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COX-2 Inhibitors After Cardiac Surgery - COX-2 Inhibitors After Cardiac Surgery
Description:
The goal of the trial was to evaluate the safety of the cyclooxygenase-2 (COX-2) inhibitors valdecoxib and its intravenous (IV) prodrug parecoxib compared with placebo for pain management following coronary artery bypass grafting (CABG).
Study Design
Study Design:
Patients Enrolled: 1,671
Mean Follow Up: 30 days
Mean Patient Age: Mean age 62 years
Female: 14
Patient Populations:
Undergoing elective, primary CABG with cardiopulmonary bypass; age 18-80 years; New York Heart Association class I, II, or III or an ejection fraction of ≥35%; body mass index ≤40; and weight >55 kg
Exclusions:
Thromboembolic event within three months, myocardial infarction within seven days, gastric or duodenal ulcer within 60 days, receipt of a radiographic contrast agent within 24 hours, poorly controlled diabetes mellitus, any preoperative coagulopathy, CABG without cardiopulmonary bypass, CABG with concomitant valvular or vascular surgery, cardiopulmonary bypass >3.5 hours, evidence of a new myocardial infarction, use of an intra-aortic balloon pump, cardiac index of ≤1.5 l/min/m2 of body-surface area, receipt of >2 pharmacologic infusions to support blood pressure, symptomatic dysrhythmia, a new neurologic deficit, clinically significant bleeding, hemoglobin ≤8 g/dl, urinary output <50 ml/h, creatinine level of at least 1.8 mg/dl, or an increase in the creatinine level >30% since initial screening
Primary Endpoints:
The combined incidence of predefined adverse events in the following four categories: cardiovascular events, renal events, surgical-wound complications, and GI complications
Drug/Procedures Used:
Patients were randomized to one of three groups: 1) IV parecoxib (40 mg) on the morning after surgery and then 20 mg every 12 hours for three days, followed by oral valdecoxib (20 mg) every 12 hours through day 10; 2) placebo IV every 12 hours for three days, followed by oral valdecoxib (20 mg) every 12 hours through day 10; or 3) placebo for the entire 10 days.
Concomitant Medications:
Aspirin (75-325 mg per day) through day 10. All patients had access to standard opioid medications.
Principal Findings:
Patients were randomized to parecoxib plus valdecoxib (n=555), placebo plus valdecoxib (n=556), or placebo (n=560). Both baseline and operative characteristics were similar in the three groups, with a mean time from end of surgery to study drug administration of ~20.5 hours. The majority of patients had one internal thoracic artery implant (81% in the parecoxib plus valdecoxib group and 85% in the other two treatment groups).
The primary endpoint of occurrence of at least one adverse event occurred more frequently in both the parecoxib plus valdecoxib group and the placebo plus valdecoxib group compared with the placebo group (7.4% for each treated group vs. 4.0% for placebo, risk ratio [RR] 1.9, p=0.02 for each group vs. placebo). Incidence of cardiovascular adverse events was significantly higher in the parecoxib plus valdecoxib group compared with placebo (2.0% vs. 0.5%, RR 3.7, p=0.03; placebo plus valdecoxib group 1.1%, RR 2.0, p=0.31).
There was no significant difference in the incidence of the other adverse event groupings, including renal failure or dysfunction (1.1% for parecoxib plus valdecoxib group, 0.7% for placebo plus valdecoxib group, 0.5% for placebo), upper gastrointestinal (GI) events (1.1%, 0.7%, and 0.4%, respectively), or surgical wound events (3.7%, 5.0%, and 2.9%, respectively). There was also no significant difference detected in mortality (0.7%, 0.6%, and 0.2%, respectively). The need for narcotic consumption was lower in the parecoxib plus valdecoxib group (22.4%) compared with 33.4% in the placebo plus valdecoxib group and 39.2% in the placebo group.
Interpretation:
Among patients undergoing CABG with cardiopulmonary bypass, short-term treatment with COX-2 inhibition for pain management was associated with an increase in overall adverse events and in cardiovascular adverse events compared with placebo. A smaller earlier study of parecoxib and valdecoxib suggested a possible increase in adverse events, but the study was not powered to detect whether the difference was significant.
The authors note that in patients undergoing CABG with cardiopulmonary bypass, the higher incidence of serious adverse events outweighs any analgesic benefit, and they state that selective COX-2 inhibitors should be avoided in CABG patients given the present study, as well as other recent studies in patients receiving other selective COX-2 inhibitors for the prevention of colorectal cancer, which have also shown a higher incidence of serious arterial thromboembolic events compared with placebo.
References:
Presented by Dr. Andrew Whelton at the March 2005 ACC Annual Scientific Session, Orlando, FL.
Nussmeier NA, Whelton AA, Brown MT, et al. Complications of the COX-2 Inhibitors Parecoxib and Valdecoxib after Cardiac Surgery. N Engl J Med 2005 Feb 15; [Epub ahead of print].
Keywords: Cyclooxygenase 2 Inhibitors, Coronary Disease, Pain Management, Prodrugs, Isoxazoles, Renal Insufficiency, Body Mass Index, Mammary Arteries, Narcotics, Cardiopulmonary Bypass, Colorectal Neoplasms, Coronary Artery Bypass, Sulfonamides
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