Do recent reports about the adverse effects of proton pump inhibitors change providers’ prescription practice?

Do recent reports about the adverse effects of proton pump inhibitors change providers’... SUMMARY Proton pump inhibitors (PPI) are utilized for a variety of indications, including treatment of gastroesophageal reflux disease, peptic ulcer disease, and prevention of gastrointestinal (GI) bleeding. Several studies have documented an increasing prevalence of inappropriate PPI use. Furthermore, recent media reports have highlighted new research data suggesting a possible association between chronic PPI use and several adverse medical outcomes, leading to frequent patient inquiries about these associations. Thus, providers face the challenge of counseling patients about the balance of risks and benefits related to PPI use. We aimed to explore providers’ knowledge and attitudes toward reported adverse effects of PPI use and compare providers’ prescription practices. A comprehensive, non-incentivized electronic survey was sent to all providers (residents, fellows, advanced practice providers, and consultants across 8 internal medicine specialties) at our tertiary academic medical center. The survey contained 21 questions covering provider demographics and responses to challenging clinical scenarios dealing with PPI use. Chi-square was used to compare responses from providers. The survey was distributed to 254 providers, of which 94 (24 GI and 70 non-GI) completed the survey (37% response rate). Among those 94 providers, 48 were consultants, 17 were advanced practice providers, and 29 were trainees. Non-GI providers included cardiology, pulmonary, endocrinology, family medicine, general internal medicine, hematology/oncology, and nephrology. Over half of the providers (51 [54%]) described their practice as outpatient setting, 29 (31%) providers defined their practice as a mixed setting (inpatient and outpatient), while 14 (15%) designated it as inpatient only. Nineteen (80%) GI providers and 48 (69%) non-GI providers discussed the risks and benefits with patients (P = 0.64). Fifteen (63%) GI providers and 33 (47%) non-GI providers indicated that recent reports changed their practice (P = 0.49). More GI providers (5 [21%]) lowered the dose of PPI compared with non-GI (1[1%]) (P = 0.004); 18 (26%) of non-GI and 3 (13%) of GI providers discontinued PPI and substituted it with a histamine 2 (H2) blocker (P = 0.29). A larger but nonsignificant percentage of trainees (8 [28%]) switched PPI to H2 blockers compared with consultants (8 [17%]; P = 0.39). Six (25%) of GI providers and 14 (20%) of non-GI providers were concerned about Clostridium difficile infection (P = 0.58). Twenty-four (34%) of the non-GI were worried about kidney diseases compared with 3 (13%) of the GI providers (P = 0.1). Ten (21%) consultants were concerned about risk of osteoporosis compared with 3 (10%) trainees (P = 0.38), while 8 (28%) trainees were worried about the risk of C. difficile infection compared with 10 (21%) consultants (P = 0.69). Most providers (85 [90%]) agreed that educational activities would be helpful to address these challenges. More GI providers lowered the dose of PPI compared with non-GI; non-GI providers were more likely to discontinue PPI and substitute it with an H2 blocker. Educating patients and providers about potential adverse effects of PPI is imperative. INTRODUCTION Proton pump inhibitors (PPI) were first prescribed in the late 1980s, and have since become ubiquitous. They irreversibly block the gastric hydrogen potassium adenosinetriphosphatase ATPase (H+/K+ ATPase) and thus inhibit gastric acid secretion.1 PPI are indicated for the prevention and treatment of gastric acid-related conditions, including management of gastroesophageal reflux disease with or without erosive esophagitis,2 treatment, and prevention of peptic ulcer disease associated with the use of nonsteroidal anti-inflammatory drugs,3,4 eradication of Helicobacter pylori in combination with antibiotics, and pathologic hypersecretory conditions such as the Zollinger–Ellison syndrome.5,6 PPI are also used to treat Barrett esophagus to lower the risk of developing esophageal adenocarcinoma.7,8 Despite the accepted safety for these medications for many years, recent large retrospective studies have raised concerns regarding the potential for adverse events; these include interactions between PPI and clopidogrel9,10 that were later on disproved by additional studies.11,12 In late 2006, Yang et al.,13 published a case-control study using the general practice research database of around 150 000 patients that showed an increased adjusted odd ratio (1.44) of hip fracture with more than 1 year of PPI use, suggesting an association;13 other studies have also shown increased risk of fractures and osteoporosis.14,15 Intense acid suppression induced by PPI may be associated with mineral malabsorption, namely calcium, iron, and magnesium.16 However, other studies have not found an association between PPI use and osteoporosis or accelerated bone mineral density loss.17–19 Additional studies have suggested associations between long-term PPI usage and kidney disease, including allergic interstitial nephritis, acute kidney injury, and chronic kidney disease.20–22 An increased risk of infection has also been described in relation to long-term PPI use, including pneumonia, Clostridium difficile colitis, and small intestinal bacterial overgrowth.23–25 More recently, cohort studies suggested links between PPI use and dementia in an older population.26,27 However, other studies showed no association between PPI use and dementia or cognitive function28,29 and pneumonia.30 In addition, a recent study by Xie et al.31 looked at a national large-scale database, found a higher risk of death associated with PPI users compared with H2 blockers. However, their patient sample was mainly older, white male US veterans and cause of death was not mentioned; thus the findings could be attributed to confounders other than exposure to PPI. It is important to note that most of these observational studies have low odds ratios ranging from 0.33 to 3, which fall in the zone of potential bias.32 The widespread use of PPI and recent reporting of possible associated adverse events have led patients and providers to ask questions about the risk of prescribing and maintaining patients on PPI. Providers face challenges regarding appropriate use and safety of PPI. We aimed to explore providers’ knowledge and attitudes toward reported adverse associations of PPI use and their prescribing practices across different medical specialties (gastroenterology [GI] and non-GI). METHODS A comprehensive, non-incentivized, electronic cross-sectional survey using Survey Monkey® was prepared and sent via email to medical providers at a single, tertiary academic medical center in a metropolitan city (Appendix A). After the survey was sent, 2 consecutive reminders were sent. The surveys were conducted between May 30 and September 26 of 2016. The study was approved by the Mayo Clinic Institutional Review Board. The survey included 21 questions seeking providers’ titles, level of training and specialty, PPI prescribing practices, and clinical scenarios dealing with the use of PPI. The survey was sent to trainees (residents and fellows), advanced practice providers (nurse practitioners and physician assistants), and consultants across 8 specialties practicing in