Selective COX-2 inhibitors and risk of thromboembolic events – regulatory aspects

Hans-Karl Heim; Karl Broich

doi:10.1160/TH06-08-0462

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 96(04): 423-432
DOI: 10.1160/TH06-08-0462

Theme Issue Article

Schattauer GmbH

Selective COX-2 inhibitors and risk of thromboembolic events – regulatory aspects

Hans-Karl Heim

¹Bundesinstitut für Arzneimittel und Medizinprodukte, Bonn, Germany

,

Karl Broich

¹Bundesinstitut für Arzneimittel und Medizinprodukte, Bonn, Germany

› Author Affiliations

Abstract

Summary

In the 1990s, the pharmaceutical industry developed selective COX-2 inhibitors (coxibs) as alternatives to conventional nonsteroidal anti-inflammatory drugs (NSAIDs), with the expectation of similar analgetic and anti-inflammatory efficacy but a reduced risk of adverse gastrointestinal (GI) effects. Marketing authorisation (MA) was granted for rofecoxib and celecoxib as first representatives of this new pharmacological class at the end of the 1990s in the EU. In the following years MAs were granted for the ´second generation` coxibs etoricoxib, parecoxib/valdecoxib and lumiracoxib. However, data from large clinical ´outcome studies` as well as epidemiological data raised concerns about the cardiovascular (CV) safety of the coxibs. In consequence, two comprehensive review processes (referrals) were initiated by the European Medicines Agency (EMEA).As a result, in the EU the use of coxibs has been contraindicated in patients with established coronary heart disease, cerebrovascular disease and peripheral arterial disease and a number of warning statements concerning CV, GI and skin toxicity have been introduced in the coxib product informations. This article provides a description of the regulatory actions taken and discusses some specific aspects of the past and future regulatory assessment of coxibs.

Keywords

Cyclooxygenase 2 inhibitors - anti-inflammatory agents - non-steroidal - cardiovascular diseases - gastrointestinal diseases - legislation - drug

