Clopidogrel in Cardiology Patients

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Clopidogrel in Cardiology Patients

• Rachel Hughes
• Specialist cardiology pharmacist
• GSTFT
• 22/11/07

2
Introduction

• Evidence for clopidogrel use
• Stroke
• NSTEMI/ACS
• STEMI
• PCI BMS/DES
• Risk benefit profile
• SELCN guidance
• Clopidogrel cards

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Platelet Function
TxA2
Thrombin
aspirin
ADP
ticlopidine clopidogrel
heparin
Platelet
abciximab
Glycoprotein IIb/IIIa
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CAPRIE study Lancet 1996, 348 1329-1339

• N 19,185, multicentre double-blind trial
• Clopidogrel reduces the risk of death/MI/stroke
  in patients with previous MI, stroke or PVD by
  RRR 8.7 compared to high-dose aspirin
• For every 1000 patients treated 5 combined end
  points would be prevented
• NNT 200 patients
• A/E diarrhoea, rash
• Increased cost to NHS 200,000
• Super aspirin will save your life

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Ringleb, P. A. et al. Stroke 200435528-532
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CURE NEJM 2001 345 494-502

• Clopidogrel vs placebo in 12,562 pts with ACS
• Inclusions
• ECG changes (no ST elevation) or
• ? cardiac enzymes
• 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

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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
• Combined with heparin and GP2b3aI (standard)
• Primary outcome composite of CV death/MI/ stroke

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CURE - Results

• Primary endpoint
• 9.3 clopidogrel vs. 11.4 placebo
• ARR 2.1 plt0.001 (on top of standard
  treatment)
• primarily due to reductions in AMI (5.2 vs. 6.7)
• Reductions in
• In-hospital refractory or severe ischaemia
• heart failure
• revascularisation procedures

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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.
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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 gp 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

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NICE TA80- Clopidogrel and NSTEMI/ACS (July 2004)

• Clopidogrel, together with a low dose of aspirin,
  should be used for people with non-ST-segment-elev
  ation acute coronary syndrome who have a moderate
  to high risk of a major heart attack (myocardial
  infarction) or death.
• New ECG changes
• Blood tests- damage to cardiac tissue
• Treatment with clopidogrel and low-dose aspirin
  should be continued for up to 12 months after the
  most recent attack. After this time, doctors
  should give the normal treatment, which includes
  a low dose of aspirin.

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Timing of Release of Various Biomarkers After
Acute Myocardial InfarctionAnderson, J. L. et
al. J Am Coll Cardiol 200750e1-e157
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COMMIT trial

• Lancet 2005 366 160721
• n45 852 acute MI plus aspirin 162 mg Tx
  until discharge or up
• to 4 weeks in hospital (mean 15 d) composite
  end point
• death, reinfarction,
• or stroke

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PCI- CLARITY JAMA 2005294122432
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NICE guidelines for STEMI

• After an ST elevation MI patients treated with a
  combination of aspirin and clopidogrel should
  continue this treatment for at least 4 weeks.
  Thereafter, standard treatment including low-dose
  aspirin should be given, unless there are other
  indications to continue dual antiplatelet therapy

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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)

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PCI - Primary Outcome at 30 days
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PCI-CURE End of Follow-up
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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

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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
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Meta-Analysis of Stent Trials Incidence of
Serious Adverse Events (Death or MI) Based on
Latest Available Follow-up
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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.
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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)
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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.

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You never tell us the duration

• Most common complaint from primary to secondary
  care regarding clopidogrel prescriptions
• Audited communication with primary care on
  discharge from secondary care
• Is the indication clear?
• Is the duration clear?
• Was pharmacy involved in clarifying the duration?
• Audited all discharge prescriptions issued during
  Oct 06 from cardiology across 4 of the 6 acute
  trusts in SE London

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October 2006 audit results

• 249 prescriptions for clopidogrel from 4 acute
  Trusts were audited
• Indication for clopidogrel were clear on 185 /
  249 (74)
• For 69 of 249 patients (26) the indication
  unclear
• Duration of clopidogrel clear on 174 / 249 (70)
• For 75 of 249 patients (30) the duration of
  clopidogrel was unclear
• Duration added or amended by pharmacist on 49/249
  (20) of TTAs

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Duration Recommendations

• Agree a standard set of durations for use across
  the sector
• Request that acute Trust pharmacy departments do
  not dispense clopidogrel unless indication and
  duration of therapy is clear
• For one month supply at discharge secondary
  care to give full supply so no need to add to GP
  repeat prescribing systems
• All patients to be issued with clopidogrel cards
  by secondary care

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Communication from secondary to primary care-
progress.

• 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

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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

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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

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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

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Alternatives to clopidogrel

• Ticlopidine works in the same way as clopidogrel,
  but is unlicensed in the UK
• A higher risk of developing neutropenia during
  treatment (2)
• 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.

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In summary Take Home Messages

• 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
  (GI/intracranial haemorrhage)
• 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