nsaids in the ischaemic heart disease patient

South Asian Clinical Toxicology Research Collaboration

NSAIDS in the ischaemic heart NSAIDS in the ischaemic heart disease patientdisease patient

Andrew Dawson

SACTRC Program Director

University of Peradeniya

Sri Lanka


2002 Medico-legal2002 Medico-legal 13 November 2000

– Roxithromycin and celecoxib 25 November 2000

– generalised itchy rash ceased celecoxib 15 December 2000

– Restarted celecoxib 15 December 2000

– sudden onset of severe pain in her legs – acute thrombosis


QuestionsQuestions 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?


ObjectivesObjectives 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


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


6January 11, 2008

What’s a COX?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


Membrane Phospholipids

Arachidonic Acid

ProstaglandinsThromboxanes

ProstaglandinsProstacyclins

endotoxins cycokinesmitogens

COX-1Inhibited by• NSAIDS

COX-2Inhibited by• NSAIDS•COX-2 inhibitors

Indu

ced


Cyclo oxygenase inhibitonCyclo oxygenase inhibiton


COX InhibitionCOX Inhibition


Relative SelectivityRelative Selectivity


11January 11, 2008

MechanismsMechanisms

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


Clinical StudiesClinical 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


14January 11, 2008

CLASS and VIGOR trialsCLASS 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


15January 11, 2008

Rofecoxib: studies related to Rofecoxib: studies related to Ischemic eventsIschemic 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.


16January 11, 2008

Rofecoxib: meta-analysis for Rofecoxib: meta-analysis for Ischemic eventsIschemic 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.


COX-2 inhibition in CABGCOX-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


COX-2 inhibition in CABGCOX-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.


19January 11, 2008

Celecoxib: APC Celecoxib: APC (adenomatous (adenomatous polyp prevention trial), 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.


BMC MedicineBMC Medicine 2005, 2005, 3:3:1717


Clinical BalanceClinical Balance


RiskRisk


Australian Drug Reaction Australian Drug Reaction Advisory Committee 2002 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

24January 11, 2008


COX InhibitorsCOX 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)


COX & low cardiovascular riskCOX & 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)


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)

COX & high cardiovascular riskCOX & high cardiovascular risk


Thank you for attentionThank you for attention

[email protected]

Copy of the talk on www.wikitox.org


29January 11, 2008

COX2i: Heart FailureCOX2i: 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).


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.)

nsaids in the ischaemic heart disease patient

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