Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
Rofecoxib in acute injury
- Peter Leman, Shaun Greene, Niall O'Connor, Sion Jones (8 October 2004)
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comparing effect of consumer laws on the pharmaceuticl and tobacco industries
- Desmond A . Gale (8 October 2004)
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Why use rofecoxib for acute injury?
- Jeffrey Mann (8 October 2004)
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VIOXX AND OTHER COX2 DRUGS
- CELIO LEVYMAN,MD,MSc (9 October 2004)
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COX 2 DRUGS RISKS
- CELIO LEVYMANMD,MSc (9 October 2004)
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Primacy of the patients' interests in randomised trials
- Tony Stevens, Wilson Roger, Grainger Roy. (12 October 2004)
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The rofecoxib scandal
- Pontus Harten, Frank Moosig (14 October 2004)
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most embarrasing...
- manan vasenwala (15 October 2004)
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Rofecoxib withdrawal: when the river sounds, stones are coming.
- Juan Carlos Maldonado (16 October 2004)
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Peter Leman, Clinical Senior Lecturer Emergency Department, Royal Perth Hospital, Perth, Australia, Shaun Greene, Niall O'Connor, Sion Jones
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Merck have voluntarily withdrawn rofecoxib due to an increase in vascular events after 18 months of continuous use.(BMJ 2004,;329:816). However, the role of the drug for short term pain relief has been explored in many studies and no increased adverse events have thus far been reported.{1,2,3,4} We have recently completed a randomised double dummy placebo controlled trial of 150 patients comparing rofecoxib to diclofenac in acute limb injury. Initial results show improved efficacy over the first 240 minutes of treatment with pain scores being reduced by a greater amount in the rofecoxib (50mg) group (repeated measures ANOVA, p=0.05) compared with the diclofenac (50mg) group. There were no significant baseline differences in either patients or injuries between the 2 groups. In the subsequent post discharge 5 day model comparing rofecoxib 50mg once daily and diclofenac SR 75mg twice daily no significant differences in pain scores were seen (repeated measures ANOVA, p=0.28), though these were expectably generally small by the end of the study. However, the patients receiving rofecoxib provided higher global rating of drug efficacy (2.8/5 vs 2.4/5, p=0.048) and after 5 days of treatment had higher overall global health scores on a visual analogue scale (85.0 vs. 76.0, p=0.006). There were no differences in either GI or other adverse effects when both drugs were compared, and no differences in rescue analgesia use. This leaves us with a useful dataset illustrating the efficacy of a Cox 2 specific anti-inflammatory in an acute injury (rather than post- operative) model. The relevance of this data may be generalisable across the Cox-2 selective class of drugs. However, for acute injury at least, it seems that rofecoxib is probably as good as, and perhaps a bit better than, a non-selective drug. 1. Korn S, Vassil TC, Kotey PN, Fricke JR. Comparison of rofecoxib and oxycodone plus acetaminophen in the treatment of acute pain: a randomized, double-blind, placebo-controlled study in patients with moderate to severe postoperative pain in the third molar extraction model. Clin Ther. 2004;26(5):769-78 2. Chang DJ, Desjardins PJ, Bird SR, Black P, Chen E, Petruschke RA, Geba GP. Comparison of rofecoxib and a multidose oxycodone/ acetaminophen regimen for the treatment of acute pain following oral surgery: a randomized controlled trial. Curr Med Res Opin. 2004;20(6):939-49. 3. Cheng TT, Lai HM, Chiu CK, Chem YC. A single-blind, randomized, controlled trial to assess the efficacy and tolerability of rofecoxib, diclofenac sodium, and meloxicam in patients with acute gouty arthritis.. Clin Ther. 2004;26(3):399-406 4. Jackson ID, Heidemann BH, Wilson J, Power I, Brown RD Double- blind, randomized, placebo-controlled trial comparing rofecoxib with dexketoprofen trometamol in surgical dentistry. Br J Anaesth. 2004;92(5):675-80 Competing interests: The study mentioned by the authors was funded in part by Merck. |
