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

Abstract

Study ObjectiveLong-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-β-cyclodextrin (HPβCD) when given for ≤5days postoperatively. DesignA pooled analysis of CV AEs from 2 pivotal phase III clinical trials examining the efficacy and safety of intravenous (IV) HPβCD-diclofenac vs placebo and the active comparator ketorolac was conducted. SettingPostoperative, with treatment initiated in the postanesthesia care unit ≤6hours postsurgery. PatientsOverall, 608 abdominal/pelvic and orthopedic surgery patients met inclusion criteria and received ≥1 study medication dose. InterventionsPatients received either HPβCD-diclofenac, ketorolac, or placebo via IV bolus injection every 6hours, for ≤5days postsurgery. MeasurementsCV AEs, reported by study investigators, were evaluated through the treatment period and follow-up (≤37days after last study medication dose), and relative CV AE risks were estimated. Main ResultsIV HPβCD-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 HPβCD-diclofenac, ketorolac, and placebo groups, respectively. ConclusionsAlthough 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 HPβCD-diclofenac does not present an added CV safety risk over placebo.