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.