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Desmond A . Gale, Honorary Director Tobacco Control Program Barbados Cancer Society retired
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The news that Merck & Co.have withdrawn Vioxx, after medical and scientific surveys had shown that its use increased the risk pf heart attacks, strokes and other cardiovascular diseases, raises the question of when or whether governmental agencies responsible for public health and safety and protection of the consumer will demand the withdrawal of tobacco, that according to WHO is the only legal product which when used as intended by its manufacturers endangers or destroys the freedom and wrecks the health of all habitual users, and kills 50% of those who do not quit, 25% prematurely. Ministries responsible for public health and consumer protection have a moral obligation to do so and in Barbados the Ministry of Commerce and Consumer Affairs has the authority to make such a demand in accordance the Consumer Protection and Consumer Guarantee Act enacted and proclaimed in January 2003. Furthermore there is nothing in our Constitution that could preclude such an intervention. The banning or ordering the withdrawal of tobaco products in Barbados would give practical expression to the wishes of most people where the use of tobacco is no longer socially acceptable, where the prevalence of tobacco smoking is the lowest in the Americas i.e.6% to 9% in adults,2% or less in children, where by voluntary agreements smoking is prohibited in 80% of private homes, 86% of government offices and 92% of private workplaces, and where 90% of smokers accept without protest the prohibition of smoking in workplaces and public places because they recognise that clean air is as essential for health as clean and nutritious food and drink, and that freedom to breathe clean air is a basic inalienable human right. Yours truly D,A.Gale Competing interests: None declared |
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Jeffrey Mann, Retired physician Salt Lake City, UT 84103
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In response to an article detailing the CV risks of long-term rofecoxib therapy, Peter Leman felt impelled to write a rapid response letter stating that rofecoxib can be used to treat acute injury without any risk of serious adverse effects. Peter Leman concludes his letter by stating that "for acute injury at least, it seems that rofecoxib is probably as good as, and perhaps a bit better than, a non-selective drug." What Peter Leman fails to mention that is that many NSAIDS are much cheaper than rofecoxib and they can be readily obtained over-the-counter without a prescription. Why should a person use an expensive drug like rofecoxib for an acute injury when so many cheaper, and equally effective, NSAIDs are available? Jeff Mann Competing interests: None declared |
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CELIO LEVYMAN,MD,MSc, Senior Neurologist Headache and Neurology Clinic,Sao Paulo,Brazil
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The cardiovascular complications of VIOXX,that resulted in the retreat of the market for Merck in 80 countries,yet questioned since 2000 in NEJM and in JAMA,lead immediately to think us in other medicines of that group. From the elucidation in the way of action of the NSAID ,especially of the aspirin as platelet antiaggregant,due to complete inativation of the cyclo-oxigenase,as larger concerns were due to the gastric side effects. With the emergence of COX2 and the selective inhibition of that pathway,the subject gastrointestinal seemed to be really very little resolved,but was spoken in leaving the tromboxane-sintethase and consequent activation of the platelet aggregation without care,included the recent knowledge of specific genes ?On that way, it is inexplicable one the action cardiovascular and neurological for-diseases of that class of medicines. The one that more frightens is that such given were already available there are some years in serious works in the medical literature,and the laboratory just put a warning in the packings:at least there was the retreat of the market.And what can be saying of the other inhibitors of COX2 being still sold? Competing interests: None declared |
