Cardiovascular safety of hydroxypropyl-β-cyclodextrin-diclofenac in the management of acute postsurgical pain: a pooled analysis of 2 randomized, double-blind, placebo- and active comparator-controlled phase III clinical trials

Study Objective: Long-term use of nonsteroidal anti-inflammatory drugs, including selective and nonselective cyclooxygenase inhibitors, has been suggested to be associated with cardiovascular (CV) safety risks. Data are limited regarding CV risks associated with short-term nonsteroidal anti-inflammatory drug use, including injectable formulations, although it has been suggested that even a single dose may increase CV adverse event (AE) risk. The objective of this study was to examine the CV safety of an injectable diclofenac formulation solubilized with hydroxypropyl-beta-cyclodextrin (HP beta CD) when given for <= 5 days postoperatively. Design: A pooled analysis of CV AEs from 2 pivotal phase III clinical trials examining the efficacy and safety of intravenous (IV) HP beta CD-diclofenac vs placebo and the active comparator ketorolac was conducted. Setting: Postoperative, with treatment initiated in the postanesthesia care unit <= 6 hours postsurgery. Patients: Overall, 608 abdominal/pelvic and orthopedic surgery patients met inclusion criteria and received >= 1 study medication dose. Interventions: Patients received either HP beta CD-diclofenac, ketorolac, or placebo via IV bolus injection every 6 hours, for <= 5 days postsurgery. Measurements: CV AEs, reported by study investigators, were evaluated through the treatment period and follow-up <= 37 days after last study medication dose), and relative CV AE risks were estimated. Main Results: IV HP beta CD-diclofenac was not associated with increased treatment-emergent CV AE incidence vs placebo (11.6% vs 12.2%; relative risk, 0.96 [95% confidence interval, 0.56-1.62]). Serious CV AEs as well as treatment-related AEs were uncommon, and there were no reports of myocardial infarction or cerebrovascular accident. CV AEs were uncommon during the follow-up period, occurring in 1.3%, 0%, and 1.4% of patients in the HP beta CD-diclofenac, ketorolac, and placebo groups, respectively. Conclusions: Although a longer duration follow-up study in a larger patient population would expand our understanding of potential CV risks, the present analysis suggests that postoperative use of HP beta CD-diclofenac does not present an added CV safety risk over placebo. (C) 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).