To the Editor:
We appreciate the comments by Dr. Jarolem on the use of selective COX-2 (cyclooxygenase-2) inhibitors for the management of pain following spinal fusion surgery. Despite the recent controversies concerning the cardiovascular risk of coxibs, we continue to believe that this class of NSAIDs represents a significant therapeutic advance in the perioperative management of orthopaedic pain. Since the publication of a recent editorial by Drs. Bhattacharyya and Smith(1) addressing the cardiovascular risks of coxibs from the orthopaedic perspective, there have been significant regulatory changes concerning the use of all nonsteroidal anti-inflammatory drugs (NSAIDs). In light of the rapid climate of change surrounding this class of analgesics, this review will highlight the important developments within the class of COX-2 and non-selective NSAIDs.
Merck & Co. (Whitehouse Station, New Jersey) voluntarily withdrew rofecoxib from the worldwide market on September 30, 2004 after examining the interim results from the Adenomatous Polyp Prevention on Vioxx (APPROVe) study(2). This long-term, randomized, prospective, placebo-controlled, double-blind multicenter study was designed to investigate the effects of three years of treatment with rofecoxib 25 mg daily on the risk of recurrent neoplastic polyps of the large bowel in patients with a history of colorectal adenomas. A total of 46 patients in the rofecoxib group had a confirmed thrombotic event during 3059 patient-years follow-up (1.50 events per 100 patient-years), as compared with 26 patients in the placebo group during 3327 patient-years of follow-up (0.78 event per patient-years); the corresponding relative risk was 1.92 (95 percent confidence interval, 1.19 to 3.11; P=0.008). The increased risk became apparent after 18 months of treatment; during the first 18 months, the event rates were similar in the two groups.
Subsequently, on December 17, 2004, Pfizer Inc. (New York, New York) informed the Food and Drug Administration (FDA) that it was halting its Adenoma Prevention with Celecoxib (APC) trial because of an increase in the incidence of cardiovascular events. The APC trial examined the efficacy of celecoxib (200 mg or 400 mg twice daily) with placebo for thirty-three months for the prevention of colorectal adenomas(3). Celecoxib was associated with a dose-related increase in the composite end point of death from cardiovascular causes, myocardial infarction, stroke, or heart failure. These cardiovascular events occurred in 7 of 679 patients in the placebo group (1.0 percent), as compared with 16 of 685 patients receiving 200 mg of celecoxib twice daily (2.3 percent; hazard ratio 2.3; 95 percent confidence interval, 0.9 to 5.5) and with 23 of 671 patients receiving 400 mg celecoxib twice daily (3.4 percent; hazard ratio, 3.4; 95 percent confidence interval, 1.4 to 7.8). Similar to the APPROVe study, the increased risk did not become apparent until after 12 months of treatment.
The results of the APC trial were inconsistent with a second trial investigating the efficacy of celecoxib for the prevention of colorectal neoplasia. The Prevention of Spontaneous Adenomatous Polyps (PreSAP) trial(4) included patients taking 400 mg of celecoxib daily (n=933) or placebo (n=628) for an average of 32 months. This study revealed no increased cardiovascular risk for celecoxib patients compared with those taking placebo. These cardiovascular events occurred in 12 of 628 patients in the placebo group (1.9 percent), as compared with 20 of 933 patients receiving 400 mg of celecoxib daily (2.1 percent; 95 percent confidence interval, 0.6 to 2.3). The relative risk of celecoxib compared to placebo was 1.1. These findings were based on an identical analysis used to assess cardiovascular risk in the APC trial, and the analysis was conducted by the same independent cardiovascular safety review board.
