Rao SV - AIMRADIAL 2013 - Bivalirudin and radial

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Bivalirudin for all

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Rao SV - AIMRADIAL 2013 - Bivalirudin and radial

  1. 1. Bivalirudin for All! Sunil V. Rao MD
  2. 2. Disclosures   Consultant, Honoraria   The Medicines Company, Terumo Corporation, Astra Zeneca   Research funding     Ikaria Off-label uses   May be discussed in this presentation
  3. 3. The case for bivalirudin   PCI – goals of therapy   Role of anticoagulation   Interaction between access site and antithrombotic strategies   Can we select patients for different approaches?   Summary
  4. 4. The case for bivalirudin   PCI – goals of therapy   Role of anticoagulation   Interaction between access site and antithrombotic strategies   Can we select patients for different approaches?   Summary
  5. 5. PCI and Thrombosis: An Obligatory Event Thrombin Tissue Factor Generation Platelet Activation Adhesion Molecules Vessel Wall Injury and Inflammation
  6. 6. Goals of PCI   Procedure success   Minimize ischemic sequelae     Large MI   Stent thrombosis     Atherothrombotic emboli Side branch occlusion Minimize bleeding risk
  7. 7. Twenty-five year trends in PCI outcomes N=24,410 procedures at the Mayo Clinic Singh M., et. al. Circulation 2007
  8. 8. Bleeding & Outcomes N=26,452 pts from PURSUIT, GUSTO IIb, PARAGON A & B Kaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity log rank p-value for all four categories <0.0001 log-rank p-value for no bleeding vs. mild bleeding = 0.02 log-rank p-value for mild vs. moderate bleeding <0.0001 log-rank p-value for moderate vs. severe <0.001 Rao SV, et al. Am J Cardiol. 2005
  9. 9. Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Year 1 year Estimate Both MI and Major Bleed (N=94) Major Bleed only (without MI) (N=551) MI only (without Major Bleed) (N=611) No MI or Major Bleed (N=12,557) 28.9% 12.5% 8.6% 3.4% 30 28.9% Mortality (%) 25 20 15 12.5% 10 8.6% 5 3.4% 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization Mehran R, et. al. Lancet 2010
  10. 10. The case for bivalirudin   PCI – goals of therapy   Role of anticoagulation   Interaction between access site and antithrombotic strategies   Can we select patients for different approaches?   Summary
  11. 11. Sites of action for anticoagulants Factor Xa Fondaparinux Otamixaban Apixaban Factor IIa (thrombin) Unfractionated Heparin Enoxaparin Bivalirudin
  12. 12. Role of anticoagulants in PCI TRANSRADIAL PCI   Minimize thrombus on the equipment   Minimize platelet activation   Minimize atherothrombotic emboli   Minimize bleeding risk   Reduce radial artery occlusion
  13. 13. Quadruple Endpoin (N=6010)t 30 Day Primary Endpoint Components p <0.001 Lincoff AM, et. al. JAMA 2003
  14. 14. ACUITY Trial Design   Moderate- and high-risk UA or NSTEMI patients undergoing an invasive strategy Prospective, randomized, active-controlled trial Heparin(s)† + GP IIb/IIIa (n=4,603) Moderateand highrisk ACS Bivalirudin R* + GP IIb/IIIa (n=4,604) (N=13,819) Aspirin in all; clopidogrel dosing and timing per local practice Bivalirudin alone (n=4,612) Medical Angiography within 72 h   management PCI CABG *Stratified by preangiography thienopyridine use or administration. †UFH or enoxaparin. Stone GW, et. al. NEJM 2007
  15. 15. ACUITY: Net Clinical Outcome Composite Endpoint UFH/enoxaparin+GPI vs bivalirudin+GPI vs bivalirudin alone Cumulative Events (%) 15 10 Estimate 5 UFH/enoxaparin+GPI (N=4603) Bivalirudin+GPI (N=4604) Bivalirudin alone (N=4612) P (log rank) 11.7% 11.8% 0.89 10.1% 0.014 0 0 5 10 15 20 25 30 35 Days from Randomization UFH, unfractionated heparin; GPI, glycoprotein IIb/IIIa inhibitor. Stone GW. NEJM 2007.
  16. 16. HORIZONS- MI Trial Design ≥3400* pts with STEMI with symptom onset ≤12 hours Aspirin, thienopyridine R 1:1 UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) Bivalirudin monotherapy (± provisional GP IIb/IIIa) Emergent angiography, followed by triage to… CABG – Primary PCI – Medical Rx 3000 pts eligible for stent randomization Bare metal stent R 1:3 TAXUS paclitaxel-eluting stent Clinical FU at 30 days, 6 months, 1 year, and then yearly through 5 years Stone GW et al. NEJM 2008.
  17. 17. HORIZONS-MI Primary Endpoints at 30 Days Diff = -2.9% [-4.9, -0.8] Diff = -3.3% [-5.0, -1.6] Diff = 0.0% [-1.6, 1.5] RR = 0.76 [0.63, 0.92] RR = 0.60 [0.46, 0.77] RR = 0.99 [0.76, 1.30] PNI ≤ 0.0001 PNI ≤ 0.0001 Psup = 0.95 Psup = 0.005 Psup ≤ 0.0001 1° endpoint 1° endpoint Major 2° endpoint Stone GW et al. NEJM 2008;358:2218-30