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CELIO LEVYMANMD,MSc, Senior Neurologist Headache and Neurology Clinic,Sao Paulo,Brazil
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The coxibs polemical recently launched by the withdraw of Vioxx by Merck from the market could be imagined before. In middle-1980 I have made a study for a Mastership degree with platelet aggregation disorders and migraine, when we only have knowledge about one COX. When COX 2 inhibitors appeared, some sensation about protection of gastric diseases, despite thromboxane pathway itself alone, with PGE1, remains in mind (1). However, more recent studies let to better understand this kind of mechanism: Fitzlgerald (2), (3) and Shnitzler (4), and these studies confirmed the abandon of thromboxane way and the prostaglandin endothelium protection, and, as the author says, the depression of PG1 could leave to a higher risk of myocardium infarction and stroke, higher blood pressure, accelerate atherogenesis and rupture of an athermanous plaque. Topol (5) goes further, showing a possible catastrophe in the future: after all, there are other coxibs in the market now. Perhaps Merck have took their decision because the FDA pressure;however,retired the higher profit drug Vioxx by itself.Pzifer announces that Celebrex was more studied and have not show dangerous side effects. Can it be true? When we imagine that since year 2000 there are alerts in regard to potential side effects of coxibs drugs in the literature, and just now some kind of attitude was taken, that is a very preoccupation about other similar drugs in sale now. What the health authorities of many countries will do? (6) 1 – Levyman, C. – Estudo da função plaquetária em portadores de enxaqueca clássica e comum [Study of platelet function in classic and common migraine suffers], Master in Neurology Thesis, Federal University of Sao Paulo, 1988. 2 – Fitzgerald,GA – Coxibs and cardiovascular disease.N Engl J Med 351:17,2004 3 – Fitzgerald,GA – COX2 and beyond:approaches to prostaglandin inhibition in human disease.Nat Rev Drug Discov 2:879-90,2003 4 – Shnitzler et al – Comparision of lumiracoxib with naproxen and ibubrofen in the Theraphetics Arthritis Research and Gastrointestinal Events Trial (TARGET), reducing in ulcer complication: a randomized controlled trial. Lancet 364:665-74, 2004 5 – Topol,EJ – Failing the public health – Refecoxib,Merck and FDA.N England J Med 351:17:2004 6 – Singh, D – Merck withdraws arthritis drug worldwide.BMJ 329:816, 2004 Competing interests: None declared |
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Tony Stevens, Consumer Liaison Lead NCRN Coordinating Centre, Arthington House, Cookridge Hospital, Leeds LS16 6QB, Wilson Roger, Grainger Roy.
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Dear Sir Patients and the public recognise the need for large scale randomised trials to test new therapies or agents. However, trialists must also recognise the responsibilities they owe to the patients they enrol into their studies. Recent events have caused concern that these responsibilities are not always being fully discharged. The result of adverse publicity is that potential trial participants may be dissuaded from entering studies because of a perceived (or real?) lack of concern for their welfare and their rights. The early stopping of the MA17 trial, with data released to the media before the trial participants or health professionals had been given time to assess the implications, engendered wide debate in the medical press about how far the patient’s interests were really being considered. (1) Recent articles in the media that a number of pharmaceutical companies may be withholding safety data on some of their products have also caused serious concern. Within the last few months, a case was brought against GlaxoSmithKline by the New York Attorney General, forcing publication of undisclosed trial data on allegedly harmful effects