Proton pump inhibitor side effects and drug interactions: Much ado about nothing?

The development and introduction of the first proton pump inhibitor (PPI), omeprazole (Prilosec), for the management of acid-peptic disorders marks one of the great success stories in gastroenterology. Until the latter part of the 20th century, complications of acid-peptic disease were among the most common problems faced in gastroenterology. Severe peptic strictures were once a highly prevalent cause of dysphagia, and operations for peptic ulcer disease were routinely learned by surgical trainees.

PPIs (Table 1) are substituted benzimidazole derivatives that have potent antisecretory effects on gastric acid. They block the terminal step in acid production by irreversibly inhibiting the function of the hydrogen-potassium adenosine triphosphatase present on the luminal aspect of parietal cell membranes in the stomach.

The success of these drugs, with sales total-ling $13.6 billion worldwide in 2009,¹ is not just a result of their potency and effectiveness in improving symptoms and complications of acid-peptic disease. Their safety among pharmacologic agents has been unparalleled. When the drugs were first introduced, their use was limited to short courses out of concern that gastric carcinoids could develop, but decades of use have not shown this issue to be of clinical relevance. Serious, acute adverse effects are also exceedingly uncommon.

However, recent reports have questioned the long-term safety of PPIs. Furthermore, these drugs are too often used in patients who have no valid indication for them,^2,3 exposing these patients to unnecessary risks.

The goals of this review are to analyze the recent literature about the risks of PPIs and to provide a rational approach for managing patients on PPI therapy in light of these concerns.

DO PPIs REDUCE THE EFFECT OF CLOPIDOGREL?

Clopidogrel (Plavix) is a potent antiplatelet agent commonly used in patients with atherosclerotic cardiac or cerebrovascular disease, sometimes in combination with aspirin. Because of the risk of significant gastrointestinal bleeding, a 2008 multisociety task force recommended prescribing a PPI when both clopidogrel and aspirin are used as dual antiplatelet therapy.⁴

However, recent studies have advanced the concern that cotherapy with a PPI reduces the effectiveness of clopidogrel. The pharmacologic basis for this interaction is that the two drugs share a common metabolic pathway (Figure 1). Clopidogrel is an inactive prodrug that requires cytochrome P450 (CYP) enzymes to become active. PPIs, on the other hand, are metabolized from their active to their inactive state by the CYP enzymes. PPIs competitively inhibit one of the principal enzymes, CYP2C19, important in the activation of clopidogrel.⁵ Pharmacodynamic studies have shown that adding a PPI to clopidogrel leads to reduced platelet inhibition.^6–9

Studies of clopidogrel plus PPIs: Discrepant results

This concern prompted epidemiologic studies to assess the clinical importance of this pharmacologic interaction (Table 2). Three large observational studies found a small but statistically significant increase in adverse cardiovascular outcomes in patients who were taking clopidogrel and a PPI compared with those who were taking clopidogrel without a PPI.^10–12 On the other hand, five studies of similar design found no significant increase in cardiovascular events.^9,13–16

To date, only one prospective randomized controlled trial has specifically investigated the effect of PPIs on cardiovascular outcomes in patients using clopidogrel. In this trial, patients on dual antiplatelet therapy with clopidogrel and aspirin were randomized to receive either omeprazole 20 mg or placebo. Analysis of the data revealed no significant increase in the composite end point of cardiovascular events (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.68–1.44, P = .96), but a statistically significant decrease in composite gastrointestinal events (HR 0.34, 95% CI 0.18–0.63, P < .001).¹⁷

Unfortunately, this trial had to be terminated before the prespecified sample size and duration of follow-up were reached because the study sponsor declared bankruptcy.

One additional recent retrospective cohort study¹⁶ likewise found no significant risk of serious cardiovascular disease related to PPI use in clopidogrel users. It also found that the adjusted incidence of hospitalization for upper gastrointestinal bleeding was 50% lower in patients who used PPIs than in those who did not (HR 0.50, 95% CI 0.39–0.65).