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

         South Asian Clinical Toxicology Research Collaboration
            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

                             South Asian Clinical Toxicology Research Collaboration
                   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?


                           South Asian Clinical Toxicology Research Collaboration
                        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
                                    South Asian Clinical Toxicology Research Collaboration
   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
       l   Type, duration
    – Patient Factors
       l   Underlying cardiovascular risk


                               South Asian Clinical Toxicology Research Collaboration
                   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                                                        6
                                  South Asian Clinical Toxicology Research Collaboration
         Membrane Phospholipids



               Arachidonic Acid                          endotoxins
                                                         cycokines
                                                         mitogens




COX-1                               COX-2
Inhibited by                        Inhibited by
• NSAIDS                            • NSAIDS
                                    •COX-2 inhibitors




 Prostaglandins               Prostaglandins
 Thromboxanes                  Prostacyclins


                      South Asian Clinical Toxicology Research Collaboration
Cyclo oxygenase inhibiton




            South Asian Clinical Toxicology Research Collaboration
COX Inhibition




     South Asian Clinical Toxicology Research Collaboration
Relative Selectivity




         South Asian Clinical Toxicology Research Collaboration
                   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                                                 11
                           South Asian Clinical Toxicology Research Collaboration
South Asian Clinical Toxicology Research Collaboration
              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




                          South Asian Clinical Toxicology Research Collaboration
            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                                                                14
                                               South Asian Clinical Toxicology Research Collaboration
      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.

January 11, 2008                                                 15
                            South Asian Clinical Toxicology Research Collaboration
      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.


January 11, 2008                                                          16
                                     South Asian Clinical Toxicology Research Collaboration
       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


                                         South Asian Clinical Toxicology Research Collaboration
      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.

                              South Asian Clinical Toxicology Research Collaboration
    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

        lBertagnolli, MM, Eagle, CJ, Zauber, AG, et al. Celecoxib for the
         prevention of sporadic colorectal adenomas. N Engl J Med 2006;
         355:873.
January 11, 2008                                                19
                                    South Asian Clinical Toxicology Research Collaboration
BMC Medicine 2005, 3:17




           South Asian Clinical Toxicology Research Collaboration
South Asian Clinical Toxicology Research Collaboration
Clinical Balance




       South Asian Clinical Toxicology Research Collaboration
Risk




 South Asian Clinical Toxicology Research Collaboration
      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                                                24
                           South Asian Clinical Toxicology Research Collaboration
                 COX Inhibitors
Proven cardioprotective efficacy              Low-dose aspirin (1a)
Potential cardioprotective efficacy           Naproxen (3a)
(inter-individual variablity)
Potential to decrease cardioprotective        Ibuprofen (3a)
effect of low-dose aspirin                    Flubiprofen (5)
                                              Indomethacin (5)
                                              Naproxen (5)
Proven gastroprotective efficacy              Rofecoxib (withdrawn)
(COX -2 )                                     (1b)
                                              Lumiracoxib (FDA
                                              approval pending) (1b)



                              South Asian Clinical Toxicology Research Collaboration
   COX & low cardiovascular risk
Chronic treatment low cardiovascular     Naproxen (2b, 2a)
and low GI risk                          Ibuprofen (2b, 2a)


Chronic treatment low cardiovascular     Naproxen + proton pump
and high GI risk                         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)

                                   South Asian Clinical Toxicology Research Collaboration
COX & high cardiovascular risk
Chronic treatment high cardiovascular      Naproxen + Clopidogrel
and low GI risk                            •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      Naproxen + proton pump
and high GI risk                           inhibitor + clopidogrel (5)

                                           Ibuprofen + proton pump
                                           inhibitor + clopidogrel (5)

                                  South Asian Clinical Toxicology Research Collaboration
      Thank you for attention
adawson@sactrc.org

Copy of the talk on www.wikitox.org




                      South Asian Clinical Toxicology Research Collaboration
            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                                                      29
                                 South Asian Clinical Toxicology Research Collaboration
   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.)




                          South Asian Clinical Toxicology Research Collaboration
South Asian Clinical Toxicology Research Collaboration

				
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