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Acid Suppression and Antibiotics Administered During Infancy Are Associated with Celiac Disease

Author/s: 
Boechler, M., Susi, A., Hisle-Gorman, E., Rogers, P. L., Nylund, C. M.

Objective
To investigate why certain at-risk individuals develop celiac disease, we examined the association of proton pump inhibitors (PPI), histamine-2 receptor antagonist (H2RA), and antibiotic prescriptions in the first six months of life with an early childhood diagnosis of celiac disease.
Study design
A retrospective cohort study was performed using the Military Healthcare System (MHS) database. Children with a birth record from October 1, 2001- September 30, 2013, were identified. Outpatient prescription records were queried for antibiotic, PPI, and H2RA prescriptions in the first 6 months of life. Cox proportional hazards regression was used to calculate the hazard ratio (HR) of developing CD based on medication exposure. ICD-9 codes identified children with an outpatient visit for celiac disease.
Results
968,524 children met inclusion criteria with 1,704 cases of celiac in this group. Median follow up for the cohort was about 4.5 years. PPI’s (HR, 2.23; 95% CI, 1.76-2.83), H2RA’s (HR, 1.94 95% CI, 1.67-2.26) and antibiotics (HR 1.14 95%CI 1.02-1.28) were all associated with an increased hazard of celiac disease.
Conclusion
There is an increased risk of developing celiac disease if antibiotics, PPI’s and H2RA’s are prescribed in the first 6 months of life. Our study highlights modifiable factors such as medication stewardship that may change the childhood risk of CD.

Keywords 
Infancy Retrospective Studies children prescriptions celiac disease

Association Between Acute Gastroenteritis and Continuous Use of Proton Pump Inhibitors During Winter Periods of Highest Circulation of Enteric Viruses

Author/s: 
Vilcu, AM, Sabatte, L, Blanchon, T, Souty, C, Maravic, M, Lemaitre, M, Steichen, O, Hanslik, T

IMPORTANCE:

An increased risk of acute bacterial enteric infections has been reported among patients receiving proton pump inhibitor (PPI) therapy. The risk of acute gastroenteritis (AGE) of viral origin associated with continuous PPI exposure has been less studied.

OBJECTIVE:

To investigate the association between continuous PPI therapy and AGE occurrence during winter epidemic periods when the circulation of enteric viruses is the highest.

DESIGN, SETTING, AND PARTICIPANTS:

A matched cohort study was performed using a prospectively collected drug dispensing database from a large panel of community pharmacies in continental France. All patients recorded in the database during the 2015 to 2016 winter season, with documented age, sex, and use of an identifiable regular panel pharmacy, were eligible for the study. Each patient exposed to continuous PPI therapy was matched to 3 unexposed patients, according to year of birth, sex, and identifiable regular panel pharmacy. Analyses were performed between January 2017 and December 2018.

EXPOSURE:

Continuous PPI use during the 2015 to 2016 AGE winter epidemic.

MAIN OUTCOMES AND MEASURES:

The occurrence of at least 1 AGE episode during the 2015 to 2016 AGE winter epidemic was the main outcome. Episodes of AGE were identified using a previously validated algorithm based on drug dispensing data. Relative risks of AGE were estimated using a multivariable log-binomial model adjusted for age, sex, and treatments for chronic conditions.

RESULTS:

There were 233 596 patients receiving PPI therapy (median [interquartile range] age, 71 [62-81] years; 55.8% female) and 626 887 matched patients not receiving PPI therapy (median [interquartile range] age, 70 [61-80] years; 56.3% female) included in the analyses. At least 1 AGE epidemic episode was identified in 3131 patients (1.3%) receiving PPI therapy and in 4327 patients (0.7%) not receiving PPI therapy. The adjusted relative risk of AGE for those receiving PPI therapy was 1.81 (95% CI, 1.72-1.90) for all ages considered, 1.66 (95% CI, 1.54-1.80) among those aged 45 to 64 years, 2.19 (95% CI, 1.98-2.42) among those aged 65 to 74 years, and 1.98 (95% CI, 1.82-2.15) among those aged 75 years and older.

CONCLUSIONS AND RELEVANCE:

Continuous PPI therapy was associated with an increased risk of developing AGE during periods of highest circulation of enteric viruses. These findings support the hypothesis that PPI use is associated with an increased risk of enteric viral infections.

Keywords 
proton pump inhibitor PPI Gastroenteritis Season

Proton Pump Inhibitor Use and Risk of Chronic Kidney Disease

Author/s: 
Lazarus, Benjamin, Chen, Yuan, Wilson, Francis P., Sang, Yingying, Chang, Alex R., Coresh, Josef, Grams, Morgan E.

Context

Proton pump inhibitors (PPIs) are among the most commonly used drugs worldwide, and have been linked to acute interstitial nephritis. Less is known about the relationship between PPI use and chronic kidney disease (CKD).

Objective

To quantify the association between PPI use and incident CKD in a population-based cohort.

