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) 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

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)

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

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

Study Design Atrial Fibrillation G02-536 w_script.ppt 4/14/2017 1:36:46 PM Risk Factors CHF Hypertension Age  75 Diabetes OR Stroke, TIA or Systemic embolus Study Design At least 2 or 3 required* Atrial Fibrillation Rivaroxaban Randomize Double Blind / Double Dummy (n ~ 14,000) Warfarin 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%

Primary Efficacy Outcome Stroke and non-CNS Embolism Rivaroxaban Warfarin Event Rate 1.71 2.16 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

Primary Efficacy Outcome Stroke and non-CNS Embolism   Rivaroxaban Warfarin Event Rate HR (95% CI) P-value On Treatment N= 14,143 1.70 2.15 0.79 (0.65,0.95) 0.015 ITT N= 14,171 2.12 2.42 0.88 (0.74,1.03) 0.117 Rivaroxaban better Warfarin better Event Rates are per 100 patient-years Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations

Key Secondary Efficacy Outcomes Rivaroxaban Warfarin Event Rate HR (95% CI) P-value Vascular Death, Stroke, Embolism 4.51 4.81 0.94 (0.84, 1.05) 0.265 Stroke Type Hemorrhagic Ischemic Unknown Type 0.26 1.62 0.15 0.44 1.64 0.14 0.58 (0.38, 0.89) 0.99 (0.82, 1.20 1.05 (0.55, 2.01) 0.012 0.916 0.871 Non-CNS Embolism 0.16 0.21 0.74 (0.42, 1.32 0.308 Myocardial Infarction 1.02 1.11 0.91 (0.72, 1.16) 0.464 All Cause Mortality Vascular Non-vascular Unknown Cause 4.52 2.91 1.15 0.46 4.91 3.11 1.22 0.57 0.92 (0.82, 1.03) 0.94 (0.81, 1.08) 0.94 (0.75, 1.18) 0.80 (0.57, 1.12) 0.152 0.350 0.611 0.195 Event Rates are per 100 patient-years Based on Intention-to-Treat Population

Primary Safety Outcomes Rivaroxaban Warfarin Event Rate or N (Rate) HR (95% CI) P-value Major >2 g/dL Hgb drop Transfusion (> 2 units) Critical organ bleeding Bleeding causing death 3.60 2.77 1.65 0.82 0.24 3.45 2.26 1.32 1.18 0.48 1.04 (0.90, 1.20) 1.22 (1.03, 1.44) 1.25 (1.01, 1.55) 0.69 (0.53, 0.91) 0.50 (0.31, 0.79) 0.576 0.019 0.044 0.007 0.003 Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) Intraparenchymal 37 (0.33) 56 (0.49) 0.67 (0.44, 1.02) 0.060 Intraventricular 2 (0.02) 4 (0.04) Subdural 14 (0.13) 27 (0.27) 0.53 (0.28, 1.00) 0.051 Subarachnoid 1 (0.01) Event Rates are per 100 patient-years Based on Safety on Treatment Population

Conclusions Efficacy: Safety: Conclusion: 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.

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

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

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

EMPHASIS-HF NYHA Class II HF (N=2737) LV EF < 30% EMPHASIS-HF: Major results Outcome Eplerenone (%) Placebo (%) Adjusted hazard ratio (95% CI) p Cardiovascular death/heart-failure hospitalization 18.3 25.9 0.63 (0.54–0.74) <0.001 Cardiovascular death 10.8 13.5 0.76 (0.61–0.94) 0.01 Heart-failure hospitalization 12.0 18.4 0.58 (0.47–0.70) Hospitalization for hyperkalemia 0.3 0.2 1.15 (0.25–5.31) 0.85 NYHA Class II HF (N=2737) LV EF < 30% Eplerenone 25-50mg QD vs. Placebo

“a small phase II trial in the eyes of someone in the ACS world” 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”

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.

