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John H. Alexander, MD Director, Heart Center SBR Co-Director, DCRI CV Research

American Heart Association Update “Highlights of the AHA” “Duke at the AHA” Cardiology Grand Rounds November 23, 2010. John H. Alexander, MD Director, Heart Center SBR Co-Director, DCRI CV Research. John Alexander: Disclosures (2010).

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John H. Alexander, MD Director, Heart Center SBR Co-Director, DCRI CV Research

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  1. American Heart Association Update “Highlights of the AHA” “Duke at the AHA” Cardiology Grand Rounds November 23, 2010 John H. Alexander, MD Director, Heart Center SBR Co-Director, DCRI CV Research

  2. John Alexander: Disclosures (2010) Research Support: Bristol Myers Squibb, CSL Behring, Medtronic Japan, Merck, NIH, Pfizer, Regado Biosciences Consulting: Astra Zeneca, Boeringer Ingelheim, Bristol Myers Squibb, CSL Behring, Medsphere, Novartis, Ortho-McNeil-Jannsen, Otsuka Pharmaceuticals, Regado Biosciences Disclosures available: https://dcri.org/about-us/conflict-of-interest

  3. Agenda • Hot Science • Duke at the AHA • Modern Communication “The grand rounds tomorrow is intended to generate discussion on how to incorporate the late-breaking science into our clinical practice. So please join us and prepare to discuss.” (Tracy Wang, MD - 11/22/10)

  4. Hot Science • ROCKET-AF • EMPHISIS-HF • ASCEND-HF • GRAVITAS • RACE-ER • REVEAL • DEFINE ● sdfjaliex

  5. Hot Science • ROCKET-AF • EMPHASIS-HF • ASCEND-HF • GRAVITAS • RACE-ER • REVEAL • DEFINE ● sdfjaliex “It is Rocket Science!”

  6. Risk Factors • CHF • Hypertension • Age  75 • Diabetes • OR • Stroke, TIA or Systemic embolus Study Design At least 2 or 3 required* Atrial Fibrillation Rivaroxaban Warfarin Randomize Double Blind / Double Dummy (n ~ 14,000) 20 mg daily 15 mg for Cr Cl 30-49 ml/min INR target - 2.5 (2.0-3.0 inclusive) Monthly Monitoring Adherence to standard of care guidelines Primary Endpoint: Stroke or non-CNS Systemic Embolism * Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%

  7. Primary Efficacy OutcomeStroke and non-CNS Embolism Warfarin Rivaroxaban Cumulative event rate (%) HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <0.001 Days from Randomization No. at risk: Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634 Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655 Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population

  8. Primary Efficacy OutcomeStroke and non-CNS Embolism Rivaroxaban better Warfarinbetter Event Rates are per 100 patient-years Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations

  9. Key Secondary Efficacy Outcomes Event Rates are per 100 patient-years Based on Intention-to-Treat Population

  10. Primary Safety Outcomes Event Rates are per 100 patient-years Based on Safety on Treatment Population

  11. Conclusions • Efficacy: • Rivaroxaban was non-inferior to warfarin for prevention of stroke and non-CNS embolism. • Rivaroxaban was superior to warfarin while patients were taking study drug. • By intention-to-treat, rivaroxaban was non-inferior to warfarin but did not achieve superiority. • Safety: • Similar rates of bleeding and adverse events. • Less ICH and fatal bleeding with rivaroxaban. • Conclusion: • Rivaroxaban is a proven alternative to warfarin for moderate or high risk patients with AF.

  12. Non-inferiority Superiority p-value p-value Dabigatran 110 vs. Warfarin <0.001 0.34 Dabigatran 150 vs. Warfarin <0.001 <0.001 Margin = 1.46 0.50 0.75 1.00 1.25 1.50 HR (95% CI) Stroke or Systemic Embolism

  13. 0.04 # at Risk Year 0.5 1.0 1.5 2.0 2.5 D110 6015 5900 5771 4666 3006 1420 D150 6076 5958 5817 4735 3080 1451 W 6022 5887 5759 4632 2933 1343 0.03 Cumulative Hazard Rates 0.02 Warfarin 0.01 Dabigatran150 Dabigatran110 0.0 0 0.5 1.0 1.5 2.0 2.5 Years All Intracranial Bleeding

