Table 1.
Literature summary of studies that reported an adjusted odds ratio or hazard ratio.
| Study | Study design | Population | Mean age (years) | % Older adults* | Outcomes | Risk estimate (95% CI) |
|---|---|---|---|---|---|---|
| Bone fractures and falls | ||||||
| Chiu and colleagues10 | Case-control | Taiwan; Taiwan National Health Insurance Research database | 75 | NR | Risk of hip fracture with <29 defined daily doses of PPI | Adjusted OR 1.04 (0.73–1.49) |
| Risk of hip fracture with 29–70 defined daily doses of PPI | Adjusted OR 1.67 (1.11–2.51) |
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| Risk of hip fracture with >71 defined daily doses of PPI | Adjusted OR 2.51 (1.77–3.55) |
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| Eom and colleagues11 | Meta-analysis | Europe, Canada, United States, Taiwan | NR | NA | Risk of fracture with use of PPI | Pooled OR 1.29 (1.18–1.41) |
| Risk of facture with use of H2RA | Pooled OR 1.10 (0.99–1.23) |
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| Ngamruengphong and colleagues12 | Meta-analysis | Europe, Canada, United States; observational study populations | NR | NA | Risk of hip fracture with use of PPI | Pooled OR 1.25 (1.14–1.37) |
| Risk of vertebral fracture with use of PPI | Pooled OR 1.50 (1.32–1.72) |
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| Risk of wrist/forearm fracture with use of PPI | Pooled OR 1.09 (0.95–1.24) |
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| Pouwels and colleagues13 | Case-control | Netherlands; PHARMO Record Linkage System | 75.7 cases; 75.3 controls |
NR | Risk of hip/femur fracture with current use of PPI | Adjusted OR 1.20 (1.04–1.40) |
| Ye and colleagues14 | Meta-analysis | Europe, Canada, United States; observational study populations | NR | NA | Risk of hip fracture with use of PPI | Pooled OR 1.24 (1.15–1.34) |
| Khalili and colleagues15 | Prospective cohort | United States; women enrolled in Nurses’ Health Study | 67.0 PPI users; 66.6 nonusers |
NR | Risk of hip fracture with use of PPI for at least 2 years | Adjusted HR 1.36 (1.12–1.65) |
| Yu and colleagues16 | Meta-analysis | United States, Canada, Europe, Taiwan | NR | NA | Risk of hip fracture with use of PPI | Adjusted OR 1.30 (1.19–1.43) |
| Risk of hip fracture with use of H2RA | Adjusted OR 1.10 (0.94–1.30) |
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| Cea-Soriano and colleagues17 | Cohort with nested case-control | United Kingdom; Health Improvement Network Database | 68.6 men 69.1 women |
73% | Risk of falls with current use of PPI | Adjusted OR 0.95 (0.89–1.02) |
| Risk of falls with current use of H2RA | Adjusted OR 1.01 (0.90–1.14) |
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| Fraser and colleagues18 | Prospective cohort | Canada; community-dwelling | 67.6 PPI users; 61.9 nonusers |
NR | Risk of first nontraumatic fracture with use of PPI | Adjusted HR 1.40 (1.11–1.77) |
| Lee and colleagues19 | Case-Control | Korea; Korean Health Insurance Review and Assessment Service database | 77.7 | 100% | Risk of hip fracture with PPI use | Adjusted OR 1.34 (1.24–1.44) |
| Risk of hip fracture with PPI use not on bisphosphonate treatment | Adjusted OR 1.30 (1.19–1.42) |
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| Risk of hip fracture with PPI use and on bisphosphonate treatment | Adjusted OR 1.71 (1.31–2.23) |
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| Adams and colleagues20 | Case-control | United States; Males in Kaiser Permanente healthcare system | NR | 85.3% | Risk of hip fracture with use of omeprazole in men | Adjusted OR 1.13 (1.01–1.27) |
