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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.

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Presentation on theme: "Two-Year Follow-up from a Prospective, Randomized Trial of Heparin Plus Glycoprotein IIb/IIIa Inhibitors vs. Bivalirudin and Paclitaxel-Eluting vs. Bare-Metal."— Presentation transcript:

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 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: 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 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 Emergent angiography, followed by triage to… Primary PCI CABG– Medical Rx – UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) Bivalirudin monotherapy (± provisional GP IIb/IIIa) Aspirin, thienopyridine R 1: pts eligible for stent randomization R 3:1 Bare metal EXPRESS stent Paclitaxel-eluting TAXUS stent Clinical FU at 30 days, 6 months, 1 year, and then yearly through 5 years; angio FU at 13 months 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 UFH + GP IIb/IIIa N=1802 Bivalirudin N=1800 R 1:1 Randomized * Biomarkers WNL and no DS >50% by core lab determination (30 day FU only) 1-Year FU Eligible 2-Year FU N=1672 (94.4%)N=1693 (95.6%) N=1772N=1771 Withdrew Withdrew Lost to FU Lost to FU pts with STEMI Not true MI* Not true MI* Year FU N=1733 (97.8%)N=1730 (97.7%) Withdrew Withdrew Lost to FU Lost to FU

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

7 Two-Year Major Bleeding (non-CABG)* *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 p<0.001 HR [95%CI]= 0.64 [0.51, 0.81] 6.4% 6.4% 9.6% 9.6% Major Bleeding (%) Months Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Number at risk Bivalirudin alone Heparin+GPIIb/IIIa

8 Two-Year Major Adverse CV Events* *MACE = All cause death, reinfarction, ischemic TVR or stroke p= 0.99 HR [95%CI]= 1.00 [0.86, 1.17] 18.7% 18.8% MACE (%) Months Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Number at risk Bivalirudin alone Heparin+GPIIb/IIIa

9 Two-Year All-Cause Mortality p= HR [95%CI]= 0.75 [0.56, 1.00] 4.6% 4.6% 6.1% 6.1% All-Cause Mortality (%) Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Months 3.1% 2.1% 1 month P=0.049 Number at risk Bivalirudin alone Heparin+GPIIb/IIIa

10 p= HR [95% CI]= 0.59 [0.41, 0.86] 2.5% 2.5% 4.2% 4.2% Cardiac Mortality Months Two-Year Mortality: Cardiac and Non Cardiac Number at risk Bivalirudin alone Heparin+GPIIb/IIIa Mortality (%) Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) p= 0.69 HR [95% CI]= 1.10 [0.69, 1.76] 2.2% 2.2% 2.0% 2.0% Non Cardiac Mortality Months

11 Two-Year Reinfarction p= HR [95%CI]= 0.75 [0.56, 0.98] 5.1% 5.1% 6.9% 6.9% Reinfarction (%) Number at risk Bivalirudin alone Heparin+GPIIb/IIIa Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Months

12 Two-Year Death or Reinfarction p= HR [95%CI]= 0.75 [0.61, 0.93] 9.1% 9.1% 12.0% Death or reinfarction (%) Number at risk Bivalirudin alone Heparin+GPIIb/IIIa Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Months

13 Two-Year MACE Components* UFH + GPI (N=1802)Bivalirudin(N=1800) HR [95%CI] P Value Death6.1%4.6% 0.75 [0.56,1.00] Cardiac - Cardiac4.2%2.5% 0.59 [0.41,0.86] Non cardiac - Non cardiac2.0%2.2% 1.10 [0.69,1.76] 0.69 Reinfarction6.9%5.1% 0.75 [0.56,0.98] Q-wave - Q-wave3.4%3.1% 0.92 [0.63,1.34] Non Q-wave - Non Q-wave3.9%2.2% 0.56 [0.37,0.83] Death or reinfarction 12.0%9.1% 0.75 [0.61,0.93] Ischemic TVR 11.0%12.7% 1.17 [0.96,1.42] Ischemic TLR - Ischemic TLR8.7%10.2% 1.19 [0.95,1.49] Ischemic remote TVR - Ischemic remote TVR3.8%4.5% 1.19 [0.85,1.66] 0.31 Stroke1.7%1.5% 0.88 [0.52,1.52] 0.65 *All Kaplan-Meier estimates, CEC adjudicated

