Black Box Warning: Is Ketorolac Safe for Use After Cardiac Surgery? Lisa Oliveri, BSc,*† Katie Jerzewski, BSc,*† and Alexander Kulik, MD, MPH*† Objective: In 2005, after the identification of cardiovascu- similar to those expected using Society of Thoracic Surgery lar safety concerns with the use of nonsteroidal anti- database risk-adjusted outcomes. In unadjusted analysis, inflammatory drugs (NSAIDs), the FDA issued a black box patients who received ketorolac had similar or better post- warning recommending against the use of NSAIDs following operative outcomes compared with patients who did not cardiac surgery. The goal of this study was to assess the receive ketorolac, including gastrointestinal bleeding (1.2% v postoperative safety of ketorolac, an intravenously admin- 1.3%; p ¼ 1.0), renal failure requiring dialysis (0.4% v 3.0%; istered NSAID, after cardiac surgery. p ¼ 0.001), perioperative myocardial infarction (1.0% v 0.6%; Design: Retrospective observational study. p ¼ 0.51), stroke or transient ischemic attack (1.0% v 1.7%; Setting: Single center, regional hospital. p ¼ 0.47), and death (0.4% v 5.8%; p o 0.0001). With adjust- Participants: A total of 1,309 cardiac surgical patients ment in a multivariate model, treatment with ketorolac was (78.1% coronary bypass, 28.0% valve) treated between 2006 not a predictor for adverse outcome in this cohort (odds and 2012. ratio: 0.72; p ¼ 0.23). Interventions: A total of 488 of these patients received Conclusions: Ketorolac appears to be well-tolerated for ketorolac for postoperative analgesia within 72 hours of use when administered selectively after cardiac surgery. surgery. Although a black box warning exists, the data highlights Measurement and Main Results: Ketorolac-treated the need for further research regarding its perioperative patients were younger, had better preoperative renal func- administration. tion, and underwent less complex operations compared & 2014 Elsevier Inc. All rights reserved. with non-ketorolac patients. Ketorolac was administered, on average, 8.7 hours after surgery (mean doses: 3.1). KEY WORDS: analgesia, postoperative, cardiac surgery, Postoperative outcomes for ketorolac-treated patients were safety, ketorolac, NSAIDs AIN MANAGEMENT AFTER SURGERY is critical to postoperative setting after CABG surgery”.10 This FDA black Pmaintaining the physical and psychological well-being box warning was issued as a result of two landmark studies that of a patient. A common problem, poorly controlled pain after evaluated the safety of the cyclooxygenase-2 (COX-2) inhib- surgery, increases heart rate, systemic vascular resistance, and itors parecoxib and valdecoxib after cardiac surgery. Inves- circulating catecholamines, placing patients at risk of myo- tigators noted that the perioperative administration of these cardial ischemia, stroke, bleeding, and other complications.1 agents significantly increased the risk of adverse cardiovascular Postoperative analgesia after cardiac surgery most commonly events after CABG, including myocardial infarction (MI), involves the use of intravenous and oral opioids. Narcotic stroke, cardiac arrest, and pulmonary embolism.11,12 As a medications provide excellent analgesia, but undesirable consequence, valdecoxib was taken off the market, and the side effects constitute major limitations, such as respiratory black box warning was issued for all NSAIDs after cardiac depression, sedation, and nausea. To limit these adverse surgery. effects without sacrificing adequate pain management, non- In contrast to COX-2 inhibitors, ketorolac is a traditional steroidal anti-inflammatory drugs (NSAIDs), such as keto- NSAID without COX-2 selectivity (COX-1/COX-2 ratio rolac, increasingly are being applied in the postoperative 0.36).13 Although ketorolac has been shown to be an effective setting.2 Although NSAIDs have potential side effects (bleed- analgesic,6–9 to the authors’ knowledge, little data are available ing, gastrointestinal ulceration, and renal dysfunction), several evaluating the safety profile of ketorolac administration after studies have noted low complication rates associated with their cardiac surgery. In spite of the warnings regarding the theoretic short-term use after coronary artery bypass graft surgery risks, ketorolac has been administered selectively to cardiac (CABG) when administered to appropriately selected surgery patients for the past 6 years at this hospital as a method patients.3–5 of improving postoperative pain control and reducing opioid Despite the analgesic properties and safety profile of use. The aim of the current study was to review the safety of ketorolac,6–9 the United States Food and Drug Administration ketorolac when administered to select patients recovering from (FDA) recommended in 