Design, Setting and Participants

10,482 participants in the Atherosclerosis Risk in Communities (ARIC) study with an estimated glomerular filtration rate (eGFR) of ≥60mL/min/1.73m2 were followed from a baseline visit (1996–1999) to December 31, 2011. Findings were replicated in an administrative cohort of 248,751 patients with eGFR ≥60mL/min/1.73m2 from Geisinger Health System.

Exposure

Self-reported PPI use in ARIC, or an outpatient PPI prescription in the replication cohort. Histamine-2 receptor (H2) antagonist use was considered a negative control and active comparator.

Main Outcome Measure

Incident CKD, using diagnostic codes indicating CKD at hospital discharge or death. In the replication cohort, incident CKD was defined by outpatient eGFR <60 mL/min/1.73 m2.

Results

Compared to non-users, PPI-users were more often white, obese, and taking antihypertensive medication. In ARIC, PPI use was associated with incident CKD in unadjusted analysis (hazard ratio [HR], 1.45; 95% confidence interval [CI], 1.11–1.90), analysis adjusted for demographic, socioeconomic, and clinical parameters (HR, 1.50; 95% CI, 1.14–1.96), and in analysis with PPI ever-use modeled as a time-varying variable (adjusted HR, 1.35; 95% CI, 1.17–1.55). The association persisted when baseline PPI users were compared directly to H2-antagonist users (adjusted HR, 1.39; 95% CI, 1.01–1.91), and to propensity-score matched non-users (HR, 1.76; 95% CI, 1.13–2.74). In the replication cohort, PPI use was associated with CKD in all analyses, including a time-varying new user design (adjusted HR 1.24; 95% CI, 1.20–1.28). Twice-daily PPI dosing was associated with a higher risk (adjusted HR, 1.46; 95% CI, 1.28–1.67) than once-daily dosing (adjusted HR, 1.15; 95% CI, 1.09–1.21).

Conclusions

PPI use is associated with a 20%–50% higher risk of incident CKD. Future research should evaluate whether limiting PPI use reduces the incidence of CKD.

Keywords 
proton pump inhibitors chronic kidney disease interstitial nephritis

Proton‐Pump Inhibitors and Long‐Term Risk of Community‐Acquired Pneumonia in Older Adults

Author/s: 
Zirk-Sadowski, Jan, Masoli, Jane A., Delgada, Joao, Hamilton, Willie, Strain, W. David, Henley, William, Melzer, David, Ble, Alessandro

Objectives

To estimate associations between long‐term use of proton pump inhibitors (PPIs) and pneumonia incidence in older adults in primary care.

Design

Longitudinal analyses of electronic medical records.

Setting

England

Participants

Individuals aged 60 and older in primary care receiving PPIs for 1 year or longer (N=75,050) and age‐ and sex‐matched controls (N=75,050).

Measurements

Net hazard ratios for pneumonia incidence in Year 2 of treatment were estimated using the prior event rate ratio (PERR), which adjusts for pneumonia incidence differences before initiation of treatment. Inverse probability weighted models adjusted for 78 demographic, disease, medication, and healthcare usage measures.

Results

During the second year after initiating treatment, PPIs were associated with greater hazard of incident pneumonia (PERR‐adjusted hazard ratio=1.82, 95% confidence interval=1.27–2.54), accounting for pretreatment pneumonia rates. Estimates were similar across age and comorbidity subgroups. Similar results were also obtained from propensity score– and inverse probability–weighted models.

Conclusion

In a large cohort of older adults in primary care, PPI prescription was associated with greater risk of pneumonia in the second year of treatment. Results were robust across alternative analysis approaches. Controversies about the validity of reported short‐term harms of PPIs should not divert attention from potential long‐term effects of PPI prescriptions on older adults.

Keywords 
pneumonia primary care proton pump inhibitors

Proton pump inhibitor-related headaches: A nationwide population-based case-crossover study in Taiwan

Author/s: 
Liang, Jen-Feng, Chen, Yung-Tai, Fuh, Jong-Ling, Li, Szu-Yuan, Chen, Tzeng-Ji, Tang, Chao-Hsiun, Wang, Shuu-Jiun

Background

Headaches resulting from proton pump inhibitor (PPI) use could cause discontinuation of PPI in as many as 40% of patients who experience such headaches. Previous studies focusing on acute headache risk from PPI use are rare and limited to clinical trials of a single PPI.

Objectives

To investigate the association between PPI use and headache with a nationwide population-based case-crossover study.

Methods

Records containing the first diagnosis of any headache, including migraine and tension-type headaches, were retrieved from Taiwan National Health Insurance Database (1998–2010). We compared the rates of PPI use for cases and controls during time windows of 7, 14, and 28 days. The adjusted self-matched odds ratios (ORs) and 95% confidence intervals (CIs) from a conditional logistic regression model were used to determine the association between PPI use and headache.