A third long-term study with celecoxib was initiated to investigate the effects of COX-2 inhibition in the prevention of Alzheimer’s disease. The Alzheimer’s Disease Anti-Inflammatory Prevention Trial (ADAPT)(5), sponsored by the National Institute of Health, enrolled approximately 2,500 volunteers greater than 70 years of age who were at risk for developing Alzheimer’s disease. This prospective, double-blind, randomized trial compared the effects of celecoxib 200 mg twice daily to naproxen 220 mg twice daily or placebo for up to three years. On December 20, 2004 the National Institute of Health suspended this clinical trial because of an increase in cardiovascular and cerebrovascular events among those patients taking naproxen compared to placebo(6). Preliminary data from this study did not indicate an increased risk for heart attack or stroke for celecoxib. This study is of significant clinical importance. While previous prospective, long-term coxib studies have used placebo for comparison, this is the first trial to use a nonspecific NSAID as a comparator drug.
We are now left to question whether the increased cardiac risk associated with cyclooxygenase inhibition unique to COX-2 inhibitors or is it characteristic for all NSAIDs? A joint meeting of the FDA’s Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee convened on February 16-18, 2005 to discuss the safety of COX-2 inhibitors and non-specific NSAIDs(7). The FDA Advisory Committee reaffirmed that COX-2 inhibitors are important treatment options for pain management and that the preponderance of data demonstrates that the cardiovascular risk associated with celecoxib is similar to those associated with commonly used older non-specific NSAIDs. The Committee concluded that rigorous scientific studies are needed to characterize the longer-term cardiovascular risks of all NSAIDs. After this meeting, on April 7, 2005, the FDA announced a series of changes to the entire class of NSAIDs(8). These included a FDA boxed warning for the potential increased risk of cardiovascular events and gastrointestinal bleeding associated with all prescription NSAIDs, including celecoxib. The manufacturers were asked to revise their labeling to include a Medication Guide for patients to help make them aware of the potential for cardiovascular and gastrointestinal adverse events. In addition, the FDA is asking the manufacturers of all over-the-counter (OTC) NSAIDs to revise their labels to include more specific information about the potential cardiovascular and gastrointestinal risks, and information to assist consumers in the safe use of these drugs. Finally, the FDA concluded the overall risk versus benefit profile of valdecoxib is unfavorable, and has requested that Pfizer voluntarily withdraw valdecoxib from the market. This request was based on: 1) The lack of adequate data on the cardiovascular safety of long-term use of valdecoxib, along with the increased risk of adverse cardiovascular events in short-term coronary artery bypass surgery (CABG) trials(9,10) that the FDA believes may be relevant to chronic use; 2) Reports of serious and potentially life-threatening skin reactions, including deaths, in patients taking valdecoxib. The risk of these reactions in individual patients is unpredictable, occurring in patients with and without a prior history of sulfa allergy, and after both short- and long-term use; and 3) Lack of demonstrated advantages for valdecoxib compared with other NSAIDs. Pfizer has agreed to suspend sales and marketing of valdecoxib pending further discussions with the FDA.
With rofecoxib and valdecoxib removed from the market, we are currently left with celecoxib as the only FDA approved COX-2 NSAID for the management of pain. With the current cardiovascular controversies surrounding COX-2 NSAIDs, and the concern that these drugs may delay fracture-healing and tendon-healing(11,12), should we prescribe celecoxib for the management of acute orthopaedic pain? We continue to believe that coxibs offer a significant advantage compared to non-specific NSAIDs for a variety of orthopaedic surgical procedures. Although the preoperative administration of nonspecific NSAIDs may provide effective analgesia, their ability to decrease platelet aggregation and increase bleeding time(13) may increase the risk of perioperative bleeding(14,15). Prior to the introduction of coxibs, all of our patients undergoing elective total joint arthroplasty were instructed to discontinue their use of NSAIDs 7-10 days prior to surgery. Continuing NSAIDs before total hip arthroplasty has been associated with a two-fold increase in the incidence of perioperative bleeding(16). We have observed that discontinuing NSAIDs before total joint arthroplasty results in an arthritic flare, not only in the operative joint, but also in other arthritic joints, leading to increased preoperative pain (17). Increased pain before total joint arthroplasty is the leading cause for increased postoperative pain, prolonged hospital admission, and impaired rehabilitation (18). The administration of perioperative coxibs for total joint arthroplasty has demonstrated a reduction in perioperative pain and improvement in outcomes without an added risk of increased perioperative bleeding(17,19). Further, a retrospective review of over 1500 patients receiving coxibs for 5 to 14 days following total joint arthroplasty at our institution revealed no increased risk for cardiovascular events compared to non-NSAID users (unpublished data).
