Interpretation
The VA cohort study found an excess of deaths in its sample that was twelve times as many participants as the COMPASS RCT and follow-up that was over three times longer. Furthermore, the Shiraev 2018 SR pooled analysis was heavily weighted by a study using the Danish national level administrative data collected from routine care transactions. It would be difficult to create an RCT of an adverse drug event on the scale of either study.
The median exposure to PPI was longer than in the COMPASS RCT (4.6 years vs < 3 years). With only 3 years of follow-up, COMPASS did not have statistical power to detect 10% increases in risk for several of its pre-specified outcomes. For example, COMPASS’s point estimate hazard ratio of 1.17 (0.94 to 1.45) for chronic kidney disease was similar to the VA’s hazard ratio of 1.16 (1.01 to 1.33) for acute kidney injury.
In the COMPASS RCT, pantoprazole increased enteric infections (mostlyC. difficile) with an odds ratio of 1.33 (1.01–1.75), absolute risk increase 0.4%. However, the incident rates for most serious harm, such as cardiovascular disease, hospitalizations, chronic kidney disease or dementia, were consistently higher among pantoprazole users compared to placebo group. The COMPASS authors admit this limitation, yet conclude perhaps inappropriately that PPIs “are not associated with any long-term harm” 13
The Xie et al, 2019 analysis using VA cohort data went farther than detecting a mortality difference between a new PPI user group and a new H2Ra user group. They traced excess deaths to the underlying cause of death using ICD-10 (international classification of diseases, 10th revision) codes. Table 3 provides cause specific mortality from cardiovascular disease and chronic kidney disease from Xie et al, 201918. The cardiovascular disease outcome findings from the COMPASS RCT which were available are provided for comparison13. Cause specific mortality data is consistent with the overall data analysis as well as consistent with findings of SRs that report on cardiovascular 21 and kidney disease26. This consistency is an indication of the study’s internal validity – the findings are consistent within the study. And the study is consistent with other data which is an indication of external validity – that the findings may be applicable beyond this study population.
There were 17.47 excess deaths from cardiovascular diseases per 1000 patients (95% CI: 5.47-28.80), NNH of 58, and 6.25 excess deaths from chronic kidney diseases per 1000 patients (95% CI: 3.22-9.24) in the Xie et al., 2019 study (Table 3) during 10 years of follow up18. Moayyedi et al, 2019 did not find an association between PPI therapy and an increased risk of death due cardiovascular causes (HR = 1.03; 95% CI: 0.89-1.20) compared with placebo however there was an overlap in confidence intervals and the COMPASS RCT was shorter in duration and follow-up19.