Tong J Gan1, Neil Singla2, Stephen E Daniels3, Peter G Lacouture4, Lauren H Min5, Christian R D Reyes5, Daniel B Carr6. 1. Department of Anesthesiology, Stony Brook University, HSC Level 4, Rm 060 Stony Brook, NY 11794-8480, USA. 2. Lotus Clinical Research, LLC, Pasadena, CA 91105, USA. 3. Premier Research, Austin, TX 78705, USA. 4. Magidom Discovery, LLC, Lindenhurst, IL 60046 USA; Brown University School of Medicine, Providence, RI 02912 USA. 5. Hospira, a Pfizer company, Lake Forest, IL 60045, USA. 6. Javelin Pharmaceuticals, Inc, Cambridge, MA, USA (now Hospira, a Pfizer company, Lake Forest, IL 60045, USA); Department of Anesthesiology, Tufts Medical Center, Boston, MA 02111, USA. Electronic address: daniel.carr@tufts.edu.
Abstract
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-β-cyclodextrin (HPβCD) when given for ≤5days postoperatively. DESIGN: A 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. SETTING: Postoperative, with treatment initiated in the postanesthesia care unit ≤6hours postsurgery. PATIENTS: Overall, 608 abdominal/pelvic and orthopedic surgery patients met inclusion criteria and received ≥1 study medication dose. INTERVENTIONS: Patients received either HPβCD-diclofenac, ketorolac, or placebo via IV bolus injection every 6hours, for ≤5days postsurgery. MEASUREMENTS: CV 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 RESULTS:IV 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. 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 HPβCD-diclofenac does not present an added CV safety risk over placebo.
RCT Entities:
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-β-cyclodextrin (HPβCD) when given for ≤5days postoperatively. DESIGN: A 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. SETTING: Postoperative, with treatment initiated in the postanesthesia care unit ≤6hours postsurgery. PATIENTS: Overall, 608 abdominal/pelvic and orthopedic surgery patients met inclusion criteria and received ≥1 study medication dose. INTERVENTIONS:Patients received either HPβCD-diclofenac, ketorolac, or placebo via IV bolus injection every 6hours, for ≤5days postsurgery. MEASUREMENTS: CV 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 RESULTS: IV 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. 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 HPβCD-diclofenac does not present an added CV safety risk over placebo.
Authors: Tong J Gan; Neil Singla; Stephen E Daniels; Douglas A Hamilton; Peter G Lacouture; Christian Rd Reyes; Daniel B Carr Journal: J Pain Res Date: 2016-12-20 Impact factor: 3.133