2005 that the labeling for ketorolac CABG and other cardiac surgery. include a contraindication “for use in patients in the immediate METHODS The authors performed a retrospective observational study, drawing From the *Charles E. Schmidt College of Medicine, Florida Atlantic this cohort (N = 1,309) from the hospital Society of Thoracic Surgery University, Boca Raton, Florida; and †Lynn Heart and Vascular (STS) database that includes preoperative, intraoperative, and post- Institute, Boca Raton Regional Hospital, Boca Raton, Florida. operative clinical information regarding all patients who have under- Address reprint requests to Alexander Kulik, Lynn Heart and Vas- gone cardiac surgery procedures at Boca Raton Regional Hospital since cular Institute, Boca Raton Regional Hospital, 801 Meadows Road, 2006. In addition, the hospital clinical pharmacy database was used to Suite 104, Boca Raton, Florida, 33486. E-mail: [email protected] identify all cardiac surgery patients who received ketorolac (ketorolac © 2014 Elsevier Inc. All rights reserved. tromethamine, also known as Toradol, West-Ward Pharmaceuticals, 1053-0770/2605-0031$36.00/0 Eatontown, New Jersey) in the postoperative period (n = 488). This http://dx.doi.org/10.1053/j.jvca.2013.07.014 pharmacy database is an audited and verified source for all inpatient 274 Journal of Cardiothoracic and Vascular Anesthesia, Vol 28, No 2 (April), 2014: pp 274–279 KETOROLAC AFTER CARDIAC SURGERY 275 medication administration and contains a record of all medications, renal insufficiency, gastrointestinal bleeding, or death. Risk-stratified including dosing amounts and frequencies. Additional data were (expected) outcomes for the patients who received ketorolac were collected as part of a retrospective chart review to confirm demographic calculated through the application of the STS database based on patient and clinical information. The current study was approved by the demographic and operative characteristics. institutional review board of the Boca Raton Regional Hospital, Boca Standard descriptive statistical analyses were used. Continuous data Raton, Florida. Because of the retrospective nature of the study, the are presented as a mean Ϯ standard deviation, and categoric data are need for patient informed consent was waived by the institutional presented as proportions. Comparisons between patients who did (n ¼ review board. 488) or did not (n ¼ 821) receive ketorolac were performed using Patients who underwent cardiac surgical procedures, including on- unpaired two-sided Student’s t tests or a Fisher’s exact test, as pump or off-pump CABG, valve surgery, atrial fibrillation (Maze) appropriate. Subgroup analysis was performed focusing only on procedures, and pericardial window surgery were included. Patients isolated primary (non-redo) CABG patients (n ¼ 775) who did (n ¼ were included from September 2006 (program initiation date) to July 328) or did not receive ketorolac (n ¼ 447), and also focusing only on 2012. Patients were categorized based on whether they did or did not male patients under the age of 70 who underwent isolated primary receive ketorolac after surgery. Ketorolac treatment was not a random- CABG surgery (n ¼ 287) who did (n ¼ 167) or did not (n ¼ 120) ized intervention. In general, patients were selected for ketorolac receive ketorolac. administration by the operating surgeon if they reported moderate or Multivariate logistic regression analysis was used to identify severe pain after surgery despite opioid analgesia, to facilitate early independent predictors of the composite adverse outcome. All factors extubation and ambulation. Ketorolac was not administered to patients that differed between the two groups (Table 1) were considered in the who had pain that was well-controlled with opioid medications or to model. Factors tested in the model included the use of ketorolac, age, those with obvious contraindications to NSAID administration (NSAID gender, BMI, diabetes, hypertension, hyperlipidemia, previous MI, allergy, history of gastrointestinal bleeding, or renal dysfunction with ejection fraction, preoperative hematocrit, preoperative creatinine, redo creatinine 42.0 mg/dL). Patients who were expected to have longer surgery, off-pump surgery, cardiopulmonary bypass time, and the need postoperative ventilation times (eg, after complicated redo or combined for valve intervention. Stepwise forward selection and backward operations) typically did not receive ketorolac postoperatively, because elimination techniques were used, with p ¼ 0.20 for entry and removal patient comfort usually could be achieved with opioid and anesthetic criteria, except for the use of ketorolac, which was forced into the agents. model. Odds ratios (OR) are reported with 95% confidence