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ANTI-THROMBOTIC THERAPY IN ACUTE CORONARY SYNDROMES. NO CONFLICT OF INTEREST TO DECLARE. ANTI-THROMBOTIC THERAPY IN ACUTE CORONARY SYNDROMES. CHANGES IN A PROFESSIONAL LIFETIME (1975 – 2007). 1970’s Appreciation of the problem. Fulton et al (1972) Lancet 1 : 860-5

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anti thrombotic therapy in acute coronary syndromes3

ANTI-THROMBOTIC THERAPY IN ACUTE CORONARY SYNDROMES

CHANGES IN A PROFESSIONAL LIFETIME

(1975 – 2007)

Ian Starkey

1970 s appreciation of the problem
1970’sAppreciation of the problem

Fulton et al (1972) Lancet 1: 860-5

Duncan et al (1976) BMJ 1: 981-5

251 men aged under 70 with new or worsening angina

Only treatment was GTN + beta-blocker

39 MI’s (9 fatal) – 72% within 6/52

i.e. 15% progress to MI (11% within 6/52)

Ian Starkey

identification of the high risk patient
Identification of the high-risk patient

“If a high-risk group (at risk of a heart attack) could be defined precisely, anti-arrhythmic or other drugs could be given in the hope of preventing the ventricular arrhythmias responsible for sudden death”.

Fulton et al (1972)

Ian Starkey

1980 s the value of investigation and treatment
1980’sThe value of investigation and treatment
  • Intravenous Heparin
  • Coronary angiography and surgical treatment for those with suitable coronary artery disease
  • Aspirin

Ian Starkey

1980 s appreciation of the value of heparin
1980’sAppreciation of the value of Heparin

Telford & Wilson (1981) Lancet 1, 1225-8

First double-blind placebo-controlled trial of drug therapy in patients with “intermediate coronary syndrome”

214 patients randomised to receive IV Heparin, oral Atenolol, both or neither for seven days

Ian Starkey

telford wilson 1981 incidence of trans mural mi
Telford & Wilson (1981)Incidence of Trans-mural MI

TreatmentNumberIncidence of MISignificance

Placebo 54 9 (17%)

Atenolol 60 8 (13%) NSS

Heparin 51 1 ( 2%) 0.024

Heparin/Atenolol 49 2 ( 4%)

Incidence of trans-mural MI reduced by 80% (from 17/114 to 3/100) with Heparin

Benefit of Heparin was maintained over next 7 weeks

Ian Starkey

1980 s coronary angiography is useful and safe
1980’sCoronary angiography is useful and safe

Brooks et al (1981) Br Heart J45: 35-41

100 patients with unstable angina treated with bedrest, beta-blockade and nitrates

92 underwent coronary angiography (including 46 with recurrent chest pain) without complications

51 had urgent CABG surgery

Ian Starkey

1980 s aspirin therapy beneficial
1980’sAspirin therapy beneficial
  • Lewis et al (1983)

Incidence of death/MI reduced by 51% in patients taking Aspirin for 12/52

  • Cairns et al (1985)

Incidence of cardiac death/MI reduced by 51% in patients taking Aspirin for ~18/12

Ian Starkey

heparin or aspirin
Heparin or Aspirin?
  • Conflicting evidence from comparative trials
  • Most studies suggest that IV Heparin is more effective than Aspirin in the acute phase

Ian Starkey

heparin and aspirin
Heparin and Aspirin
  • Patients in initial studies of Aspirin did not receive IV Heparin
  • Combination therapy has a sound theoretical basis
  • Meta-analysis of six randomised trials (Oler et al, 1996) showed a 33% reduction in incidence of MI/death in patients treated with Heparin and Aspirin compared with Aspirin alone.

