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Proton pump inhibitors (PPIs) are among the most widely used class of drugs prescribed over the long term in all of clinical medicine with 8–10% of ambulatory adults have been prescribed a PPI in the past 30 days. However, numerous studies have raised doubts about the long term safety of PPI use. The purpose of this review is threefold: (i) To provide an overview of the current evidence demonstrating associations between PPI use and adverse health outcomes and the likelihood of the associations being causal (Why?); (ii) To be able to identify long-term PPI users in whom the intensity of PPI therapy could be reduced or in whom PPIs could be eliminated outright (Who?); and (iii) To provide strategies on how to reduce or stop chronic PPI therapy while maintaining symptom control and reducing the risk for symptom or upper GI disease recurrence (How?).