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 25 November 2000 15 December 2000
Roxithromycin and celecoxib
25 November 2000
generalised itchy rash ceased celecoxib
15 December 2000
Restarted celecoxib
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 & 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 Volume Number 1 January 2006

5. Mechanistic Extent of Risk
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
January 11, 2008

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. Cyclo oxygenase inhibiton

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
January 11, 2008

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
January 11, 2008

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
Assuming one year of Rx, for every 139 patients treated for a year, one additional cardiovascular event will occur.
January 11, 2008

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 ).
Juni, P, Nartey, L, Reichenbach, S, et al. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 2004; 364:2021.
January 11, 2008

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 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:

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, Celecoxib 200 mg BD
RR 3.4, 95% CI, 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.
Placebo – 7 CV events/676 subjects
Celecoxib 200 mg twice daily - 18 events among 683 subjects (RR 2.6, 95% CI, )
Celecoxib 400 mg twice daily - 23 events among 669 subjects (RR 3.4, 95% CI, )
January 11, 2008

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
January 11, 2008

25. COX Inhibitors Proven cardioprotective efficacy Low-dose aspirin (1a)
Potential cardioprotective efficacy (inter-individual variablity)
Naproxen (3a)
Potential to decrease cardioprotective effect of low-dose aspirin
Ibuprofen (3a)
Flubiprofen (5)
Indomethacin (5)
Naproxen (5)
Proven gastroprotective efficacy (COX -2 )
Rofecoxib (withdrawn) (1b)
Lumiracoxib (FDA approval pending) (1b)

26. COX & low cardiovascular risk
Chronic treatment low cardiovascular and low GI risk
Naproxen (2b, 2a)
Ibuprofen (2b, 2a)
Chronic treatment low cardiovascular and high GI risk
Naproxen + proton pump inhibitor (2b, 2a)
Ibuprofen + proton pump inhibitor (2b, 2a)
Diclofenac + proton pump inhibitor (2b, 2a)
Possibly celecoxib (although GI advantage vs. tNSAID not proven) (3, 2)

27. COX & high cardiovascular risk
Chronic treatment high cardiovascular and low GI risk
Naproxen + Clopidogrel
to avoid potential interaction with low-dose aspirin
GI toxicity of this combination is likely = tNSAID + low-dose aspirin and may warrant addition of a proton pump inhibitor) (5)
Ibuprofen + clopidogrel (see comment above) (5)
Chronic treatment high cardiovascular and high GI risk
Naproxen + proton pump inhibitor + clopidogrel (5)
Ibuprofen + proton pump inhibitor + clopidogrel (5)

28. Thank you for attention
Copy of the talk on

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).
January 11, 2008

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: )

31. Figure1. Luminalgeometryispreservedthroughpronouncedneo-
intimaformationinarteriestransplantedfromIPKOmice.Histologi-
calanalysis(A)andquantitativemorphometryrevealedthatboth
luminalarea(B)andtotalvesselarea(C)weresignificantlyreduced
inWTtransplants(whitebars)(*P 0.05)from3to6weeksafter
transplant.LumenareainIPKOarteries(blackbars)wascompara-
bletoWTarteriesby6weeks.Thisinvolvedpronouncedandpro-
gressiveneointimalproliferation(D)thatexceededwhatwas
observedinWTtransplants(*P 0.05).Despiteadivergent
responsetostress,thepercentstenosiswascomparableinthe2
groups6weeksaftertransplant(E)(bar 100 m).