- Email: [email protected]
Vioxx Redux
1056
The American Journal of Medicine, Vol 118, No 9, September 2005
References 1. Alpert JS. The Vioxx debacle. Am J Med. 2005;118:203–204. 2. Dai C, Stafford RS, Alexander C. National trends in cyclooxygenase-2 inhibitor use since market release. Arch Intern Med. 2005;165:171–177. 3. Bombardier C, Laine L, Reicin A, Shapiro D, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000;343:1520 –1528. 4. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286:954 –959. 5. Maetzel A, Krahn M, Naglie G. The cost effectiveness of rofecoxib and celecoxib in patients with osteoarthritis or rheumatoid arthritis. Arthritis Rheum. 2003;49:283–292. 6. Spiegel BM, Targownik L, Dulai GS, Gralnek IM. The cost-effectiveness of cyclooxygenase-2 selective inhibitors in the management of chronic arthritis. Ann Intern Med 2003;10:795– 806.
The Reply: Drs. Good and Kelley make an important point. We physicians are as much to blame for our inappropriate use of drugs as the industry or Food and Drug Administration is. I agree that more attention should be spent by individual physicians on their prescribing practices. However, busy practicing doctors work hard to avoid patient call-backs. Often this results in prescribing a medication that is perceived as causing fewer side effects even if that has not been proven as yet. Thanks for writing to The American Journal of Medicine. Joseph S. Alpert, MD Robert S. and Irene P. Flinn Professor of Medicine and Head, Department of Medicine, University of Arizona Health Sciences Center Tuscson, Ariz doi:10.1016/j.amjmed.2005.04.018 To the Editor: “The Vioxx Debacle” illuminates a number of problems in our system of drug testing, approval, marketing, and clinical application. Dr. Alpert suggests that Merck is unlikely to have “suppressed this information (evidence of harmful effects of Vioxx) consciously.” Every Merck employee is well aware of the potential for staggering lawsuits . . . Merck as a corporation may be severely damaged if not destroyed . . and if Merck executives knew about the cardiovascular risks and suppressed them, they also knew that they might be accused of a felony.” The presumption of innocence pending proof of guilt is appropriate—it is the American way. But there is another component of the American way, which is unbridled capitalism. The litany of corporate scandals these past 5 to 10 years indicates that some in corporate America are willing to risk their personal freedom and the company’s integrity for short-term profits. Greed has always been a powerful motivator, and in the case of Vioxx, the courts will determine whether Merck has
followed Enron et al in the parade of alleged corporate malfeasance. I was surprised, however, to observe that Dr. Alpert did not mention doctors’ roles in this scandal. Although it is true that physicians who prescribed Vioxx (and similar medications) may not have been aware of the data regarding cardiac toxicity, a simple PubMed search demonstrates mumblings of potential cardiotoxicity as early as 2001.1 Sales representatives who detailed the drug were also aware of this, because I recall challenging them about this issue and they attributed the rumors to anecdotal, nonsystematic evidence. Nonetheless, sales of Vioxx and its relatives increased robustly. As physicians we should ask ourselves how these medications came to dominate the market of non-narcotic pain medications. Was there evidence to suggest that these medications were superior to preexisting (and inexpensive) COX-1 nonsteroidal anti-inflammatory agents? Even a casual review suggests that (inexpensive and over-thecounter) ibuprofen (600 mg 3 times per day) was as effective and well-tolerated as Vioxx in treating patients with osteoarthritis.2 Similar results were noted in adults with migraines.3 In children undergoing tonsillectomy, ibuprofen may even be superior.4 There is little doubt that the medical literature can be “spun” to make either argument, and the cited studies hardly provide definitive evidence. But the fact remains that physicians began to prescribe very large amounts of COX-2 inhibitors with insufficient data to demonstrate superiority over time-honored, time-tested, inexpensive COX-1 inhibitors. In medical school we are taught that medications should be administered on the basis of effectiveness, side effects, and cost, in that order of importance. It would seem that COX-2 inhibitors were widely used before effectiveness data were conclusive. Perhaps physicians were persuaded that the theoretically superior (gastrointestinal and renal) side-effect profile justified the transition. But then the appropriate clinical argument would be to preserve COX-2 inhibitors for patients at high-risk of toxicity and/or who experience untoward effects with COX-1 agents. Instead, it is my opinion that these medications were, simply stated, overprescribed. I submit that this cautionary tale should prompt not only greater scrutiny of a particular company and the Food and Drug Administration, but also examination of our practices. When we allow pharmaceutical companies to herd us, we potentially do our patients a disservice. There is ever-increasing evidence that these companies use attractive, young sales representatives, direct-to-consumer advertising, and “drug lunches” in a not-so-covert attempt to buy us. The American Medical Association, through increased restrictions of these activities, has made it more difficult, but obviously not impossible. The germane question that we might ask ourselves is whether a free sandwich influences our medical decision-making. “The Vioxx Debacle” suggests that a sandwich yields mighty returns.