| Ding and colleagues21 | Retrospective cohort | United States; pharmacy claims data, survey data, Medicare data | 79 | 100% | Risk of any fracture with use of PPI | Adjusted HR 1.27 (1.12–1.43) |
| Risk of hip fracture with use of PPI | Adjusted HR 1.32 (1.01–1.71) |
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| Risk of vertebral fracture with use of PPI | Adjusted HR 1.69 (1.26–2.27) |
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| Lewis and colleagues22 | Prospective cohort – Study 1 | Australia; patients enrolled in Calcium Intake Fracture Outcome study | 79.9 | 100% | Risk of falls and fracture-related hospitalizations with long-term use of PPI | Adjusted OR 2.17 (1.25–3.77) |
| Lewis and colleagues22 | Prospective cohort – Study 2 | Australia; outpatient | 76.7 | 100% | Risk of self-reported falling with long-term use of PPI | Adjusted OR 1.51 (1.00–2.27) |
| Clostridium difficile infection | ||||||
| Cunningham and colleagues23 | Case-control | United Kingdom; inpatient | NR | NR | Risk of CDI with use of PPI in preceding 8 weeks | Unadjusted OR 2.5 (1.5–4.2) |
| Dial and colleagues24 | Retrospective cohort | Canada; inpatient | NR | NR | Risk of CDAD with use of PPI | Adjusted OR 2.1 (1.2–3.5) |
| Dial and colleagues24 | Case-control | Canada; inpatient | 75.5 cases; 73 controls |
NR | Risk of CDAD with use of PPI | Adjusted OR 2.7 (1.4–5.2) |
| Dial and colleagues25 | Case-control | United Kingdom; General Practice Research Database | 71 | 74% | Risk of community-acquired CDAD with use of PPI | Adjusted RR 2.9 (2.4–3.4) |
| Risk of community-acquired CDAD with use of H2RA | Adjusted RR 2.0 (1.6–2.7) |
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| Lowe and colleagues26 | Nested case-control | Canada; outpatient | 78.7 cases; 78.0 controls |
100% | Risk of hospitalization for CDAD with outpatient use of PPI in preceding 90 days | Adjusted OR 0.9 (0.8–1.1) |
| Aseeri and colleagues27 | Case-control | United States; inpatient | NR | 58.5% | Risk of CDAD with use of PPI | Adjusted OR 3.6 (1.7–8.3) |
| Linsky and colleagues28 | Retrospective cohort | United States; inpatient and outpatient | 74 | NR | Risk of recurrent CDI with use of PPI | Adjusted HR 1.42 (1.10–1.83) |
| Deshpande and colleagues29 | Meta-analysis | Canada, United Kingdom, United States, South Korea; inpatient, outpatient, nursing home | NR | NA | Risk of CDI with use of PPI | Pooled OR 2.15 (1.81–2.55) |
| Janarthanan and colleagues30 | Meta-analysis | United States, Europe, Canada, South Korea; inpatient and community | NR | NA | Risk of CDAD with use of PPI | Pooled RR 1.69 (1.40–1.97) |
| Kwok and colleagues31 | Meta-analysis | United States, Europe, Canada, India, South Korea; inpatient and outpatient | NR | NA | Risk of CDI with use of PPI | Pooled OR 1.74 (1.47–2.85) |
| Risk of CDI with use of H2RA | Pooled OR 0.71 (0.53–0.97) |
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| Risk of CDI with concomitant use of PPI and antibiotic | Pooled OR 1.96 (1.03–3.70) |
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| Tleyjeh and colleagues32 | Meta-analysis | United States, Europe, Canada, Asia; inpatient and outpatient | NR | NA | Risk of CDI with use of PPI | Adjusted OR 1.51 (1.26–1.83) |
| Freedberg and colleagues33 | Retrospective cohort | United States; inpatient | 64 | NR | Risk of recurrent CDI in inpatients with incident CDI and concurrent use of PPI | Adjusted HR 0.82 (0.58–1.16) |
| McDonald and colleagues34 | Retrospective cohort | Canada; inpatient | 71.5 PPI users (median); 69.5 nonusers (median) |
