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ANTI-THROMBOTIC THERAPY IN ACUTE CORONARY SYNDROMES

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 SYNDROMES

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  1. ANTI-THROMBOTIC THERAPY IN ACUTE CORONARY SYNDROMES Ian Starkey

  2. NO CONFLICT OF INTEREST TO DECLARE Ian Starkey

  3. ANTI-THROMBOTIC THERAPY IN ACUTE CORONARY SYNDROMES CHANGES IN A PROFESSIONAL LIFETIME (1975 – 2007) Ian Starkey

  4. 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

  5. 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

  6. 1980’sThe value of investigation and treatment • Intravenous Heparin • Coronary angiography and surgical treatment for those with suitable coronary artery disease • Aspirin Ian Starkey

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. Unfractionated HeparinAn imperfect therapy • Unpredictable anticoagulant response • Requires laboratory monitoring and dose adjustment • Short plasma half-life • Requires IV infusion Ian Starkey

  14. 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

  15. 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

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

  17. PCI in patients with “unstable angina” WGH: 1990-1999 253 28 Ian Starkey

  18. 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

  19. 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

  20. 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

  21. 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

  22. 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

  23. 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

  24. Fox K A A et al (GRACE registry) BMJ 2006;333:1091-4 Ian Starkey

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

  26. 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

  27. Our treatments are still imperfect We need drugs and other treatment regimes that are SUPERIOR Not just non-inferior! Ian Starkey

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