the inpatient and/or outpatient setting. GI providers included trainees, advance practice providers, and consultants from the GI division at our institution; non-GI providers included trainees, advance practice providers, and consultants across specialties other than GI. Residents and fellows were part of Accreditation Council for Graduate Medical Education accredited residency or fellowship programs. Consultants were providers who were board-certified in their specialties. Surveyed medical specialties included cardiology, endocrinology, family medicine, gastroenterology, general internal medicine, hematology and oncology, nephrology, and pulmonary medicine. Surveyed providers were questioned about the impact of the reported associations on their prescribing practices, specifically addressing whether they had changed their approach based on those reports (i.e. stopped PPI, changed the dose of PPI, or replaced PPI with other medications). They were also asked if their patients expressed concerns about the use of PPI. Finally, providers who did not prescribe PPI (but their patients were on PPI therapy) were asked if they contacted patients’ primary care provider to discuss concerns about PPI safety with their patients. The providers were also asked whether more education (grand rounds type of conferences) would be necessary to address these issues. Comparisons between different types of providers were performed and categorical data were compared using a 2-tailed Chi-square test. A P value <0.05 was considered significant. RESULTS The survey was sent to 254 providers, of which 94 completed it (37% response). Among the responders, 48 (51%) were consultants of different specialties, 17 (18%) were advanced practice providers, and 29 were trainees (18 [19%] residents and 11 [12%] fellows). Most (87 [93%]) routinely prescribed PPI and the remaining providers who did not routinely prescribe them said they contacted patients’ providers to address concerns about the safety of these drugs. Overall, 7 (10%) of non-GI providers referred patients to GI for further discussions regarding PPI safety. The survey was completed by 24 providers from the GI division (26% of the total respondents). Seventy providers were from non-GI departments; general internal medicine (29 [31%]), family medicine (14 [15%]), cardiology (12 [13%]), nephrology (6 [6%]), pulmonary (3 [3%]), endocrinology (3 [3%]), and hematology/oncology and nephrology (3 [3%]). Over half of the providers (51 [54%]) described their practice as outpatient setting, 29 (31%) providers defined their practice as a mixed setting (inpatient and outpatient) while 14 (15%) designated it as inpatient only. Overall, 68 (72%) providers stated that their patients asked unsolicited questions regarding the safety of PPI therapy. Most providers (85 [90.4%]) agreed that scholastic sessions and educational activities (e.g. grand rounds) would be useful to help address these challenges. GI versus non-GI GI providers were more likely than non-GI providers to report that their patients were concerned about osteoporosis and/or fractures (42% vs. 14%, P = 0.01) (Table 1). Of the GI providers, 33% mentioned that their patients were concerned about dementia compared with 26% of the non-GI providers’ patients (P = 0.65). On the other hand, more non-GI providers were worried about dementia compared with GI (21% vs. 3%, P = 0.01) (Table 2). Of the GI providers, 25% were concerned about C. difficile infection compared with 20% of the non-GI providers (P = 0.82). Table 1 Adverse effects of PPI concerning to patients as reported by 94 providers Adverse effects GI (n = 24) Non-GI (n = 70) P value Osteoporosis or fracture 10 (42) 10 (14) 0.01 Dementia 8 (33) 18 (26) 0.65 Kidney disease 2 (8) 17 (24) 0.17 Cardiovascular disease (heart attack or arrhythmias) 3 (13) 1 (1) 0.08 Clopidogrel interaction 0 5 (7) 0.41 Other 1 (4) 19 (28) 0.03 Adverse effects GI (n = 24) Non-GI (n = 70) P value Osteoporosis or fracture 10 (42) 10 (14) 0.01 Dementia 8 (33) 18 (26) 0.65 Kidney disease 2 (8) 17 (24) 0.17 Cardiovascular disease (heart attack or arrhythmias) 3 (13) 1 (1) 0.08 Clopidogrel interaction 0 5 (7) 0.41 Other 1 (4) 19 (28) 0.03 GI, gastroenterologists; non-GI, specialists not gastroenterologists; PPI, proton pump inhibitors. View Large Table 1 Adverse effects of PPI concerning to patients as reported by 94 providers Adverse effects GI (n = 24) Non-GI (n = 70) P value Osteoporosis or fracture 10 (42) 10 (14) 0.01 Dementia 8 (33) 18 (26) 0.65 Kidney disease 2 (8) 17 (24) 0.17 Cardiovascular disease (heart attack or arrhythmias) 3 (13) 1 (1) 0.08 Clopidogrel interaction 0 5 (7) 0.41 Other 1 (4) 19 (28) 0.03 Adverse effects GI (n = 24) Non-GI (n = 70) P value Osteoporosis or fracture 10 (42) 10 (14) 0.01 Dementia 8 (33) 18 (26) 0.65 Kidney disease 2 (8) 17 (24) 0.17 Cardiovascular disease (heart attack or arrhythmias) 3 (13) 1 (1) 0.08 Clopidogrel interaction 0 5 (7) 0.41 Other 1 (4) 19 (28) 0.03 GI, gastroenterologists; non-GI, specialists not gastroenterologists; PPI, proton pump inhibitors. View Large Table 2 Adverse effects of PPI concerning to 94 providers Adverse effect GI (n = 24) Non-GI (n = 70) P value Clostridium difficile infection 6 (25) 14 (20) 0.82 Osteoporosis or fracture 3 (12) 13 (19) 0.71 Dementia 5 (21) 2 (3) 0.01 Kidney disease 3 (12) 24 (34) 0.07 Electrolyte abnormalities 2 (9) 1 (1) 0.32 Other 5 (21) 16 (23) 0.83 Adverse effect GI (n = 24) Non-GI (n = 70) P value Clostridium difficile infection 6 (25) 14 (20) 0.82 Osteoporosis or fracture 3 (12) 13 (19) 0.71 Dementia 5 (21) 2 (3) 0.01 Kidney disease 3 (12) 24 (34) 0.07 Electrolyte abnormalities 2 (9) 1 (1) 0.32 Other 5 (21) 16 (23) 0.83 GI, gastroenterologists; non-GI, specialists not gastroenterologists; PPI, proton pump inhibitors. View Large Table 2 Adverse effects of PPI concerning to 94 providers Adverse effect GI (n = 24) Non-GI (n = 70) P value Clostridium difficile infection 6 (25) 14 (20) 0.82 Osteoporosis or fracture 3 (12) 13 (19) 0.71 Dementia 5 (21) 2 (3) 0.01 Kidney disease 3 (12) 24 (34) 0.07 Electrolyte abnormalities 2 (9) 1 (1) 0.32 Other 5 (21) 16 (23) 0.83 Adverse effect GI (n = 24) Non-GI (n = 70) P value Clostridium difficile infection 6 (25) 14 (20) 0.82 Osteoporosis or fracture 3 (12) 13 (19) 0.71 Dementia 5 (21) 2 (3) 0.01 Kidney disease 3 (12) 24 (34) 0.07 Electrolyte abnormalities 2 (9) 1 (1) 0.32 Other 5 (21) 16 (23) 0.83 GI, gastroenterologists; non-GI, specialists not gastroenterologists; PPI, proton pump inhibitors. View Large Nineteen (80%) of GI providers discussed the risk and benefits of long-term PPI therapy with their patients compared with 48 (69%) of the non-GI (P = 0.64). Among the surveyed providers, 15 (63%) of the GI and 33 (47%) of the non-GI providers acknowledged changing their prescribing practices because of recent reports regarding the potential conditions associated with the long-term use of PPI (P = 0.49). More GI providers lowered the dose of PPI compared with non-GI (5 [21%] vs. 1 [1%], P = 0.004); whereas 18 (26%) of non-GI providers discontinued PPI and substituted it with an H2 blocker compared with 3 (13%) of the GI (P = 0.29) (Fig. 1). No provider reported stopping PPI therapy without adding any other form of acid suppression. Fig. 1 View largeDownload slide Responses of GI versus non-GI providers facing challenges of PPI adverse effects. GI indicates gastroenterologist; H2, histamine; non-GI, specialists not gastroenterologists; PPI, proton