Long-term Risk of Ischemic Stroke Associated with Rofecoxib
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
The association between rofecoxib use and ischemic stroke has not been shown in clinical trials. These trials were limited by short-term follow-up and non-placebo controls. Extended follow-up data from the APPROVe trial has shed some light on the incidence of ischemic stroke after rofecoxib use.
Materials and Methods
Review of published and unpublished data from APPROVe. We searched the Food and Drug Administration and Merck websites to obtain unpublished data. Statistical analyses were performed by the APPROVe investigators and are reported as relative risks (RR) with their 95% confidence intervals (CI).
APPROVe evaluated the effect of rofecoxib 25 mg/d versus matching placebo on recurrent colon polyps in 2,586 patients with a history of colorectal adenomas. Although the published data from APPROVe showed a nonsignificant relative risk of ischemic stroke (RR 1.99, 95% CI 0.74 to 5.39, p = 0.174), extended follow-up data from Merck’s website recently revealed a significant three-fold increase in ischemic stroke in patients randomized to rofecoxib (RR 2.91, 95% CI 1.15 to 7.39, p = 0.024). Notably, seven out of eighteen ischemic strokes occurred after rofecoxib use had been discontinued.
Based on extended follow-up data, APPROVe is the first trial to report an increase in ischemic stroke risk with rofecoxib compared to placebo. The finding of ischemic strokes after rofecoxib use had been discontinued should be further studied to determine whether patients previously exposed to rofecoxib remain at an increased risk.
- Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001;286:954–9. CrossRef
- Levesque LE, Brophy JM, Zhang B. The risk for myocardial infarction with cyclooxygenase-2 inhibitors: a population study of elderly adults. Ann Intern Med 2005;142:481–9.
- 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, 2.
- Juni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 2004;364:2021–9. CrossRef
- Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. 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. CrossRef
- Konstam MA, Weir MR, Reicin A, Shapiro D, Sperling RS, Barr E, et al. Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib. Circulation 2001;104:2280–8.
- Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005;352:1092–102. CrossRef
- Merck. APPROVe extension statistical package. http://www.merck.com/newsroom/vioxx_withdrawal/pdf/APPROVe_Extension_Statistical_Package.pdf. 26-5-2006. 4-7-2006.
- Andersohn F, Schade R, Suissa S, Garbe E. Cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs and the risk of ischemic stroke: a nested case-control study. Stroke 2006;37:1725–30. CrossRef
- McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A 1999;96:272–7. CrossRef
- FitzGerald GA. Coxibs and cardiovascular disease. N Engl J Med 2004;351:1709–11. CrossRef
- FitzGerald GA. COX-2 and beyond: Approaches to prostaglandin inhibition in human disease. Nat Rev Drug Discov 2003;2:879–90. CrossRef
- Kannel WB. Fifty years of Framingham Study contributions to understanding hypertension. J Hum Hypertens 2000;14:83–90. CrossRef
- Aw TJ, Haas SJ, Liew D, Krum H. Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure. Arch Intern Med 2005;165:490–6. CrossRef
- Fosslien E. Cardiovascular complications of non-steroidal anti-inflammatory drugs. Ann Clin Lab Sci 2005;35:347–85.
- Bogaty P, Brophy JM, Noel M, Boyer L, Simard S, Bertrand F, Dagenais GR. Impact of prolonged cyclooxygenase-2 inhibition on inflammatory markers and endothelial function in patients with ischemic heart disease and raised C-reactive protein: a randomized placebo-controlled study. Circulation 2004;110:934–9. CrossRef
- Thal LJ, Ferris SH, Kirby L, Block GA, Lines CR, Yuen E, Assaid C, Nessly ML, Norman BA, Baranak CC, Reines SA. A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment. Neuropsychopharmacology 2005;30:1204–15. CrossRef
- Lagakos SW. Time-to-event analyses for long-term treatments—the APPROVe trial. N Engl J Med 2006;355:113–7. CrossRef
- Long-term Risk of Ischemic Stroke Associated with Rofecoxib
Cardiovascular Drugs and Therapy
Volume 21, Issue 2 , pp 117-120
- Cover Date
- Print ISSN
- Online ISSN
- Kluwer Academic Publishers-Plenum Publishers
- Additional Links
- cox-2 inhibitor
- cerebrovascular accident
- Industry Sectors
- Author Affiliations
- 1. Department of Medicine, Sir Mortimer B. Davis Jewish General Hospital, McGill University, 3755 Cote Ste Catherine Suite A-118, Montreal, Quebec, Canada
- 2. Division of Clinical Epidemiology, Sir Mortimer B. Davis Jewish General Hospital, McGill University, 3755 Cote Ste Catherine Suite A-118, Montreal, Quebec, Canada
- 3. Division of Cardiology, Sir Mortimer B. Davis Jewish General Hospital, McGill University, 3755 Cote Ste Catherine Suite A-118, Montreal, Quebec, Canada