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Two-Year Follow-up from a Prospective, Randomized Trial of Heparin Plus Glycoprotein IIb/IIIa Inhibitors vs. Bivalirudin and Paclitaxel-Eluting vs. Bare-Metal Stents in STEMI Gregg W. Stone MD For the HORIZONS-AMI Investigators. Disclosures. Gregg W. Stone MD

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  1. Two-Year Follow-up from a Prospective, Randomized Trial of Heparin Plus Glycoprotein IIb/IIIa Inhibitors vs. Bivalirudin and Paclitaxel-Eluting vs. Bare-Metal Stents in STEMI Gregg W. Stone MD For the HORIZONS-AMI Investigators

  2. Disclosures • Gregg W. Stone MD • Advisory Board for Boston Scientific and Abbott Vascular • Research support from The Medicines Company

  3. Background At 1-year in the 2x2 factorial prospective, randomized HORIZONS-AMI trial: Bivalirudin alone compared to heparin plus GPIIb/IIIa inhibitors resulted in comparable rates of MI and stent thrombosis, with significantly reduced rates of major bleeding and mortality (all-cause and cardiac) TAXUS PES compared to EXPRESS BMS reduced clinical and angiographic restenosis, with comparable rates of death, reinfarction and stent thrombosis Whether these findings are sustained at 2 years has not been reported

  4. Harmonizing Outcomes with Revascularization and Stents in AMI 3602 pts with STEMI with symptom onset ≤12 hours Aspirin, thienopyridine UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) Bivalirudin monotherapy (± provisional GP IIb/IIIa) Emergent angiography, followed by triage to… R 1:1 R 3:1 CABG – – Primary PCI Medical Rx 3006 pts eligible for stent randomization Paclitaxel-eluting TAXUS stent Bare metal EXPRESS stent Clinical FU at 30 days, 6 months, 1 year, and then yearly through 5 years; angio FU at 13 months

  5. Harmonizing Outcomes with Revascularization and Stents in AMI 3602 pts with STEMI R 1:1 UFH + GP IIb/IIIa N=1802 Bivalirudin N=1800 Randomized • • • Not true MI* • • • 30 29 N=1772 N=1771 1-Year FU Eligible • • • Withdrew • • • • • • Lost to FU • • • 26 13 22 19 N=1733 (97.8%) N=1730 (97.7%) 1-Year FU • • • Withdrew • • • • • • Lost to FU • • • 13 48 12 25 N=1672 (94.4%) N=1693 (95.6%) 2-Year FU * Biomarkers WNL and no DS >50% by core lab determination (30 day FU only)

  6. Pharmacology Randomization: Aspirin and Thienopyridine Use Regular* aspirin use (%) Regular* thieno. use (%) 98.1% 97.3% 97.0% 96.1% 95.2% 93.7% 93.3% 87.7% 97.1% 96.7% 96.3% 92.9% 92.7% 95.2% 95.7% 87.1% 67.8% 65.6% Antiplatelet agent use (%) 35.8% All P = NS All P = NS 32.7% Bivalirudin alone (n=1800) *Taken >50% of days since last visit Heparin + GPIIb/IIIa (n=1802)

  7. Two-Year Major Bleeding (non-CABG)* Bivalirudin alone (n=1800) 12 Heparin + GPIIb/IIIa (n=1802) 10 9.6% 8 6.4% Major Bleeding (%) 6 4 HR [95%CI]= 0.64 [0.51, 0.81] 2 p<0.001 0 0 3 6 9 12 15 18 21 24 Months Number at risk 1800 1603 1571 1540 1290 Bivalirudin alone 1802 1535 1505 1453 1218 Heparin+GPIIb/IIIa *Intracranial intraocular, retroperitoneal, access site bleed requiring intervention/surgery, hematoma ≥5 cm, hgb ↓ ≥3g/dL with or ≥4g/dL w/o overt source; reoperation for bleeding; or blood product transfusion

  8. Two-Year Major Adverse CV Events* Bivalirudin alone (n=1800) 24 Heparin + GPIIb/IIIa (n=1802) 18.8% 20 18.7% 16 MACE (%) 12 HR [95%CI]= 1.00 [0.86, 1.17] 8 p= 0.99 4 0 0 3 6 9 12 15 18 21 24 Months Number at risk Bivalirudin alone 1800 1584 1513 1400 1159 1802 1577 1518 1399 1142 Heparin+GPIIb/IIIa • *MACE = All cause death, reinfarction, ischemic TVR or stroke

  9. Two-Year All-Cause Mortality Bivalirudin alone (n=1800) 8 Heparin + GPIIb/IIIa (n=1802) 7 6.1% 6 5 4.6% 3.1% All-Cause Mortality (%) 4 HR [95%CI]= 3 0.75 [0.56, 1.00] 2 2.1% p= 0.049 1 month P=0.049 1 0 0 3 6 9 12 15 18 21 24 Months Number at risk 1800 1690 1658 1627 1359 Bivalirudin alone 1802 1669 1637 1579 1324 Heparin+GPIIb/IIIa