pump inhibitor. Fig. 1 View largeDownload slide Responses of GI versus non-GI providers facing challenges of PPI adverse effects. GI indicates gastroenterologist; H2, histamine; non-GI, specialists not gastroenterologists; PPI, proton pump inhibitor. Consultants versus trainees Among surveyed providers, 8 (28%) of the trainees reported patients’ concern about kidney diseases (acute and chronic) compared with 8 (17%) of the consultants (P = 0.39), dementia (8 [27%] vs. 7 [14%], P = 0.28), fractures and osteoporosis (6 [21%] vs. 5 [10%], P = 0.38) and C. difficile infection (6 [21%] vs. 13 [28%], P = 0.69) (Fig. 2). Fig. 2 View largeDownload slide Comparison of consultants versus trainees reporting PPI adverse effects. Fig. 2 View largeDownload slide Comparison of consultants versus trainees reporting PPI adverse effects. A greater percentage of trainees than consultants discussed risks and benefits with their patients (27 [92%] vs. 30 [63%], P = 0.01). Thirteen (45%) trainees and 27 (56%) of consultants acknowledged that recent reports changed their practice (P = 0.46). Eight (28%) of trainees switched PPI to H2 blockers compared with 8 (17%) of the consultants (P = 0.39). None stopped PPI therapy without adding any other form of acid suppression (Fig. 3). Fig. 3 View largeDownload slide Responses of consultants versus trainees facing challenges of PPI adverse effects. Fig. 3 View largeDownload slide Responses of consultants versus trainees facing challenges of PPI adverse effects. Clinical vignettes When asked about using PPI for patients with coronary artery disease who require clopidogrel, a higher percentage of GI than non-GI providers chose to continue omeprazole (14 [58%] vs. 31 [44%], P = 0.48). Seventy-eight (83%) of all surveyed providers combined continued PPI in patients with reflux esophagitis with peptic stricture and history of polycystic kidney disease. Most surveyed providers (85 [90%]) agreed that scholastic sessions and educational activities (e.g. Grand Rounds) would be useful to help address these challenges. DISCUSSION In this survey, we found that in response to the recent concerns regarding adverse effects of long-term PPI therapy, there are differences in PPI prescribing practices among physicians with different specialties and levels of training, working in the same institution. We observed that more GI providers lowered the dose of PPI compared with non-GI (P = 0.004); whereas non GI-providers discontinued PPI and substituted it with an H2 blocker at a higher, though not statistically significant, frequency compared with GI providers (P = 0.29) (Fig. 1). More trainees than consultants discussed risks and benefits with their patients (P = 0.01). Some trainees and slightly more than half of consultants acknowledged that recent reports changed their practice (P = 0.46). Numerically, more trainees (28%) than consultants (17%) switched PPI to H2 blockers, however this difference did not reach statistical significance (P = 0.39). No provider reported stopping PPI therapy without adding any other form of acid suppression. PPI are widely prescribed by GI and other specialty providers. Omeprazole was the first PPI launched in the United States in 1990, after which lansoprazole, rabeprazole, pantoprazole, esomeprazole, and dexlansoprazole were approved. The use of PPI represents an important cost burden to health care systems. For example, in 2008, esomeprazole alone was ranked in seventh place among the top most dispensed medications in the US market, with an associated cost of over $5.8 billion. By 2014, the same medication was the third most commonly sold medication generating over $6.3 billion.33 In the context of appropriate prescription of PPI, problems arise with both overprescribing these medications when they may not be necessary (outside of guideline recommendations or well-established indications), but also under prescribing when these medications are clearly needed. Recent studies have found that that 35% to 73% of prescribed PPI were not based on guidelines for proper indications and duration of therapy.34–36 Not only is important to keep in mind the possible long-term use indications but more importantly from the beginning, prescribe them for the right reasons. It has been shown that when the patterns of prescribing PPI in the ambulatory practice setting were studied, over one-third of the prescribed PPI had no documented appropriate indication for therapy and around half of the studied cohort did not have documented re-evaluation for possible step-down therapy, thus accounting for 1034 patient-years of PPI use and improperly increasing the cost of care.37 Due to the study design (cross-sectional online survey), few limitations should be considered. Surveys with closed-ended questions may have a lower validity rate than other question types. Also, in some circumstances, the respondents might not have felt comfortable when answering some questions, as those answers (even though they were anonymous) might make them feel discouraged to provide precise, honest answers. Despite the fact that our survey has a good response rate of about 37% (generally internal surveys to organizations receive 35% ± 20% response rates),38,39 data errors due to question nonresponses may exist. For providers who did not answer the survey, their responses might be quite different than those who responded, thus creating bias. The majority of the respondents in our survey agreed that scholastic sessions and educational activities are necessary and would be helpful to inform the providers about updated guidelines for the use of PPI. In the future, and as suggested by our surveyed providers, periodic scholastic activities and educational sessions like grand rounds would be useful to update providers regarding reports and studies associated with adverse events related to PPI. In conclusion, our survey results show that the negative reports related to PPI use have raised concerns not only among prescribing providers but also patients, and they have influenced the prescribing practices in our tertiary care academic medical practice. It should be emphasized that educational activities are necessary to ensure PPI are used appropriately. Acknowledgments, funding, and disclosures Conflict of interest/study support: Guarantor of the article: Francisco C. Ramirez Financial support: None. Potential competing interests: None. SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article at the publisher's website: Appendix A.pdf. Notes Specific author contributions: All authors actively participated in the study, contributed to writing the manuscript, and approved the final draft submitted. Francisco C. Ramirez, Marcelo F. Vela, Mohanad Al-Qaisi, and Allon Kahn were responsible for survey design, data collection, data analysis, and manuscript preparation. Francisco C. Ramirez, Marcelo F. Vela, Mohanad Al-Qaisi, Allon Kahn, Michael D. Crowell, and George E. Burdick actively participated in critical writing and reviewing the manuscript. References 1 Wolfe M M , Soll A H . The physiology of gastric acid secretion . N Engl J Med 1988 ; 319 : 1707 – 15 . Google Scholar CrossRef Search ADS PubMed 2 Vigneri S , Termini R , Leandro G et al. A comparison of five maintenance therapies for reflux esophagitis . N Engl J Med 1995 ; 333 : 1106 – 10 . Google Scholar CrossRef Search ADS PubMed 3 Hawkey C J , Karrasch J A , Szczepañski L et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs . N Engl J Med 1998 ; 338 : 727 – 34 . Google Scholar CrossRef Search ADS PubMed 4 Scheiman J M , Yeomans N D , Talley N J et al. Prevention of ulcers by esomeprazole in at-risk patients using non-selective NSAIDs and COX-2 inhibitors . Am J Gastroenterol 2006 ; 101 : 701 – 10 . Google Scholar CrossRef Search ADS PubMed 5 Jensen R T , Fraker D L . Zollinger-Ellison Syndrome. Advances in treatment of gastric hypersecretion and the gastrinoma . JAMA 1994 ; 271 : 1429 – 35 . Google Scholar CrossRef Search ADS PubMed 6 Hirschowitz B I , Simmons J , Mohnen J . Clinical outcome using lansoprazole in acid hypersecretors with and without Zollinger-Ellison syndrome: a 13-year prospective study . Clin Gastroenterol Hepatol 2005 ; 3 : 39 – 48 . Google Scholar CrossRef Search ADS PubMed 7 Sarr M G , Hamilton S R , Marrone G C et al. Barrett's esophagus: Its prevalence and association with adenocarcinoma in patients with symptoms of gastroesophageal reflux . Am J Surg 1985 ; 149 : 187 – 93 . Google Scholar CrossRef Search ADS PubMed 8 Rex D K , Cummings O W , Shaw M et al. Screening for Barrett's esophagus in colonoscopy patients with and without heartburn . Gastroenterology 2003 ; 125 : 1670 – 7 . Google Scholar CrossRef Search ADS PubMed 9 Juurlink D N , Gomes T , Ko D T et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel . Can Med Assoc J 2009 ; 180 : 713 – 8 . Google Scholar CrossRef Search ADS 10 Ho P M , Maddox T M , Wang L et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome . JAMA 2009 ; 301 : 937 – 44 . Google Scholar CrossRef Search ADS PubMed 11 O’Donoghue M L , Braunwald E , Antman E M et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials . Lancet North Am Ed 2009 ; 374 : 989 – 97 . Google Scholar CrossRef Search ADS 12 Abraham N S , Hlatky M A , Antman E M et al. ACCF/ACG/ AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. A Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents . J Am Coll Cardiol 2010 ; 56 : 2051 – 66 . Google Scholar CrossRef Search ADS PubMed 13 Yang Y X , Lewis J D , Epstein S et al. Long-term proton pump inhibitor therapy and risk of hip fracture . JAMA 2006 ; 296 : 2947 – 53 . Google Scholar CrossRef Search ADS PubMed 14 Targownik L E , Lix L M , Metge C J et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures . Can Med Assoc J 2008 ; 179 : 319 – 26 . Google Scholar CrossRef Search ADS 15 Munson J C , Bynum J P , Bell J E et al. Patterns of prescription drug use before and after fragility fracture . JAMA Intern Med 2016 ; 176 : 1531 – 8 . Google Scholar CrossRef Search ADS PubMed 16 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 : 1237 – 41 . Google Scholar CrossRef Search ADS PubMed 17 Targownik L E , Goertzen A L , Luo Y et al. Long-term proton pump inhibitor use is not associated with changes in bone strength and structure . Am J Gastroenterol 2017 ; 112 : 95 – 101 . Google Scholar CrossRef Search ADS PubMed 18 Targownik L E , Lix L M , Leung S et al. Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss . Gastroenterology 2010 ; 138 : 896 – 904 . Google Scholar CrossRef Search ADS PubMed 19 Targownik L E , Leslie W D , Davison K S et al. The relationship between proton pump inhibitor use and longitudinal change in bone mineral density: a population-based study [corrected] from the Canadian Multicentre Osteoporosis Study (CaMos) . Am J Gastroenterol 2012 ; 107 : 1361 – 9 . Google Scholar CrossRef Search ADS PubMed 20 Antoniou T , Macdonald E M , 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 : E166 – 71 . Google Scholar CrossRef Search ADS PubMed 21 Lazarus B , Chen Y , Wilson F P et al. PRoton pump inhibitor use and the risk of chronic kidney disease . JAMA Intern Med 2016 ; 176 : 238 – 46 . Google Scholar CrossRef Search ADS PubMed 22 Yildirim T , Yilmaz R , Baydar D E et al. Lansoprazole-induced acute allergic interstitial nephritis in a renal transplant recipient: a case report . Int Urol Nephrol 2012 ; 44 : 1903 – 6 . Google Scholar CrossRef Search ADS PubMed 23 de Jager C P , Wever P C , Gemen E F et al. Proton pump inhibitor therapy predisposes to community-acquired Streptococcus pneumoniae pneumonia . Aliment Pharmacol Ther 2012 ; 36 : 941 – 9 . Google Scholar CrossRef Search ADS PubMed 24 Kwok C S , Arthur A K , Anibueze C I et al. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis . Am J Gastroenterol 2012 ; 107 : 1011 – 9 . Google Scholar CrossRef Search ADS PubMed 25 Dial S , Delaney J A , Barkun A N et al. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease . JAMA 2005 ; 294 : 2989 – 95 . Google Scholar CrossRef Search ADS PubMed 26 Gomm W , von Holt K , Thome F et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis . JAMA Neurol 2016 ; 73 : 410 – 6 . Google Scholar CrossRef Search ADS PubMed 27 Kuller L H . Do proton pump inhibitors increase the risk of dementia? JAMA Neurol 2016 ; 73 : 379 – 81 . Google Scholar CrossRef Search ADS PubMed 28 Goldstein F C , Steenland K , Zhao L et al. Proton pump inhibitors and risk of mild cognitive impairment and dementia . J Am Geriatr Soc 2017 ; 65 : 1969 – 74 . Google Scholar CrossRef Search ADS PubMed 29 Lochhead P , Hagan K , Joshi A D et al. Association between proton pump inhibitor use and cognitive function in women . Gastroenterology 2017 ; 153 : 971 – 979.e4 . Google Scholar CrossRef Search ADS PubMed 30 Dublin S , Walker R L , Jackson M L et al. Use of proton pump inhibitors and H2 blockers and risk of pneumonia in older adults: a population-based case-control study . Pharmacoepidem Drug Safe 2010 ; 19 : 792 – 802 . Google Scholar CrossRef Search ADS 31 Xie Y , Bowe B , Li T et al. Risk of death among users of proton pump inhibitors: a longitudinal observational cohort study of United States veterans . BMJ Open 2017 ; 7 : e015735 . Google Scholar CrossRef Search ADS PubMed 32 Grimes D A , Schulz K F . False alarms and pseudo-epidemics: the limitations of observational epidemiology . Obstet Gynecol 2012 ; 120 : 920 – 7 . Google Scholar CrossRef Search ADS PubMed 33 http://www.medscape.com/viewarticle/829246#vp_1 . July 2017. 34 Haroon M , Yasin F , Gardezi S K et al. Inappropriate use of proton pump inhibitors among medical inpatients: a questionnaire-based observational study . JRSM Short Rep 2013 ; 4 : 2042533313497183 . Google Scholar CrossRef Search ADS PubMed 35 Reid M , Keniston A , Heller J C et al. Inappropriate prescribing of proton pump inhibitors in hospitalized patients . J Hosp Med 2012 ; 7 : 421 – 5 . Google Scholar CrossRef Search ADS PubMed 36 Jarchow-Macdonald A A , Mangoni A A . Prescribing patterns of proton pump inhibitors in older hospitalized patients in a Scottish health board . Geriatr Gerontol Int 2013 ; 13 : 1002 – 9 . Google Scholar CrossRef Search ADS PubMed 37 Heidelbaugh J J , Goldberg K L , Inadomi J M . Magnitude and economic effect of overuse of antisecretory therapy in the ambulatory care setting . Am J Manag Care 2010 ; 16 : e228 – 34 . Google Scholar PubMed 38 Baruch Y . Response rate in academic studies-a comparative analysis . Human Relations 1999 ; 52 : 421 – 38 . 39 Baruch Y , Holtom B C . Survey response rate levels and trends in organizational research . Human Relations 2008 ; 61 : 1139 – 60 . Google Scholar CrossRef Search ADS © The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diseases of the Esophagus Oxford University Press

Do recent reports about the adverse effects of proton pump inhibitors change providers’ prescription practice?

Loading next page...