Perioperative coxib administration offers significant advantages for anterior cruciate ligament (ACL) repair surgery. In a retrospective study of 1200 patients undergoing ACL surgery, the preemptive administration of coxibs demonstrated a reduction in the incidence of pain, opioid use, postoperative nausea and vomiting, recovery room length of stay, and unplanned admission to the hospital
(20). In addition, the perioperative coxib administration for 14 consecutive days had no deleterious effect on bone or ligament healing at one year follow-up. Although intravenous ketorolac can provide effective analgesia for ACL surgery(21) it is currently contraindicated for use as a preemptive analgesic(22). We have observed increased perioperative bleeding with the preemptive administration of either ketorolac or ibuprofen for outpatient ACL surgery and have since discontinued its use(23). We are currently performing a prospective, randomized, double-blind study assessing the effect of administering COX-2 NSAIDs on bone and ligament healing in patients receiving coxibs for ACL surgery.
Finally, we have recently shown the efficacy of celecoxib for spinal fusion surgery(24). This prospective, randomized, double-blind study revealed improved analgesia with no deleterious effects on bone healing. In addition, we have reported that patients who were administered celecoxib reported a significantly (P<0.01) lower incidence of chronic donor site pain (4/40, 10%) in the celecoxib group compared to the placebo group (12/40, 30%) at 1 year following surgery(25).
In summary, the perioperative administration of coxibs provides for improved analgesia and outcomes with a reduction in opioid-related side effects following a variety of orthopaedic surgeries. The short-term administration of celecoxib results in no significant deleterious effect on bone or ligament healing or adverse cardiovascular outcomes. The long-term administration of coxibs, including celecoxib, has not been evaluated following orthopaedic surgery. However, we believe the possible adverse cardiovascular risks associated with celecoxib are no different than that posed by nonspecific NSAIDs. In light of the recent controversial events involving NSAIDs, we believe celecoxib offers a significant therapeutic advance in the management of pain, and continue to administer this drug short-term for orthopaedic surgery.
References
1. Battacharyya T, Smith RM. Cardiovascular risks of coxibs: The
orthopaedic perspective. J Bone Joint Surg Am 2005;87:245-6.
2. Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan
K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA.
Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators.
Cardiovascular events associated with rofecoxib in a colorectal adenoma
chemoprevention trial. N Engl J Med 2005;352:1092-102.
3. Solomon SD, McMurray JV, Pfeffer MA, Wittes J, Fowler R, Finn P,
Anderson WF, Zauber A, Hawk E, Bertagnolli M. Adenoma Prevention with
Celecoxib (APC) Study investigators. Cardiovascular risk associated with
celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J
Med 2005;352:1071-80.
4. Levin B. Overview of colorectal chemoprevention trials. March 12,
2002. Available
at:http://www.fda.gov/ohrms/dockets/ac/02/slides/384s1_03_Levin.ppt.
Accessed April 14, 2005.
5. National Institute of Health. Use of non-steroidal anti-
inflammatory drugs suspended in large Alzheimer’s disease prevention
trial. December 20, 2004. Available at:
http://www.nih.gov/news/pr/dec2004/od20.htm. Accessed April 14, 2005.
6. Associated Press. Concerns raised about naproxen. Alzheimer’s
study halted over heart attack increase. December 20, 2004. Available at:
http://us.cnn.com/2004/HEALTH/12/20/study.halted.ap. Accessed April 14,
2005
7. Drug Safety and Risk Management Advisory committee. Feruary 16-18
2005 Joint meeting with the Arthritis Drug Advisory Committee. February
18, 2005. Available at:
http://fda.gov/ohrms/dockets/ac/cder05.html#DrugSafetyRiskMgmt. Accessed
April 14, 2005.
