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Adverse Effects of Etoricoxib: Other Considerations
LETTERS TO THE LETTERS TOEDITOR THE EDITOR Duration of Anesthesia, Vascular Surgical Trauma, and Venous Thromboembolism To the Editor: Jaffer et al,1 in the June 2005 issue of the Mayo Clinic Proceedings, reported a marked association between the duration of anesthesia and postoperative venous thromboembolism (VTE) in patients who underwent joint arthroplasty. The authors stated that during anesthesia, venous stasis occurs (venographically evidenced), probably resulting from both the supine position and the effects of anesthesia (increased venous capacitance). They concluded that longer duration of anesthesia may be an important risk factor for postoperative VTE. Although venous stasis is a very important pathogenic factor for the development of VTE, it is useful to remember that surgery of the knee joint (extremely close to the vein) has a risk of VTE similar to surgeries that usually induce greater tissue trauma (hip or abdominal surgery).2 Furthermore, in patients recovering from hip replacement, 90% of proximal thrombi occur on the operated side,2 suggesting a local venous problem. Time-consuming arthroplasty results usually from anatomical difficulties and/or from inexperience or inability of the surgeon, which may lead to greater local trauma. The pressure and traction exerted by bones or instruments over adjacent tissues are sometimes enormous, and the veins are extremely close to the hip and knee joints. Usually, the greater the difficulty, the greater the traction. Vascular endothelium, which has antithrombotic properties, is friable and is removed easily from vessels with simple cotton; vascular endothelium probably is removed when vessels are compressed as well. We suggest that the marked association between the duration of anesthesia and postoperative VTE may also result from local vascular or endothelial trauma caused by anatomical difficulties and/or by surgeon inexperience or inability. Fernando Martins do Vale, MD, PhD Instituto Farmacologia e Laboratório Neurociências Lisboa, Portugal 1. Jaffer AK, Barsoum WK, Krebs V, Hurbanek JG, Morra N, Brotman DJ. Duration of anesthesia and venous thromboembolism after hip and knee arthroplasty. Mayo Clin Proc. 2005;80:732-738. 2. Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003;107:(23, suppl 1)I-9–I-16.
In reply: We wholeheartedly agree with Dr Martins do Vale’s comment that local trauma to the veins during knee and hip replacement is 1 plausible mechanism by which longer duration of orthopedic surgery predisposes patients to VTE. Indeed, in our original article, we stated that it was impossible to conclude that longer duration of anesthesia is a causal factor for VTE and that it may be just a marker for any number of © 2005 Mayo Foundation for Medical Education and Research
Mayo Clin Proc.
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complexities or complications that may occur in the operating room. Nevertheless, regardless of the mechanism, we believe that anesthesia duration serves as a measurable and useful indicator for situations in which a surgeon encounters technical issues (such as a difficult joint disarticulation, extensile scar tissue, or contracture releases) or for situations in which a less experienced surgeon takes longer to perform a difficult joint replacement. Furthermore, in keeping with our findings and with the comments of Dr Martins do Vale, revision surgery not only takes longer than primary arthroplasty but also involves more tissue trauma because the tissue has been subjected to both remote and present trauma and the scar tissue around the joint is less pliable and more likely to damage vascular structures when manipulated. These technical factors remain difficult to quantify, but in our experience, all translate into longer duration of anesthesia. In conclusion, we concur that local trauma may simultaneously extend the duration of surgery and contribute to overall risk of VTE, but since these factors are difficult (if not impossible) to quantify, they were not analyzed in our study. Amir K. Jaffer, MD Wael K. Barsoum, MD Viktor Krebs, MD Cleveland Clinic Foundation Cleveland, Ohio Daniel J. Brotman, MD Johns Hopkins Hospital Baltimore, Md
Adverse Effects of Etoricoxib: Other Considerations To the Editor: We read with interest the article by Wiesenhutter et al1 on etoricoxib, published in the April 2005 issue of the Mayo Clinic Proceedings. The article described etoricoxib as having a favorable gastrointestinal safety and tolerability profile. We agree with the authors’ description of the favorable gastrointestinal safety and tolerability of etoricoxib. However, it is necessary to compare its safety and tolerability profiles for aspirin users and non–aspirin users. In the Celebrex Long-term Arthritis Safety Study (CLASS),2 the risk of gastrointestinal bleeding among non–aspirin users was less for those using celecoxib than for those using ibuprofen or diclofenac. However, among aspirin users, there was no significant difference in gastrointestinal bleeding in patients using celecoxib, ibuprofen, or diclofenac. Of course, there was a difference in the permitted dosage of aspirin in CLASS vs the Wiesenhutter et al study. Up to 325 mg/d of aspirin was permitted in CLASS but only up to 100 mg/d in the Wiesenhutter et al study. Even though the risk of gastrointestinal bleeding increases with increasing doses of aspirin, Weil et al3 found that the odds ratio for adverse upper