14 Adverse Events Between 30 Days and 2-Years UFH + GPI (N=1802)Bivalirudin(N=1800) P Value Death3.1%2.6% Cardiac - Cardiac1.3%0.7% Non cardiac - Non cardiac1.8%1.9%0.76 Reinfarction5.2%3.2%0.005 Death or reinfarction 7.9%5.5%0.006 Ischemic TVR 9.5%10.2%0.53 Stroke1.0%0.7%0.41 MACE14.7%13.9%0.53 Major bleeding (non CABG) 1.0%1.3%0.55 NACE15.2%14.6%0.63 *Kaplan-Meier estimates, landmark analysis, CEC adjudicated

15 2-Year Stent Thrombosis (ARC Definite/Probable) p= 0.73 HR [95%CI]= 0.94 [0.67, 1.32] 4.3% 4.3% 4.6% 4.6% Stent Thrombosis (%) Number at risk Bivalirudin alone Heparin+GPIIb/IIIa Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Months

16 2-Year Stent Thrombosis* (N=3,202) UFH + GPI (N=1591)Bivalirudin(N=1611)PValue ARC definite or probable, 24 hours 0.3%1.5%< definite, 24 hours - definite, 24 hours0.2%1.5%< probable, 24 hours - probable, 24 hours0.1%0.0%0.32 ARC definite or probable, >24h – 2y 4.4%2.9% definite, >24 hours – 2 year - definite, >24 hours – 2 year3.6%2.6% probable, >24 hours – 2 year - probable, >24 hours – 2 year0.8%0.3%0.08 ARC definite or probable, 2 years 4.6%4.3% definite, 2-year - definite, 2-year3.8%3.9% probable, 2-year - probable, 2-year0.8%0.3%0.05 *All Kaplan-Meier estimates; all CEC adjudicated

17 TAXUS DES N=2257 EXPRESS BMS N=749 Randomized 1 year FU N=2223 (98.5%)N=729 (97.3%) Withdrew Withdrew Lost to FU Lost to FU R 3: pts eligible for stent rand. Primary Medical Rx193 Primary CABG 62 Deferred PCI 2 Index PCI, not eligible - PTCA only119 - Stented220 UFH + GPI (n=1802) Bivalirudin (n=1800) R 1: pts with STEMI 93.1% of all stented pts were randomized 2 year FU N=2157 (95.6%)N=715 (95.5%) Withdrew Withdrew Lost to FU Lost to FU month angiographic FU Harmonizing Outcomes with Revascularization and Stents in AMI

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

19 Primary Efficacy Endpoint: Ischemic TLR P<0.001 HR [95%CI]= 0.58 [0.44, 0.76] 6.8% 6.8% 11.6% Ischemic TLR (%) TAXUS DES (n=2257) EXPRESS BMS (n=749) Number at risk TAXUS DES EXPRESS BMS Months

20 Primary Efficacy Endpoint: Ischemic TLR P<0.001 HR [95%CI]= 0.58 [0.44, 0.76] 6.8% 6.8% 11.6% Ischemic TLR (%) TAXUS DES (n=2257) EXPRESS BMS (n=749) Number at risk TAXUS DES EXPRESS BMS Months p= yr HR [95%CI]= 0.60 [0.43, 0.84] 13 mo angio FU