  14. Hot Science • ROCKET-AF • EMPHASIS-HF • ASCEND-HF • GRAVITAS • RACE-ER • REVEAL • DEFINE ● sdfjaliex

  15. EMPHASIS-HF EMPHASIS-HF: Major results NYHA Class II HF (N=2737) LV EF < 30% Eplerenone 25-50mg QD vs. Placebo

  16. Hot Science • ROCKET-AF • EMPHASIS-HF • ASCEND-HF • GRAVITAS • RACE-ER • REVEAL • DEFINE ● sdfjaliex “a small phase II trial in the eyes of someone in the ACS world”

  17. Background • Acute heart failure is a major health problem responsible for several million hospitalizations worldwide each year. • Standard therapy has not changed since 1970s and includes diuretics and variable use of vasodilators or inotropes. • In 2001, nesiritide was approved by the FDA to reduce PCWP and improve dyspnea, based on efficacy at 3 hrs. • However, in 2005 two meta-analyses raised concerns regarding the risks of mortality and renal injury. • Subsequently, an independent panel* was convened by Scios Inc and recommended that a clinical trial be conducted to definitively answer the question of nesiritide’s safety and efficacy.

  18. Co-Primary objectives To assess whether nesiritide vs placebo, in addition to standard care provides: • Reduction in rate of HF rehospitalization or all-cause mortality through Day 30 • Significant improvement in self-assessed dyspnea at 6 or 24 hrs using 7-point Likert scale 60 Markedly Better 40 Moderately Better Minimally Better 20 No Change % Subjects 0 Minimally Worse 20 Moderately Worse 40 Markedly Worse

  19. Study design and drug procedures Nesiritide • Double – blind placebo controlled • IV bolus (loading dose) of 2 µg/kg nesiritide or placebo • Investigator’s discretion for bolus • Followed by continuous IV infusion of nesiritide 0.01 µg/kg/min or placebo for up to 7 days • Usual care per investigators including diuretics and/or other therapies as needed • Duration of treatment per investigator based on clinical improvement Acute HF < 24 hrs from IV RX 24–168 hrs Rx Placebo Co-primary endpoint: Dyspnea relief at 6 and 24 hrs Co-primary endpoint: 30-day death or HF rehosp All-cause mortality at 180 days

  20. Co-Primary outcome: 30-day all-cause mortality or HF rehospitalization P=0.31 Hazard Ratio 0.93 (95% CI: 0.8,1.08) 12 10.1 9.4 10 Placebo Nesiritide 8 6.1 6.0 % 6 4.0 3.6 4 2 0 30-day Death/HF Rehospitalization 30-day Death HF Rehospitalization Risk Diff (95 % CI) -0.7 (-2.1; 0.7) -0.4 (-1.3; 0.5) -0.1 (-1.2; 1.0)

  21. Co-Primary Endpoint: 6 and 24 hour dyspnea 6 Hours 24 Hours 70 68.2% P=0.007 70 66.1% P=0.030 60 60 42.1% 44.5% 50 27.5 30.4 50 40 40 15.0 13.4 30 30 % Subjects 20 % Subjects 20 38.6 37.8 29.5 28.7 10 10 0 0 10 10 22.1 21.2 32.8 34.1 20 20 8.6 9.5 30 30 40 40 3398 Placebo 3371 Nesiritide 20.3 21.7 50 60 3416 Nesiritide 3444Placebo Markedly Better Moderately Better No Change Minimally Better Minimally Worse Moderately Worse Markedly Worse

  22. Renal Safety Placebo Nesiritide End of Treatment Creatinine Discharge or 10 day Creatinine 1.0 1.0 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 Cum Dist Cum Dist 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0 0 0 0 2 2 4 4 6 6 8 8 Creatinine (mg/dL) Creatinine (mg/dL)

  23. Hypotension

  24. Conclusions • Nesiritide did not reduce the rate of recurrent heart failure hospitalization or death at 30 days. • Nesiritide reduced dyspnea to a modest degree, consistent with previous findings but did not meet pre-specified protocol criteria for statistical significance at 6 and 24 hours. • Nesiritide did not affect 30-day all cause mortality nor did it worsen renal function as had been suggested by prior meta-analyses of smaller studies.