Ian Starkey

unfractionated heparin an imperfect therapy
Unfractionated HeparinAn imperfect therapy
  • Unpredictable anticoagulant response
  • Requires laboratory monitoring and dose adjustment
  • Short plasma half-life
  • Requires IV infusion

Ian Starkey

1990 s low molecular weight heparin s
1990’sLow molecular-weight Heparin(s)
  • Meta-analysis of 12 trials (Eikelboom et al, 2000)
  • LMWH at least as effective as UFH in aspirin-treated patients with acute coronary syndromes (approx. 50% reduction of MI/death at 7 days)

Ian Starkey

low molecular weight heparins are they all the same
Low Molecular Weight HeparinsAre they all the same?
  • ESSENCE and TIMI 11B suggest that Enoxaparin is superior to UFH
  • No convincing evidence that other LMWH preparations are better than UFH
  • LMWH (preferably Enoxaparin) can be used in place of UFH with practical advantages

Ian Starkey

meanwhile back in the cath lab
Meanwhile, back in the cath lab!
  • Increased enthusiasm for invasive investigation and treatment of patients with acute coronary syndromes

Ian Starkey

meanwhile back in the cath lab18
Meanwhile, back in the cath lab!
  • Increased enthusiasm for invasive investigation and treatment of patients with ACS
  • Clinical trials support the use of Abciximab at the time of PCI, especially in high-risk patients
  • Increased awareness of risk of bleeding in patients receiving combination anti-thrombotic and anti-platelet therapy
  • Uncertainty about how patients on Enoxaparin should be treated in cath lab

Ian Starkey

cardiac laboratory procedures in patients treated with enoxaparin treatment strategies
Cardiac laboratory procedures in patients treated with Enoxaparin Treatment strategies
  • Switch to IV UFH on the day of the procedure

Uncertain scheduling in many labs

Uncertain degree of anticoagulation

Unnecessary

  • Continue LMWH on the day of the procedure

Supplement background dosage with IV LMWH (EXTRACT-TIMI 25)

Supplement background dosage with IV UFH (OASIS-5)

Ian Starkey

pci in patients treated with enoxaparin treatment strategies
PCI in patients treated with Enoxaparin Treatment strategies
  • EXTRACT TIMI-25
    • No additional Enoxaparin if last SC dose <8 hrs before
    • 0.3mg/kg Enoxaparin IV if last SC dose 8-12hrs earlier
  • OASIS-5
    • No additional Heparin if last SC dose <6 hrs before
    • If last SC dose > 6 hrs earlier:

IV UFH - 100u/Kg if no GPI

- 65u/Kg if GPI

Ian Starkey

2000 s alternatives to lmwh
2000’sAlternatives to LMWH
  • Fondaparinux (OASIS-5)
    • Non-inferior to Enoxaparin in reducing the risk of ischaemic events at 9 days
    • Substantially reduces major bleeding (2.2% vs 4.1%)
    • Significant reduction in death rate at 30 days and 180 days

NEJM 2006; 354: 1464-76

Ian Starkey

2000 s alternatives to lmwh22
2000’sAlternatives to LMWH
  • Bivalirudin (ACUITY)
    • Compared to Heparin + GPI, non-inferior rate of composite ischaemia endpoint
    • Significant reduction in major bleeding (3.0% vs 5.7%)

NEJM 2006: 355:2203-16

Ian Starkey

slide23
But ……

Are the latest trials asking the correct questions?

  • Both OASIS-5 (Fondaparinux) and ACUITY (Bivalirudin) sought to show (and showed) NON-INFERIORITY compared to LMWH
  • Both showed a reduction in risk of major bleeding (commonest single cause is access site bleeding)
  • Access site bleeding can be reduced by other means (e.g. radial artery access, etc)

Ian Starkey

slide25

“Go back to sleep, Chuck. You’re just having a nightmare – of course we’re still in hell.”

Ian Starkey

are our current treatments so good
Are our current treatments so good
  • that we need new drugs that only reduce bleeding risk?
  • It may depend on the cost
    • Fondaparinux ~£60.00 Maybe

- Bivalirudin ~£620.00 Maybe not!

Ian Starkey

our treatments are still imperfect
Our treatments are still imperfect

We need drugs and other treatment regimes that are

SUPERIOR

Not just non-inferior!

Ian Starkey