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 40 20 % Subjects Markedly Better Minimally Worse Moderately Better Moderately Worse Minimally Better Markedly Worse No Change

Dyspnea relief at 6 and 24 hrs All-cause mortality at 180 days Study design and drug procedures Nesiritide 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 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

30-day Death/HF Rehospitalization Co-Primary outcome: 30-day all-cause mortality or HF rehospitalization P=0.31 Hazard Ratio 0.93 (95% CI: 0.8,1.08) 9.4 3.6 6.0 12 10.1 4.0 6.1 10 Placebo Nesiritide 8 % 6 4 2 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)

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

End of Treatment Creatinine Discharge or 10 day Creatinine Renal Safety Anytime Through Day 30 Placebo (n=3509) Nesiritide (n=3498) P-value >25% decrease eGFR 29.5% 31.4% 0.11 End of Treatment Creatinine Creatinine (mg/dL) Cum Dist 2 4 6 8 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Discharge or 10 day Creatinine Nesiritide Placebo

Hypotension Placebo (n=3509) Nesiritide (n=3498) Risk Difference (95% CI) P- value Any hypotension (Through Day 10/discharge) 15.3% (538) 26.6% (930) 11.3 (9.4 to 13.1) <.001 Asymptomatic Hypotension 12.4% (436) 21.4% (748) 9.0 (7.2 to 10.7) Symptomatic Hypotension 4.0% (141) 7.1% (250) 3.1 (2.1 to 4.2)

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.

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

GRAVITAS Study Design R 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)

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

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 N=1105 N=1013 N=940 N=1109 N=1012 N=944 Post-PCI 30 d 6 mo Post-PCI 30 d 6 mo ITT population

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

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

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. In summary,

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

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

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

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

Reperfusion Strategy Overall population, Eligible Patients P = 0.0003 for PCI group trend

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

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

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

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

Infarct size in IRA territory 2-6 days by cMRI 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

Results: Primary endpoint Mean (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

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

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

Background: CETP 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 X inhibition CETP FC 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 triglycerides that are transferred in the reverse direction. CETP inhibitors increase HDL-C and some also lower LDL-C, and therefore have the potential to reduce coronary events. HDL picks up free cholesterol (FC) from extrahepatic tissues. HDL FC is subsequently esterified by LCAT to form cholesteryl esters (CE) The HDL CE may then be delivered to the liver by either of two pathways: 1. A direct pathway following binding of HDL to hepatic SR-B1 2. An indirect pathway involving the CETP-mediated transfer of CE from HDL to VLDL and LDL with subsequent delivery to the liver following binding of LDL to the LDL receptor." After click: Inhibition of CETP prevents the transfer of CE from HDL to the VLDL/LDL fractions and results in an increase in concentration of HDL-C and a decrease in the cholesterol content of the VLDL/LDL. CE HDL LCAT Bile Free Cholesterol (FC) in Extrahepatic tissues FC 45

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

Study Design R Study drug stopped if LDL-C<25mg/dL during treatment 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 Randomized, double-blind, placebo-controlled trial Eligible patients at screening had the following: CHD or CHD risk equivalents Were on a statin with or without other lipid drugs had LDL-C <100. Major Exclusion Criteria Chronic heart failure Uncontrolled hypertension Hepatic disease Severe renal impairment Treatment with warfarin, digoxin or potent inhibitors/inducers of CYP3A4 Patients entered a 2 week single blind placebo run-in period Patients were randomized to anacetrapib, 100 mg, or placebo for 18 months, followed by a 3-month, poststudy follow-up. At the time the study started there was uncertainty on the safety of very low LDL-C. Patients with LDL-C<25 mg/dL (2 consecutive measurements) during the study were discontinued. 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 Screening Treatment Phase

Effects on LDL-C and HDL-C Study Week Baseline Wk 6 Wk 12 Wk 18 Wk 24 Wk 30 Wk 46 Wk 62 Wk 76 HDL-C (mg/dL) (SE) 20 40 60 80 100 120 Anacetrapib Placebo Anacetrapib n = 776 757 718 687 647 607 572 543 Placebo n = 766 761 741 744 736 711 691 666 20 40 60 80 100 -39.8% (p<0.001) +138.1% (p<0.001) LDL-C (mg/dL) (SE) The point estimates are for wk 24 Anacetrapib Placebo 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