  10. Two-Year Mortality: Cardiac and Non Cardiac Heparin + GPIIb/IIIa (n=1802) Bivalirudin alone (n=1800) Cardiac Mortality Non Cardiac Mortality 5 5 4.2% 4 4 HR [95% CI]= 1.10 [0.69, 1.76] 3 3 p= 0.69 Mortality (%) 2.5% 2.2% 2.0% 2 2 HR [95% CI]= 0.59 [0.41, 0.86] 1 1 p= 0.005 0 0 0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24 Months Months Number at risk Bivalirudin alone 1800 1690 1658 1627 1359 1800 1690 1658 1359 1627 Heparin+GPIIb/IIIa 1802 1669 1637 1579 1324 1802 1669 1637 1324 1579

  11. Two-Year Reinfarction Bivalirudin alone (n=1800) 10 Heparin + GPIIb/IIIa (n=1802) 9 8 6.9% 7 6 5.1% Reinfarction (%) 5 4 HR [95%CI]= 3 0.75 [0.56, 0.98] 2 p= 0.038 1 0 0 3 6 9 12 15 18 21 24 Months Number at risk 1800 1644 1603 1554 1298 Bivalirudin alone 1802 1621 1576 1500 1244 Heparin+GPIIb/IIIa

  12. Two-Year Death or Reinfarction Bivalirudin alone (n=1800) 15 Heparin + GPIIb/IIIa (n=1802) 12.0% 12 9.1% 9 Death or reinfarction (%) 6 HR [95%CI]= 0.75 [0.61, 0.93] 3 p= 0.007 0 0 3 6 9 12 15 18 21 24 Months Number at risk 1800 1644 1603 1554 1298 Bivalirudin alone 1802 1621 1576 1500 1244 Heparin+GPIIb/IIIa

  13. Two-Year MACE Components* *All Kaplan-Meier estimates, CEC adjudicated

  14. Adverse Events Between 30 Days and 2-Years *Kaplan-Meier estimates, landmark analysis, CEC adjudicated

  15. 2-Year Stent Thrombosis(ARC Definite/Probable) Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 6 5 4.6% 4.3% 4 Stent Thrombosis (%) 3 HR [95%CI]= 0.94 [0.67, 1.32] 2 p= 0.73 1 0 0 3 6 9 12 15 18 21 24 Months Number at risk Bivalirudin alone 1611 1509 1475 1444 1206 Heparin+GPIIb/IIIa 1591 1482 1449 1386 1153

  16. 2-Year Stent Thrombosis* (N=3,202) *All Kaplan-Meier estimates; all CEC adjudicated

  17. Harmonizing Outcomes with Revascularization and Stents in AMI UFH + GPI (n=1802) Bivalirudin (n=1800) 3602 pts with STEMI R 1:1 Primary Medical Rx 193 Primary CABG 62 Deferred PCI 2 Index PCI, not eligible - PTCA only 119 - Stented 220 3006 pts eligible for stent rand. 93.1% of all stented pts were randomized R 3:1 TAXUS DES N=2257 EXPRESS BMS N=749 Randomized • • • Withdrew • • • • • • Lost to FU • • • 18 16 7 13 1 year FU N=2223 (98.5%) N=729 (97.3%) 13 month angiographic FU 942 307 12 54 • • • Withdrew • • • • • • Lost to FU • • • 6 8 2 year FU N=2157 (95.6%) N=715 (95.5%)

  18. TAXUS DES (n=2257) Stent Randomization: Aspirin and Thienopyridine Use EXPRESS BMS (n=749) Regular* aspirin use (%) Regular* thieno. use (%) 99.4% 99.1% 98.7% 98.5% 98.3% 97.5% 97.5% 94.6% 98.9% 97.8% 98.6% 98.3% 97.5% 97.1% 96.2% 72.8% 87.5% P<0.001 Antiplatelet agent use (%) 63.8% All P=NS P<0.001 36.8% 30.7% P=0.004 *Taken >50% of days since last visit

  19. Primary Efficacy Endpoint: Ischemic TLR TAXUS DES (n=2257) 15 EXPRESS BMS (n=749) 12 11.6% 9 Ischemic TLR (%) 6.8% 6 HR [95%CI]= 0.58 [0.44, 0.76] 3 P<0.001 0 0 3 6 9 12 15 18 21 24 Months Number at risk TAXUS DES 2257 2105 2041 1949 1618 EXPRESS BMS 749 677 654 611 507

  20. Primary Efficacy Endpoint: Ischemic TLR TAXUS DES (n=2257) 15 EXPRESS BMS (n=749) 12 11.6% 13 mo angio FU 9 Ischemic TLR (%) 6.8% 6 HR [95%CI]= 0.58 [0.44, 0.76] 3 1-yr HR [95%CI]= P<0.001 0.60 [0.43, 0.84] p= 0.002 0 0 3 6 9 12 15 18 21 24 Months Number at risk TAXUS DES 2257 2105 2041 1949 1618 EXPRESS BMS 749 677 654 611 507