of paroxetine in adolescents. Similarly, the decision by Merck to withdraw Vioxx worldwide on October 7th, following an FDA report leaked to the Wall Street Journal, indicating that Vioxx may have caused 27,000 cardiovascular events, with up to 7000 deaths, despite studies since 1999 indicating the potential dangers, has caused widespread concern. In response, the Lancet has called for the release of data from the regulators and other pharmaceutical companies in relation to the possibility of similar adverse effects from other Cox 2 inhibitors. (2) The pharmaceutical companies must recognise that they have a duty to protect the individual rights of subjects enrolled into their investigative studies. Remarks such as the comment made recently by Sir Tom McKillop, CEO of AstraZeneca, that ‘If we put consumer protection as the only thing the regulator needs to worry about, that will be a huge block to progress and innovation’, will only reinforce public distrust. This distrust goes wider than the pharmaceutical companies specifically, it reaches out to all clinical trials. (3) The current ICH GCP Guidelines state that the study participant should be ‘informed of all aspects of the particular study that are relevant to their decision’. We would argue that this is impossible unless research is based on collaborative partnerships between patients and professionals, with full access to all the data being available to potential and existing trial participants. It is only by following such procedures that research can be properly conducted. The issue is not solely ethical - it will help reduce treatment uncertainties, assist patients to understand potential risks and benefits, and improve the public perception of clinical research. Yours truly, Dr Tony Stevens Consumer Liaison Lead, National Cancer Research Network Roger Wilson Chair, National Cancer Research Institute Consumer Liaison Group Roy Grainger Vice Chair, National Cancer Research Institute Consumer Liaison Group (1) Baum M. (2004) Current status of aromatase inhibitors in the management of breast cancer and critique of the NCIC MA-17 trial. Cancer Control 11. 217-221. (2) Horton R (2004) Editorial Lancet 364, 9 October (3) Independent 9 Oct 2004 p59 Man of science with a passionate belief in innovation Competing interests: None declared |
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Pontus Harten, Rheumatologist D 24103 Kiel, Frank Moosig
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At the beginning of May 2004, we suggested the following short paper for publication in the BMJ. Our aim was to warn physicians and patients about the more and more confirming data about the cardiovascular risks of rofecoxib. The Harvard-Study by Solomon et al. had again shown a significantly higher risk (2-3 times) for myocardial infarction under rofecoxib. The risk was highest in the the first 30 days of application. Our aim was to warn physicians and patients about the more and more confirming data about the cardiovascular risks of rofecoxib. The BMJ refused to publish it without further explanation. Maybe it was too polemic. Soon after, in August 2004 the 1.4 million patients, FDA-sponsored Kaiser-Permanente Study underlined the association of myocardial infarction under rofecoxib. Both studies showed a significantly higher risk especially for the elderly (above 65 years). This is exactly the population for which NICE recommend it. Manufacturer MERCK did what they always did after every of all the studies with similar results: in several press notes, they argumented that retrospective data in general are statistically misleading and the conclusions of these studies are false. Then came the prospective APPROVe Study and MERCK removed rofecoxib from the market. In sharp opposite to the results of Solomon et al. in APPROVe the incidence of complications under rofecoxib rose as late as after 18 months application of rofecoxib. Maybe it is because the Approve study population had to have no evidence of cardiovascular risks. It can be assumed that most of the millions of rofecoxib-patients took rofecoxib only for days or weeks. Under this aspects the wave of law suits could be exspected to be lower if MERCK took