PPPI: proton pump inhibitor, H2RA: histamin-2 receptor antagonist, n: number, OR: odds ratio, HR: hazard ratio, CI: confidence interval, NNH: number needed to harm, COMPASS: Cardiovascular Outcomes for People Using Anticoagulant Strategies, RCT: randomized controlled trial,

Appraisal of included studies: The included studies used different study designs and can be evaluated using the three sets of quality criteria appropriate for their respective design. Such heterogeneity is appropriate for considerations of medication harm in the real world. Each publication has been peered reviewed and meets sufficient criteria to be valid for the research question, methods and findings presented.

Common to all the included studies is the challenge of misclassification of drug use. Prescription data may not truly reflect drug consumption. Users may have stopped taking PPIs or H2RAs or started taking PPI as over-the-counter medications during the follow up period.

Findings for all included studies may be subject to bias by indication if patients who are more ill are more likely to be prescribed PPI therapy. The logic is that people who are prescribed PPIs are sicker and what has caused them to be sick (and then die) is the residual confounder that also caused them to be prescribed a PPI. Healthy populations were not however well represented in the study populations of any of the analyses and each demonstrated that the control population was comparable on comorbidities as well as characteristics such as age and sex.

The representativeness across all included studies is problematic as the populations were primarily Caucasian. It is known that up to 20% of Asians (vs 3% Caucasians) have low CYP2C19 enzyme activity and are therefore poor metabolisers of PPIs with a doubling of plasma PPI levels and therefore greater exposure ^21,22.

Each study also has limitations within the respective study design. These are highlighted here.

Systematic review : The pooled analysis by SR by Shiraev 2018 included studies if they “examined death or atherosclerotic events (including myocardial infarct, stroke, or peripheral arterial events), and compared a group exposed to PPIs with a control group (not exposed to PPIs), in any group of patients” ²¹. The search cut-off date of October 2016 was not inclusive of more recent studies including the 2019 studies included in this review. The Danish national health set study that dominates the Shiraev 2018 pooled analysis is limited to a study population after a first heart attack²⁰. The advantage of analyses representative of a geographical population being inclusive of all health care transactions in a publicly funded health care system is the real-world perspective.

RCT: There are several reasons for cautious interpretation of the COMPASS trial results. Serious harms such as cardiovascular disease, kidney diseases or cancers develop over relatively long time periods because of the slow onset. The duration of exposure and follow-up and consistency with the VA cohort means that serious but relatively rare harm may not have been detected. The authors recognized that low event rates for some outcomes limited their ability “to exclude a modest risk increase” from pantoprazole. Of the three included studies the COMPASS trial was the only one with potential conflict of interest due to funding of the research and investigators. There is also the challenge of consistently detecting adverse events with a multi-site, multi-country interview protocol on a 6-monthly schedule.

The COMPASS trial is also not consistent with other RCTs which show a clear positive reduction of GI complications in patients taking PPI and no clinical effects on cardiovascular events ^3,23-25. Surprisingly, COMPASS found no benefit of using pantoprazole to prevent upper GI bleeding in this population. The COMPASS effectiveness trial in people using antithrombotic drugs (14), have yet to prove that net benefits exceed harms during long-term use in older people. The data confirmed that no benefit of using pantoprazole that would prevent upper GI bleeding in the selected population. This raises questions on the role of PPIs in the in the prevention of bleeding associated with antithrombotic therapy?