Gibt es Gründe für die Gabe von COX-2-Hemmern?

S. Reichenbach; L. Nartey; B. Tschannen; P. Jüni

doi:10.1055/s-2003-41919

ZFA - Zeitschrift für Allgemeinmedizin, Table of Contents

ZFA (Stuttgart) 2003; 79(6): 288-293
DOI: 10.1055/s-2003-41919

Pharmakotherapie

Gibt es Gründe für die Gabe von COX-2-Hemmern?

Is there a rationale for the use of COX-2 inhibitors?S. Reichenbach¹ ² ³ , L. Nartey¹ , B. Tschannen¹ , P. Jüni¹ ² ³

¹Institut für Sozial- und Präventivmedizin, Universität Bern, Finkenhubelweg 11, CH-3012 Bern
²Klinik für Rheumatologie und klinische Immunologie, Inselspital, Universität Bern, Schweiz
³MRC Health Services Research Collaboration, Department of Social Medicine, University of Bristol, United Kingdom

Abstract

Zusammenfassung

Anfang der 90er Jahre wurden zwei Isoformen der Cyclooxygenase (COX) entdeckt: COX-1 und COX-2. Die anti-inflammatorische Wirkung der nicht-steroidalen Antirheumatika (NSAR) wurde einer COX-2-Hemmung, die damit verbundenen Nebenwirkungen jedoch einer COX-1-Hemmung zugeschrieben. Somit boomte die Entwicklung einer neuen Generation von NSAR: der COX-2-Hemmer. Aufgrund aggressiver Marketingstrategien werden zwei ihrer Vertreter, Rofecoxib und Celecoxib, zunehmend in der Behandlung von Schmerzen unterschiedlichster Genese eingesetzt. Wahrscheinlich ist das gängige Konzept einer im Vergleich zu konventionellen NSAR maßgeblich verbesserten Arzneimittelsicherheit der COX-2-Hemmer jedoch falsch. Aktuell bestehen keinerlei

Hinweise auf eine erhöhte gastrointestinale Sicherheit des mäßig COX-2-selektiven Celecoxib gegenüber konventionellen NSAR. Demgegenüber steht die Evidenz vermehrter kardiovaskulärer Komplikationen des hochgradig COX-2-selektiven Rofecoxib. Somit findet sich aktuell kein Grund für die Verabreichung von COX-2-Hemmern. Stattdessen sollten einfache Analgetika (Paracetamol) und, falls nötig, konventionelle NSAR (primär Diclofenac oder Naproxen) eingesetzt werden, eventuell in Kombination mit einem Protonenpumpenblocker (z.B. Omeprazol).

Summary

In the early 1990s two isoforms of Cyclooxygenase (COX) were found: COX-1 and COX-2. It was suggested that the anti-inflammatory properties of non-steroidal anti-inflammatory drugs (NSAIDs) were related to a COX-2 inhibition, whereas their adverse effects occurred because of a COX-1 inhibition. This led to a massive era of pharmaceutical development, which has resulted in the introduction of a group of new NSAIDs: the COX-2 inhibitors. Due to an aggressive marketing, two of them, rofecoxib and celecoxib, are increasingly used for a variety of painful conditions. However, the view that COX-2 inhibitors are safer than conventional NSAIDs is likely to be flawed. Currently there is no evidence suggesting that the modestly COX-2 selective drug celecoxib is safer than conventional NSAIDs for the gastrointestinal tract, while there is considerable evidence that the highly COX-2 selective drug rofecoxib has increased cardiovascular toxicity compared with traditional NSAIDs. Currently, there is no rationale for the use of COX-2 inhibitors. Rather, simple analgesics (paracetamol) and, if necessary, traditional NSAIDs (mainly diclofenac or naproxen) should be used, potentially combined with a proton-pump inhibitor (e.g. omeprazole).