rofecoxib away because of the results of the APPROVe study. Today, MERCK´s president Peter Kim and vice president Alise Reicin invited to a press meeting. Reicin is co-author of the VIGOR Study, co- author of the often (by MERCK´S employees) cited meta-analysis that failed to show any CV risk of rofecoxib and also author of papers and literature reviews with the same content. In this conference they said, that they did not know the risks of rofecoxib before the APPROVe data came out.. Our paper from May 2004: The cardiovascular risks of rofecoxib Beginning in 1999, the market launch of the cyclo-oxygenase-2 (COX-2) specific inhibitors celecoxib and rofecoxib was the most successful in the history of medicine. In 2001 Celecoxib (annual turnover: $3.1bn) held the seventh position, Rofecoxib (annual turnover: $2.6bn) the tenth position of the best selling drugs worlwide (1). Since the VIGOR (Vioxx Gastrointestinal Research) study was published in 2000 in the New England Journal of Medicine, rofecoxib has been associated with cardiovascular complications (2). This large (n=8076), multicentre, multinational study compared the gastrointestinal tolerability and safety of 50 mg/d of rofecoxib versus 1000 mg/d of naproxen in patients with rheumatoid arthritis. The patients were followed up for a median of 9 months, low-dose aspirin was not permitted. The analgesic effect was comparable, and gastrointestinal complications were reduced by about 50%, but in patients treated with rofecoxib myocardial infarction was five times more common (20 v 4) than in those treated with naproxen (2). When the Food and Drug Administration (FDA) re-analysed the study data it was found that serious adverse effects (defined as life threatening, death, requiring hospitalisation or surgery and others) occurred more often in patients receiving rofecoxib than in those receiving naproxen (9.3% v 7.8%) (3). Under rofecoxib a total of 19 % of hospital admissions were due to cardivascular causes (naproxen: 9 %). In total cardiovascular complications occurred in 109/4047 patients (2.7%) and 33/4029 patients (0.8%), respectively (3). The FDA rejected the meta- analysis presented by manufacturers Merck in support of the tolerability of rofecoxib and the antithrombotic effect of naproxen as not valid because of methodological deficiencies (4). Patients’ age, comorbidities, cardiovascular risk, and rofecoxib dosages varied notably; only 638 of the 28 349 study participants had actually taken the original VIGOR dosis (5). A Cochrane literature analysis review found similar results: gastrointestinal complications were statistically lower (RR 0.46; 0.34- 0.63) under rofecoxib, but the risks of having a cardiovascular events (RR 2,36;1.38-4.02) or a non-fatal myocardial infarction (RR 4,48;1.52-13.23) were statistically significant higher than in patients taking naproxen (6). A recently published analysis of the original VIGOR data showed that life expectancy in patients taking rofecoxib was reduced by 4.4 months in patients with a high risk of gastrointestinal complications and by 7.8 months in those with a low risk (7). At the same time as the VIGOR study the similarly conceived multicentre, multinational CLASS (Celebrex Longtime Arthritis Safety Study) study testing the rival product celecoxib (n= 7968; 72 % with osteoarthritis) was published in the Journal of the American Medical Association (8). Manufacturers Pfizer/Pharmacia had originally conducted two studies over 12 repectively 15 months. The dosage of celecoxib was high (800 mg/d) and was compared with diclofenac (2´75 mg) and ibuprofen (3´800 mg). The studies choosen primary endpoint was complicated ulcers defined as obstruction, perforation and bleeding. The authors (as in the VIGOR trial all sponsored by the drug`s manufacturer) pooled the data, combined both endpoints symptomatic and complicated ulcers and published it not in their entirety but for a mere six months. These results showed a significantly improved gostrointestinal tolerability of celecoxib (8). The FDA statisticians refuted this in an analysis of the entire dataset. Most of the ulcers complications associated with celecoxib had occurred after six months. Celecoxib had not achieved