Proton pump inhibitor side effects and drug interactions: Much ado about nothing?
ABSTRACTProton pump inhibitors (PPIs) are widely prescribed for acid-peptic disease. In general, the safety of this class of drugs has been excellent. However, in the past several years, epidemiologic studies have indicated possible risks that are biologically plausible.
KEY POINTS
- The US Food and Drug Administration has issued alerts that PPIs may increase the rate of osteoporosis-related fractures and may decrease the effectiveness of clopidogrel (Plavix) for preventing serious cardiovascular events.
- Other concerns include increased rates of pneumonia, Clostridium difficile infection, and other infections.
- A prudent approach to managing these concerns in day-to-day practice is required: PPIs, like any other drugs, should be prescribed only if indicated.
Do factors other than PPIs account for the higher risk in some of the studies?
The discrepant results of these studies suggest that the higher risk of cardiovascular events may be due, either completely or in part, to a factor other than the pharmacologic interaction of PPIs and clopidogrel. It is difficult to infer causality from the available data. In situations in which no randomized controlled trials exist, one looks to observational (case-control or cohort) studies to try to obtain the best estimate of the actual risk. With PPIs and clopidogrel, a randomized controlled trial was performed but terminated before patient enrollment was complete.
The increased risk found in some of these studies may be real, may be due to chance, or may even represent an increased risk from PPIs alone (although data do not support this possibility).18 However, the major concern in observational studies is the inability to account for unmeasured confounders, a problem virtually eliminated by randomization strategies in prospective studies.
In the studies that found a higher risk with the combination of omeprazole plus clopidogrel, the principal concern is confounding by indication, in which distortions of the risk estimates arise from an imbalance in prognostic factors between compared treatment groups that remains unmeasured.19 Stated another way, physicians who believed some patients to be “sicker” or to have a higher risk of serious events may have treated them with a PPI on the basis of factors that remained unaccounted for in the epidemiologic investigation.
This possibility has been reinforced by findings from a nonrandomized subgroup analysis of a randomized controlled trial in which patients who had been receiving a PPI had a higher rate of cardiovascular events whether they received clopidogrel or placebo.20
FDA alert: Avoid using omeprazole or esomeprazole with clopidogrel
Nonetheless, on November 17, 2009, the US Food and Drug Administration (FDA) issued an alert to health care professionals and the public about the potential interaction between clopidogrel and omeprazole.21 In this alert, the FDA stated that the use of omeprazole or esomeprazole (Nexium) with clopidogrel should be avoided.
An algorithm to use when considering clopidogrel plus a PPI
Physicians are now left in a bind between the minimal, if any, pooled risk seen in the available data and the FDA recommendation. What is the best action to take?
First, assess the need for dual antiplatelet therapy. If dual antiplatelet therapy (clopidogrel plus aspirin) is required, then a PPI is warranted for gastric protection because the risk of life-threatening bleeding outweighs any increased risk of cardiovascular events.4
If antiplatelet monotherapy (clopidogrel alone) is required, then assess the reason for antisecretory therapy.
For complicated disease, such as gastroesophageal reflux disease with Barrett esophagus or peptic strictures, PPI therapy is warranted to prevent progression or recurrence of complications. If the antisecretory therapy is being provided for noncomplicated symptomatic disorders such as nonerosive gastroesophageal reflux disease or dyspepsia, then one should try to “step down” the therapy by lowering the PPI dose as much as possible while still controlling symptoms to the patient’s tolerance, then possibly stepping further by substituting a histamine-2-receptor antagonist, an antacid, or “on-demand” use of PPIs.22,23
However, if the rationale for antisecretory therapy is simply for gastrointestinal protection, then further risk stratification for gastro intestinal bleeding should be undertaken.4 For patients with a high risk of future gastrointestinal bleeding, such as those with prior episodes of bleeding or concurrent use of nonsteroidal anti-inflammatory drugs, antisecretory therapy is still recommended. Therefore, if a patient is on monotherapy with clopidogrel, has no complicated or symptomatic gastrointestinal disorder, and does not have a high risk of gastrointestinal bleeding, then therapy with a PPI should be reconsidered.
There are no strong data to indicate that one particular PPI should be used or avoided if one of the above criteria indicates the concurrent need for clopidogrel and a PPI. In their health alert about the potential interaction, the FDA did not issue the same warning for PPIs other than omeprazole and esomeprazole, but fell short of recommending a change to another PPI because of a lack of data to support or refute a similar interaction.
Because the half-lives of clopidogrel and PPIs are short, separating their administration could in theory decrease or eliminate the risk of competitive inhibition. The PPI could be given in the morning before breakfast and the clopidogrel could be given at night, or the clopidogrel could be given at lunchtime and the PPI before dinner. Although the FDA does not believe this strategy will reduce this interaction,21 one expert in the field has suggested it.18