Letters
1057 Constantine A. Manthous, MD Associate Clinical Professor of Medicine Yale University School of Medicine Hamden, Conn doi:10.1016/j.amjmed.2005.04.024
References 1. Comarow A. Pain relief at a price. A blow to the heart? US News World Rep. 2001;131(8):45. 2. Day R, Morrison B, Luza A, Castaneda O, Strusberg A, Nahir M, et al. A randomized trial of the efficacy and tolerability of the COX-2 inhibitor rofecoxib vs. ibuprofen in patients with osteoarthritis. Arch Intern Med. 2000;160(12):1781–1787. 3. Misra UK, Jose M, Kalita J. Rofecoxib versus ibuprofen for acute treatment of migraine: a randomised placebo controlled trial. Postgrad Med J. 2004;80(950):720 –723. 4. Pickering AE, Bridge HS, Nolan J, Stoddart PA. Double-blind, placebocontrolled analgesic study of ibuprofen or rofecoxib in combination with paracetamol for tonsillectomy in children. Br J Anaesth. 2002;88(1):72–77.
search-based approach to pharmaceutical development. Although this experience emphasizes the difficulties in determining the risks associated with new medications, I agree with you that the way to improve our systemic problems is not by merely pointing fingers. I also agree with your personal view that we need a system of post-approval drug safety monitoring that is at least partly financially supported by drug companies. Congratulations on your assumption of the editorship of The American Journal of Medicine. It looks like the journal is in good hands. David I. Daikh, MD, PhD Assistant Professor of Medicine Division of Rheumatology University of California, San Francisco Staff Physician San Francisco VA Medical Center San Francisco, Calif doi:10.1016/j.amjmed.2005.04.028 To the Editor:
The Reply: I thank Dr. Manthous for his thoughtful and cogent response to my editorial on the Vioxx debacle. I think he makes many important arguments concerning the possibility of “unbridled capitalism” on the part of Merck throughout this unfortunate event. This may well be an example of inappropriate behavior on the part of industry, but, in the great American tradition of innocent before proven guilty, I would like to reserve judgment on Merck and the Food and Drug Administration until the entire story has been uncovered. If Merck is guilty, either overtly or complicitly, I will be disappointed but enlightened about their possibly dangerous behavior. Certainly, it is important for physicians to remember when speaking to representatives of industry to remind themselves who is paying the salary of the representative. Thanks again for writing to The American Journal of Medicine. Joseph Alpert, MD Robert S. and Irene P. Flinn Professor of Medicine and Head, Department of Medicine University of Arizona Health Services Center Tuscson, Ariz doi:10.1016/j.amjmed.2005.04.021 To the Editor: I thank you for your very thoughtful and well-reasoned editorial in the March issue of the The American Journal of Medicine. In the increasingly emotionally and politically charged atmosphere surrounding the coxibs and the drug approval process in general, it is more important than ever for the medical profession to support a rational and re-