LS Mean Percent (95% CI) Placebo-Adjusted Lipid Parameters Parameter LS Mean Percent (95% CI) Placebo-Adjusted Change from Baseline Week 24 Week 76 Non-HDL-C -31.7* (-33.6, -29.8) -29.4* (-31.6, -27.3) Apo B -21.0* (-22.7, -19.3) -18.3* (-20.2, -16.4) Apo A-1 44.7* (42.8, 46.5) 42.3* (40.5, 44.1) TC 13.7* (12.0, 15.3) 15.6* (13.8, 17.3) TG -6.8 (-9.9, -3.9) -5.3 (-8.9, -1.7) Lp(a) -36.4 (-40.7, -32.3) -38.8 (-44.5, -33.9) ApoE 29.2* (24.7, 33.7) 35.3* (30.6, 40.1) *p<0.001; means for all variables except for triglycerides, lipoprotein(a), for which medians are shown

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

Anacetrapib treatment had robust effects on HDL-C, LDL-C, non HDL-C and Lp(a) with sustained effects over 18 months. Anacetrapib had an acceptable side-effect profile with no effects on blood pressure, electrolytes or aldosterone. Within the power of the study, anacetrapib did not exhibit adverse cardiovascular effects seen with a prior CETP inhibitor The long term safety and efficacy of anacetrapib will now be tested in a large clinical outcomes trial.

30,000 patients with occlusive arterial disease in North America, Europe and Asia Background LDL-lowering with atorvastatin Randomized to anacetrapib 100 mg vs. placebo Scheduled follow-up: 4 years Primary outcome: Coronary death, myocardial infarction or coronary revascularization www.revealtrial.org

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

PI3K Regulates 2-Adrenergic Receptor Stimulated EGFR Transactivation Kevin M. Alexander, Supachoke Mangmool, Chetan B. Patel, Kunhong Xiao, and Howard A. Rockman   Duke University Medical Center Durham, NC

β-AR Mediated EGFR Transactivation Noma et. al. (2007) J. Clin. Invest. and Engelhardt (2007) J. Clin. Invest.

PI3K is Required for 2AR Mediated EGFR Transactivation β2AR stable HEK-293 cells Src Activity EGFR Phosphorylation Both the lipid and protein kinase activity of PI3K are necessary for 2AR mediated EGFR transactivation. PI3K protein kinase activity appears to lead to Src activation.

PI3K is Required for 2AR-EGFR Complex Formation Fluorescence Resonance Energy Transfer (FRET) Inhibition

Quantification of Src Phosphorylation Using Stable Isotope Labelling with Amino Acids in Cell Culture (SILAC) Grow two populations of HEK-293 cells expressing HA-Src and β2AR “Light” medium “Heavy” medium L-Arg L-Lys HCl [13C6, 15N2 ]-L-Lys HCl (+8) [13C6, 15N4]-L-Arg (+10) LY + ISO ISO Mix, IP, trypsin digest, and IMAC phosphopeptide enrichment Phosphopeptide analysis by LC-MS 100 100 Extracted Ion Chromatogram (XIC) Light peptide A peptide B peptide C peptide D peptide E peptide F Relative Abundance Relative Abundance Heavy Measure area under the curve

Sites of Src Phosphorylation by PI3K SH3 SH2

PI3K Regulates β2AR Stimulated EGFR Transactivation Function of PI3K in β2AR stimulated EGFR transactivation 1. Formation of PIP3 2. Src phosphorylation

Agenda Hot Science Duke at the AHA Modern Communication

Duke At the AHA An Award Presentations Fellow Presentations LBCT & LBSS The Duke Reception

Award Dr. Victor Dzau receives the 2010 Research Achievement Award at the AHA Opening Sessions

Duke Presentations

Duke Presentations Saturday November 13th 5 Sunday November 14th 23 Monday November 15th 57 Tuesday November 16th 52 Wednesday November 17th 18 Total 155