September 2005;80(9):1233-1236, 1238, 1240-1241
•
www.mayoclinicproceedings.com
1233
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
LETTERS TO THE EDITOR
gastrointestinal events was 2.3 with a daily 75-mg dose of aspirin, increasing to 3.2 with a 150-mg dose. Therefore, it is important to analyze the data separately for aspirin users and non–aspirin users. Furthermore, we cannot easily conclude that etoricoxib was well tolerated. Wiesenhutter et al reported long-term assessment of the cardiovascular safety of etoricoxib in 2 large ongoing studies with up to 2 years of treatment. We agree that long-term follow-up should be conducted. As shown by the Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial,4 thrombotic events associated with rofecoxib use increased after 18 months of treatment, and congestive heart failure, pulmonary edema, or cardiac failure increased after 5 months of treatment. Therefore, a 12-week follow-up in the Wiesenhutter et al study is too short to detect any cardiovascular adverse effects. More time is needed to prove the safety of etoricoxib. In the Wiesenhutter et al study, the authors concluded that in patients with osteoarthritis, treatment with etoricoxib, 30 mg/d, provides sustained therapeutic efficacy that is clinically comparable to ibuprofen, 2400 mg/d. However, until now, the usual dosage of etoricoxib has been 60 mg/d to 120 mg/d. Therefore, if 30 mg/d is enough to control the pain of osteoarthritis, a 30-mg tablet should be marketed and recommended because the adverse effect profile may be dose related, as was shown in the rofecoxib study.5 The effects of rofecoxib discontinuation were serious in terms of patients being separated from a drug that provided good analgesia, adverse effects including hypertension and peripheral edema, and other concerns. Thus, we hope for newer cyclooxygenase 2 inhibitors that are safer and more effective. Perhaps etoricoxib is one such drug.
mg, for patients with osteoarthritis. The first issue they raised was the safety and tolerability of etoricoxib with respect to low-dose aspirin users and nonusers. This study was not of sufficient size to specifically evaluate gastrointestinal (GI) safety and tolerability in the context of aspirin use. Although the treatment groups were balanced with respect to the proportion of aspirin users, they constituted only about 22% of the enrolled patient population. Furthermore, there were no reported upper GI bleeding events in this study. Currently available clinical data suggest that aspirin increases the risk of upper GI events in patients treated with either selective cyclooxygenase inhibitors or nonselective nonsteroidal antiinflammatory drugs (NSAIDs), but data that address the effect of aspirin on relative risk are limited. Therefore, we agree that additional clinical data are needed to adequately assess the safety of selective cyclooxygenase 2 inhibitors, including etoricoxib and nonselective NSAIDs, in the context of aspirin use. The conclusion that etoricoxib was well tolerated compared with placebo and ibuprofen over a 12-week period is justified in the context of this study. However, as stated in our article and by Dr Kim and colleagues, long-term data regarding cardiovascular safety with etoricoxib are needed. Ongoing studies with etoricoxib are designed to assess its long-term cardiovascular safety compared with that of diclofenac, the world’s most commonly used traditional NSAID. Regarding the dose, there are patients who benefit from lower doses of anti-inflammatory drugs, depending on their degree of pain and their tolerance of adverse effects. The goal of our study was to help provide important information about lower-dose etoricoxib. Additional studies and discussions with regulatory agencies will determine whether commercialization of a lower dose(s) is possible.
Jeong A. Kim, MD Youn Seon Choi, MD Su Hyun Kim, MD Korea University Seoul, South Korea 1. Wiesenhutter CW, Boice JA, Ko A, et al, Protocol 071 Study Group. Evaluation of the comparative efficacy of etoricoxib and ibuprofen for treatment of patients with osteoarthritis: a randomized, double-blind, placebocontrolled trial. Mayo Clin Proc. 2005;80:470-479. 2. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. JAMA. 2000;284:1247-1255. 3. Weil J, Colin-Jones D, Langman M, et al. Prophylactic aspirin and risk of peptic ulcer bleeding. BMJ. 1995;310:827-830. 4. Bresalier RS, Sandler RS, Quan H, et al, Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005;352:1092-1102. 5. Graham DJ, Campen D, Hui R, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet. 2005;365:475-481.
