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Bivalirudin SCAI-ACC/i2 2008 presentations

Bivalirudin SCAI-ACC/i2 2008 presentations

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Bivalirudin SCAI-ACC/i2 2008 presentations

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  1. Bivalirudin SCAI-ACC/i2 2008 presentations • HORIZONS AMI subgroups: • Impact of clopidogrel Dangas et al • Diabetes Witzenbichler et al • Renal impairment Mehran et al • Gender Grinfeld et al • Age Dudek et al • Abciximab, eptifibatide strata Gualiumi et al • US, non-US Brodie et al

  2. Impact of clopidogrel loading dose on the safety and effectiveness of bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction: The HORIZONS AMI trial George Dangas, Giulio Guagliumi, Bernhard Witzenbichler, Deepak Bhatt, Frederick Feit, Magnus Ohman, S. Chiu Wong, Helen Parise, Roxana Mehran, Gregg W. Stone

  3. Background In the HORIZONS AMI trial, in pts undergoing primary PCI. bivalirudin monotherapy (Biv) compared to UFH plus GP IIb/IIIa inhibitors resulted in: – Reduced 30 day rates of major bleeding, – Comparable composite major adverse cardiovascular events (MACE) – Enhanced freedom from net adverse clinical events (NACE). All pts were to receive a clopidogrel loading dose in the ER, either 300 mg or 600 mg, and randomization was stratified by this decision. Whether the beneficial effects of Biv are independent of the clopidogrel loading dose has not been reported.

  4. Baseline Characteristics Dangas et al, SCAI-ACCi2 2008

  5. Baseline Characteristics Dangas et al, SCAI-ACCi2 2008

  6. Drug Administration Dangas et al, SCAI-ACCi2 2008

  7. Procedural characteristics (PCI) Dangas et al, SCAI-ACCi2 2008

  8. Procedural characteristics (PCI) Dangas et al, SCAI-ACCi2 2008

  9. Overall: Primary Outcomes (ITT) P<.0001 P=0.002 P=0.001 • *NACE = MACE or major bleeding • **Not related to CABG • ***MACE = All cause death, reinfarction, ischemic TVR or stroke Dangas et al, SCAI-ACCi2 2008

  10. Primary Outcomes (ITT) • The impact of Biv was independent of the dose of clopidogrel loading. Interaction P values for the above 3 endpoints = 0.48 (NACE) 0.41 (Major bleeding), and 0.75 (MACE). 300 mg LD 600 mg LD P=0.15 P=0.01 P=0.56 P=0.01 P=0.002 P=0.71 Dangas et al, SCAI-ACCi2 2008

  11. Overall: 30 Day MACE Components* *CEC adjudicated Dangas et al, SCAI-ACCi2 2008

  12. BIV group: 30 Day MACE Components* *CEC adjudicated Dangas et al, SCAI-ACCi2 2008

  13. Overall: 30 Day Stent Thrombosis *Protocol definition of stent thrombosis, CEC adjudicated Dangas et al, SCAI-ACCi2 2008

  14. BIV group: 30 Day Stent Thrombosis *Protocol definition of stent thrombosis, CEC adjudicated Dangas et al, SCAI-ACCi2 2008

  15. Overall: 30 Day Bleeding Endpoints *Life threatening Dangas et al, SCAI-ACCi2 2008

  16. Prediction of 30-day Adverse Outcomes • Multivariate Predictors Using Logistic Regression Model Dangas et al, SCAI-ACCi2 2008

  17. Prediction of 30-day Adverse Outcomes • Multivariate Predictors Using Cox proportional hazards model Dangas et al, SCAI-ACCi2 2008

  18. Conclusions In patients with STEMI undergoing primary PCI: • 600 mg loading dose of clopidogrel was associated with significantly lower 30- day mortality, reinfarction and stent thrombosis rates compared with 300 mg loading dose. • 600 mg loading dose of clopidogrel did not increase the risk of bleeding compared with 300 mg loading dose. • Biv monotherapy significantly reduces major bleeding and NACE, independently of the clopidogrel loading dose. • By multivariate analysis, 600 mg loading dose of clopidogrel was an independent predictor of lower 30-day MACE (compared with 300 mg LD, Odds Ratio=0.72), but was not independently associated with death, reinfarction or major bleeding. Dangas et al, SCAI-ACCi2 2008

  19. Impact Of Diabetes Mellitus On The Safety And Effectiveness Of Bivalirudin In Patients With Acute Myocardial Infarction Undergoing Primary Angioplasty: The HORIZONS AMI Trial Bernhard Witzenbichler, Giulio Guagliumi, Martin Desaga, Janusz Kochman, Dennis W. Nilsen, Ariel Finkelstein, Morris Mosseri, Helen Parise, Roxana Mehran, Gregg W. Stone