Dr. Joseph S. Alpert’s thoughts regarding COX-2 drugs are temperate and well conceived.1 Like others, Alpert cites the Cleveland Clinic cardiology group’s 2001 article published in JAMA as having “demonstrated an increase in clinical cardiovascular events in patients receiving Vioxx.”2 Alpert does not mention that the study also showed a higher incidence of cardiovascular (CV) events in patients taking Celebrex. Be that as it may, and despite the JAMA article also being cited by others as indicating CV hazards of COX-2 inhibitors, a careful reading of the JAMA article does not suggest the authors’ conclusion (ie, that CVS problems occur more commonly with the use of the COX-2 drugs Vioxx and Celebrex) to be correct. The JAMA article authors’ purpose in doing the study was to consider whether COX-2 inhibitors pose CV system hazards. They answered this question by comparing the rate of CV events (specifically myocardial infarctions [MIs]) in patients taking COX-2 drugs (rofecoxib and celecoxib) with the rate of CV events in patients taking placebo pills. They did this by annualizing the MI rates for both the Celecoxib Long-Term Safety Study (CLASS) and Vioxx Gastrointestinal Outcomes Research (VIGOR) studies and comparing them with the placebo group from a previously published meta-analysis.3 Their conclusion was that the annualized MI rates for rofecoxib (0.74%) and celecoxib (0.80%) were statistically significantly higher compared with the placebo group (0.52%) of the meta-analysis. Several points have to be made. (1) The Cleveland Clinic group annualized the MI rate from incomplete data from the VIGOR and CLASS trials. Their calculated annual MI rate (0.74% for rofecoxib and 0.80% for celecoxib) is therefore at odds with the actual MI rate (0.50% in both studies). Thus, comparing the actual numbers (0.50%) with the placebo (0.52%) dramatically changes the implication of the Cleveland Clinic group’s study. (2) Strand and Hochberg
The American Journal of Medicine, Vol 118, No 9, September 2005
References 1. Alpert JS. The Vioxx debacle. Am J Med. 2005;118:203–204. 2. Dai C, Stafford RS, Alexander C. National trends in cyclooxygenase-2 inhibitor use since market release. Arch Intern Med. 2005;165:171–177. 3. Bombardier C, Laine L, Reicin A, Shapiro D, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000;343:1520 –1528. 4. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286:954 –959. 5. Maetzel A, Krahn M, Naglie G. The cost effectiveness of rofecoxib and celecoxib in patients with osteoarthritis or rheumatoid arthritis. Arthritis Rheum. 2003;49:283–292. 6. Spiegel BM, Targownik L, Dulai GS, Gralnek IM. The cost-effectiveness of cyclooxygenase-2 selective inhibitors in the management of chronic arthritis. Ann Intern Med 2003;10:795– 806.
