Complications of Proton Pump Inhibitor Therapy

Abstract

Safety issues associated with proton pump inhibitors (PPIs) have recently attracted widespread media and lay attention. Gastroenterologists are frequently asked about the appropriateness of PPI therapy for specific patients. Furthermore, some patients may have had PPI therapy discontinued abruptly or inappropriately due to safety concerns. Faced with such a wide variety of potentially serious adverse consequences, prescribers need to evaluate the evidence objectively to discern the likelihood that any reported association might actually be causal. Here, we review many of the proposed adverse consequences of PPI therapy and apply established criteria for the determination of causation. We also consider the potential contribution of residual confounding in many of the reported studies. Evidence is inadequate to establish causal relationships between PPI therapy and many of the proposed associations. Residual confounding related to study design and the overextrapolation of quantitatively small estimates of effect size have probably led to much of the current controversy about PPI safety. In turn, this has caused unnecessary concern among patients and prescribers. The benefits of PPI therapy for appropriate indications need to be considered, along with the likelihood of the proposed risks. Patients with a proven indication for a PPI should continue to receive it in the lowest effective dose. PPI dose escalation and continued chronic therapy in those unresponsive to initial empiric therapy is discouraged.

Proton Pump Inhibitors: Are They a Real Threat to the Patient?

“…Even though the current evidence seems consensual in establishing an association between PPI use and CDI, the risk associated with PPIs is only modest when compared to other drugs, like antibiotics [13]. Evaluating Hill criteria, the current evidence has a moderate strength, and both temporality and plausibility are present; however, other criteria have not been established yet [7]. …”

“…Another study assessing the safety of PPI treatment, including data from 2 controlled randomized clinical trials, with 12- and 5-year follow-up, was not able to find significant differences between users and nonusers regarding enteric infections [19]. Evaluating Hill criteria, the current evidence has a moderate strength, and temporality, consistency, biological gradient, plausibility, and analogy are present; however, other criteria have not been established yet [7]. …”

“…However, not all authors report an increased risk of SBP in PPI users, and a meta-analysis including 10 case-control and 6 cohort studies found that the association of PPIs with SBP was only observed in case-control studies (OR 2.97) and did not find an association between PPI intake and in-stay and 30-day mortality [23]. Evaluating Hill criteria, the current evidence has a weak strength, and only temporality and plausibility are present [7]. …”

“…Actually, another study found that the risk for CAP was limited to patients starting PPI within the last 30 days and that this risk increased progressively with a shorter duration of treatment, reaching an OR of 6.53 when it was started in the 2 days before CAP diagnosis [25]. These results led some authors to propose that the association between PPI use and CAP is a result of a protopathic bias, which occurs when a drug is used to treat an early sign of the outcome, creating the appearance that it is actually associated with the outcome [7]. …”

“…In this review, we will discuss the proposed mechanisms by which PPIs may induce adverse effects, evaluate the current evidence, and summarize current recommendations (Table 1). To help in the interpretation of the current evidence, we will also report, when available, the application of Hill criteria [7]. These include 9 parameters (strength of association, consistency, specificity, temporality, biological gradient, biological plausibility, coherence, experiment, and analogy) and try to differentiate between causality and association [8].…”