Duke Fellow Presentations (5) Gerald Bloomfield Studying Non-Communicable Cardiovascular Diseases in sub-Saharan Africa: One Fellow's Journey Early Career: Global Cardiovascular Research Training, Opportunities and Experiences Todd Kiefer, Lawrence Park, Christophe Tribouilloy, Claudia Cortes, Riccardo Utilli, Andrew Wang Heart Failure Complicating Infective Endocarditis: An Analysis of In-Hospital Mortality from the International Collaboration on Endocarditis Prospective Cohort Study Valvular Heart Disease: Diagnosis, Pathophysiology and Medical Management II Robin Mathews, Eric D. Peterson, Anita Y. Chen, Tracy Wang, Chee T. Chin, Gregg C. Fonarow, Christopher P. Cannon, Matthew T. Roe, Karen P. Alexander Prediction of In-Hospital Major Bleeding Among Patients With Acute Myocardial Infarction: Results From 90,273 Patients in the Acute Coronary Treatment Intervention Outcomes Network Registry®- Get With the Guidelines™ (AR-G) Best of AHA Specialty Conferences Poster Session: QCOR 2010 Robb D. Kociol, Li Liang, Adrian F. Hernandez, Lesley H. Curtis, Paul A. Heidenreich, Clyde W. Yancy, Gregg C. Fonarow, Eric D. Peterson Are We Targeting the Right Economic Metric for Heart Failure? Association of Hospital 30-Day Heart Failure Readmission Rates and Total Inpatient Days Sumeet Subherwal, Eric D. Peterson, Anita Y. Chen, Richard G. Bach, Brian F. Gage, Deepak L. Bhatt, Stephen D. Wiviott, Jeffrey B. Washam, Matthew T. Roe, Karen P. Alexander, Tracy Y. Wang Is Bleeding Risk Augmented With Acute Therapies Across Increasing INR Levels Among NSTEMI Patients on Home Warfarin Therapy? Atrial Fibrillation/Arrhythmias: Epidemiology, Quality of Care and Outcomes

Duke Fellow Presentations (9) Chee Tang Chin, John C Messenger, Lisa A Kaltenbach, Michael A Kutcher, H Vernon Anderson, Matthew T Roe, Tracy Y Wang Comparison of Acute Coronary Syndrome Patients Undergoing Percutaneous Coronary Intervention for Previously Stented versus De Novo Culprit Lesions: Insights from the National Cardiovascular Data Registry CathPCI Registry Acute Coronary Syndromes and Percutaneous Coronary Intervention: Quality of Care and Outcomes Sergio Leonardi, Amanda Stebbins, Renato D Lopes, Yuliya Lokhnygina, Deepak L Bhatt, Gregg W Stone, Michael A Lincoff, Harold L Dauerman, C. Michael Gibson, Harvey D White, Keyur Parick, Luis Gruberg, Howard C Herrmann, Brent T McLaurin, Shaun Goodman, Robert A Harrington, Kenneth W Mahaffey 7118 - Pre-Treatment With Thienopyridines Reduces The Amount of Myonecrosis in Acute Coronary Syndrome Patients Invasively Managed: Insights from the CHAMPION trials What's New in the Treatment of Patients with Acute Coronary Syndromes? Kevin M Alexander, Supachoke Mangmool, Chetan B Patel, Kunhong Xiao, Howard A Rockman 15645 - Phosphoinositde 3-Kinase Regulates β2-Adrenergic Receptor Stimulated Epidermal Growth Factor Receptor Transactivation Vascular Signaling Thomas T Tsai, John C Messenger, J Matthew Brennan, Uptal D Patel, David Dai, Robert Piana, Kevin J Anstrom, Eric L Eisenstein, Rachel S Dokholyan, Eric D Peterson, Pamela S Douglas 19884 - Contemporary Risk of Follow-up Adverse Events in Older Patients with Chronic Kidney Disease and Dialysis Undergoing Percutaneous Coronary Interventions: A Report from the Merged NCDR CMS Registry The Role of Comorbidities in Cardiovascular Disease

