematic review . Heart. 2013;99(8):520-527.PubMedGoogle ScholarCrossref 13. Melloni C, Washam JB, Jones WS, et al. Conflicting results between randomized trials and observational studies on the impact of proton pump inhibitors on cardiovascular events when coadministered with dual antiplatelet therapy: systematic review . Circ Cardiovasc Qual Outcomes. 2015;8(1):47-55.PubMedGoogle ScholarCrossref

Journal

JAMA Internal MedicineAmerican Medical Association

Published: Feb 1, 2016

Keywords: antiplatelet agents,kidney failure, chronic,clostridium difficile infections,fractures,gastroesophageal reflux disease,gastrointestinal bleeding,dyspepsia,hypomagnesemia,pneumonia,proton pump inhibitors,adverse effects of medication,cardiovascular event,adverse effects,inappropriate drug prescribing

References