Study |
PPI exposure and ascertainment |
Lost to follow-up |
Definition of outcome and ascertainment |
Risk of bias |
Banjerjee et al.[12] |
Any PPI, no other details |
Not specified |
MACE defined as death, MI, revascularization and stroke. Monitoring not stated |
Abstract only, no further details |
Bhatt et al.[13] |
Omeprazole |
Not specified |
MACE was prespecified composite of CV death, nonfatal MI, CABG or PCI, or ischaemic stroke, adjudicated by independent committee |
Abstract only, low risk of confounding as there were no baseline differences |
Ching et al.[14] |
Esomeprazole, lansoprazole, omeprazole, pantoprazole |
None |
MACE defined as recurrent MI, revascularization and death. Monitoring not stated |
Abstract only, analysis was adjusted for age, gender, glycoprotein IIb/IIIa inhibitors and stent size; no further details |
Dunn et al.[15] |
Any PPI, no other details |
38 (3.6%) losses |
MACE was prespecified as death, MI or stroke and adjudicated by blinded independent committee |
Despite adjustment for confounding, PPI exposure alone without clopidogrel still showed significantly increased risk above that of patients taking neither PPI nor clopidogrel |
Gaspar et al.[16] |
Omeprazole, rabeprazole and lansoprazole were considered (pantoprazole excluded as investigators judged it to be metabolized by another route). Prescription and clinical records used to define exposure |
None |
Not specified |
Abstract only, baseline differences were present, multivariate analysis was performed to assess effect of PPI exposure. Authors concede that compliance was not assessed and prescription records may be incomplete |
Gupta et al.[17] |
Rabeprazole, omeprazole and lansoprazole for unclear duration, data obtained from discharge summary |
None. Mean follow-up of 50 months |
Reviewed medical records. MACE defined as composite of death, nonfatal MI and target vessel failure |
Risk of confounding as baseline differences were present; adjusted risk ratios were presented. Duration of exposure and treatment compliance unclear |
Hall et al.[18] |
Omeprazole, lanosprazole, pantoprazole |
Not specified |
MACE defined as death/MI, monitoring not stated |
Abstract only; adjusted for confounders such as comorbid conditions and concomitant medications. Despite adjustment, PPI exposure alone without clopidogrel still showed significantly increased risk above that of patients taking neither PPI nor clopidogrel, thus suggesting possibility of residual confounding |
Ho et al.[19] |
Omeprazole, rabeprazole, lansoprazole and pantoprazole for unclear duration based on pharmacy dispensing records |
Vital status available for all between October 2003 and September 2006, with median follow-up of 521 days |
A vital status file and chart review (including ICD-9 codes) using Veterans Administration database for mortality and MACE (death or rehospitalization for ACS) |
Risk of confounding as baseline differences were present; this was adjusted for using multivariate logistic regression |
Jarai et al.[20] |
Any PPI, no other details |
Not specified |
MACE consisted of death or target vessel revascularization. Monitoring not stated |
Abstract only, no information on exposure and outcome ascertainment, propensity score was used in patient matching |
Juurlink et al.[21] |
Pantoprazole and any other PPI, on Ontario drug prescriptions computerized record |
None |
Outcomes checked on Health Insurance (using ICD codes) and Health Registered Person databases |
Data were adjusted for demographic differences, concomitant medication and comorbidity. Authors state limitations that include possible miscoding of outcome, and inability to verify compliance with exposure |
O'Donoghue et al.[22] |
Omeprazole, pantoprazole, esomeprazole, lansoprazole at time or randomization, and at various intervals of follow-up |
None |
MACE defined as CV death, nonfatal MI, or nonfatal stroke. Independent committee adjudicated events |
Propensity score was used to adjust for covariates. Variations in PPI exposure with time were checked in sensitivity analysis – no material effect on results was detected |
Pezalla et al.[23] |
Any PPI use ascertained through pharmacy claims database |
None |
Health insurance and pharmacy database, using ICD codes for MI |
Potential confounding as baseline differences were present, and authors attempted to correct for only a few comorbid factors |
Ramirez et al.[24] |
Any PPI, no other details |
None |
Not specified |
Abstract only, no information on intervention and outcome ascertainment, risk of confounding as potential baseline differences were present |
Rassen et al.[25] |
Omeprazole, esomeprazole, lansoprazole, pantoprazole, or rabeprazole, recorded on pharmacy database |
82% were eligible for matched propensity analysis, median follow-up was 29–30 days, with 2% completing maximum follow-up of 180 days |
Study endpoints were ascertained up to 180 days of follow-up. MI recorded via discharge coding in health insurance database; death through vital statistics and government agencies |
Propensity score was used to match patients |
Sarafoff et al.[26] |
Any PPI, no other details |
None |
Not specified |
High; abstract only, no information on intervention and outcome ascertainment, risk of confounding as baseline differences were present |
Simon et al.[27] and Simon et al.[28] |
Omeprazole and PPI for unspecified duration |
222 were not included |
Investigators contacted patients' physicians, the patients or their family and registry offices at places of birth. Blinded independent committee adjudicated events, endpoints ascertained at 1 year |
Uncertain about ascertainment of PPI exposure; but there was blinding of outcome ascertainment |
Stanek et al.[29] |
Omeprazole, esomeprazole, pantoprazole and lansoprazole based on prescription claims |
Not specified |
Outcomes recorded via ICD-9 codes on claims database |
Abstract only, no information on compliance. Risk of confounding was addressed in multivariate analysis |
Stockl et al.[30] |
Any PPI, no other details |
None |
Not specified |
Abstract only, patients were propensity score-matched based on CV risk; no further details |
Sweeny et al.[31] |
Esomeprazole, lansoprazole, omeprazole and pantoprazole |
37 excluded from analysis, mean follow-up of 2 years |
New York State Interventional database and Social Security Death Index |
Abstract only, outcome ascertainment was done, no information on checking of drug exposure, but multivariate adjustment was done for confounders |
Torgusen et al.[32] |
Any PPI, no other details |
None |
MACE defined as death, MI or revascularization. Monitoring not stated |
Abstract only, author stated that PPI-exposed patients were more complex and sicker than unexposed, and used multivariate regression to adjust |
Yasuda et al.[33] |
Lansoprazole, omeprazole, rabeprazole for unspecified duration; review of hospital records |
None |
Review of hospital records and coronary angiography at 6–16 months after stent placement |
Intervention exposure and outcomes were not ascertained, risk of confounding as baseline differences were present |
Zairis et al[34] |
Any PPI, no other details |
None |
Not specified |
High, abstract only, no information on intervention and outcome ascertainment, low risk of confounding because of baseline difference |