In reply: We thank Dr Kim and colleagues for their comments regarding our clinical study, which evaluated etoricoxib, 30 1234
Mayo Clin Proc.
•
Judith A. Boice, PhD Merck Research Laboratories Rahway, NJ Craig W. Wiesenhutter, MD Coeur d’Alene Arthritis Clinic Coeur d’Alene, Idaho
Molecular Autopsy vs Postmortem Genetic Testing To the Editor: The article by Tester et al1 in the May 2005 issue of the Mayo Clinic Proceedings is a beautiful example of the application of molecular techniques in the investigation of unexplained sudden death. Such results not only further our understanding of this topic but also provide a specific diagnosis and a sense of closure for the family of the deceased. However, in the current article and in one published in the Mayo Clinic Proceedings in 2004, Tester et al1,2 seemed to use the term molecular autopsy as if this were an independent standalone procedure. In fact, the molecular autopsy represents a new tool that can be added to our existing armamentarium of tests that are available during postmortem evaluations.
September 2005;80(9):1233-1236, 1238, 1240-1241
•
www.mayoclinicproceedings.com
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
In reply: We wholeheartedly agree with Dr Martins do Vale’s comment that local trauma to the veins during knee and hip replacement is 1 plausible mechanism by which longer duration of orthopedic surgery predisposes patients to VTE. Indeed, in our original article, we stated that it was impossible to conclude that longer duration of anesthesia is a causal factor for VTE and that it may be just a marker for any number of © 2005 Mayo Foundation for Medical Education and Research
Mayo Clin Proc.
•
complexities or complications that may occur in the operating room. Nevertheless, regardless of the mechanism, we believe that anesthesia duration serves as a measurable and useful indicator for situations in which a surgeon encounters technical issues (such as a difficult joint disarticulation, extensile scar tissue, or contracture releases) or for situations in which a less experienced surgeon takes longer to perform a difficult joint replacement. Furthermore, in keeping with our findings and with the comments of Dr Martins do Vale, revision surgery not only takes longer than primary arthroplasty but also involves more tissue trauma because the tissue has been subjected to both remote and present trauma and the scar tissue around the joint is less pliable and more likely to damage vascular structures when manipulated. These technical factors remain difficult to quantify, but in our experience, all translate into longer duration of anesthesia. In conclusion, we concur that local trauma may simultaneously extend the duration of surgery and contribute to overall risk of VTE, but since these factors are difficult (if not impossible) to quantify, they were not analyzed in our study. Amir K. Jaffer, MD Wael K. Barsoum, MD Viktor Krebs, MD Cleveland Clinic Foundation Cleveland, Ohio Daniel J. Brotman, MD Johns Hopkins Hospital Baltimore, Md
Adverse Effects of Etoricoxib: Other Considerations To the Editor: We read with interest the article by Wiesenhutter et al1 on etoricoxib, published in the April 2005 issue of the Mayo Clinic Proceedings. The article described etoricoxib as having a favorable gastrointestinal safety and tolerability profile. We agree with the authors’ description of the favorable gastrointestinal safety and tolerability of etoricoxib. However, it is necessary to compare its safety and tolerability profiles for aspirin users and non–aspirin users. In the Celebrex Long-term Arthritis Safety Study (CLASS),2 the risk of gastrointestinal bleeding among non–aspirin users was less for those using celecoxib than for those using ibuprofen or diclofenac. However, among aspirin users, there was no significant difference in gastrointestinal bleeding in patients using celecoxib, ibuprofen, or diclofenac. Of course, there was a difference in the permitted dosage of aspirin in CLASS vs the Wiesenhutter et al study. Up to 325 mg/d of aspirin was permitted in CLASS but only up to 100 mg/d in the Wiesenhutter et al study. Even though the risk of gastrointestinal bleeding increases with increasing doses of aspirin, Weil et al3 found that the odds ratio for adverse upper
September 2005;80(9):1233-1236, 1238, 1240-1241
•
www.mayoclinicproceedings.com
1233
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
LETTERS TO THE EDITOR
gastrointestinal events was 2.3 with a daily 75-mg dose of aspirin, increasing to 3.2 with a 150-mg dose. Therefore, it is important to analyze the data separately for aspirin users and non–aspirin users. Furthermore, we cannot easily conclude that etoricoxib was well tolerated. Wiesenhutter et al reported long-term assessment of the cardiovascular safety of etoricoxib in 2 large ongoing studies with up to 2 years of treatment. We agree that long-term follow-up should be conducted. As shown by the Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial,4 thrombotic events associated with rofecoxib use increased after 18 months of treatment, and congestive heart failure, pulmonary edema, or cardiac failure increased after 5 months of treatment. Therefore, a 12-week follow-up in the Wiesenhutter et al study is too short to detect any cardiovascular adverse effects. More time is needed to prove the safety of etoricoxib. In the Wiesenhutter et al study, the authors concluded that in patients with osteoarthritis, treatment with etoricoxib, 30 mg/d, provides sustained therapeutic efficacy that is clinically comparable to ibuprofen, 2400 mg/d. However, until now, the usual dosage of etoricoxib has been 60 mg/d to 120 mg/d. Therefore, if 30 mg/d is enough to control the pain of osteoarthritis, a 30-mg tablet should be marketed and recommended because the adverse effect profile may be dose related, as was shown in the rofecoxib study.5 The effects of rofecoxib discontinuation were serious in terms of patients being separated from a drug that provided good analgesia, adverse effects including hypertension and peripheral edema, and other concerns. Thus, we hope for newer cyclooxygenase 2 inhibitors that are safer and more effective. Perhaps etoricoxib is one such drug.
