Clopidogrel in Cardiology Patients

1
Clopidogrel in Cardiology Patients

• Duncan McRobbie
• Associate Chief Pharmacist for Clinical Services
  and Cardiothoracic Lead Pharmacist
• GSTFT
• 14/11/07

2
CAPRIE Lancet 1996 348, 1329-3339

• Aspirin 300mg vs. clopidogrel 75mg in 19,185 pts
• previous MI, stroke or PVD over 1.9 years
• Primary endpoint death / MI / stroke
• ARR with Clopidogrel 0.51
• Reduced events from 5.83 (placebo) to 5.32
  p0.043
• Greatest benefit in pts with PAD at enrolment
• NNT to prevent 1 event with Clopidogrel 200 pts
• Cost per event avoided 192,000
• Reduced GI bleeds with Clopidogrel (0.49 cf.
  0.71) when compared to Aspirin 300mg.

3
CAPRIE (Cont) Lancet 1996 348, 1329-3339
Adverse experiences ( denotes plt0.05)
4
CURE NEJM 2001 345 494-502

• Clopidogrel vs placebo in 12,562 pts with ACS
• Inclusions
• ECG changes (no ST elevation) or
• ?cardiac enzymes
• Inclusion criteria changed mid-trial
• Exclusions
• C/I to antithrombotic or antiplatelet therapy
• pts. with high risk of bleeding (?criteria)
• severe heart failure
• PCI or CV surgery within past 3 months
• GPIIb/IIIa within last 3 days

5
CURE - Methods

• Pts randomised within 24 hrs of admission
• Regimen Clopidogrel 300mg loading dose then
  75mg daily vs placebo
• Treated for an average of 9 months (3 - 12
  months)
• All patients received baseline Aspirin
• Aspirin doses varied
• Primary outcome composite of CV death/MI/ stroke
• Second primary outcome plus refractory ischaemia

6
CURE - Results

• Primary endpoint
• 9.3 clopidogrel vs. 11.4 placebo
• ARR 2.1 plt0.001
• primarily due to reductions in AMI (5.2 vs. 6.7)
• Second primary end-point
• from 16.5 clopidogrel vs. 18.8 placebo
• ARR 2.3, plt0.001
• Reductions in
• In-hospital refractory or severe ischaemia
• heart failure
• revascularisation procedures

7
Primary Outcome - Death / MI / Stroke
Cumulative Hazard Rates for the First Primary
Outcome (Death from cardiovascular Causes,
Nonfatal Myocardial Infarction, or Stroke) during
the 12 Months of the Study.
8
Secondary Endpoints
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Adverse Effects

• Major Bleeds
• (disabling bleed, intra-ocular bleed causing
  blindness or
• bleed requiring gt 2 units transfusion)
• 3.7 clopidogrel grp vs. 2.7 placebo
• Absolute increased risk of bleed of 1 p 0.001
• no difference in life-threatening bleeds
• Minor bleeds
• (5.1 vs. 2.4)
• majority of bleeds - GI

10
PCI-CURE Lancet 2001, 358 527-533

• CURE sub-study in 2,658 patients undergoing
  coronary intervention
• Studying effect of EARLY treatment and LONG-TERM
  therapy
• Pts randomised early to Clopidogrel 75mg daily or
  placebo (as for CURE)
• Underwent PCI (median of 10 days post
  randomisation) and majority treated with
  Clopidogrel open-label for 4 weeks post-PCI
• Then, re-entered trial at 40 days
  post-randomisation to end of follow-up (average 9
  months)

11
PCI-CURE Results

• Prior to PCI
• Clopidogrel reduced MI / refractory ischaemia
  from 15.3 (placebo) to 12.1 ARR, 3.2 p0.008
• Primary end-point PCI to 30 days
• death / MI / stroke / urgent revascularisation
• Clopidogrel reduce the primary outcome event rate
  at 30 days from 6.4 (placebo) to 4.5 p0.03
• Absolute risk reduction of 1.9 at 30 days
• From PCI to end of follow up
• 2 reduction in risk of MI / death

12
PCI - Primary Outcome at 30 days
13
PCI-CURE End of Follow-up
14
PCI-CURE Events from 30 days to end of follow-up

• Figures derived from PCI-CURE, as published in
  the Lancet
• In context
• prevention of 1 event for every 166 treated
• prevention of 3 to 4 ACS events in 555 pts
  (50 acute)
• additional cost to NHS - 180,000 to 250,000
  per annum

15
PCI-CURE results

• Overall reduction in risk of death or MI of 3.8
  from time of randomisation to end of follow-up
• 12.6 placebo vs. 8.8 Clopidogrel p0.002
• Majority of benefit gained from randomisation to
  30 days post-PCI
• No significant difference in outcome between
  Clopidogrel and placebo groups from 30 days to
  end of follow-up
• Similar ARR of 0.5, as in CAPRIE study
• No excess of bleeds in the Clopidogrel-treated
  group