Duke Fellow Presentations (14) Jonathan P Piccini, Bradley G. Hammill, Moritz F. Sinner, Paul N. Jensen, Adrian F. Hernandez, Susan R. Heckbert, Emelia J. Ben, Lesley H. Curtis Incidence of Atrial Fibrillation and Associated Mortality among Medicare Beneficiaries from 1993 to 2007 Epidemiology and Outcomes in Atrial Fibrillation Robin Mathews, Anita Y Chen, Chee T Chin, Tracy Y Wang, Kevin L Thomas, Matthew T Roe, Eric D Peterson Short- and Long-term Outcomes Among Black vs. White Patients with Non-ST-segment Elevation Myocardial Infarction Diagnosis and Outcomes Chee Tang Chin, Robert V Kelly, Mauricio G Cohen, Marc Cohen, J Richard Trout, Gregg W Stone, Jan T Christenson, Robert J Freedman Jr, Ramachandra C Reddy, Debra Joseph, E Magnus Ohman The Impact of Anticoagulation During Intra-Aortic Balloon Counterpulsation Pump Placement on In-Hospital Outcomes in 18,875 Patients Undergoing Cardiac Revascularization Heart Failure: Pacing and Other Therapeutic Devices Sergio Leonardi, L. Kristin Newby, E. Magnus Ohman, Paul W Armstrong Lack of Implementation of ESC/ACC Definition of Myocardial Infarction in Contemporary Randomized Clinical Trials From Acute Thrombotic to Chronically Occluded Coronary Arteries Zubin J Eapen, Shelby D Reed, Lesley H Curtis, Adrian F Hernandez, Eric D Peterson Do Heart Failure Disease Management Programs Make Financial Sense Under a Bundled Payment System? Heart Failure: Disease Management, Quality of Care, Anemia

Duke Fellow Presentations (18) Rajendra H Mehta, Jonathan P Piccini, James T Tcheng, Martin Fahy, Roxana Mehran, Gregg W Stone, On Behalf of HORIZONS-AMI Investigators Prognostic Significance of Post-Procedural Sustained Ventricular Tachycardia or Fibrillation in Patients Undergoing Primary Percutaneous Coronary Intervention: Insights from the HORIZONS AMI Trial From Acute Thrombotic to Chronically Occluded Coronary Arteries Robin Mathews, Eric D. Peterson, Shuang Li, Matthew T. Roe, Stephen D. Wiviott, Jorge F. Saucedo, Elliott M. Antman, Tracy Y. Wang Under-utilization of Emergency Medical Service Transport Among Contemporary Patients with ST Elevation Myocardial Infarction: Findings from the National Cardiovascular Data Registry ACTION - Get With The Guidelines J. Matthew Brennan, Eric D Peterson, Yue Zhao, Sean O'Brien, Rachel Dokholyan, Pamela S Douglas, Fred H Edwards Predictors of Bioprosthetic Aortic Valve Failure: Results in 73,616 Patients from the Society of Thoracic Surgeons (STS) Adult Cardiac Surgery National Database Cardiac Surgery: Valvular Heart Disease (Not Including Percutaneous Valves) IV Jonathan P. Piccini, Jennifer A. White, Rajendra H. Mehta, Sana M. Al-Khatib, Pierluigi Tricoci, Charles V. Pollack Jr, Gilles Montalescot, Frans Van de Werf, C. Michael Gibson, Robert A. Harrington, L. Kristin Newby Sustained Ventricular Tachycardia and Ventricular Fibrillation are Infrequent Events but are Associated with Increased Arrhythmic and All-cause Death Following Non-ST-Segment Elevation Acute Coronary Syndromes Noninvasive Arrhythmia Testing/Risk Assessment

Late Breaking Clinical Trials Duke LBCT & LBSS Late Breaking Clinical Trials ROCKET-AF ASCEND-HF Late Breaking Sciences Sessions RACE-ER REVEAL

Interviews at the DCRI Reception “The Duke Reception” Sponsors Duke Heart Center Duke Division of Cardiology Duke Clinical Research Institute Interviews at the DCRI Reception Networking Current Faculty & Fellows Heart Center, Division, DCRI Staff Former Fellows Academic & Industry Collaborators

Agenda Hot Science Duke at the AHA Modern Communication

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Dr. Hisao Ogawa reviews: ROCKET-AF and RELY, A Japanese Perspective in Japanese. Dr. Robert Harrington, Dr. Robert Califf, Dr. C. Michael Gibson present: AHA 2010 wrap-up. Dr. Robert Califf, Dr. Manesh Patel, Dr. Kenneth Mahaffey, and Dr. Keith Fox discuss: Stroke Prevention Using the Oral Direct Factor Xa Inhibitor Rivaroxaban Compared with Warfarin in Patients with Nonvalvular Atrial Fibrillation (ROCKET-AF). Dr. Matthew Price presents: Standard Versus High-Dose Clopidogrel According to Platelet Function Testing After PCI: Results of the GRAVITAS Trial. Dr. Robert Califf, Dr. Adrian Hernandez, Dr. Christopher O'Connor and Dr. Randy Starling discuss: Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Dr. Clyde Yancy presents ASCEND: Historical perspective, implications for patients Failure Trial (ASCEND-HF). Dr. Anthony Furlan and Dr. Duane Pinto discuss: CLOSURE I Trial: A Prospective, Multicenter, Randomized Controlled Trial to Evaluate the Safety and Efficacy of the STARFlex Septal Closure System Versus Best Medical Therapy in Patients with a Stroke or Transient Ischemic Attack due to Presumed Paradoxical Embolism through a Patent Foramen Ovale.