NR | Risk of CDI recurrence within 90 and days with continuous use of PPI | Adjusted HR 1.5 (1.1–2.0) |
| CAP | ||||||
| Laheij and colleagues35 | Nested case-control | Netherlands; Integrated Primary Care Information research database | NR | 58.1% | Risk of CAP with current use of PPI | Adjusted OR 1.73 (1.33–2.25) |
| Risk of CAP with current use of H2RA | Adjusted OR 1.59 (1.14–2.23) |
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| Risk of CAP with current use of PPI and H2RA | Adjusted OR 1.76 (1.18–2.61) |
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| Gulmez and colleagues36 | Case-control | Denmark; inpatient | 55.5 | 59.2% | Risk of CAP with current use of PPI | Adjusted OR 1.5 (1.3–1.7) |
| Risk of CAP with past use of PPI | Adjusted OR 1.2 (0.9–1.6) |
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| Risk of CAP with recent initiation of PPI | Adjusted OR 5.0 (2.1–11.7) |
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| Sarkar and colleagues37 | Nested case-control | United Kingdom; General Practice Research Database | 73.5 cases; 49.5 controls |
NR | Risk of CAP with current long-term use of PPI | Adjusted OR 1.02 (0.97–1.08) |
| Risk of CAP with PPI initiated in previous 2 days | Adjusted OR 6.53 (3.95–10.80) |
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| Risk of CAP with PPI initiated in previous 7 days | Adjusted OR 3.79 (2.66–5.42) |
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| Risk of CAP with PPI initiated in previous 14 days | Adjusted OR 3.21 (2.46–4.18) |
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| Dublin and colleagues38 | Nested case-control | United States; inpatient and outpatient | 77 | 100% | Risk of CAP with current PPI or H2RA use | Adjusted OR 1.03 (0.86–1.24) |
| Johnstone and colleagues39 | Meta-analysis | Canada, Europe; inpatient and outpatient | NR | NA | Risk of CAP with use of PPI | Pooled OR 1.36 (1.12–1.65) |
| Eom and colleagues11 | Meta-analysis | Canada, United States, Europe, Australia; inpatient and outpatient | NR | NA | Risk of CAP with use of PPI | Adjusted OR 1.27 (1.11– 1.46) |
| Risk of CAP with use of H2RA | Adjusted OR 1.22 (1.09–1.36) |
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| Meijvis and colleagues41 | Case-control | Netherlands; inpatient cases and population controls | 62 | NR | Risk of CAP with current PPI exposure | Adjusted OR 1.6 (1.2–2.2) |
| Risk of CAP with initiation of PPI in last 30 days | Adjusted OR 3.1 (1.4–7.1) |
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| de Jager and colleagues42 | Prospective cohort | Netherlands; emergency room patients | NR | 46% non-PPI users; 69% PPI users | Risk of oropharyngeal flora as cause of CAP with PPI therapy | Adjusted OR 2.0 (1.22–3.72) |
| Hermos and colleagues43 | Nested case-control | United States; veterans | 65.8 | NR | Risk of CAP with current PPI exposure | Adjusted OR 1.29 (1.15–1.45) |
| Lambert and colleagues44 | Meta-analysis | United States, Canada, Europe, Asia; inpatient and outpatient | NR | NA | Risk of CAP with PPI therapy | Pooled OR 1.49 (1.16–1.92) |
| Risk of hospitalization for CAP with PPI therapy | Pooled OR 1.61 (1.12–2.31) |
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| Vitamin B12 deficiency | ||||||
| Mitchell and Rockwood45 | Prospective cohort | Canada; outpatient and institutionalized patients with cognitive impairment | 78.7 | 100% | Risk of initiation of vitamin B12 supplementation with PPI/H2RA use at baseline | Adjusted OR 2.61 (1.31–5.23) |