 
/lp/ou_press/do-recent-reports-about-the-adverse-effects-of-proton-pump-inhibitors-Ex495Csf0f
Publisher
Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.
ISSN
1120-8694
eISSN
1442-2050
D.O.I.
10.1093/dote/doy042
Publisher site
See Article on Publisher Site

Abstract

SUMMARY Proton pump inhibitors (PPI) are utilized for a variety of indications, including treatment of gastroesophageal reflux disease, peptic ulcer disease, and prevention of gastrointestinal (GI) bleeding. Several studies have documented an increasing prevalence of inappropriate PPI use. Furthermore, recent media reports have highlighted new research data suggesting a possible association between chronic PPI use and several adverse medical outcomes, leading to frequent patient inquiries about these associations. Thus, providers face the challenge of counseling patients about the balance of risks and benefits related to PPI use. We aimed to explore providers’ knowledge and attitudes toward reported adverse effects of PPI use and compare providers’ prescription practices. A comprehensive, non-incentivized electronic survey was sent to all providers (residents, fellows, advanced practice providers, and consultants across 8 internal medicine specialties) at our tertiary academic medical center. The survey contained 21 questions covering provider demographics and responses to challenging clinical scenarios dealing with PPI use. Chi-square was used to compare responses from providers. The survey was distributed to 254 providers, of which 94 (24 GI and 70 non-GI) completed the survey (37% response rate). Among those 94 providers, 48 were consultants, 17 were advanced practice providers, and 29 were trainees. Non-GI providers included cardiology, pulmonary, endocrinology, family medicine, general internal medicine, hematology/oncology, and nephrology. Over half of the providers (51 [54%]) described their practice as outpatient setting, 29 (31%) providers defined their practice as a mixed setting (inpatient and outpatient), while 14 (15%) designated it as inpatient only. Nineteen (80%) GI providers and 48 (69%) non-GI providers discussed the risks and benefits with patients (P = 0.64). Fifteen (63%) GI providers and 33 (47%) non-GI providers indicated that recent reports changed their practice (P = 0.49). More GI providers (5 [21%]) lowered the dose of PPI compared with non-GI (1[1%]) (P = 0.004); 18 (26%) of non-GI and 3 (13%) of GI providers discontinued PPI and substituted it with a histamine 2 (H2) blocker (P = 0.29). A larger but nonsignificant percentage of trainees (8 [28%]) switched PPI to H2 blockers compared with consultants (8 [17%]; P = 0.39). Six (25%) of GI providers and 14 (20%) of non-GI providers were concerned about Clostridium difficile infection (P = 0.58). Twenty-four (34%) of the non-GI were worried about kidney diseases compared with 3 (13%) of the GI providers (P = 0.1). Ten (21%) consultants were concerned about risk of osteoporosis compared with 3 (10%) trainees (P = 0.38), while 8 (28%) trainees were worried about the risk of C. difficile infection compared with 10 (21%) consultants (P = 0.69). Most providers (85 [90%]) agreed that educational activities would be helpful to address these challenges. More GI providers lowered the dose of PPI compared with non-GI; non-GI providers were more likely to discontinue PPI and substitute it with an H2 blocker. Educating patients and providers about potential adverse effects of PPI is imperative. INTRODUCTION Proton pump inhibitors (PPI) were first prescribed in the late 1980s, and have since become ubiquitous. They irreversibly block the gastric hydrogen potassium adenosinetriphosphatase ATPase (H+/K+ ATPase) and thus inhibit gastric acid secretion.1 PPI are indicated for the prevention and treatment of gastric acid-related conditions, including management of gastroesophageal reflux disease with or without erosive esophagitis,2 treatment, and prevention of peptic ulcer disease associated with the use of nonsteroidal anti-inflammatory drugs,3,4 eradication of Helicobacter pylori in combination with antibiotics, and pathologic hypersecretory conditions such as the Zollinger–Ellison syndrome.5,6 PPI are also used to treat Barrett esophagus to lower the risk of developing esophageal adenocarcinoma.7,8 Despite the accepted safety for these medications for many years, recent large retrospective studies have raised concerns regarding the potential for adverse events; these include interactions between PPI and clopidogrel9,10 that were later on disproved by additional studies.11,12 In late 2006, Yang et al.,13 published a case-control study using the general practice research database of around 150 000 patients that showed an increased adjusted odd ratio (1.44) of hip fracture with more than 1 year of PPI use, suggesting an association;13 other studies have also shown increased risk of fractures and osteoporosis.14,15 Intense acid suppression induced by PPI may be associated with mineral malabsorption, namely calcium, iron, and magnesium.16 However, other studies have not found an association between PPI use and osteoporosis or accelerated bone mineral density loss.17–19 Additional studies have suggested associations between long-term PPI usage and kidney disease, including allergic interstitial nephritis, acute kidney injury, and chronic kidney disease.20–22 An increased risk of infection has also been described in relation to long-term PPI use, including pneumonia, Clostridium difficile colitis, and small intestinal bacterial overgrowth.23–25 More recently, cohort studies suggested links between PPI use and dementia in an older population.26,27 However, other studies showed no association between PPI use and dementia or cognitive function28,29 and pneumonia.30 In addition, a recent study by Xie et al.31 looked at a national large-scale database, found a higher risk of death associated with PPI users compared with H2 blockers. However, their patient sample was mainly older, white male US veterans and cause of death was not mentioned; thus the findings could be attributed to confounders other than exposure to PPI. It is important to note that most of these observational studies have low odds ratios ranging from 0.33 to 3, which fall in the zone of potential bias.32 The widespread use of PPI and recent reporting of possible associated adverse events have led patients and providers to ask questions about the risk of prescribing and maintaining patients on PPI. Providers face challenges regarding appropriate use and safety of PPI. We aimed to explore providers’ knowledge and attitudes toward reported adverse associations of PPI use and their prescribing practices across different medical specialties (gastroenterology [GI] and non-GI). METHODS A comprehensive, non-incentivized, electronic cross-sectional survey using Survey Monkey® was prepared and sent via email to medical providers at a single, tertiary academic medical center in a metropolitan city (Appendix A). After the survey was sent, 2 consecutive reminders were sent. The surveys were conducted between May 30 and September 26 of 2016. The study was approved by the Mayo Clinic Institutional Review Board. The survey included 21 questions seeking providers’ titles, level of training and specialty, PPI prescribing practices, and clinical scenarios dealing with the use of PPI. The survey was sent to trainees (residents and fellows), advanced practice providers (nurse practitioners and physician