title: 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: 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.
  
  
  METHODS
  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.
  
  
  METHODS
  Postoperative, with treatment initiated in the postanesthesia care unit ≤6hours postsurgery.
  
  
  METHODS
  Overall, 608 abdominal/pelvic and orthopedic surgery patients met inclusion criteria and received ≥1 study medication dose.
  
  
  METHODS
  Patients received either HPβCD-diclofenac, ketorolac, or placebo via IV bolus injection every 6hours, for ≤5days postsurgery.
  
  
  METHODS
  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.
  
  
  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.affiliation: Department of Anesthesiology, Stony Brook University, HSC Level 4, Rm 060 Stony Brook, NY 11794-8480, USA.
authors.forename: Tong J
authors.initials: TJ
authors.lastname: Gan
authors.affiliation: Lotus Clinical Research, LLC, Pasadena, CA 91105, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Singla
authors.affiliation: Premier Research, Austin, TX 78705, USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Daniels
authors.affiliation: Magidom Discovery, LLC, Lindenhurst, IL 60046 USA; Brown University School of Medicine, Providence, RI 02912 USA.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Lacouture
authors.affiliation: Hospira, a Pfizer company, Lake Forest, IL 60045, USA.
authors.forename: Lauren H
authors.initials: LH
authors.lastname: Min
authors.affiliation: Hospira, a Pfizer company, Lake Forest, IL 60045, USA.
authors.forename: Christian R D
authors.initials: CR
authors.lastname: Reyes
authors.affiliation: 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.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Carr
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D059787:Acute Pain / Q000188:drug therapy*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects; D002318:Cardiovascular Diseases / Q000139:chemically induced*; D004008:Diclofenac / Q000009:adverse effects*; D004311:Double-Blind Method; D005079:Excipients / Q000009:adverse effects; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D010149:Postoperative Pain / Q000188:drug therapy*; D055815:Young Adult; D047392:beta-Cyclodextrins / Q000009:adverse effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005079:Excipients; D047392:beta-Cyclodextrins; D004008:Diclofenac; D000073738:2-Hydroxypropyl-beta-cyclodextrin
keywords: Nonopioid analgesics; Nonsteroidal anti-inflammatory agents; Orthopedic surgery; Postoperative pain; Safety