| Force and colleagues46 | Case-control | United States; Medicaid patients | 71.2 | NR | Risk of initiation of vitamin B12 supplementation with ⩾10 of 12 months of PPI/H2RA | Unadjusted OR 1.82 (1.08–3.09) |
| Valuck and Ruscin47 | Case-control | United States; university-based geriatric outpatient | 82 | 100% | Risk of vitamin B12 deficiency with past use of PPI/H2RA | Adjusted OR 2.00 (0.87–4.37) |
| Risk of vitamin B12 deficiency with current use <12 months of PPI/H2RA | Adjusted OR 1.01 (0.47–2.28) |
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| Risk of vitamin B12 deficiency with current use ⩾12 months of PPI/H2RA | Adjusted OR 4.45 (1.47–13.34) |
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| Cotter and O’Keeffe48 | Case-control | United Kingdom, inpatient | 80 | NR | Risk of vitamin B12 deficiency with current use of PPI | Unadjusted OR 0.92 (0.53–1.60) |
| Lam and colleagues49 | Case-control | United States; inpatient and outpatient | NR | 67.2% | Risk of vitamin B12 deficiency with ⩾2-year supply of PPI | Adjusted OR 1.65 (1.58–1.73) |
| Risk of vitamin B12 deficiency with ⩾2-year supply of H2RA | Adjusted OR 1.25 (1.17–1.34) |
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| Jung and colleagues50 | Meta-analysis | United States, Canada, and Ireland; inpatient and outpatient | NR | NA | Risk of vitamin B12 deficiency with ⩾10 months of PPI/H2RA | Pooled OR 1.83 (1.36–2.46) |
| Kidney disease and injury | ||||||
| Leonard and colleagues51 | Case-control | United Kingdom, General Practice Research Database | 60.2 AIN cases; 60.0 AIN controls 68.6 AKI cases; 66.9 AKI controls |
NR | Risk of AIN with use of PPI | Adjusted OR 3.20 (0.80–12.79) |
| Risk of AKI with use of PPI | Adjusted OR 1.05 (0.97–1.14) |
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| Antoniou and colleagues52 | Prospective cohort | Canada; outpatients hospitalized for AKI | 74 years (median) |
100% | Risk of AKI with use of PPI | Unadjusted HR 2.52 (2.27–2.79) |
| Risk of AIN with use of PPI | Unadjusted HR 3.00 (1.47–6.14) |
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| Lazarus and colleagues53 | Prospective cohort | United States; Atherosclerosis Risk in Communities study | 62.8 PPI users 63.1 H2RA users 62.5 nonusers |
NR | Association between PPI use and Incident CKD | Adjusted HR 1.50 (1.14–1.96) |
| Xie and colleagues54 | Prospective cohort | United States, Veterans Affairs database | 56.85 PPI users; 55.40 H2RA users |
NR | Association between PPI use and incident eGFR <60 ml/min/1.73 m2 | Adjusted OR 1.22 (1.18–1.26) |
| Association between PPI use and incident CKD | Adjusted OR 1.28 (1.23–1.34) |
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| Dementia | ||||||
| Haenisch and colleagues55 | Prospective cohort | Germany; elderly primary care patients | 79.6 | 100% | Risk of any dementia with use of PPI | Adjusted HR 1.38 (1.04–1.83) |
| Risk of Alzheimer’s disease with use of PPI | Adjusted HR 1.44 (1.01–2.06) |
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| Gomm and colleagues56 | Prospective cohort | Germany; inpatient and outpatient claims data | 83.8 | 100% | Risk of incident dementia with use of PPI | Adjusted HR 1.44 (1.36–1.52) |
*
Older adults defined as age 60 years and older.
AIN, acute interstitial nephritis; AKI, acute kidney injury; CAP, community-acquired pneumonia; CI, confidence interval; CDI, Clostridium difficile infection; CDAD, Clostridium difficile-associated diarrhea; eGFR, estimated glomerular filtration rate; H2RA, histamine-2 receptor antagonist; HR, hazard ratio; NA, not applicable; NR, not reported; OR, odds ratio; PPI, proton-pump inhibitor; RR, risk ratio.