the primary end point (9). As it was discussed in a BMJ editorial, under the chosen study conditions ulcer complications of celecoxib (0,68 %) were not significantly better than ibuprofen (0,75) and of diclofenac (0,62%) (9,10). In a Warning Letter the FDA banned both the manufacturers of celecoxib and rofecoxib from claiming that their products are better tolerated than traditional non-steroidal anti-inflammatory drugs (NSAIDs) (11,12). In recent years retrospective studies with large populations of patients have been published with respect to the cardiovascular risk associated with rofecoxib. The findings are conflicting. In studies sponsored by Merck no cardiovascular risk for rofecoxib emerges (13, 14). One meta-analysis found an increased cardiovascular complication rate for both rofecoxib and celecoxib (15). Analysing data of more than 150.000 patients Mamdani et al. failed to show an increased risk for myocardial infarction in patients taking rofecoxib (16). Ray et al. found a statistically increased rate for heart infarction in patients taking more tha 25 mg/d of rofecoxib (17). No similiar results were published for celecoxib. Authors of the CLASS-Study group in a series of publications showed significantly increased occurrences of heart failure, new-onset hypertension, destabilized hypertension, oedema, renal failure, and raised costs for rofecoxib compared with celecoxib (18,19,20,21,22). A recently presented study reached the same conclusions. The relative risk for myocardial infarction or stroke in patients with treated hypertension taking rofecoxib was statistically significant higher (RR 2.45; 95%CI 1.71 -3.51; P<0.0001) than in conventional NSAIDs or celecoxib (23). These conflicting findings are put into context, however, by new data. Published in the May 2004 issue of Circulation the renowned Brigham and Women’s Hospital, Harvard Medical School, Boston, presented the data of a study that had been sponsored by both manufacturers simultaneously (24). Two of the authors do not have industry affiliations. The study retrospectively analyses data from 54 475 patients aged 65 or older, who receive their medication through a state sponsored initiative. Every one of 10 895 patients admitted to hospital for myocardial infarction was compared with four controls, matched for age, sex, and index month. The prevalence of of aspirin use was the same above all drug user categories. A significantly increased, dose-dependent risk for myocardial infarction was found for rofecoxib compared with celecoxib (OR 1.24; 95 CI 1.05-1.46; p = 0.011) and patients not using NSAIDs (OR 1.14; 95% CI 1.00-1.31; p=0.054). Compared with Celecoxib (>200 mg/d), the risk is higher above 25 mg/d rofecoxib (Odds Ratio 1.7, 95% CI 1.07-2.71, p=0.026) than below 25 mg (OR 1.21, 95% CI 1.01 to 1.44; p=0.036). The risk is highest in the first 30 days of application (OR 1.40, 95% CI 1.12 to 1.75; P=0.005) (24). The same study group in an additional retrospective data analysis found a significantly raised risk for new-onset hypertension with rofecoxib (OR 1.6; 95% CI 1.2-2.1) compared with celecoxib, with conventional NSAIDs(OR 1.4; 95% CI 1.1-1.9), or without NSAIDs (OR 1.6;95% CI 1.3-2.0) (25). Two recent published and independent cost-effectiveness analyses reached the conclusion that the expensive COX-2 inhibitors are cost- effective only in patients with a history of upper gastrointestianl bleeding (26), or, for rofecoxib, in patients older than 76, for celecoxib older than 81 (27). Especially these patients, however, have a higher risk for coronary heart disease and hypertension. In summon, the benefit of the COX-2 specific inhibitors rofecoxib and celecoxib appears to be limited. Pontus Harten, M. D. Internal Medicine/Rheumatologist Sophienblatt 1 D-24103 Kiel Germany Frank Moosig, M.D. Internal Medicine IInd. Medical Clinic of the University of Kiel Chemnitzstrasse 33 D-24116 KIEL Germany References 1. http.//www.imshealth.com/ims/portal/front/articleC/0,2777,6599_3665_1003999,00.html 2. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000;343:1520-1528 3. Villalba L. Vioxx Gastrointestinal Outcome Research. Advisory Committee Presentation for Vioxx (rofecoxib). http://www.fda.gov/ohrms/dockets/ac/01/slides/3677s2_06_villalba/sld001.htm 4. Konstam MA, Weir MR, Reicin A, Shapiro D, Sperling RS, Barr E, Gertz BJ. Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib. Circulation 2002;104:2280-2288. 5. Li Q. Advisory Committee Presentation in Vioxx (Rofecoxib): Discussion on the metaanalysis for cardiovascular risk assessment. http://www.fda.gov/ohrms/dockets/ac/01/slides/3677s2_05_li/index.htm 6. Garner S, Fidan D, Frankish R, Judd M, Towheed T, Wells G, Tugwell P. Rofecoxib for the treatment of rheumatoid arthritis. Cochrane Database Syst Rev 2002;2:CD003685. 7. Choi HK, Seeger JD, Kuntz KM. Effects of rofecoxib and naproxen on life expectancy among patients with rheumatoid arthritis: a decision analysis. Am J Med 2004;116:621-629 8. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, Makuch R, Eisen G, Agrawal NM, Stenson WF, Burr AM, Zhao WW, Kent JD, Lefkowith JB, Verburg KM, Geis GS. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. JAMA 2000; 284(10):1247-1255. 9. Goldkind L. Advisory Committee Presentation for celebrex (celecoxib): Gastrointestinal review: Highlights of the CLASS Study. http://www.fda.gov/ohrms/dockets/ac/01/slides/3677s1_03_goldkind/sld041.htm 10. Juni P, Rutjes AWS, Dieppe PA. Are selective COX-2 inhibitoers superior to traditional non-steroidal anti-inflammatory drugs ? Br Med J 2002;324:1287-1288 11. Celecoxib-Warning letter: http://www.fda.gov/cder/warn/2001/DD8432.pdf 12. Rofecoxib-Warning letter: http://www.fda.gov/cder/warn/2001/9456.pdf 13. Reicin AS, Shapiro D, Sperling RS, Barr E, Yu Q. Comparison of cardiovascular thrombotic events in patients with osteoarthritis treated with rofecoxib versus nonselective nonsteroidal anti-inflammatory drugs (ibuprofen, diclofenac, and nabemutone). Am J Cardiol 2002;89(8):971-972 14. Weir MR, Sperling RS, Reicin A, Gertz BJ. Selective COX-2 inhibition and cardiovascular effects: a review of the rofecoxib development program. Am Heart J 2003;146:561-562 15. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001;286:954-959. 16. Mamdani M, Rochon P, Juurlink DN, Anderson GM, Kopp A, Naglie G, Austin PC, Laupacis A. Effect of selective cyclooxygenase -2 inhibitors and naproxen on short term risk of acute myocardial infarction in the elderly. Arch Intern Med 2003, 163(4):481-486. 17. Ray WA, Stein CM, Daugherty JR, Hall K, Arbogast PG, Griffin MR. COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet 2002;360:1071-1073 18. Whelton A, Fort JG, Puma JA, Normandin D, Bello AE, Verburg KM; SUCCESS VI Study Group. Cyclooxygenase-2 specific inhibitors and cardiorenal function: a randomized, controlled trial of celecoxib and rofecoxib in older osteoarthritis patients. Am J Ther 2001; 8:85-95. 19. Whelton A, White WB, Bello AE, Puma JA, Fort JG for the SUCCESS- VII Investigators. Effects of celecoxib and rofecoxib on blood pressure and edema in patients >or=65 years of age with systemic hypertension and osteoarthritis. Am J Cardiol 2002;91(7):959-963. 20. Zhao SZ, Burke TA, Whelton A, von Allmen H, Henderson SC. Blood pressure destabilization and related health care utilization among hypertensive patients using nonspecific NSAIDs and COX-2 specific inhibitors. Am J Manag Care 2002;8(15 Suppl):S401-413. 21. Zhao SZ, Burke TA, Whelton A, von Allmen H, Henderson SC. Cost of heart failure among hypertensive users of nonspecific NSAIDs and COX-2 specific inhibitors. Am J Manag Care 2002;(15Suppl):S414-27 22. Zhao SZ, Reynolds MW, Lejkowith J, Whelton A, Arellano FM. A comparison of renal related adverse drug reactions between rofecoxib and celecoxib, based on the World Health Organization/Uppsala Monitoring Centre safety database. Clin Ther 2001;23:1478-1491 23. Whelton A, Spalding WM, White WB, Reeves MJ, Suh SS, Fort JG. Rofecoxib increases cardiovascular events in arthritis patients but celecoxib and nonspecific nonsteroidal anti-inflammatory drugs do not: results from a large New England Health Care Claims database. J Am Coll Cardiol 2004;43(Suppl.),415A,838-2(Abstract) 24. Solomon DH, Schneeweiss S, Glynn RJ, Kiyota Y, Levin R, Mogun H, Avorn J. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation 2004;109:2068- 2073 25. Salomon DH, Schneeweiss S, Levin R, Avorn J. The relationsship between COX-2 specific inhibitors and hypertension. Arthritis Rheum 2003;48(Suppl.)9: s71 (abstract) 26. Maetzel A, Krahn M, Naglie G. The cost effectiveness of rofecoxib and celecoxib in patients with osteoarthritis of rheumatoid arthritis. Arthritis Rheum 2003;49:283-292. 27. Spiegel BM, Targownik L, Dulai GS, Gralnek IM. The cost- effectiveness of cyclooxygenase-2 selective inhibitors in the managment of chronic arthritis. Ann Intern Med 2003;138:795-806 Competing interests: None declared |