21 Secondary Efficacy Endpoint: Ischemic TVR

22 Primary Safety Endpoint: Safety MACE* * Safety MACE = death, reinfarction, stroke, or stent thrombosis

23 Two-Year All-Cause Mortality

24 Two-Year Cardiac Mortality

25 Two-Year Reinfarction

26 Two-Year Stent Thrombosis (ARC Definite or Probable) p= 0.99 HR [95%CI]= 1.00 [0.66, 1.51] 4.1% 4.1% Stent Thrombosis (%) TAXUS DES (n=2257) EXPRESS BMS (n=749) Number at risk TAXUS DES EXPRESS BMS Months

27 2-Year Stent Thrombosis* TAXUS(N=2238)EXPRESS(N=744)PValue ARC definite or probable, 30 days 2.2%2.7% definite, 30 days - definite, 30 days1.8%2.3% probable, 30 days - probable, 30 days0.4%0.4%0.86 ARC definite or probable, >30d - 1y 1.0%0.7% definite, >30 days – 1-year - definite, >30 days – 1-year0.9%0.7% probable, >30 days – 1-year - probable, >30 days – 1-year0.1%0.0%0.42 ARC definite or probable, 1y - 2y 1.1%0.7% definite, 1-year – 2-year - definite, 1-year – 2-year1.1%0.6% probable, 1-year – 2-year - probable, 1-year – 2-year0.0%0.1%0.41 ARC definite or probable, 2 years 4.1%4.1% definite, 2-year - definite, 2-year3.7%3.6% probable, 2-year - probable, 2-year0.5%0.6%0.88 *All Kaplan-Meier estimates; all CEC adjudicated

28 Two Year Composite Safety Endpoints* TAXUS(N=2257)EXPRESS(N=749) HR [95%CI] P Value Safety MACE 11.0%11.2% 0.98 [0.77,1.26] 0.89 Death, all-cause 4.3%5.2% 0.83 [0.57,1.20] Cardiac - Cardiac2.7%3.3% 0.83 [0.52,1.33] Non cardiac - Non cardiac1.6%2.0% 0.82 [0.44,1.52] 0.53 Reinfarction5.7%6.1% 0.92 [0.65,1.30] Q-wave - Q-wave3.1%2.9% 1.06 [0.65,1.72] Non Q-wave - Non Q-wave3.0%3.2% 0.91 [0.57,1.47] 0.71 Stent thrombosis 4.1%4.1% 1.00 [0.66,1.51] ARC definite - ARC definite3.7%3.6% 1.01 [0.65,1.57] ARC probable - ARC probable0.6%0.5% 0.91 [0.29,2.87] 0.88 Stroke1.4%1.1% 1.24 [0.57,2.70] 0.59 *Kaplan-Meier estimates

29 Adverse Events Between 1 and 2 Years* TAXUS(N=2257)EXPRESS(N=749) HR [95%CI] P Value Safety MACE 3.4%3.5% 0.96 [0.60,1.53] 0.86 Death, all-cause 0.8%1.8% 0.46 [0.22,0.97] Cardiac - Cardiac0.3%0.6% 0.49 [0.14,1.74] Non cardiac - Non cardiac0.5%1.2% 0.45 [0.18,1.12] 0.08 Reinfarction2.3%1.5% 1.58 [0.80,3.12] Q-wave - Q-wave1.1%0.9% 1.20 [0.49,2.97] Non Q-wave - Non Q-wave1.4%0.6% 2.30 [0.81,6.55] 0.11 Stent thrombosis 1.1%0.7% 1.51 [0.58,3.98] ARC definite - ARC definite1.1%0.6% 1.81 [0.62,5.25] ARC probable - ARC probable0.05%0.14% 0.33 [0.02,5.24] 0.41 Stroke0.4%0.5% 0.87 [0.23,3.29] 0.84 Ischemic TLR 2.6%4.7% 0.55 [0.35,0.85] Ischemic TVR 3.4%5.2% 0.65 [0.43,0.97] 0.03 *Kaplan-Meier estimates

30 Two-Year Mortality (All-Cause)

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: 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: 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 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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