  20. Background • Outcomes in the HORIZONS AMI trial were analyzed according to the presence of medically treated diabetes mellitus (DM) at the time of admission. • This subgroup analysis was pre-specified in the protocol / statistical analysis plan. • Since subgroups are generally underpowered, these analyses will be considered exploratory and hypothesis generating. Witzenbichler et al ACC 2008

  21. Baseline characteristics • 593 of 3.599 study patients (16.5%) in HORIZONS had medically treated diabetes. Baseline characteristics demonstrate that diabetics represent a significantly higher risk group compared to non-diabetics. Witzenbichler et al ACC 2008

  22. Baseline characteristics (ii) Witzenbichler et al ACC 2008

  23. Endpoints in non-diabetics, by study drug • Non-Diabetics (n=3006) RR=0.60 [0.61, 0.94] P=0.006 RR=0.55 [0.41, 0.74] P=0.001 RR=1.14 [0.83, 1.56] P= n.s. • *MACE = All cause death, reinfarction, ischemic TVR or stroke Witzenbichler et al ACC 2008

  24. Endpoints in diabetics, by study drug • Diabetics (n=593) RR=0.60 [0.61, 0.94] P=0.006 RR=0.55 [0.41, 0.74] P=0.001 RR=1.14 [0.83, 1.56] P= n.s. • *MACE = All cause death, reinfarction, ischemic TVR or stroke Witzenbichler et al ACC 2008

  25. 30-day MACE components among diabetics Witzenbichler et al ACC 2008

  26. 30 day bleeding endpoints among diabetics Witzenbichler et al ACC 2008

  27. Conclusions • Compared to patients without diabetes mellitus, those with diabetes had greater rates of major bleeding (8.8% vs. 6.2%, P=0.02), MACE (8.1% vs. 5.0%, P=0.002) and NACE (14.2% vs. 10.0%, P=0.003). • Among the diabetic subgroup: • Bivalirudin significantly reduced cardiac death at 30 days (p=0.037). • Total and hemorrhagic stroke rate occurred more often in the UFH + GPI group, whereas non-cardiac death rate was slightly increased in the Bivalirudin group, although based on small patient numbers. • All other 30 day endpoints including stent thrombosis rate were not significantly different among diabetics between the two treatment arms • In patients with AMI undergoing primary PCI, Bivalirudin monotherapy significantly reduces major bleeding and net adverse clinical events, effects which are independent of diabetic status (interaction P value for major bleeding = 0.22, for MACE = 0.10, and NACE = 0.90). Witzenbichler et al ACC 2008

  28. Impact of Baseline Renal Function on the Safety and Effectiveness of Bivalirudin in Patients with Acute MI Undergoing Primary Angioplasty: The HORIZONS AMI trial Roxana Mehran, Bernhard Witzenbichler, Giulio Guagliumi, Victor Guetta, Harry Suryapranata, Kurt Huber, Jochen Wöehrle, Chris Metzger, George Dangas, Helen Parise, Gregg W. Stone For the HORIZONS AMI Investigators

  29. Background and Objectives • In HORIZONS, bivalirudin monotherapy compared to heparin + GPI resulted in reduced rates of major bleeding and NACE, with comparable composite MACE in pts undergoing primary PCI. • Whether the beneficial effects of Biv are independent of renal function, an important prognostic determinate after primary PCI, has not been reported. • We evaluated 30-day outcomes overall and by randomized antithrombin treatment according to baseline renal function. Mehran et al ACC 2008

  30. Baseline Characteristics Mehran et al ACC 2008

  31. 30-Day Outcomes by Renal Function P<0.0001 for all • *Not related to CABG • **MACE = All cause death, reinfarction, ischemic TVR or stroke Mehran et al ACC 2008

  32. 30-Day Outcomes among Renally Impaired Patients (CrCl <60 mL/min) by Treatment P=0.95 P=0.32 P=0.47 • *Not related to CABG • **MACE = All cause death, reinfarction, ischemic TVR or stroke Mehran et al ACC 2008

  33. 30-Day Outcomes among Pts with Normal Renal Function (CrCl ≥60 mL/min) by Treatment P=0.004 P=0.0002 P=0.73 • *Not related to CABG • **MACE = All cause death, reinfarction, ischemic TVR or stroke Mehran et al ACC 2008

  34. Conclusions • Patients with AMI and impaired renal function (CrCl <60 mL/min) undergoing primary PCI have significantly worse 30-day ischemic and bleeding outcomes compared to patients with normal renal function. • There was no significant difference in 30-day outcomes among patients with impaired renal function treated with bivalirudin monotherapy or heparin + GPI in HORIZONS-AMI study. • Among patients with normal renal function, bivalirudin monotherapy significantly reduces major bleeding and net adverse clinical events. Mehran et al ACC 2008