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manan vasenwala, consultant-cardiologist k.k.heart center, aligarh-202002.india
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i have been an avid prescriber of roficoxib. this revelations have come rather late. i can only groan in despair when my patients come with my old prescriptions bearing roficoxib. perhaps i should knock my head against a wall or something, since i can't catch hold of those responsible for the mess. Competing interests: None declared |
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Juan Carlos Maldonado, Investigator. Pharmacology Unit. Biomedical Centre. Central University of Ecuador. POBox: 17-11-6120
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In my country a popular proverb says: “when the river sounds…stones are coming”. When the “rofecoxib river” was rumbling?. I am sure you can remember that an Spanish independent drug bulletin was criticised by MSD some time ago [1]. In that bulletin the safety of rofecoxib was questioned because a randomized clinical trial (the VIGOR Study) showed a higher cardiovascular risk associated with rofecoxib [2]. This risk was also quantified in another report about the cardiovascular events associated with Cox-2 selective inhibitors [3]. A lot of letters and papers in the most relevant journals were talking about the same thing. For example, in a brief review Harten & Moosing [4] tried again to put into the table more warnings relatives to rofecoxib. Moreover, a recent study [6] reports that the risk of gastrointestinal bleeding with rofecoxib was higher (OR=7.2; CI95%= 2.3- 23.0) compared with the risk for other non-steroidal anti-inflammatory drugs: ibuprofen (OR=3.1; CI95%=2.0-4.9), diclofenac (OR=3.7; CI95%=2.6- 5.4) or meloxicam (OR=5.7; CI95%=2.2-15.0). A few patients were exposed to celecoxib and the study can not estimate the risk for this drug. These results confirms that Cox-2 inhibitors are not free of gastrointestinal adverse events. And now, the pharmaceutical company initiated a voluntary withdrawal from the market, because a new study (APPROVe) found a similar cardiovascular risk associated with rofecoxib [5]. In the note published this week by BMJ I read that “the new data relate specifically to rofecoxib and is not generalised to other cyclo-oxygenase-2 selective inhibitors”. This is a wrong way to see the problem. The cardiovascular risk must be a class effect, but the risk could be different for the other Cox-2 selective inhibitors and it needs confirmation. Meanwhile, another non-steroidal anti-inflammatory drugs are available, and these have the same clinical efficacy than Cox-2 selective inhibitors. Also, they are cheaper and probably with a better safety profile, as ibuprofen. Juan Carlos Maldonado, MD. Investigator. Pharmacology Unit. Biomedical Centre. Central University of Ecuador. References: 1- Gibson L. Drug company sues Spanish bulletin over fraud claim. BMJ 2004; 328: 188. 2- Bombardier C, Laine L, Reicin A, et al., for the VIGOR Study Group. N Engl J Med 2000; 343: 1520-8. 3- Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001; 286: 954-9. 4- Harten P, Moosing F. The rofecoxib scandal: The cardiovascular risks of rofecoxib. (Rapid response to Merck withdraws arthritis drug worldwide). BMJ 2004. [http://bmj.bmjjournals.com/cgi/eletters/329/7470/816-a]. 5- Singh D. Merck withdraws arthritis drug worldwide. BMJ 2004; 329: 816. 6- Laporte JR, Ibañez L, Vidal X, Vendrell L, Leone R. Upper gastrointestinal bleeding associated with the use of NSAIDs newer versus older agents. Drug Saf 2004; 27: 411-20. Competing interests: None declared |
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