assistants), and consultants across 8 specialties practicing in the inpatient and/or outpatient setting. GI providers included trainees, advance practice providers, and consultants from the GI division at our institution; non-GI providers included trainees, advance practice providers, and consultants across specialties other than GI. Residents and fellows were part of Accreditation Council for Graduate Medical Education accredited residency or fellowship programs. Consultants were providers who were board-certified in their specialties. Surveyed medical specialties included cardiology, endocrinology, family medicine, gastroenterology, general internal medicine, hematology and oncology, nephrology, and pulmonary medicine. Surveyed providers were questioned about the impact of the reported associations on their prescribing practices, specifically addressing whether they had changed their approach based on those reports (i.e. stopped PPI, changed the dose of PPI, or replaced PPI with other medications). They were also asked if their patients expressed concerns about the use of PPI. Finally, providers who did not prescribe PPI (but their patients were on PPI therapy) were asked if they contacted patients’ primary care provider to discuss concerns about PPI safety with their patients. The providers were also asked whether more education (grand rounds type of conferences) would be necessary to address these issues. Comparisons between different types of providers were performed and categorical data were compared using a 2-tailed Chi-square test. A P value <0.05 was considered significant. RESULTS The survey was sent to 254 providers, of which 94 completed it (37% response). Among the responders, 48 (51%) were consultants of different specialties, 17 (18%) were advanced practice providers, and 29 were trainees (18 [19%] residents and 11 [12%] fellows). Most (87 [93%]) routinely prescribed PPI and the remaining providers who did not routinely prescribe them said they contacted patients’ providers to address concerns about the safety of these drugs. Overall, 7 (10%) of non-GI providers referred patients to GI for further discussions regarding PPI safety. The survey was completed by 24 providers from the GI division (26% of the total respondents). Seventy providers were from non-GI departments; general internal medicine (29 [31%]), family medicine (14 [15%]), cardiology (12 [13%]), nephrology (6 [6%]), pulmonary (3 [3%]), endocrinology (3 [3%]), and hematology/oncology and nephrology (3 [3%]). Over half of the providers (51 [54%]) described their practice as outpatient setting, 29 (31%) providers defined their practice as a mixed setting (inpatient and outpatient) while 14 (15%) designated it as inpatient only. Overall, 68 (72%) providers stated that their patients asked unsolicited questions regarding the safety of PPI therapy. Most providers (85 [90.4%]) agreed that scholastic sessions and educational activities (e.g. grand rounds) would be useful to help address these challenges. GI versus non-GI GI providers were more likely than non-GI providers to report that their patients were concerned about osteoporosis and/or fractures (42% vs. 14%, P = 0.01) (Table 1). Of the GI providers, 33% mentioned that their patients were concerned about dementia compared with 26% of the non-GI providers’ patients (P = 0.65). On the other hand, more non-GI providers were worried about dementia compared with GI (21% vs. 3%, P = 0.01) (Table 2). Of the GI providers, 25% were concerned about C. difficile infection compared with 20% of the non-GI providers (P = 0.82). Table 1 Adverse effects of PPI concerning to patients as reported by 94 providers Adverse effects GI (n = 24) Non-GI (n = 70) P value Osteoporosis or fracture 10 (42) 10 (14) 0.01 Dementia 8 (33) 18 (26) 0.65 Kidney disease 2 (8) 17 (24) 0.17 Cardiovascular disease (heart attack or arrhythmias) 3 (13) 1 (1) 0.08 Clopidogrel interaction 0 5 (7) 0.41 Other 1 (4) 19 (28) 0.03 Adverse effects GI (n = 24) Non-GI (n = 70) P value Osteoporosis or fracture 10 (42) 10 (14) 0.01 Dementia 8 (33) 18 (26) 0.65 Kidney disease 2 (8) 17 (24) 0.17 Cardiovascular disease (heart attack or arrhythmias) 3 (13) 1 (1) 0.08 Clopidogrel interaction 0 5 (7) 0.41 Other 1 (4) 19 (28) 0.03 GI, gastroenterologists; non-GI, specialists not gastroenterologists; PPI, proton pump inhibitors. View Large Table 1 Adverse effects of PPI concerning to patients as reported by 94 providers Adverse effects GI (n = 24) Non-GI (n = 70) P value Osteoporosis or fracture 10 (42) 10 (14) 0.01 Dementia 8 (33) 18 (26) 0.65 Kidney disease 2 (8) 17 (24) 0.17 Cardiovascular disease (heart attack or arrhythmias) 3 (13) 1 (1) 0.08 Clopidogrel interaction 0 5 (7) 0.41 Other 1 (4) 19 (28) 0.03 Adverse effects GI (n = 24) Non-GI (n = 70) P value Osteoporosis or fracture 10 (42) 10 (14) 0.01 Dementia 8 (33) 18 (26) 0.65 Kidney disease 2 (8) 17 (24) 0.17 Cardiovascular disease (heart attack or arrhythmias) 3 (13) 1 (1) 0.08 Clopidogrel interaction 0 5 (7) 0.41 Other 1 (4) 19 (28) 0.03 GI, gastroenterologists; non-GI, specialists not gastroenterologists; PPI, proton pump inhibitors. View Large Table 2 Adverse effects of PPI concerning to 94 providers Adverse effect GI (n = 24) Non-GI (n = 70) P value Clostridium difficile infection 6 (25) 14 (20) 0.82 Osteoporosis or fracture 3 (12) 13 (19) 0.71 Dementia 5 (21) 2 (3) 0.01 Kidney disease 3 (12) 24 (34) 0.07 Electrolyte abnormalities 2 (9) 1 (1) 0.32 Other 5 (21) 16 (23) 0.83 Adverse effect GI (n = 24) Non-GI (n = 70) P value Clostridium difficile infection 6 (25) 14 (20) 0.82 Osteoporosis or fracture 3 (12) 13 (19) 0.71 Dementia 5 (21) 2 (3) 0.01 Kidney disease 3 (12) 24 (34) 0.07 Electrolyte abnormalities 2 (9) 1 (1) 0.32 Other 5 (21) 16 (23) 0.83 GI, gastroenterologists; non-GI, specialists not gastroenterologists; PPI, proton pump inhibitors. View Large Table 2 Adverse effects of PPI concerning to 94 providers Adverse effect GI (n = 24) Non-GI (n = 70) P value Clostridium difficile infection 6 (25) 14 (20) 0.82 Osteoporosis or fracture 3 (12) 13 (19) 0.71 Dementia 5 (21) 2 (3) 0.01 Kidney disease 3 (12) 24 (34) 0.07 Electrolyte abnormalities 2 (9) 1 (1) 0.32 Other 5 (21) 16 (23) 0.83 Adverse effect GI (n = 24) Non-GI (n = 70) P value Clostridium difficile infection 6 (25) 14 (20) 0.82 Osteoporosis or fracture 3 (12) 13 (19) 0.71 Dementia 5 (21) 2 (3) 0.01 Kidney disease 3 (12) 24 (34) 0.07 Electrolyte abnormalities 2 (9) 1 (1) 0.32 Other 5 (21) 16 (23) 0.83 GI, gastroenterologists; non-GI, specialists not gastroenterologists; PPI, proton pump inhibitors. View Large Nineteen (80%) of GI providers discussed the risk and benefits of long-term PPI therapy with their patients compared with 48 (69%) of the non-GI (P = 0.64). Among the surveyed providers, 15 (63%) of the GI and 33 (47%) of the non-GI providers acknowledged changing their prescribing practices because of recent reports regarding the potential conditions associated with the long-term use of PPI (P = 0.49). More GI providers lowered the dose of PPI compared with non-GI (5 [21%] vs. 1 [1%], P = 0.004); whereas 18 (26%) of non-GI providers discontinued PPI and substituted it with an H2 blocker compared with 3 (13%) of the GI (P = 0.29) (Fig. 1). No provider reported stopping PPI therapy without adding any other form of acid suppression. Fig. 1 View largeDownload slide Responses of GI versus non-GI providers facing challenges of PPI adverse effects. GI indicates