Results

Overall, 314,210 patients with an initial diagnosis of any headache during the study period were enrolled. The adjusted ORs for headache risk after PPI exposure were calculated for three time periods (within 7 days = 1.41, p = 0.002, 95% CI 1.14–1.74; within 14 days = 1.36, p < 0.001, 95% CI 1.16–1.59; within 28 days = 1.20, p = 0.002, 95% CI 1.07–1.35). Subgroup analyses showed female patients had an increased risk of headache. Among PPIs, lansoprazole and esomeprazole had the highest risks of headache incidence, which were similar to that of nitrates.

Conclusion

PPI usage is associated with an increased risk for acute headache. Female patients and use of lansoprazole or esomeprazole present the greatest risks of headache.

Keywords 
headache proton pump inhibitor incidence risk Taiwan

Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy With Hospitalization for Upper Gastrointestinal Tract Bleeding.

Author/s: 
Ray, Wayne A., Chung, Cecilia P., Murray, Katherine T., Smalley, Walter E., Daugherty, James R., Dupont, William D.

IMPORTANCE:

Anticoagulant choice and proton pump inhibitor (PPI) cotherapy could affect the risk of upper gastrointestinal tract bleeding, a frequent and potentially serious complication of oral anticoagulant treatment.

OBJECTIVES:

To compare the incidence of hospitalization for upper gastrointestinal tract bleeding in patients using individual anticoagulants with and without PPI cotherapy, and to determine variation according to underlying gastrointestinal bleeding risk.

DESIGN, SETTING, AND PARTICIPANTS:

Retrospective cohort study in Medicare beneficiaries between January 1, 2011, and September 30, 2015.

EXPOSURES:

Apixaban, dabigatran, rivaroxaban, or warfarin with or without PPI cotherapy.

MAIN OUTCOMES AND MEASURES:

Hospitalizations for upper gastrointestinal tract bleeding: adjusted incidence and risk difference (RD) per 10 000 person-years of anticoagulant treatment, incidence rate ratios (IRRs).

RESULTS:

There were 1 643 123 patients with 1 713 183 new episodes of oral anticoagulant treatment included in the cohort (mean [SD] age, 76.4 [2.4] years, 651 427 person-years of follow-up [56.1%] were for women, and the indication was atrial fibrillation for 870 330 person-years [74.9%]). During 754 389 treatment person-years without PPI cotherapy, the adjusted incidence of hospitalization for upper gastrointestinal tract bleeding (n = 7119) was 115 per 10 000 person-years (95% CI, 112-118). The incidence for rivaroxaban (n = 1278) was 144 per 10 000 person-years (95% CI, 136-152), which was significantly greater than the incidence of hospitalizations for apixaban (n = 279; 73 per 10 000 person-years; IRR, 1.97 [95% CI, 1.73-2.25]; RD, 70.9 [95% CI, 59.1-82.7]), dabigatran (n = 629; 120 per 10 000 person-years; IRR, 1.19 [95% CI, 1.08-1.32]; RD, 23.4 [95% CI, 10.6-36.2]), and warfarin (n = 4933; 113 per 10 000 person-years; IRR, 1.27 [95% CI, 1.19-1.35]; RD, 30.4 [95% CI, 20.3-40.6]). The incidence for apixaban was significantly lower than that for dabigatran (IRR, 0.61 [95% CI, 0.52-0.70]; RD, -47.5 [95% CI,-60.6 to -34.3]) and warfarin (IRR, 0.64 [95% CI, 0.57-0.73]; RD, -40.5 [95% CI, -50.0 to -31.0]). When anticoagulant treatment with PPI cotherapy (264 447 person-years; 76 per 10 000 person-years) was compared with treatment without PPI cotherapy, risk of upper gastrointestinal tract bleeding hospitalizations (n = 2245) was lower overall (IRR, 0.66 [95% CI, 0.62-0.69]) and for apixaban (IRR, 0.66 [95% CI, 0.52-0.85]; RD, -24 [95% CI, -38 to -11]), dabigatran (IRR, 0.49 [95% CI, 0.41-0.59]; RD, -61.1 [95% CI, -74.8 to -47.4]), rivaroxaban (IRR, 0.75 [95% CI, 0.68-0.84]; RD, -35.5 [95% CI, -48.6 to -22.4]), and warfarin (IRR, 0.65 [95% CI, 0.62-0.69]; RD, -39.3 [95% CI, -44.5 to -34.2]).

CONCLUSIONS AND RELEVANCE:

Among patients initiating oral anticoagulant treatment, incidence of hospitalization for upper gastrointestinal tract bleeding was the highest in patients prescribed rivaroxaban, and the lowest for patients prescribed apixaban. For each anticoagulant, the incidence of hospitalization for upper gastrointestinal tract bleeding was lower among patients who were receiving PPI cotherapy. These findings may inform assessment of risks and benefits when choosing anticoagulant agents.

Keywords 
warfarin apixaban dabigatran rivaroxaban proton pump inhibitor upper gastrointestinal tract anticoagulants atrial fibrillation
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