  18. 18. HORIZONS-MI: 30-day mortality Death (%) Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) 3.1% 2.1% HR [95%CI] = 0.66 [0.44, 1.00] P=0.048 Number at risk Bivalirudin Heparin + GPIIb/IIIa Time in Days 1800 1802 1758 1764 1751 1748 1746 1736 1742 1728 1729 1707 1666 1630 Stone GW et al. NEJM 2008.
  19. 19. HORIZONS MI - Three-Year All-Cause Mortality Bivalirudin alone (n=1800) All-Cause Mortality (%) 10 Heparin + GPIIb/IIIa (n=1802) 9 7.7% 8 7 6 4.8% 5 3-yr HR [95%CI]= 0.75 [0.58, 0.97] P=0.03 4 3 3.4% 2 1-yr HR [95%CI]= 0.71 [0.51, 0.98] P=0.04 1 0 0 Number at risk Bivalirudin alone Heparin+GPIIb/IIIa 5.9% 3 6 9 12 15 18 21 24 27 30 33 36 Months 1800 1802 1689 1670 1660 1643 1633 1593 1611 1568 1574 1525 1098 1043 Stone GW, et. al. Lancet 2011
  20. 20. Comparison of Bivalirudin with UFH Bertrand OF, et. al. AJC 2012
  21. 21. The case for bivalirudin   PCI – goals of therapy   Role of anticoagulation   Interaction between access site and antithrombotic strategies   Can we select patients for different approaches?   Summary
  22. 22. ACUITY: Protocol Non-CABG Major Bleeding by access site & drug strategy 30 day events (%) Radial (n=798) P = 0.01! Femoral (n=11,988) P = 0.06! 5.8% 2.2% UFH/enox + GPI Slide courtesy of M. Hamon 5.4% 2.7% Biv + GPI P = 0.29! 4.2% 3.0% Biv Alone
  23. 23. Radial access & Bivalirudin in HORIZONS MI N=3602 STEMI pts undergoing primary PCI 123 Centers in 11 countries; 6% TRI (N=200) 17 centers treated ≥ 1 patient with TRI Genereux PG, et. al. Eurointervention 2011
  24. 24. Combining radial approach and bivalirudin N=501,017 pts from NCDR CathPCI Baklanov D, et. al. Circ Intv. 2013
  25. 25. What about costs??
  26. 26. 26 OP Medication Reimbursement •  Separate APC codes for each of these medications •  Reimbursement rates updated on a quarterly basis. •  Current Medicare reimbursement rates: Drug HCPCS Code Q3 2012 Reimbursement Rate Bivalirudin J0583 $2.93 per mg ($732.50 per vial) Abciximab J0130 $556.57 per 10 mg ($556.57 per vial) Eptifibitide J1327 $23.52 per 5 mg ($352.80 for 75mg infusion vial) PLEASE SEE ACCOMPANYING FULL PRESCRIBING INFORMATION FOR ANGIOMAX Medicare Hospital Outpatient Prospective Payment System, July 2012 Addendum B, https://www.cms.gov/HospitalOutpatientPPS/AU/list.asp, accessed August 8, 2012. Slide courtesy of Adhir Shroff, MD, MPH Associate Professor of Medicine
  27. 27. MATRIX 1:1 N>6,800 Angiography Radial Access PCI Femoral Access 1:1 UFH±GPI Post-PCI Discontinue Slide courtesy of Marco Valgimigli MD 1:1 Bivalirudin 1:1 N~6,800 UFH±GPI N~3,400 ≥6 h Bivalirudin infusion
  28. 28. Slide courtesy of Olivier Bertrand
  29. 29. The case for bivalirudin   PCI – goals of therapy   Role of anticoagulation   Interaction between access site and antithrombotic strategies   Can we select patients for different approaches?   Summary
  30. 30. Models to predict bleeding in ACS/PCI       REPLACE-2 ACUITY OASIS-5   Pooled ISAR Trials   CHARISMA   GUSTO   REACH Registry   GRACE   CRUSADE   NCDR CathPCI Registry
  31. 31. Why risk stratify…?   Because sometimes we see what we want to see…
  32. 32. Baseline Major Bleeding and Mortality Risk in CRUSADE N=68,270 Mortality Risk Tertiles 1% 7.6% 23.5% (5,199) (16,044) 9.4% 15.1% 8.4% (6,403) (10,320) (5,762) 23.4% 9.9% 2% High (706) Mod Low (15,974) Low (6,748) (1,114) Mod High Bleeding Risk Tertiles Alexander KA, et. al. ACC 2008
  33. 33. GRACE Risk score: Bleeding N=20,078 patients from the OASIS 5 trial Major Bleeding in 9 days 0.07 Enoxaparin 0.06 0.05 0.04 Fondaparinux 0.03 0.02 80 100 120 140 160 180 200 GRACE Mortality Score Joyner CD, et. al. AHJ 2009
  34. 34. Bleeding – Can we discriminate appropriately?   Yes   Identification of patients at risk for adverse outcomes is possible with currently available models   But, there is significant overlap in covariates across outcome models
  35. 35. Bivalirudin for all - Summary     Bleeding is the most common complication of PCI Radial access and bivalirudin are associated with reduced bleeding over femoral access and UFH       There may be an interaction between the two that augments the safety of PCI While we can identify patients at increased bleeding risk, we cannot separate this risk from ischemic risk Since bivalirudin maintains ischemic efficacy while reducing bleeding, it is the preferred antithrombin agent
  36. 36. Thank you Radialist

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