The Reply: Drs. Good and Kelley make an important point. We physicians are as much to blame for our inappropriate use of drugs as the industry or Food and Drug Administration is. I agree that more attention should be spent by individual physicians on their prescribing practices. However, busy practicing doctors work hard to avoid patient call-backs. Often this results in prescribing a medication that is perceived as causing fewer side effects even if that has not been proven as yet. Thanks for writing to The American Journal of Medicine. Joseph S. Alpert, MD Robert S. and Irene P. Flinn Professor of Medicine and Head, Department of Medicine, University of Arizona Health Sciences Center Tuscson, Ariz doi:10.1016/j.amjmed.2005.04.018 To the Editor: “The Vioxx Debacle” illuminates a number of problems in our system of drug testing, approval, marketing, and clinical application. Dr. Alpert suggests that Merck is unlikely to have “suppressed this information (evidence of harmful effects of Vioxx) consciously.” Every Merck employee is well aware of the potential for staggering lawsuits . . . Merck as a corporation may be severely damaged if not destroyed . . and if Merck executives knew about the cardiovascular risks and suppressed them, they also knew that they might be accused of a felony.” The presumption of innocence pending proof of guilt is appropriate—it is the American way. But there is another component of the American way, which is unbridled capitalism. The litany of corporate scandals these past 5 to 10 years indicates that some in corporate America are willing to risk their personal freedom and the company’s integrity for short-term profits. Greed has always been a powerful motivator, and in the case of Vioxx, the courts will determine whether Merck has
followed Enron et al in the parade of alleged corporate malfeasance. I was surprised, however, to observe that Dr. Alpert did not mention doctors’ roles in this scandal. Although it is true that physicians who prescribed Vioxx (and similar medications) may not have been aware of the data regarding cardiac toxicity, a simple PubMed search demonstrates mumblings of potential cardiotoxicity as early as 2001.1 Sales representatives who detailed the drug were also aware of this, because I recall challenging them about this issue and they attributed the rumors to anecdotal, nonsystematic evidence. Nonetheless, sales of Vioxx and its relatives increased robustly. As physicians we should ask ourselves how these medications came to dominate the market of non-narcotic pain medications. Was there evidence to suggest that these medications were superior to preexisting (and inexpensive) COX-1 nonsteroidal anti-inflammatory agents? Even a casual review suggests that (inexpensive and over-thecounter) ibuprofen (600 mg 3 times per day) was as effective and well-tolerated as Vioxx in treating patients with osteoarthritis.2 Similar results were noted in adults with migraines.3 In children undergoing tonsillectomy, ibuprofen may even be superior.4 There is little doubt that the medical literature can be “spun” to make either argument, and the cited studies hardly provide definitive evidence. But the fact remains that physicians began to prescribe very large amounts of COX-2 inhibitors with insufficient data to demonstrate superiority over time-honored, time-tested, inexpensive COX-1 inhibitors. In medical school we are taught that medications should be administered on the basis of effectiveness, side effects, and cost, in that order of importance. It would seem that COX-2 inhibitors were widely used before effectiveness data were conclusive. Perhaps physicians were persuaded that the theoretically superior (gastrointestinal and renal) side-effect profile justified the transition. But then the appropriate clinical argument would be to preserve COX-2 inhibitors for patients at high-risk of toxicity and/or who experience untoward effects with COX-1 agents. Instead, it is my opinion that these medications were, simply stated, overprescribed. I submit that this cautionary tale should prompt not only greater scrutiny of a particular company and the Food and Drug Administration, but also examination of our practices. When we allow pharmaceutical companies to herd us, we potentially do our patients a disservice. There is ever-increasing evidence that these companies use attractive, young sales representatives, direct-to-consumer advertising, and “drug lunches” in a not-so-covert attempt to buy us. The American Medical Association, through increased restrictions of these activities, has made it more difficult, but obviously not impossible. The germane question that we might ask ourselves is whether a free sandwich influences our medical decision-making. “The Vioxx Debacle” suggests that a sandwich yields mighty returns.
Letters
1057 Constantine A. Manthous, MD Associate Clinical Professor of Medicine Yale University School of Medicine Hamden, Conn doi:10.1016/j.amjmed.2005.04.024
References 1. Comarow A. Pain relief at a price. A blow to the heart? US News World Rep. 2001;131(8):45. 2. Day R, Morrison B, Luza A, Castaneda O, Strusberg A, Nahir M, et al. A randomized trial of the efficacy and tolerability of the COX-2 inhibitor rofecoxib vs. ibuprofen in patients with osteoarthritis. Arch Intern Med. 2000;160(12):1781–1787. 3. Misra UK, Jose M, Kalita J. Rofecoxib versus ibuprofen for acute treatment of migraine: a randomised placebo controlled trial. Postgrad Med J. 2004;80(950):720 –723. 4. Pickering AE, Bridge HS, Nolan J, Stoddart PA. Double-blind, placebocontrolled analgesic study of ibuprofen or rofecoxib in combination with paracetamol for tonsillectomy in children. Br J Anaesth. 2002;88(1):72–77.