16
Factors associated with stent thrombosis
17
Independent risks of stent thrombosis Iakovou I,
Schmidt T, Bonizzoni E, et al. Incidence,
predictors, and outcome of thrombosis after
successful implantation of drug-eluting stents.
JAMA 20052932126-30
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BASKET LATE Late Thrombotic Events Following
Clopidogrel Discontinuation
19
Meta-Analysis of Stent Trials Incidence of
Serious Adverse Events (Death or MI) Based on
Latest Available Follow-up
20
Endothelialization in Drug-Eluting Stents (DES)
Versus Bare-Metal Stents (BMS) Joner M, Finn AV,
Farb A, et al. Pathology of drug-eluting stents
in humans delayed healing and late thrombotic
risk. J Am Coll Cardiol 200648193-202.
21
Crude and adjusted odds ratios for association
between use of antithrombotic drug and serious
upper gastrointestinal bleeding
BMJ, doi10.1136/bmj.38947.697558.AE (published
19 September 2006)
22
Recommended Clopidogrel Indications and
Durations(SELCN)

• STEMI should be given for at least one month
  but the optimal duration has not yet been
  established, many local consultants now recommend
  continuing for one year, as for other ACS
• Drug-eluting stents durations of more than
  one year are being recommended in high-risk
  patients by some consultants due to concerns
  regarding late stent thrombosis on cessation of
  clopidogrel therapy.

23
Communication from secondary to primary care

• September 2007 audit for SELondon
• 295 prescriptions for clopidogrel from 4 acute
  Trusts
• Indication for clopidogrel clear on 273 / 295
  (92.5)
• For 22 of 295 patients (7.5) the indication
  unclear
• Duration of clopidogrel clear on 282 / 295
  (95.6)
• For 13 of 295 patients (4.4) the duration of
  clopidogrel was unclear
• Duration added or amended by pharmacist on 49/295
  (16.6) of TTAs

24
My patient has developed a rash 3 days after
starting clopidogrel

• Clopidogrel has been associated with
  hypersensitivity reactions, most commonly with
  the development of skin rashes
• It is UNUSUAL within the first few days of
  therapy
• The most common cause of a rash is the
  administration of x-ray contrast dye during the
  angiogram and / or angioplasty

25
Recommended management of rash

• Advise the patient to PERSIST with the
  clopidogrel therapy for at least another week
• Treat the rash in the short term with an
  ANTIHISTAMINE either chlorpheniramine 4mg four
  times a day or a longer-acting non-sedating agent
• ADVISE the patient to contact the GP surgery if
  the rash worsens within the week or to seek
  urgent medical advice should any symptoms of
  serious HYPERSENSITIVITY reaction develop, such
  as difficulty breathing, swelling of the face,
  mouth or throat etc.
• DO NOT stop therapy without first consulting the
  cardiologist HIGH risk of in-stent thrombosis

26
My patient has a rash after 3 weeks of
clopidogrel treatment

• LIKELY to be caused by the clopidogrel, UNLESS
  there have been any other recent changes in
  treatment (i.e. the introduction of another new
  drug)
• Check the DURATION of clopidogrel for the
  patient
• If only a further week of therapy (ie. to
  complete a one month course), PERSIST with
  therapy, and take a short course of antihistamine
  to control the symptoms
• MORE than one month (most cases will be), then
  CONTACT the initiating cardiologist for advice on
  an alternative therapy
• Due to the high risk of stent thrombosis,
  clopidogrel should NOT be discontinued
  prematurely without discussion with the
  initiating clinician

27
Alternatives to clopidogrel

• Ticlopidine works in the same way as clopidogrel,
  but is unlicensed in the UK, due to a higher risk
  of developing neutropenia during treatment.
• Ticlopidine therapy should usually be initiated
  under the supervision of the interventional
  cardiologist at a dose of 250mg BD in combination
  with low-dose aspirin.

28
TTAs (To take away)

• The DURATION of therapy and INDICATION for
  clopidogrel should be clearly stated on the
  discharge summary and patient-held clopidogrel
  card
• RISKS of early cessation (in-stent thrombosis)
  and inappropriate continuation of therapy
  (bleeding risk)
• The need for appropriate review by GP monitor
  CP, ischaemic episodes, cardiac interventional
  history BEFORE stopping clopidogrel
• Clopidogrel is NOT an alternative to aspirin if
  GI intolerance- use aspirin plus PPI
• Rash could not be a complete CI to clopidogrel
  use consider other causes of rash and treatment
  options