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Pharmacological strategies to reduce periprocedural bleeding

Pharmacological strategies to reduce periprocedural bleeding. Jonathan Byrne King’s College Hospital. Delicate balancing act. Benefit. Risk. Bleeding. Patient factors Procedural factors Pharmacology. Ischaemic compications. Increasing risk of ischemic complications.

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Pharmacological strategies to reduce periprocedural bleeding

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  1. Pharmacological strategies to reduce periprocedural bleeding Jonathan Byrne King’s College Hospital

  2. Delicate balancing act Benefit Risk Bleeding Patient factors Procedural factors Pharmacology Ischaemic compications Increasing risk of ischemic complications Increasing risk of bleeding complcations Increasing thrombotic risk usually parallels increased bleeding risk

  3. Pharmacological strategies to reduce bleeding during PCI • Reduced dose/no heparin • LMW versus unfractionated heparin • Newer synthetic anticoaculants • Bivalirudin versus heparin/GPI • Reduced dose GPI Stable ACS High Risk ACS/PPCI Increasing risk of bleeding complcations

  4. Low dose or ‘no’ dose heparin? Current heparin dosages used in PCI are not based on randomised data Current strategies include weight adjusted/ACT adjusted or fixed dose Is it safe to use no heparin in selected ‘low risk’ patients?

  5. CIAO Study 700 stable, elective patients. Type A/B lesions. No adjunctive GPI use 3.7 Event rate (%) Higher procedural CK release in the heparin group (3.1 vs 1.7%) MACE Major Bleeding Stabile JACC 2008

  6. Low fixed dose or weight adjusted? Retrospective analysis of 698 patients Elective PCI Weight adjusted vs fixed dose UFH (3000 units) More complex angiographic lesions than CIAO . Similar levels of TnI release Kidambi Cardiovasc Ther 2010

  7. FUTURA/ OASIS 8 2026 high risk ACS patients within a larger cohort treated with fondaparinux Fixed low dose heparin (50u/kg) compared with ACT guided weight adjusted (85u/kg), regardless of GPI use Major outcome composite of major bleeding at 48 hours FUTURA/OASIS 8 JAMA 2010

  8. No benefit with low dose heparin 5.8 Low use of GPI (20%) ~40% radial access Small reduction in minor bleeds 4.8 4.7 Event rate (%) 3.9 Peri-PCI bleeding/vascular access complications Peri-PCI bleeding/death/MI/TVR FUTURA/OASIS 8 JAMA 2010

  9. STEEPLE- LMWH in elective PCI P=0.01 P=0.05 6.5 trend towards higher mortality in the low dose LMWH group 40% GPI use 5.9 5.9 Event rate (%) 5.3 4.8 2.8 1.2 1.2 Major or minor bleeding Major Bleeding Minor bleeding Monatalescot NEJM 2006

  10. Meta-analysis of 13 RCTs Dumaine Arch Intern Med 2007

  11. Avoid crossover from one to the other.. >2000 patients undergoing PCI in the SYNERGY study P=0.047 5.4 P=0.03 Event rate (%) 3.7 2.8 White Am Heart J 2006

  12. 0.06 Fondaparinux 0.04 0.05 Enoxaparin 0.03 0.04 HR 1.01 95% CI 0.90, 1.13 Cumulative hazard 0.03 Cumulative hazard 0.02 0.02 0.01 0.01 0.00 0 1 2 3 4 5 6 7 8 9 0.00 Days 0 1 2 3 4 5 6 7 8 9 Days Synthetic Xa inhibitors in ACS… Death, MI, refractory ischaemia Major bleeding • Primary efficacy endpoint: 5.8% (fondaparinux) vs 5.7% (enoxaparin) • Major bleeding: 2.2% (fondaparinux) vs 4.1% (enoxaparin) Enoxaparin HR 0.52 95% CI 0.44, 0.61 p<0.001 Fondaparinux OASIS 5 N Engl J Med 2006

  13. Enoxaparin 0.06 Fondaparinux 0.04 Cumulative hazard 0.02 0.0 0 20 40 60 80 100 120 140 160 180 Days Mortality at 6 months HR 0.89 95% CI 0.80, 1.00p=0.05 OASIS 5 N Engl J Med 2006

  14. Bivalirudin in ACS/STEMI Paucity of data comparing heparin directly with bivalirudin (without GPI) Doses of heparin used in most of the studies are higher than standard UK/European practice

  15. ISAR REACT 3 4570 patients with stable/unstable angina (with no biomarker rise Preloaded with 600mg clopidogrel 140υg/kg UFH compared with bivalirudin Triple end-point; net clinical benefit (MACE + bleeding) Kastrati N Engl J Med 2008

  16. BCIS Autumn Meeting 2008, Stoke on Trent, UK

  17. BCIS Autumn Meeting 2008, Stoke on Trent, UK

  18. ISAR REACT 3a • Lower dose (100units/kg) heparin in patients preloaded with clopidogrel • ISAR react 3 heparin group used as historical control • Same eligibility/exclusion criteria (biomarker negative ACS)

  19. **Almost identical to those seen with bivalirudin in previous study ** ** BCIS Autumn Meeting 2008, Stoke on Trent, UK Kastrati ESC 2010

  20. HR [95%CI] = 0.62 [0.40, 0.96] P=0.029 2.9% Death (%) Cardiac 1.8% Non cardiac 0.3% 0.2% Time in Days STEMI- HORIZONS AMI Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) Stone NEJM 2008

  21. HORIZONS-AMI 30 day outcomes Stone NEJM 2008

  22. Reduced dose GPI? • Early data (EPIC) suggested reduced bleeding but higher ischaemic complications with bolus abciximab • EASY PCI (transradial) - clopidogrel loading. no difference between bolus/infusion of abciximab. Bleeding rates 0.5% (TRI) • BRIEF PCI – ~700 patients (stable/ACS). Transfemoral. Clopidogrel preloaded. 2 hour versus 18 hour eptifibatide infusion

  23. Lower major bleeding rates 21.2 17.6 ~40% ACS 97% femoral access Event Rate (%) P=0.02 4.2 1 Major Bleeding Minor Bleeding Fung JACC 2009

  24. Conclusions • Tailored treatment for individual patients to balance thrombotic/bleeding risk. • Stepwise approach to antithrombotics with increasing bleeding risk • Avoid switching between antithrombins (except UFH from fondaparinux) • Pharmacology should be coupled with other bleeding avoidance strategies (TRI in particular)

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