search-based approach to pharmaceutical development. Although this experience emphasizes the difficulties in determining the risks associated with new medications, I agree with you that the way to improve our systemic problems is not by merely pointing fingers. I also agree with your personal view that we need a system of post-approval drug safety monitoring that is at least partly financially supported by drug companies. Congratulations on your assumption of the editorship of The American Journal of Medicine. It looks like the journal is in good hands. David I. Daikh, MD, PhD Assistant Professor of Medicine Division of Rheumatology University of California, San Francisco Staff Physician San Francisco VA Medical Center San Francisco, Calif doi:10.1016/j.amjmed.2005.04.028 To the Editor:
The Reply: I thank Dr. Manthous for his thoughtful and cogent response to my editorial on the Vioxx debacle. I think he makes many important arguments concerning the possibility of “unbridled capitalism” on the part of Merck throughout this unfortunate event. This may well be an example of inappropriate behavior on the part of industry, but, in the great American tradition of innocent before proven guilty, I would like to reserve judgment on Merck and the Food and Drug Administration until the entire story has been uncovered. If Merck is guilty, either overtly or complicitly, I will be disappointed but enlightened about their possibly dangerous behavior. Certainly, it is important for physicians to remember when speaking to representatives of industry to remind themselves who is paying the salary of the representative. Thanks again for writing to The American Journal of Medicine. Joseph Alpert, MD Robert S. and Irene P. Flinn Professor of Medicine and Head, Department of Medicine University of Arizona Health Services Center Tuscson, Ariz doi:10.1016/j.amjmed.2005.04.021 To the Editor: I thank you for your very thoughtful and well-reasoned editorial in the March issue of the The American Journal of Medicine. In the increasingly emotionally and politically charged atmosphere surrounding the coxibs and the drug approval process in general, it is more important than ever for the medical profession to support a rational and re-
Dr. Joseph S. Alpert’s thoughts regarding COX-2 drugs are temperate and well conceived.1 Like others, Alpert cites the Cleveland Clinic cardiology group’s 2001 article published in JAMA as having “demonstrated an increase in clinical cardiovascular events in patients receiving Vioxx.”2 Alpert does not mention that the study also showed a higher incidence of cardiovascular (CV) events in patients taking Celebrex. Be that as it may, and despite the JAMA article also being cited by others as indicating CV hazards of COX-2 inhibitors, a careful reading of the JAMA article does not suggest the authors’ conclusion (ie, that CVS problems occur more commonly with the use of the COX-2 drugs Vioxx and Celebrex) to be correct. The JAMA article authors’ purpose in doing the study was to consider whether COX-2 inhibitors pose CV system hazards. They answered this question by comparing the rate of CV events (specifically myocardial infarctions [MIs]) in patients taking COX-2 drugs (rofecoxib and celecoxib) with the rate of CV events in patients taking placebo pills. They did this by annualizing the MI rates for both the Celecoxib Long-Term Safety Study (CLASS) and Vioxx Gastrointestinal Outcomes Research (VIGOR) studies and comparing them with the placebo group from a previously published meta-analysis.3 Their conclusion was that the annualized MI rates for rofecoxib (0.74%) and celecoxib (0.80%) were statistically significantly higher compared with the placebo group (0.52%) of the meta-analysis. Several points have to be made. (1) The Cleveland Clinic group annualized the MI rate from incomplete data from the VIGOR and CLASS trials. Their calculated annual MI rate (0.74% for rofecoxib and 0.80% for celecoxib) is therefore at odds with the actual MI rate (0.50% in both studies). Thus, comparing the actual numbers (0.50%) with the placebo (0.52%) dramatically changes the implication of the Cleveland Clinic group’s study. (2) Strand and Hochberg