mg, for patients with osteoarthritis. The first issue they raised was the safety and tolerability of etoricoxib with respect to low-dose aspirin users and nonusers. This study was not of sufficient size to specifically evaluate gastrointestinal (GI) safety and tolerability in the context of aspirin use. Although the treatment groups were balanced with respect to the proportion of aspirin users, they constituted only about 22% of the enrolled patient population. Furthermore, there were no reported upper GI bleeding events in this study. Currently available clinical data suggest that aspirin increases the risk of upper GI events in patients treated with either selective cyclooxygenase inhibitors or nonselective nonsteroidal antiinflammatory drugs (NSAIDs), but data that address the effect of aspirin on relative risk are limited. Therefore, we agree that additional clinical data are needed to adequately assess the safety of selective cyclooxygenase 2 inhibitors, including etoricoxib and nonselective NSAIDs, in the context of aspirin use. The conclusion that etoricoxib was well tolerated compared with placebo and ibuprofen over a 12-week period is justified in the context of this study. However, as stated in our article and by Dr Kim and colleagues, long-term data regarding cardiovascular safety with etoricoxib are needed. Ongoing studies with etoricoxib are designed to assess its long-term cardiovascular safety compared with that of diclofenac, the world’s most commonly used traditional NSAID. Regarding the dose, there are patients who benefit from lower doses of anti-inflammatory drugs, depending on their degree of pain and their tolerance of adverse effects. The goal of our study was to help provide important information about lower-dose etoricoxib. Additional studies and discussions with regulatory agencies will determine whether commercialization of a lower dose(s) is possible.
Jeong A. Kim, MD Youn Seon Choi, MD Su Hyun Kim, MD Korea University Seoul, South Korea 1. Wiesenhutter CW, Boice JA, Ko A, et al, Protocol 071 Study Group. Evaluation of the comparative efficacy of etoricoxib and ibuprofen for treatment of patients with osteoarthritis: a randomized, double-blind, placebocontrolled trial. Mayo Clin Proc. 2005;80:470-479. 2. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. JAMA. 2000;284:1247-1255. 3. Weil J, Colin-Jones D, Langman M, et al. Prophylactic aspirin and risk of peptic ulcer bleeding. BMJ. 1995;310:827-830. 4. Bresalier RS, Sandler RS, Quan H, et al, Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005;352:1092-1102. 5. Graham DJ, Campen D, Hui R, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet. 2005;365:475-481.
In reply: We thank Dr Kim and colleagues for their comments regarding our clinical study, which evaluated etoricoxib, 30 1234
Mayo Clin Proc.
•
Judith A. Boice, PhD Merck Research Laboratories Rahway, NJ Craig W. Wiesenhutter, MD Coeur d’Alene Arthritis Clinic Coeur d’Alene, Idaho
Molecular Autopsy vs Postmortem Genetic Testing To the Editor: The article by Tester et al1 in the May 2005 issue of the Mayo Clinic Proceedings is a beautiful example of the application of molecular techniques in the investigation of unexplained sudden death. Such results not only further our understanding of this topic but also provide a specific diagnosis and a sense of closure for the family of the deceased. However, in the current article and in one published in the Mayo Clinic Proceedings in 2004, Tester et al1,2 seemed to use the term molecular autopsy as if this were an independent standalone procedure. In fact, the molecular autopsy represents a new tool that can be added to our existing armamentarium of tests that are available during postmortem evaluations.
September 2005;80(9):1233-1236, 1238, 1240-1241
•
www.mayoclinicproceedings.com
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.