  25. Hot Science • ROCKET-AF • EMPHISIS-HF • ASCEND-HF • GRAVITAS • RACE-ER • REVEAL • DEFINE ● sdfjaliex

  26. GRAVITAS Study Design Elective or Urgent PCI with DES* VerifyNow P2Y12 Test 12-24 hours post-PCI PRU ≥ 230 R High-Dose Clopidogrel† clopidogrel 600-mg, then clopidogrel 150-mg daily X 6 months Standard-Dose Clopidogrel† clopidogrel 75-mg daily X 6 months Primary Efficacy Endpoint: CV Death, Non-Fatal MI, Stent Thrombosis at 6 mo Key Safety Endpoint: GUSTO Moderate or Severe Bleeding at 6 mo Pharmacodynamics: Repeat VerifyNow P2Y12 at 1 and 6 months *Peri-PCI clopidogrel per protocol-mandated criteria to ensure steady-state at 12-24 hrs †placebo-controlled All patients received aspirin (81-162mg daily)

  27. GRAVITAS Patient Flow 5429 patients screened with VerifyNow P2Y12 12-24 hours post-PCI 2214 (41%) with high residual platelet reactivity (PRU ≥ 230) 3215 (59%) without high residual platelet reactivity (PRU < 230) Clopidogrel High Dose N=1109 Clopidogrel Standard Dose N=1105

  28. Pharmacodynamics: Effect of SD vs HD Clopidogrel Standard-Dose High-Dose 500 P = 0.98 P < 0.001 400 Persistently high reactivity @ 30 days: 62% vs 40%, p<0.001 PRU value 300 200 100 0 N=1105 N=1013 N=940 N=1109 N=1012 N=944 6 mo 6 mo Post-PCI 30 d Post-PCI 30 d ITT population

  29. Primary Endpoint: CV Death, MI, Stent Thrombosis Observed event rates are listed; P value by log rank test.

  30. Bleeding Events: Safety Population Severe or life-threatening: Fatal bleeding, intracranial hemorrhage, or bleeding that causes hemodynamic compromise requiring blood or fluid replacement, inotropic support, or surgical intervention Moderate: Bleeding that leads to transfusion but does not meet criteria for severe bleeding P by log rank test; observed event rates listed. HD, high-dose; SD, standard dose

  31. GRAVITAS: Summary • Compared with standard-dose therapy, high-dose clopidogrel achieved a modest pharmacodynamic effect in patients with high residual reactivity. • In patients with high residual reactivity measured after PCI, 6-months of high-dose clopidogrel did not reduce the rate of cardiovascular death, non-fatal MI, or stent thrombosis and did not increase GUSTO severe or moderate bleeding.

  32. Hot Science • ROCKET-AF • EMPHASIS-HF • ASCEND-HF • GRAVITAS • RACE-ER • REVEAL • DEFINE ● sdfjaliex

  33. Reperfusion of Acute Myocardial Infarction in Carolina Emergency Departments – Emergency Response (RACE-ER) Project on behalf of RACE Coordinators, Nurses, Physicians, Paramedics, and Administrators

  34. Objectives • Regional approach to overcoming systematic barriers 1) Increase reperfusion rate 2) Increase speed of reperfusion RACE 65 hospitals RACE - ER 119 hospitals RACE Pilot 2003 2006 2007 2008 2009 2005

  35. RACE Hospitals by PCI and Reperfusion Designation Primary PCI (21) Transfer for Primary PCI (52) Lytics (31) Mixed (15) (primary PCI if transport readily available

  36. Reperfusion StrategyOverall population, Eligible Patients P = 0.0003 for PCI group trend

  37. Use of Pre-hospital 12-lead ECG(Direct presenters via EMS to PCI Centers)

  38. Transfer Patients: Time to lytic or to device by designation strategy

  39. Hot Science • ROCKET-AF • EMPHASIS-HF • ASCEND-HF • GRAVITAS • RACE-ER • REVEAL • DEFINE ● sdfjaliex

  40. A Randomized, Double-blind, Placebo-controlled Trial of Intravenous Erythropoietin in Patients with ST-Segment Elevation Myocardial Infarction – Primary Results of the REVEAL Trial

