NSAIDS in the ischaemic heart disease patient

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NSAIDS in the ischaemic heart disease patient

• Andrew Dawson
• SACTRC Program Director
• University of Peradeniya
• Sri Lanka

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2002 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

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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?

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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

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• 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

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Whats 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

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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
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Cyclo oxygenase inhibiton
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COX Inhibition
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Relative Selectivity
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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 (lt5 mm Hg elevations
  in systolic blood pressure)
• COX-2 role in vascular remodelling

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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

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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
• gt8000 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

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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.

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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 3642021.

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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
  Feb127(2)605

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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 20053521081-91.

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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 355873.
  

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BMC Medicine 2005, 317
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Clinical Balance
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Risk
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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

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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)
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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)
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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)
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Thank you for attention

• adawson_at_sactrc.org
• Copy of the talk on www.wikitox.org

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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).

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• 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. 2005961240-1247.)

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