Full Text

References

References
1 Grosser T. et al. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest 2006; 116: 4-15.
2 Rabausch K. et al. Regulation of thrombomodulin expression in human vascular smooth muscle cells by COX-2-derived prostaglandins. Circ Res 2005; 96: 1-6.
3 Silverstein FE. et al. Gastrointestinal toxicity with celecoxib vs non-steroidal antiinflammatory drugs for osteoarthritis and rheumatoid arthritis – the CLASS study: a randomized controlled trial. J Am Med Assoc 2000; 284: 1247-55.
4 Bombardier C. 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.
5 Bresalier R. 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: 1092-102.
6 Lagakos SW. Time-to-event analyses for long-term treatments – the APPROVe trial. N Eng J Med 2006; 355: 2 www.nejm.org published July 13, 2006.
7 Goldstein JL. et al. Significantly improved upper gastrointestinal (UGI) tolerability with celecoxib, a COX-2 specific inhibitor, compared with conventional NSAIDs. The SUCCESS I trial [abstract]. European League Against Rheumatism. Prague, Czech Republic, June 13–16, 2001.
8 Solomon S. et al. Adenoma Prevention with Celecoxib (APC) study investigators. Cardiovascular risk associated with celecoxib ina clinical trial for colorectal adenoma prevention. N Engl J Med 2005; 352: 1071-80.
9 PreSAP trial. accessed at http://www.masterdocs.com/cox2_nci_APC_PreSAP_talk.html
10 Ott E. et al. 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.
11 Nussmeier NA. et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005; 352: 1081-91.
12 Whelton A. et al. Safety of parecoxib and valdecoxib in the treatment of postoperative pain following coronary artery bypass graft surgery or major general surgery. Presented at the American College of Cardiology Annual Scientific Session. 2005 March 6–9, 2005; Orlando, Florida: Late Breaking Clinical Trials I..
13 Farkouh ME. et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomized controlled trial. Lancet 2004; 364: 675-84.
14 Schnitzer TJ. et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 2004; 364: 665-74.
15 Baraf H. et al. Tolerability and effectiveness of etoricoxib compared to diclofenac sodium in patients with osteoarthritis: a randomized controlled study (EDGE trial) [Abstract]. Arthritis Rheum. 2004 (Suppl): 832.
16 FDA, ACM Background Document. Etoricoxib. Available at http://www.fda.gov/ohrms/dockets/-ac/05/brief-ing/2005–4090B2_01_Merck-Etoricoxib.pdf Accessed August 19, 2006.
17 ADAPT. Available at http://www.fda.gov/ohrms/dockets/ac/05/slides/2005–4090S1_12_Bayer-Hoffman-LaRoche-Naproxen.ppt Accessed August 5, 2005.
18 Hippisley-Cox J, Coupland C. Risk of myocardial infarction in patients taking cyclooxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ 2005; 330: 1366 doi:10.1136/bmj.330.7504. 1366.
19 Kearney PM. et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 2006; 332: 1302-8.
20 Shinmura K. et al. Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits. Proc Natl Acad Sci USA 2000; 97: 10197-202.
21 Burleigh ME. et al. Cycloxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor deficient mice. Circulation 2002; 105: 1816-23.
22 Schonbeck U. et al. Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am J Pathol 1999; 155: 1281-1291.
23 Billingham ME. Models of arthritis and the search for anti-arthritis drugs. Pharmacol Ther 1983; 21: 389-428.
24 Mukherjee A. et al. Predictability of the clinical potency of NSAIDs from the preclinical pharmacodynamics in rats. Inflamm Res 1996; 45: 531-40.
25 Cheng Y. et al. Role of prostacyclin in the cardiovascular response to thromboxane A₂ . Science 2002; 296: 539-541.
26 Murata T. et al. Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. Nature 1997; 388: 678-82.
27 Egan KM. et al. Accelerated atherogenesis in prostacyclin receptor deficient mice [Abstract]. Circulation 2000; 102: 850.
28 Yamada M. et al. Prostacyclin synthase gene transfer modulates cyclooxygenase-2-derived prostanoid synthesis and inhibits neointimal formation in rat balloon-injured arteries. Arterioscler Thromb Vasc Biol 2002; 22: 256-62.
29 McAdam BF. et al. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci USA 1999; 96: 272-7.
30 Catella-Lawson F. et al. Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids. J Pharm Exp Ther 1999; 289: 735-41.
31 Cheng Y. et al. Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function. J Clin Invest 2006; 116: 1391-9.
32 Hennan JK. et al. Effects of selective cyclooxygenase-2 inhibition on vascular responses and thrombosis in canine coronary arteries. Circulation 2001; 104: 820-5.
33 Umar A. et al. Interactions between aspirin and COX-2 inhibitors or NSAIDs in a rat thrombosis model. Fundam Clin Pharmacol 2004; 18: 559-63.
34 Baumgärtel D. et al. Antagonism of the antithrombotic and antiatherosclerotic actions of aspirin by rofecoxib in the cholesterol-fed rabbit. [Abstract] Circulation 2005; 112 (17) (Suppl S): U296.
35 Silverman DG. et al. Rofecoxib does not compromise platelet aggregation during anesthesia and surgery. Can J Anaesth 2003; 50: 1004-8.
36 Catella-Lawson F. et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001; 345: 1809-17.
37 Wilner KD. et al. Celecoxib does not affect the antiplatelet activity of aspirin in healthy volunteers. J Clin Pharmacol 2002; 42: 1027-30.
38 Guo Y. et al. Evidence for an essential role of cyclooxygenase-2 as a mediator of the late phase of ischemic preconditioning in mice. Basic Res Cardiol 2000; 95: 479-84.
39 Ghosh S. et al. Preconditioning the human myocardium by simulated ischemia: studies on the early and delayed protection. Cardiovasc Res 2000; 45: 339-50.
40 Noda T. et al. Evidence for the delayed effect in human ischemic preconditioning: prospective multicenter study for preconditioning in acute myocardial infarction. J Am Coll Cardiol 1999; 34: 1966-74.
41 Guo JS. et al. Antiangiogenic effect of a highly selective cyclooxygenase-2 inhibitor on gastric ulcer healing in rats. Toxicol Appl Pharmacol 2002; 183: 41-5.
42 Ma L. et al. Divergent effects of new cyclooxygenase inhibitors on gastric ulcer healing: shifting the angiogenic balance. Proc Natl Acad Sci USA 2002; 99: 13243-7.
43 Fosslien E. Biochemistry of cycloxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia. Crit Rev Clin Lab Sci 2000; 37: 431-502.
44 Watson DJ. et al. All-cause mortality and vascular events among patients with rheumatoid arthritis, ostoearthritis, or no arthritis in the UK General Practice Research Database. J Rheumatol 2003; 30: 1196-202.
45 Fontana P-G. Gastrointestinal and cardiovascular safety of lumiracoxib, ibuprofen, and naproxen. Presentation at the ´Selective COX-2 inhibitor Non Steroidal Anti-Inflammatory Drugs Expert Advisory Panel and Public Forum`. Ottawa: June 9, 2005. Available at www.fda.gov/OHRMS/DOCKETS/.AC/05/slides/2005–4090S2_06_FDA-Villalba.ppt Accessed August 19, 2006.
46 Johnson AG. NSAIDs and increased blood pressure. What is the clinical significance. Drug Saf 1997; 17: 277-89.
47 Baccouche M. Implementation of the Review 2001 – Impact on the pharmaceutical industry. Available at http://www.dgra.de/fortbildung/pdf/kongr0605-baccouche.pdf Accessed August 19, 2006.
48 Hartford CG. et al. Pharmacovigilance during the pre-approval phases. An evolving pharmaceutical industry model in response to ICH E2E, CIOMS VI, FDA and EMEA/CHMP risk-management guidelines. Drug Saf 2006; 29: 657-73.
49 Tsintis P, La Mache. CIOMS and ICH initiatives in pharmacovigilance and risk management-overview and implications. Drug Saf 2004; 27: 509-17.
50 Bahri P, Tsintis P. Pharmacovigilance-related topics at the level of the International Conference on Harmonisation (ICH): Pharmacoepidemiol Drug Saf. 2005; 14: 377-87.
51 Moseley JNS. Risk management –a european regulatory perspective. Drug Saf 2004; 27: 499-508.
52 Geba GP. et al. Gastrointestinal tolerability in primary care patients treated with naproxen or rofecoxib for osteoarthritis: the ADVANTAGE trial [Abstract]. European League Against Rheumatism. Prague, Czech Republic, June 13–16, 2001.
53 Goldstein JL. et al. SUCCESS in osteoarthritis (OA) trial: celecoxib significantly reduces the risk of upper gastrointestinal (UGI) hospitalizations compared to diclofenac and naproxen in 13,274 randomized patients with OA [Abstract]. European League Against Rheumatism. Prague, Czech Republic, June 13–16, 2001.