  41. STEMI n=110 Primary or rescue PCI TIMI 0-1 flow in IRA Successful PCI IV EPO Matching saline placebo • Infarct size in IRA territory 2-6 days by cMRI - Randomize - Study drug within 4 hrs

  42. Results: Primary endpointMean (SE) infarct size at 2-6 days after study drug admin EPO Placebo 25 20 EPO vs. placebo 15.8% vs. 15.0%, P=NS P-value adjusted for age, infarct location, enrollment phase 15 Infarct Size (%LV) 10 5 0

  43. Conclusions • These data, coupled with the lack of efficacy seen in other STEMI trials involving EPO (REVIVAL-31, HEBE III2), do not support the hypothesis that EPO favorably impacts outcome after reperfusion for STEMI • Whether earlier administration or alternate dosing provides a cardioprotective effect of EPO in humans remains to be determined 1Ott I, et. al. Circ:CV Intv 2010 2Voors AA, et. al. EHJ 2010

  44. Hot Science • ROCKET-AF • EMPHASIS-HF • ASCEND-HF • GRAVITAS • RACE-ER • REVEAL • DEFINE ● sdfjaliex

  45. Background: CETP inhibition X inhibition Cholesteryl ester transfer protein (CETP) is a plasma protein that catalyzes the transfer of CE from HDL to apoB-containing lipoproteins (VLDL and LDL-C) in exchange for Trig. LDL / VLDL LDL-R CE SR-B1 Liver CETP FC CE HDL LCAT Free Cholesterol (FC) in Extrahepatic tissues Bile FC

  46. Anacetrapib • Orally active, potent, selective CETP inhibitor • Robust lipid efficacy in Phase I-II studies • No effects on blood pressure, electrolytes, and aldosterone in preclinical and Phase I-II clinical studies • In vitro HDL functional assays: HDL particles isolated from anacetrapib-treated patients demonstrate preserved (and possibly enhanced) cholesterol efflux properties • Dose of 100 mg selected based on PK/PD modeling: minimal dose to achieve maximal effects on HDL and LDL

  47. Study Design Randomization 1:1 Ratio Study drug stopped if LDL-C<25mg/dL during treatment • Age: 18-80 years • LDL-C @ NCEP ATPIII goal < 100 mg/dL • Statin ± other lipid modifying therapy Anacetrapib 100 mg n=750 R 12 week follow-up Placebo n=750 Stable dose-regimen of lipid-modifying therapy Week -2 0 6 12 18 24 30 38 46 54 62 70 76 80 84 88 Visit 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 18 Reversibility Phase Placebo Run-in Treatment Phase Screening

  48. HDL-C Anacetrapib Anacetrapib 100 120 Placebo Placebo 100 80 80 60 HDL-C (mg/dL) (SE) 60 40 40 20 20 Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76 0 0 Anacetrapib n = 776 757 718 687 647 607 572 543 Placebo n = 766 761 741 744 736 711 691 666 Study Week Effects on LDL-C and HDL-C LDL-C -39.8% (p<0.001) +138.1% (p<0.001) LDL-C (mg/dL) (SE) Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76 Anacetrapib n = 804 771 716 687 646 604 568 540 Placebo n = 803 759 741 743 735 711 691 666 Study Week

  49. Lipid Parameters *p<0.001; means for all variables except for triglycerides, lipoprotein(a), for which medians are shown

  50. Systolic blood pressure (mmHg) 2 2 0 2 0 0 1 8 0 1 6 0 SBP 1 4 0 1 2 0 1 0 0 8 0 6 0 4 0 Baseline Baseline 6 6 1 1 2 2 1 1 8 8 2 2 4 4 3 3 0 0 3 3 8 8 4 4 6 6 5 5 4 4 6 6 2 2 7 7 0 0 7 7 6 6 L A = A n a c e t r a p i b 2 0 B = P l a c e b o 0 Week Diastolic blood pressure (mmHg) 1 4 0 1 2 0 1 0 0 DBP 8 0 6 0 4 0 2 0 L A = A n a c e t r a p i b B = P l a c e b o 0 Week Anacetrapib had no effect on BP

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