gastroenterologist; H2, histamine; non-GI, specialists not gastroenterologists; PPI, proton pump inhibitor. Fig. 1 View largeDownload slide Responses of GI versus non-GI providers facing challenges of PPI adverse effects. GI indicates gastroenterologist; H2, histamine; non-GI, specialists not gastroenterologists; PPI, proton pump inhibitor. Consultants versus trainees Among surveyed providers, 8 (28%) of the trainees reported patients’ concern about kidney diseases (acute and chronic) compared with 8 (17%) of the consultants (P = 0.39), dementia (8 [27%] vs. 7 [14%], P = 0.28), fractures and osteoporosis (6 [21%] vs. 5 [10%], P = 0.38) and C. difficile infection (6 [21%] vs. 13 [28%], P = 0.69) (Fig. 2). Fig. 2 View largeDownload slide Comparison of consultants versus trainees reporting PPI adverse effects. Fig. 2 View largeDownload slide Comparison of consultants versus trainees reporting PPI adverse effects. A greater percentage of trainees than consultants discussed risks and benefits with their patients (27 [92%] vs. 30 [63%], P = 0.01). Thirteen (45%) trainees and 27 (56%) of consultants acknowledged that recent reports changed their practice (P = 0.46). Eight (28%) of trainees switched PPI to H2 blockers compared with 8 (17%) of the consultants (P = 0.39). None stopped PPI therapy without adding any other form of acid suppression (Fig. 3). Fig. 3 View largeDownload slide Responses of consultants versus trainees facing challenges of PPI adverse effects. Fig. 3 View largeDownload slide Responses of consultants versus trainees facing challenges of PPI adverse effects. Clinical vignettes When asked about using PPI for patients with coronary artery disease who require clopidogrel, a higher percentage of GI than non-GI providers chose to continue omeprazole (14 [58%] vs. 31 [44%], P = 0.48). Seventy-eight (83%) of all surveyed providers combined continued PPI in patients with reflux esophagitis with peptic stricture and history of polycystic kidney disease. Most surveyed providers (85 [90%]) agreed that scholastic sessions and educational activities (e.g. Grand Rounds) would be useful to help address these challenges. DISCUSSION In this survey, we found that in response to the recent concerns regarding adverse effects of long-term PPI therapy, there are differences in PPI prescribing practices among physicians with different specialties and levels of training, working in the same institution. We observed that more GI providers lowered the dose of PPI compared with non-GI (P = 0.004); whereas non GI-providers discontinued PPI and substituted it with an H2 blocker at a higher, though not statistically significant, frequency compared with GI providers (P = 0.29) (Fig. 1). More trainees than consultants discussed risks and benefits with their patients (P = 0.01). Some trainees and slightly more than half of consultants acknowledged that recent reports changed their practice (P = 0.46). Numerically, more trainees (28%) than consultants (17%) switched PPI to H2 blockers, however this difference did not reach statistical significance (P = 0.39). No provider reported stopping PPI therapy without adding any other form of acid suppression. PPI are widely prescribed by GI and other specialty providers. Omeprazole was the first PPI launched in the United States in 1990, after which lansoprazole, rabeprazole, pantoprazole, esomeprazole, and dexlansoprazole were approved. The use of PPI represents an important cost burden to health care systems. For example, in 2008, esomeprazole alone was ranked in seventh place among the top most dispensed medications in the US market, with an associated cost of over $5.8 billion. By 2014, the same medication was the third most commonly sold medication generating over $6.3 billion.33 In the context of appropriate prescription of PPI, problems arise with both overprescribing these medications when they may not be necessary (outside of guideline recommendations or well-established indications), but also under prescribing when these medications are clearly needed. Recent studies have found that that 35% to 73% of prescribed PPI were not based on guidelines for proper indications and duration of therapy.34–36 Not only is important to keep in mind the possible long-term use indications but more importantly from the beginning, prescribe them for the right reasons. It has been shown that when the patterns of prescribing PPI in the ambulatory practice setting were studied, over one-third of the prescribed PPI had no documented appropriate indication for therapy and around half of the studied cohort did not have documented re-evaluation for possible step-down therapy, thus accounting for 1034 patient-years of PPI use and improperly increasing the cost of care.37 Due to the study design (cross-sectional online survey), few limitations should be considered. Surveys with closed-ended questions may have a lower validity rate than other question types. Also, in some circumstances, the respondents might not have felt comfortable when answering some questions, as those answers (even though they were anonymous) might make them feel discouraged to provide precise, honest answers. Despite the fact that our survey has a good response rate of about 37% (generally internal surveys to organizations receive 35% ± 20% response rates),38,39 data errors due to question nonresponses may exist. For providers who did not answer the survey, their responses might be quite different than those who responded, thus creating bias. The majority of the respondents in our survey agreed that scholastic sessions and educational activities are necessary and would be helpful to inform the providers about updated guidelines for the use of PPI. In the future, and as suggested by our surveyed providers, periodic scholastic activities and educational sessions like grand rounds would be useful to update providers regarding reports and studies associated with adverse events related to PPI. In conclusion, our survey results show that the negative reports related to PPI use have raised concerns not only among prescribing providers but also patients, and they have influenced the prescribing practices in our tertiary care academic medical practice. It should be emphasized that educational activities are necessary to ensure PPI are used appropriately. Acknowledgments, funding, and disclosures Conflict of interest/study support: Guarantor of the article: Francisco C. Ramirez Financial support: None. Potential competing interests: None. SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article at the publisher's website: Appendix A.pdf. Notes Specific author contributions: All authors actively participated in the study, contributed to writing the manuscript, and approved the final draft submitted. Francisco C. Ramirez, Marcelo F. Vela, Mohanad Al-Qaisi, and Allon Kahn were responsible for survey design, data collection, data analysis, and manuscript preparation. Francisco C. Ramirez, Marcelo F. Vela, Mohanad Al-Qaisi, Allon Kahn, Michael D. Crowell, and George E. Burdick actively participated in critical writing and reviewing the manuscript. References 1 Wolfe M M , Soll A H . The physiology of gastric acid secretion . N Engl J Med 1988 ; 319 : 1707 – 15 . Google Scholar CrossRef Search ADS PubMed 2 Vigneri S , Termini R , Leandro G et al. A comparison of five maintenance therapies for reflux esophagitis . N Engl J Med 1995 ; 333 : 1106 – 10 . Google Scholar CrossRef Search ADS PubMed 3 Hawkey C J , Karrasch