Dr. Renato Lopes, Dr. Alexandre Quadros, Dr Dr. Renato Lopes, Dr. Alexandre Quadros, Dr. Antonio Carlos Carvalho and Dr. Roberto Giraldez: AHA wrap-up in Portuguese. Dr. Hisao Ogawa and Dr. Yoshihiko Saito: An AHA 2010 wrap-up in Japanese. Professor Murray Esler and Dr. Duane Pinto discuss: Symplicity HTN-2: International, Multicenter, Prospective, Randomized, Controlled Trial Of Endovascular Selective Renal Sympathetic Denervation For The Treatment Of Hypertension. Dr. Jonathan Piccini and Dr. Duane Pinto discuss: Sustained Ventricular Tachycardia and Ventricular Fibrillation Are Infrequent Events but are Associated with Increased Arrhythmic and All-Cause Death Following Non-ST-Segment Elevation Acute Coronary Syndromes. Dr. Stephen Nicholls and Dr. Ravi Karra discuss the results of the ASSERT study, the first major clinical trial of an oral agent inducing Apo A1 synthesis: A new approach to HDL raising and CV risk modification. Dr. Magnus Ohman and Dr. C. Michael Gibson discuss LVADs: Improving Outcomes. Dr. Matthew Brennan and Dr. C. Michael Gibson discuss: Anticoagulation Following Bioprosthetic Aortic Valve Replacement.

Dr. Christopher Granger, Mayme Roettig, RN, MSN, and Dr Dr. Christopher Granger, Mayme Roettig, RN, MSN, and Dr. Ravi Karra discuss: Mission Lifeline Update 2010. Dr. Peter Kowey provides and expert opinion on ROCKET AF and RELY. Dr. Robert Harrington presents: Beyond 2010, The Future of Antithrombic Therapy - Old Agent Replacement, Combination Therapy, and the Impact of Generics. Dr. Kristin Newby and Dr. Duane Pinto discuss: An EARLY-ACS Update. Dr. Chistopher Cannon presents: Primary Results of the DEFINE trial: Determining the EFficacy and Tolerability of CETP INhibition with AnacEtrapib. Dr. Peter Kowey discusses: Efficacy And Safety Of Prescription Omega-3-Acid Ethyl Esters (P-OM3) For The Prevention Of Recurrent Symptomatic Atrial Fibrillation (AF). Dr. Magnus Ohman reviews: TRILOGY: An Update. Dr. Karen Alexander and Dr. Duane Pinto describe: The Coming Tsunami: Cardiovascular Disease in the Elderly.

Dr. Tracy Wang and Dr. Duane Pinto discuss: Under-Utilization of Emergency Medical Service Transport Among Contemporary Patients with ST-Elevation Myocardial Infarction – Findings from the National Cardiovascular Data Registry ACTION, Get with the Guidelines. Dr. Sara Pasquali and Grendel Burrell discuss: The Impact of Intensive Care Unit Structure on Post-operative Outcomes Following Congenital Heart Surgery: Analysis of a Multi-institutional Database. Dr. Jennifer Li, Dr. C. Michael Gibson, and Grendel Burrell discuss: Lessons from Pediatric Cardiovascular Drug Trials. Dr. Dominick Angiolillo presents: Commentary on GRAVITAS. Dr. Christopher Granger and Dr. Ravi Karra discuss: Reperfusion of Acute Myocardial Infarction in Carolina Emergency Departments - Emergency Response (RACE-ER) Project. Bradi Granger RN, PhD and Dr. Ravi Karra discuss: The Duke Translational Nursing Institute. Dr. Otavio Berwanger and Dr. Duane Pinto discuss: Acetylcystein for the Prevention of Contrast-Induced nephropaThy (ACT) Trial: a Pragmatic Multicenter Randomized Trial to Evaluate the Efficacy of Acetylcysteine for the Prevention of Renal Outcomes in Patients Undergoing Coronary and Vascular Angiography.