Key words

COX-2 inhibitors - NSAIDs - rofecoxib - celecoxib - gastrointestinal tract - cardiovascular risk

Full Text

References

Literatur

1 Boardman PL, Hart FD. Clinical measurement of the anti-inflammatory effects of salicylates in rheumatoid arthritis. Br Med J. 1967; 4 264-8
2 Brooks PM. Side-effects of non-steroidal anti-inflammatory drugs. Med J Aust. 1988; 148 248-51
3 Henry D, Lim LLY, Garcia LA Rodriguez, Perez S Gutthann, Carson JL, Griffin M. et al. . Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. BMJ. 1996; 312 1563-6
4 Meade EA, Smith WL, DeWitt DL. Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J Biol Chem. 1993; 268 6610-4
5 Kargman S, Charleson S, Cartwright M, Frank J, Riendeau D, Mancini J. et al. . Characterization of Prostaglandin G/H Synthase 1 and 2 in rat, dog, monkey, and human gastrointestinal tracts. Gastroenterology. 1996; 111 445-54
6 Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A. et al. . Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA. 2000; 284 1247-55
7 Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B. et al. . Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000; 343 1520-8
8 Brandt KD, Bradley JD. Should the initial drug be used to treat osteoarthritis pain be a nonsteroidal antiinflammatory drug?. J Rheumatol. 2001; 28 467-73
9 Jüni P, Rutjes AW, Dieppe PA. Are selective COX-2 inhibitors superior to traditional NSAIDs? Adequate analysis of the CLASS trial indicates that this may not be the case. BMJ. 2002; 324 1287-8
10 Okie S. Missing data on Celebrex. Full study altered picture of drug. Washington Post. 2001;
11 US Food and Drug Administration . Transcript of the arthritis advisory committee. Available at: http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3677t1.rtf.. 2001;
12 Berg J Hrachovec, Mora M. Reporting of 6-month vs 12-month data in a clinical trial of celecoxib. JAMA. 2001; 286 2398
13 Lu HL. Statistical Reviewer Briefing Document for the Advisory Committee. Available at: http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b1_04_stats.doc.. 2002;
14 Jüni P, Rutjes AW, Dieppe P. Are selective COX 2 inhibitors superior to traditional NSAIDs? Authors' reply. BMJ. 2002; 325 163-4
15 Silverstein F, Simon L, Faich G. Reporting of 6-month vs 12-month data in a clinical trial of celecoxib. In reply. JAMA. 2001; 286 2399-400
16 Villalba ML. FDA advisory committee briefing document. Rofecoxib overall safety. Available at: http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_03_med.pdf.. 2002;
17 Li Q. Statistical Reviewer Briefing Document for the Advisory committee. Available at: http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_04_stats.pdf.. 2002;
18 Catella-Lawson F, Crofford LJ. Cyclooxygenase inhibition and thrombogenicity. Am J Med. 2001; 110 28-32
19 Targum SL. Food and Drug Administration: cardiovascular safety review rofecoxib. Available at: http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_06_cardio.pdf.. 2002;
20 Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001; 286 954-9
21 Jüni P, Dieppe P, Egger M. Risk of myocardial infarction associated with selective COX-2 inhibitors: questions remain. Arch Intern Med. 2002; 162 2639-40
22 White WB, Faich G, Whelton A, Maurath C, Ridge NJ, Verburg KM. et al. . Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac. Am J Cardiol. 2002; 89 425-30
23 Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier B. et al. . Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med. 2001; 345 1809-17
24 Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci U S A. 1999; 96 7563-8
25 Chan FKL, Hung LCT, Suen BY, Wu JCY, Lee KC, Leung VKS. et al. . Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med. 2002; 347 2104-10
26 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 1478-91

OA Dr. Peter Jüni

Institut für Sozial- und Präventivmedizin, Universität Bern

Finkenhubelweg 11, CH-3012 Bern

Email: juni@ispm.unibe.ch

Zur Person

Dr. med. Peter Jüni

Oberarzt mit Lehrauftrag am Institut für Sozial- und Präventivmedizin der Universität Bern und an der Klinik für Rheumatologie, Inselspital Bern. Nach dem Staatsexamen Ausbildung zum Internisten und Rheumatologen, zuletzt am Zieglerspital und am Inselspital in Bern. Mehrere Forschungsaufenthalte am Department of Social Medicine der Universität Bristol, UK, als klinischer Epidemiologe und Leiter verschiedener Forschungsprojekte in der Gesundheitssystemforschung und zu methodologischen Fragen. Autor zahlreicher Publikationen in internationalen Fachzeitschriften und Buchbeiträge zur Methodik von Systematic Reviews bzw. zu klinischen Fragestellungen. Associate-Editor des International Journal of Epidemiology und Peer-Reviewer für verschiedene Fachzeitschriften, u.a. für das British Medical Journal (BMJ) und das Journal of the American Medical Association (JAMA).