NSAIDS in the ischaemic heart disease patient

1. NSAIDS in the ischaemic heart disease patient Andrew Dawson SACTRC Program Director University of Peradeniya Sri Lanka

2. 2002 Medico-legal • 13 November 2000 • Roxithromycin and celecoxib • 25 November 2000 • generalised itchy rash ceasedcelecoxib • 15 December 2000 • Restarted celecoxib • 15 December 2000 • sudden onset of severe pain in her legs • acute thrombosis

3. Questions • whether an adverse reaction to celecoxib (Celebrex) was the cause of the rash? • can celecoxib can cause or increase the likelihood of thrombosis either directly or as a manifestation of a hypersensitivity reaction? • What was known in 2000 & in 2002?

4. Objectives • Putative mechanisms • What is the risk • What variables are important • “What to do” with an individual patient • Graphics • Grosser T, Fries S, Fitzgerald. Biological basis for the cardiovascular consequences of COX-2 inhibition. The Journal of Clinical Investigation http://www.jci.org Volume 116 Number 1 January 2006

5. Mechanistic • Risk is largely explained by extent of relative inhibition of COX1 and COX2 • Basis was established before COX2 marketed • Extent of Risk • Drug Factors • Type, duration • Patient Factors • Underlying cardiovascular risk

6. What’s a COX? • COX-1 is expressed in most tissues. Functions towards gastric cytoprotection, vascular homeostasis, platelet aggregation, and kidney function • COX-2 expressed in the brain, kidney, bone, and probably in the female reproductive system. Its expression at other sites (cardiovascular), increased during states of inflammation • Increased expression of COX-2 mRNA and protein has been noted in patients with hypertension, heart failure, and diabetic nephropathy 1

7. Membrane Phospholipids Arachidonic Acid endotoxins cycokines mitogens Induced • COX-2 • Inhibited by • NSAIDS • COX-2 inhibitors • COX-1 • Inhibited by • NSAIDS Prostaglandins Thromboxanes Prostaglandins Prostacyclins

8. Cyclooxygenaseinhibiton

9. COX Inhibition

10. Relative Selectivity

11. Mechanisms • COX-2 reduced prostaglandin I2 (PGI2 or prostacyclin) production by vascular endothelium with little or no inhibition of potentially prothrombotic platelet thromboxane A2 • COX inhibition in general associated with elevations in blood pressure (<5 mm Hg elevations in systolic blood pressure) • COX-2 role in vascular remodelling

13. Clinical Studies • Pre licencing Studies of COX 2 underpowered for vascular events • Postmarketing studies patients had variable baseline cardiac risk • Initially obscured & subsequently informed risk assessment

14. CLASS and VIGOR trials • CLASS trial: • randomized double blinded 8000 adults with RA or OA. • GI Outcomes between celecoxib 400 bid (high dose) vs. diclofenac 75 od or ibuprofen 800 tid • Able to use ASA 325 • no significant increase risk MI with celecoxib • VIGOR study • randomized double blind looking at rofecoxib (50 od) vs 500 bid naproxen in RA • >8000 patients over median 9 months. • No use of ASA • significant risk of MI with rofecoxib (20 vs 4 events) • Why the difference? (a)Naproxen anti-platelet effects, bigger difference in rates vs. COX2i in CLASS (b) ASA in CLASS more protective than COX2i harmful in ischemic rates? (c) Rofecoxib prothrombotic via reduction of prostacyclin

15. Rofecoxib: studies related to Ischemic events • APPROVe trial: • RCT 2586 patients rofecoxib (25 mg/day) or placebo • 3 years. • Thrombotic events (MI, Stroke) • 1.5 per 100 patient years (Active) vs 0.78 per 100 patient years(placebo) • RR 1.92, 95% CI 1.19-3.11. • Assuming one year of Rx, for every 139 patients treated for a year, one additional cardiovascular event will occur.

16. Rofecoxib: meta-analysis for Ischemic events • 8 clinical trials • 25,273 patients were randomly assigned to rofecoxib or a control (placebo or comparison NSAID) • 2.24 RR of MI in rofecoxib group • (95% CI 1.24-4.02). • Juni, P, Nartey, L, Reichenbach, S, et al. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 2004; 364:2021.

17. COX-2 inhibition in CABG • Ott E et al Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg. 2004 Feb;127(2):605

18. COX-2 inhibition in CABG • RR 3.7 Vascular Event • (95% CI 1.0 to 13.5) • Relative Aspirin resistance • Rapid emergence of cardiovascular hazard in high risk groups • Nussmeier N et al Complications of the COX-2 Inhibitors Parecoxib and Valdecoxib after Cardiac Surgery N Engl J Med 2005;352:1081-91.

19. Celecoxib: APC (adenomatous polyp prevention trial), • 2035 patients RCT • Celecoxib (400 mg bid or 200 bid) or placebo, • 33 month followup • Relative Risk Cardiovascular event • RR 2.6, 95% CI, 1.1-6.1 Celecoxib 200 mg BD • RR 3.4, 95% CI, 1.5-7.9 Celecoxib 400 mg BD • Dose effect in low risk population • Bertagnolli, MM, Eagle, CJ, Zauber, AG, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 2006; 355:873.

20. BMC Medicine 2005, 3:17

22. Clinical Balance

23. Risk

24. Australian Drug Reaction Advisory Committee 2002 • There may be an increased risk of cardiovascular and cerebrovascular disease with rofecoxib and celecoxib • The increase in risk seems to be higher in those with pre-existing cardiovascular disease • The risk appears to be greater with rofecoxib than with celecoxib, and appears to be dose related • Rofecoxib should not be used in doses exceeding the maximum approved dose (25 mg/day) • Cardiovascular risk should be evaluated before prescribing a coxib

25. COX Inhibitors

26. COX & low cardiovascular risk

27. COX & high cardiovascular risk

28. Thank you for attention adawson@sactrc.org Copy of the talk on www.wikitox.org

29. COX2i: Heart Failure • Lancet 2004, Mamdani et al.: restrospective study examined incidence of heart failure in NSAID-naive older (66 years) individuals. • New prescriptions for rofecoxib, celecoxib, and nonselective NSAIDs were issued to 14,583, 18,908, and 5,391 patients, and heart failure in these groups compared to 100,000 controls. • Crude rates of hospitalization for heart failure per 100 patient-years of exposure were 0.9 for the controls, 2.4 for the rofecoxib, 1.3 for the celecoxib, and 1.6 for the nonselective NSAID groups. • Relative risk of hospitalization with heart failure was significantly higher in those receiving rofecoxib than those receiving celecoxib (adjusted relative risk (RR) 1.8 versus 1.0, respectively).

30. Mechanism based vascular remodeling may interact with a predisposition to hypertension and atherosclerosis in contributing to the gradual transformation of cardiovascular risk during extended periods of treatment with selective inhibitors of COX-2. (CircRes. 2005;96:1240-1247.)