Dr. Christoph Kaiser and Dr Dr. Christoph Kaiser and Dr. Duane Pinto discuss: The BASKET PROspective Evaluation Examination (BASKET PROVE): Late Cardiac Clinical Death and Myocardial Infarction Associated With Late Stent Thrombosis in Large Vessel Stenting After 1st or 2nd Generation Drug-eluting Compared to Bare-metal Stents. Dr. William Weintraub and Dr. Ravi Karra discuss: Top 100 Vocabulary Project. Dr. Richard Becker and Dr. Ravi Karra discuss: Pathways in Anticoagulation: What's Most Efficacious, Safest. Karen Pieper and Dr. Duane Pinto present: Insights from Plato: Proton Pump Inhibitor Use Is Likely a Marker for, Rather than a Cause of, a Higher Risk of Cardiovascular Events. Dr. Thomas Povsic and Dr. Duane Pinto discuss: A Prospective RADAR Pharmacokinetic and PharmacodynamicSubstudy: Pegnivacogin (RB006), a Direct Factor IXa Inhibitor, Results in Consistent and Near Complete Inhibition of Factor IX Activity in Patients with Acute Coronary Syndromes. Dr. Sunil Rao and Dr. Ravi Karra discuss: The Primary Results of the REVEAL Trial: A Randomized Placebo Controlled Trial of Intravenous Erythropoietin to Reduce Infarct Size After ST-Segement Elevation Myocardial Infarction.

Dr. Kristin Newby and Dr. Duane Pinto discuss: MURDOCK Study Progress and Substudies. Dr. Keith Aaronson and Dr. Duane Pinto discuss: Evaluation of the Heartware HVAD Left Ventricular Assist Device System for the Treatment of Advanced Heart Failure: Results of the ADVANCE Bridge to Transplant Trial. Dr. James Daubert and Dr. Duane Pinto discuss: QTc Prolongation During Therapeutic Hypothermia: Does it Deserve Attention? Dr. David Cohen and Dr. Duane Pinto discuss: PARTNER Trial (Cohort B): Health-Related Quality of Life After Transcatheter Aortic Valve Implantation vs. Non-Surgical Therapy Among Inoperable Patients With Severe Aortic Stenosis. Dr. Karen Alexander discusses: Frail Older Adults at Risk for Loss of Independence Following MI. Dr. Kenneth Ellenbogen and Dr. Duane Pinto discuss: SMART AV: Comparison of AV Optimization Methods Used in Cardiac Resynchronization Therapy (CRT). Dr. Deepak Voora and Dr. Duane Pinto discuss: A Whole Blood RNA Signature Accurately Classifies Multiple Measures of Platelet Function on Aspirin in Healthy Volunteers and Highlights a Common Underlying Pathway.

Dr. James Januzzi and Dr. Duane Pinto discuss: PROTECT: Use of NT-proBNP Testing to Guide Heart Failure Therapy in the Outpatient Setting. Dr. Chris O'Connor,  Dr. Randy Starling, and Dr. Clyde Yancy provide historical perspective and discuss the results/implications for ASCEND. Dr. Christopher O'Connor and Dr. Zubin Eapen discuss Duke's Presence at AHA, What's Happening, What to Expect. Dr. Rob Califf talks with Dr. Zubin Eapen about a Cardiology Fellow's Perspective from AHA 2010.

Daily Heart Line Memos From Chris & Marti

Post-Test Question Question: What was the most important advance by Duke Heart Center faculty or fellows from the AHA? Answer Options: ROCKET-AF ASCEND RACE-ER The Duke Cardiology Fellows Blog DUKE-TV

Post-Test Question Question: What was the most important advance by Duke Heart Center faculty or fellows from the AHA? Answer Options: ROCKET-AF ASCEND RACE-ER The Duke Cardiology Fellows Blog DUKE-TV

Have a Happy Thanks Giving! Thank You! Have a Happy Thanks Giving! Cardiology Grand Rounds November 23, 2010 John H. Alexander, MD Director, Heart Center SBR Co-Director, DCRI CV Research