8. FDA Public Health Advisory. FDA announces important changes and
additional warnings for COX-2 selective and non-selective non-steroidal
anti-inflammatory drugs (NSAIDs). April 7, 2005. Available at:
http://www.fda.gov/cder/drug/advisory/COX2.htm. Accessed April 14, 2005.
9. Ott E, Nussmeier NA, Duke PC, Feneck RO, Alston RP, Snabes MC,
Hubbard RC, Hsu PH, Saidman LJ, Mangano DT; Multicenter Study of
Perioperative Ischemia (McSPI) Research Group; Ischemia Research and
Education Foundation (IREF) Investigators. Efficacy and safety of the
cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients
undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg
2003;125:1481-92.
10. Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow
JL, Boyce SW, Verburg KM. Complications of the COX-2 inhibitors parecoxib
and valdecoxib after cardiac surgery. New Engl J Med 2005;352:1081-91.
11. Elder CL, Dahners LE, Weinhold PS. A cyclooxygenase-2 inhibitor
impairs ligament healing in the rat. Am J Sports Med 2001;29:801-5.
12. Gerstenfeld LC, Thiede M, Seibert K, Mielke C, Phippard D, Svagr
B, Cullinane D, Einhorn TA. Differential inhibition of fracture healing by
non-selective and cyclooxygenase-2 selective non-steroidal anti-
inflammatory drugs. J Orthop Res 2003;21:670-5.
13. Schafer AI. Effects of non-steroidal anti-inflammatory therapy on
platelets. Am J Med 1999;106:25S-35S.
14. Souter AJ, Fredman B, White PF. Controversies in the
perioperative use of nonsteroidal anti-inflammatory drugs. Anesth Analg
1994;79:1178-90.
15. Connelly CS, Panush RS. Should nonsteroidal anti-inflammatory
drugs be stopped before elective surgery? Arch Intern Med 1991;151:1963-6.
16. Robinson CM, Christie J, Malcolm-Smith N. Nonsteroidal
antiinflammatory drugs, perioperative blood loss, and transfusion
requirements in elective hip arthroplasty. J Arthroplasty 8:607, 1993.
17. Reuben SS, Fingeroth R, Krushell R, Maciolek H. Evaluation of the
safety and efficacy of the perioperative administration of rofecoxib for
total knee arthroplasty. J Arthroplasty 2002;17(1):26-31.
18. Brander VA, Stulberg SD, Adams AD, Harden RN, Bruehl S, Stanos
SP, Houle T. Predicting total knee replacement pain. A prospective,
observational study. Clin Orthop 2003;416:27-36.
19. Buvenandran A, Kroin JS, Tuman KJ, Lubenow TR, Elmofty D, Moric
M, Rosenburg AG. Effects of perioperative administration of a selective
cyclooxygenase 2 inhibitor on pain management and recovery of function
after knee replacement. JAMA 2003;290:2411-8.
20. Reuben SS, Gutta SB, Maciolek H, Sklar J. Effect of initiating a
multimodal analgesic regimen upon patient outcomes after anterior cruciate
ligament reconstruction for same-day surgery: a 1200-patient case series.
Acute Pain 2004;6:87-93.
21. McGuire DA, Sanders K, Hendricks SD. Comparison of ketorolac and
opioids analgesics in postoperative ACL reconstruction outpatient pain
control. Arthroscopy 1993;9:653-61.
22. Toradol® [package insert]. Nutley, NJ: Roche Pharmaceuticals,
2005.
23. Reuben SS, Sklar J. Postoperative pain management for outpatient
arthroscopic knee surgery. Current Concepts Review. J Bone Joint Surg
2000;82:1754-66.
24. Reuben SS, Ekman E. The effect of cyclooxygenase-2 inhibition on
analgesia and spinal fusion. J Bone Joint Surg Am 2005;87(3):536-42.
25. Reuben SS, Kuppinger J, Ekman EF.the effect of perioperative
celecoxib administration on acute and chronic donor site pain following
spinal fusion surgery. Anesth Analg 2005;100;S-298 [abstract].
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