  21. Secondary Efficacy Endpoint: Ischemic TVR TAXUS DES (n=2257) 15 EXPRESS BMS (n=749) 13.3% 12 8.9% 9 Ischemic TVR (%) 6 HR [95%CI]= 0.66 [0.51, 0.84] 1-yr HR [95%CI]= P<0.001 3 0.66 [0.49, 0.89] p= 0.007 0 0 3 6 9 12 15 18 21 24 Months Number at risk TAXUS DES 2257 2085 2016 1912 1587 EXPRESS BMS 749 671 646 600 498

  22. Primary Safety Endpoint: Safety MACE* TAXUS DES (n=2257) 16 EXPRESS BMS (n=749) 14 11.2% 12 11.0% 10 Safety MACE (%) 8 HR [95%CI]= 6 0.98 [0.77, 1.26] p= 0.90 4 2 0 0 3 6 9 12 15 18 21 24 Months Number at risk TAXUS DES 2257 2094 2035 1958 1619 EXPRESS BMS 749 684 667 645 530 * Safety MACE = death, reinfarction, stroke, or stent thrombosis

  23. Two-Year All-Cause Mortality TAXUS DES (n=2257) 8 EXPRESS BMS (n=749) 7 6 5.2% 5 4.3% All-Cause Mortality (%) 4 3 HR [95%CI]= 0.83 [0.57, 1.20] 2 p= 0.32 1 0 0 3 6 9 12 15 18 21 24 Months Number at risk TAXUS DES 2257 2170 2134 2083 1742 EXPRESS BMS 749 714 700 680 566

  24. Two-Year Cardiac Mortality TAXUS DES (n=2257) 6 EXPRESS BMS (n=749) 5 4 3.3% Cardiac Mortality (%) 3 2.7% 2 HR [95%CI]= 0.83 [0.52, 1.33] 1 p= 0.43 0 0 0 3 3 6 6 9 9 12 12 15 15 18 18 21 21 24 24 Months Number at risk TAXUS DES 2257 2170 2134 2083 1742 EXPRESS BMS 749 714 700 680 566

  25. Two-Year Reinfarction TAXUS DES (n=2257) 10 EXPRESS BMS (n=749) 9 8 7 6.1% 6 5.7% Reinfarction (%) 5 4 HR [95%CI]= 3 0.92 [0.65, 1.30] p= 0.64 2 1 0 0 0 3 3 6 6 9 9 12 12 15 15 18 18 21 21 24 24 Months Number at risk TAXUS DES 2257 2118 2062 1998 1645 EXPRESS BMS 749 690 674 651 538

  26. Two-Year Stent Thrombosis(ARC Definite or Probable) TAXUS DES (n=2257) EXPRESS BMS (n=749) 6 5 4.1% 4.1% 4 Stent Thrombosis (%) 3 HR [95%CI]= 1.00 [0.66, 1.51] 2 p= 0.99 1 0 0 3 6 9 12 15 18 21 24 Months Number at risk TAXUS DES 2238 2108 2061 1998 1661 EXPRESS BMS 744 696 681 661 547

  27. 2-Year Stent Thrombosis* *All Kaplan-Meier estimates; all CEC adjudicated

  28. Two Year Composite Safety Endpoints* *Kaplan-Meier estimates

  29. Adverse Events Between 1 and 2 Years* *Kaplan-Meier estimates

  30. Two-Year Mortality (All-Cause) Heparin + GPI / TAXUS (n=1111) Heparin + GPI / EXPRESS (n=368) 8 Bivalirudin / TAXUS (n=1146) Bivalirudin / EXPRESS (n=381) 7 6.1% 6 5 4.7% 4.3% All-Cause Mortality (%) 4 3.8% 3 2 Pint = 0.73 1 0 0 3 6 9 12 15 18 21 24 Months

  31. Conclusions: Pharmacology Randomization • In this large-scale, prospective, randomized trial of pts with STEMI undergoing primary PCI, at 2 years initial treatment with bivalirudin alone compared to heparin plus GPIIb/IIIa inhibitors resulted in: • A significant 36% reduction in major bleeding and a significant 25% reduction in reinfarction, with comparable rates of stent thrombosis, TVR and stroke • A significant 41% reduction in cardiac mortality and a 25% reduction in all-cause mortality, the latter representing 15 lives saved per 1000 patients treated with bivalirudin (NNT = 67 to save 1 life)

  32. Conclusions: Stent Randomization • Among pts with STEMI undergoing primary PCI, at 2 years the implantation of TAXUS paclitaxel-eluting EXPRESS stents compared to EXPRESS bare metal stents resulted in: • Significant 42% and 34% reductions in ischemic TLR and TVR respectively, with no evidence of late catch-up • Comparable rates of all-cause and cardiac mortality, reinfarction and stent thrombosis, with no safety concerns apparent • TLR, TVR and mortality were reduced between 1 and 2 years in pts treated with TAXUS EXPRESS compared to EXPRESS BMS, observations that should be considered hypothesis generating given their borderline significance and possible influence of routine angiographic follow-up

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