Presentation on theme: "NSAIDS in the ischaemic heart disease patient"— Presentation transcript:
1 NSAIDS in the ischaemic heart disease patient Andrew DawsonSACTRC Program DirectorUniversity of PeradeniyaSri Lanka
2 2002 Medico-legal 13 November 2000 25 November 2000 15 December 2000 Roxithromycin and celecoxib25 November 2000generalised itchy rash ceased celecoxib15 December 2000Restarted celecoxibsudden onset of severe pain in her legsacute thrombosis
3 Questionswhether 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 patientGraphicsGrosser 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 COX2Basis was established before COX2 marketedExtent of RiskDrug FactorsType, durationPatient FactorsUnderlying cardiovascular risk
6 What’s a COX?COX-1 is expressed in most tissues. Functions towards gastric cytoprotection, vascular homeostasis, platelet aggregation, and kidney functionCOX-2 expressed in the brain, kidney, bone, and probably in the female reproductive system. Its expression at other sites (cardiovascular), increased during states of inflammationIncreased expression of COX-2 mRNA and protein has been noted in patients with hypertension, heart failure, and diabetic nephropathy 1January 11, 2008
11 MechanismsCOX-2 reduced prostaglandin I2 (PGI2 or prostacyclin) production by vascular endothelium with little or no inhibition of potentially prothrombotic platelet thromboxane A2COX inhibition in general associated with elevations in blood pressure (<5 mm Hg elevations in systolic blood pressure)COX-2 role in vascular remodellingJanuary 11, 2008
13 Clinical StudiesPre licencing Studies of COX 2 underpowered for vascular eventsPostmarketing studies patients had variable baseline cardiac riskInitially 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 tidAble to use ASA 325no significant increase risk MI with celecoxibVIGOR studyrandomized double blind looking at rofecoxib (50 od) vs 500 bid naproxen in RA>8000 patients over median 9 months.No use of ASAsignificant 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 prostacyclinJanuary 11, 2008
15 Rofecoxib: studies related to Ischemic events APPROVe trial:RCT 2586 patients rofecoxib (25 mg/day) or placebo3 years.Thrombotic events (MI, Stroke)1.5 per 100 patient years (Active) vs 0.78 per 100 patient years(placebo)RR 1.92, 95% CIAssuming 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 trials25,273 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 resistanceRapid emergence of cardiovascular hazard in high risk groupsNussmeier 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 RCTCelecoxib (400 mg bid or 200 bid) or placebo,33 month followupRelative Risk Cardiovascular eventRR 2.6, 95% CI, Celecoxib 200 mg BDRR 3.4, 95% CI, Celecoxib 400 mg BDDose effect in low risk populationBertagnolli, 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 subjectsCelecoxib 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
24 Australian Drug Reaction Advisory Committee 2002 There may be an increased risk of cardiovascular and cerebrovascular disease with rofecoxib and celecoxibThe increase in risk seems to be higher in those with pre-existing cardiovascular diseaseThe risk appears to be greater with rofecoxib than with celecoxib, and appears to be dose relatedRofecoxib should not be used in doses exceeding the maximum approved dose (25 mg/day)Cardiovascular risk should be evaluated before prescribing a coxibJanuary 11, 2008
26 COX & low cardiovascular risk Chronic treatment low cardiovascular and low GI riskNaproxen (2b, 2a)Ibuprofen (2b, 2a)Chronic treatment low cardiovascular and high GI riskNaproxen + 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 riskNaproxen + Clopidogrelto avoid potential interaction with low-dose aspirinGI 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 riskNaproxen + proton pump inhibitor + clopidogrel (5)Ibuprofen + proton pump inhibitor + clopidogrel (5)
29 COX2i: Heart FailureLancet 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)andquantitativemorphometryrevealedthatbothluminalarea(B)andtotalvesselarea(C)weresignificantlyreducedinWTtransplants(whitebars)(*P 0.05)from3to6weeksaftertransplant.LumenareainIPKOarteries(blackbars)wascompara-bletoWTarteriesby6weeks.Thisinvolvedpronouncedandpro-gressiveneointimalproliferation(D)thatexceededwhatwasobservedinWTtransplants(*P 0.05).Despiteadivergentresponsetostress,thepercentstenosiswascomparableinthe2groups6weeksaftertransplant(E)(bar 100 m).
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