  35. Impact of gender on the safety and effectiveness of bivalirudin in patients with acute myocardial infarction undergoing primary angioplastyL Grinfeld, J Belardi, AJ Lansky, B Witzenbichler, G Guagliumi, K Zmudka, M Moeckel, A Ochala, W Ruzyllo, H Parise, R Mehran, GW Stone

  36. Objectives • To evaluate the impact of gender on the safety and effectiveness of bivaliridun monotherapy compared to UFH + the routine use of GP IIb/IIIa inhibitors in patients with AMI undergoing primary angioplasty: • Similar or reduced rates of NACE at 30 days • Similar or reduced rates of major bleeding Grinfeld et al ACC 2008

  37. Demographics Grinfeld et al ACC 2008

  38. Events by gender Grinfeld et al ACC 2008

  39. Events by gender (male) RR=0.77 [0.59, 0.97] P=0.03 RR=0.59 [0.43, 0.82] P=0.001 P= ns Grinfeld et al ACC 2008

  40. Events by gender (female) RR=0.76 [0.54, 1.08] P=0.01 RR=0.59 [0.38, 0.92] P=0.02 P= ns Grinfeld et al ACC 2008

  41. Conclusions • Women and men with AMI undergoing PCI have different risk profiles. • Women have a higher incidence of death, ischemic TVR, major and minor bleeding. • Despite these differences, bivalirudin monotherapy significantly reduces major bleeding and net adverse clinical events compared to UFH plus the routine use of GP IIb/IIIa inhibitors both in women and men. Grinfeld et al ACC 2008

  42. Impact of advanced age on the safety and effectiveness of bivalirudin in patients with acute myocardial infarction undergoing primary angioplasty: The HORIZONS AMI trialDariusz Dudek, Krzyszto Zmudka, Bernhard Witzenbichler, Giulio Guagliumi, Jan Z. Peruga, Bruce R. Brodie, Ran Kornowski, Franz Hartmann, Martin Mockel, Andrzej Ochala, Helen Parise, Roxana Mehran, Gregg W. Stone

  43. Methods • A total of 3602 patients at 123 centers in 11 countries with AMI undergoing primary PCI were randomized tobivalirudin monotherapy or unfractionated heparin plus glycoprotein IIb/IIIa inhibitors. • Outcomes were analyzed according to age above or below the median of 60.2 years: • Bivalirudin (n=1800) • age ≤60.2 years (n=923) • age >60.2 years (n=877) • UFH+GPI (n=1802) • age ≤60.2 years (n=885) • age >60.2 years (n=917) Dudek et al ACC 2008

  44. Outcomes, Age ≤ 60.2 years P=0.168 P=0.0012* P=0.354 P=0.109 *P<0.05 Dudek et al ACC 2008

  45. Outcomes, Age > 60.2 years P=0.156 P=0.013* P=0.512 P=0.033* *P<0.05 Dudek et al ACC 2008

  46. Conclusions • In patients with AMI undergoing primary PCI, bivalirudin monotherapy significantly reduces major bleeding and net adverse clinical events, effects which are independent of age. Dudek et al ACC 2008

  47. Safety and effectiveness of bivalirudin compared to either abciximab or eptifibatide in patients with acute myocardial infarction undergoing primary angioplasty: The HORIZONS AMI trialGiulio Guagliumi, Bernhard Witzenbichler, Jan Z. Peruga, Bruce R. Brodie, Dariusz Dudek, Ran Kornowski, Janusz Kochman, Yaron Almagor, Dennis Nilsen, Ajay Kirtane, Helen Parise, Roxana Mehran,Gregg W. Stone

  48. Methods • A total of 1,915 pts (53%) were randomized in the abciximab strata, and 1,687 pts (47%) were randomized in the eptifibatide strata. Subgroup analyses pre-specified in the protocol. Gualiumi et al ACC 2008

  49. Outcomes, abciximab strata (n=1915) RR=0.57 [0.39, 0.85] RR=0.91 [0.61, 1.36] RR=0.73 [0.55, 0.97] • *MACE = death, reinfarction, ischemic TVR or stroke • **NACE = (Net Adverse Clinical Events) = MACE or major bleeding Gualiumi et al ACC 2008

  50. Outcomes, eptifibatide strata (n=1687) RR=0.57 [0.39, 0.85] RR=0.91 [0.61, 1.36] RR=0.73 [0.55, 0.97] • *MACE = death, reinfarction, ischemic TVR or stroke • **NACE = (Net Adverse Clinical Events) = MACE or major bleeding Gualiumi et al ACC 2008