J A , Szczepañski L et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs . N Engl J Med 1998 ; 338 : 727 – 34 . Google Scholar CrossRef Search ADS PubMed 4 Scheiman J M , Yeomans N D , Talley N J et al. Prevention of ulcers by esomeprazole in at-risk patients using non-selective NSAIDs and COX-2 inhibitors . Am J Gastroenterol 2006 ; 101 : 701 – 10 . Google Scholar CrossRef Search ADS PubMed 5 Jensen R T , Fraker D L . Zollinger-Ellison Syndrome. Advances in treatment of gastric hypersecretion and the gastrinoma . JAMA 1994 ; 271 : 1429 – 35 . Google Scholar CrossRef Search ADS PubMed 6 Hirschowitz B I , Simmons J , Mohnen J . Clinical outcome using lansoprazole in acid hypersecretors with and without Zollinger-Ellison syndrome: a 13-year prospective study . Clin Gastroenterol Hepatol 2005 ; 3 : 39 – 48 . Google Scholar CrossRef Search ADS PubMed 7 Sarr M G , Hamilton S R , Marrone G C et al. Barrett's esophagus: Its prevalence and association with adenocarcinoma in patients with symptoms of gastroesophageal reflux . Am J Surg 1985 ; 149 : 187 – 93 . Google Scholar CrossRef Search ADS PubMed 8 Rex D K , Cummings O W , Shaw M et al. Screening for Barrett's esophagus in colonoscopy patients with and without heartburn . Gastroenterology 2003 ; 125 : 1670 – 7 . Google Scholar CrossRef Search ADS PubMed 9 Juurlink D N , Gomes T , Ko D T et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel . Can Med Assoc J 2009 ; 180 : 713 – 8 . Google Scholar CrossRef Search ADS 10 Ho P M , Maddox T M , Wang L et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome . JAMA 2009 ; 301 : 937 – 44 . Google Scholar CrossRef Search ADS PubMed 11 O’Donoghue M L , Braunwald E , Antman E M et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials . Lancet North Am Ed 2009 ; 374 : 989 – 97 . Google Scholar CrossRef Search ADS 12 Abraham N S , Hlatky M A , Antman E M et al. ACCF/ACG/ AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. A Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents . J Am Coll Cardiol 2010 ; 56 : 2051 – 66 . Google Scholar CrossRef Search ADS PubMed 13 Yang Y X , Lewis J D , Epstein S et al. Long-term proton pump inhibitor therapy and risk of hip fracture . JAMA 2006 ; 296 : 2947 – 53 . Google Scholar CrossRef Search ADS PubMed 14 Targownik L E , Lix L M , Metge C J et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures . Can Med Assoc J 2008 ; 179 : 319 – 26 . Google Scholar CrossRef Search ADS 15 Munson J C , Bynum J P , Bell J E et al. Patterns of prescription drug use before and after fragility fracture . JAMA Intern Med 2016 ; 176 : 1531 – 8 . Google Scholar CrossRef Search ADS PubMed 16 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 : 1237 – 41 . Google Scholar CrossRef Search ADS PubMed 17 Targownik L E , Goertzen A L , Luo Y et al. Long-term proton pump inhibitor use is not associated with changes in bone strength and structure . Am J Gastroenterol 2017 ; 112 : 95 – 101 . Google Scholar CrossRef Search ADS PubMed 18 Targownik L E , Lix L M , Leung S et al. Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss . Gastroenterology 2010 ; 138 : 896 – 904 . Google Scholar CrossRef Search ADS PubMed 19 Targownik L E , Leslie W D , Davison K S et al. The relationship between proton pump inhibitor use and longitudinal change in bone mineral density: a population-based study [corrected] from the Canadian Multicentre Osteoporosis Study (CaMos) . Am J Gastroenterol 2012 ; 107 : 1361 – 9 . Google Scholar CrossRef Search ADS PubMed 20 Antoniou T , Macdonald E M , 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 : E166 – 71 . Google Scholar CrossRef Search ADS PubMed 21 Lazarus B , Chen Y , Wilson F P et al. PRoton pump inhibitor use and the risk of chronic kidney disease . JAMA Intern Med 2016 ; 176 : 238 – 46 . Google Scholar CrossRef Search ADS PubMed 22 Yildirim T , Yilmaz R , Baydar D E et al. Lansoprazole-induced acute allergic interstitial nephritis in a renal transplant recipient: a case report . Int Urol Nephrol 2012 ; 44 : 1903 – 6 . Google Scholar CrossRef Search ADS PubMed 23 de Jager C P , Wever P C , Gemen E F et al. Proton pump inhibitor therapy predisposes to community-acquired Streptococcus pneumoniae pneumonia . Aliment Pharmacol Ther 2012 ; 36 : 941 – 9 . Google Scholar CrossRef Search ADS PubMed 24 Kwok C S , Arthur A K , Anibueze C I et al. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis . Am J Gastroenterol 2012 ; 107 : 1011 – 9 . Google Scholar CrossRef Search ADS PubMed 25 Dial S , Delaney J A , Barkun A N et al. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease . JAMA 2005 ; 294 : 2989 – 95 . Google Scholar CrossRef Search ADS PubMed 26 Gomm W , von Holt K , Thome F et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis . JAMA Neurol 2016 ; 73 : 410 – 6 . Google Scholar CrossRef Search ADS PubMed 27 Kuller L H . Do proton pump inhibitors increase the risk of dementia? JAMA Neurol 2016 ; 73 : 379 – 81 . Google Scholar CrossRef Search ADS PubMed 28 Goldstein F C , Steenland K , Zhao L et al. Proton pump inhibitors and risk of mild cognitive impairment and dementia . J Am Geriatr Soc 2017 ; 65 : 1969 – 74 . Google Scholar CrossRef Search ADS PubMed 29 Lochhead P , Hagan K , Joshi A D et al. Association between proton pump inhibitor use and cognitive function in women . Gastroenterology 2017 ; 153 : 971 – 979.e4 . Google Scholar CrossRef Search ADS PubMed 30 Dublin S , Walker R L , Jackson M L et al. Use of proton pump inhibitors and H2 blockers and risk of pneumonia in older adults: a population-based case-control study . Pharmacoepidem Drug Safe 2010 ; 19 : 792 – 802 . Google Scholar CrossRef Search ADS 31 Xie Y , Bowe B , Li T et al. Risk of death among users of proton pump inhibitors: a longitudinal observational cohort study of United States veterans . BMJ Open 2017 ; 7 : e015735 . Google Scholar CrossRef Search ADS PubMed 32 Grimes D A , Schulz K F . False alarms and pseudo-epidemics: the limitations of observational epidemiology . Obstet Gynecol 2012 ; 120 : 920 – 7 . Google Scholar CrossRef Search ADS PubMed 33 http://www.medscape.com/viewarticle/829246#vp_1 . July 2017. 34 Haroon M , Yasin F , Gardezi S K et al. Inappropriate use of proton pump inhibitors among medical inpatients: a questionnaire-based observational study . JRSM Short Rep 2013 ; 4 : 2042533313497183 . Google Scholar CrossRef Search ADS PubMed 35 Reid M , Keniston A , Heller J C et al. Inappropriate prescribing of proton pump inhibitors in hospitalized patients . J Hosp Med 2012 ; 7 : 421 – 5 . Google Scholar CrossRef Search ADS PubMed 36 Jarchow-Macdonald A A , Mangoni A A . Prescribing patterns of proton pump inhibitors in older hospitalized patients in a Scottish health board . Geriatr Gerontol Int 2013 ; 13 : 1002 – 9 . Google Scholar CrossRef Search ADS PubMed 37 Heidelbaugh J J , Goldberg K L , Inadomi J M . Magnitude and economic effect of overuse of antisecretory therapy in the ambulatory care setting . Am J Manag Care 2010 ; 16 : e228 – 34 . Google Scholar PubMed 38 Baruch Y . Response rate in academic studies-a comparative analysis . Human Relations 1999 ; 52 : 421 – 38 . 39 Baruch Y , Holtom B C . Survey response rate levels and trends in organizational research . Human Relations 2008 ; 61 : 1139 – 60 . Google Scholar CrossRef Search ADS © The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Diseases of the EsophagusOxford University Press

Published: Jun 4, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off