john h. alexander, md director, heart center sbr co-director, dcri cv research

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

All Rights Reserved, Duke Medicine 2008

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

●


Hot Science

• ROCKET-AF• EMPHASIS-HF• ASCEND-HF• GRAVITAS• RACE-ER• REVEAL• DEFINE

● “It is Rocket Science!”

Rivaroxaban Warfarin

Primary Endpoint: Stroke or non-CNS Systemic Embolism

INR target - 2.5 (2.0-3.0 inclusive)

20 mg daily15 mg for Cr Cl 30-49 ml/min

Atrial Fibrillation

RandomizeDouble Blind / Double Dummy

(n ~ 14,000)

Monthly MonitoringAdherence to standard of care guidelines

Study Design

* Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%

Risk Factors• CHF • Hypertension • Age 75 • Diabetes OR• Stroke, TIA or Systemic embolus

At least 2 or 3 required*

Primary Efficacy OutcomeStroke and non-CNS Embolism

Event Rates are per 100 patient-yearsBased on Protocol Compliant on Treatment Population

No. at risk:Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655

Warfarin

HR (95% CI): 0.79 (0.66, 0.96)

P-value Non-Inferiority: <0.001

Days from Randomization

Cu

mu

lati

ve e

ven

t ra

te (

%)

Rivaroxaban


Event Rate

1.71 2.16

Rivaroxaban Warfarin Event Rate

Event Rate

HR(95% CI) P-value

On Treatment

N= 14,1431.70 2.15 0.79

(0.65,0.95) 0.015

ITTN= 14,171

2.12 2.42 0.88 (0.74,1.03) 0.117

Rivaroxabanbetter

Warfarinbetter

Primary Efficacy OutcomeStroke and non-CNS Embolism

Event Rates are per 100 patient-yearsBased on Safety on Treatment or Intention-to-Treat thru Site Notification populations


Event Rate 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

0.261.620.15

0.441.640.14

0.58 (0.38, 0.89)0.99 (0.82, 1.201.05 (0.55, 2.01)

0.0120.9160.871

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

4.522.911.150.46

4.913.111.220.57

0.92 (0.82, 1.03)0.94 (0.81, 1.08)0.94 (0.75, 1.18)0.80 (0.57, 1.12)

0.1520.3500.6110.195

Key Secondary Efficacy Outcomes

Event Rates are per 100 patient-yearsBased on Intention-to-Treat Population


Event Rate or N (Rate)

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

3.602.771.650.820.24

3.452.261.321.180.48

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)

0.5760.0190.0440.0070.003

Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) 0.019

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 4 (0.04) 1 (0.01)

Event Rates are per 100 patient-yearsBased on Safety on Treatment Population

Primary Safety Outcomes

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.

Stroke or Systemic Embolism

0.50 0.75 1.00 1.25 1.50

Dabigatran 110 vs. Warfarin

Dabigatran 150 vs. Warfarin

Non-inferiorityp-value

<0.001

<0.001

Superiorityp-value

0.34

<0.001

Margin = 1.46

HR (95% CI)

All Intracranial Bleeding

Years

Cum

ulat

ive

Haz

ard

Rat

es

0.0

0.01

0.02

0.03

0.04

0 0.5 1.0 1.5 2.0 2.5

Dabigatran110

Dabigatran150

Warfarin

# at Risk Year 0.5 1.0 1.5 2.0 2.5

D110

D150

W

6015 5900 5771 4666 3006 1420

6076 5958 5817 4735 3080 1451

6022 5887 5759 4632 2933 1343


Hot Science


●

EMPHASIS-HF: Major results

EMPHASIS-HF

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) <0.001

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


Hot Science


●

“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.

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

Co-Primary objectives

60

40

20

0

20

40

% S

ub

ject

s

Markedly Better

Minimally Worse

Moderately Better

Moderately Worse

Minimally Better

Markedly Worse

No Change

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

Study design and drug procedures

Nesiritide

Placebo

24–168 hrs RxAcute HF < 24 hrs from IV RX

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

Co-Primary outcome: 30-day all-cause mortality or HF rehospitalization

10.1

4.0

6.1

Hazard Ratio 0.93 (95% CI: 0.8,1.08)

9.4

3.6

6.0

Placebo

Nesiritide

HF Rehospitalization30-day Death/HF Rehospitalization

30-day Death0

2

4

6

8

10

12

Risk Diff (95 % CI) -0.7 (-2.1; 0.7) -0.4 (-1.3; 0.5) -0.1 (-1.2; 1.0)

%

P=0.31

70

60

50

40

30

20

10

0

10

20

30

40%

Su

bje

cts

24 Hours

Markedly Better

Minimally Worse

Moderately Better

Moderately Worse

Minimally Better

Markedly Worse

No Change

Co-Primary Endpoint: 6 and 24 hour dyspnea

70

60

50

40

30

20

10

0

10

20

30

40

% S

ub

ject

s

50

60

6 Hours

3444Placebo

13.4

28.7

34.1

21.7

P=0.030

3416Nesiritide

15.0

29.5

32.8

20.3 3398Placebo

27.5

38.6

22.1

9.5

3371Nesiritide

30.4

37.8

21.2

P=0.007

8.6

42.1% 44.5%

66.1% 68.2%

Renal Safety

Anytime Through Day 30Placebo(n=3509)

Nesiritide(n=3498)

P-value

>25% decrease eGFR 29.5% 31.4% 0.11

End of Treatment Creatinine

Creatinine (mg/dL)

Cu

m D

ist

0 2 4 6 80

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

Creatinine (mg/dL)

Cu

m D

ist

0 2 4 6 80

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

NesiritidePlacebo

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 Hypotension12.4%(436)

21.4%(748)

9.0(7.2 to 10.7)

<.001

Symptomatic Hypotension4.0%(141)

7.1%(250)

3.1(2.1 to 4.2)

<.001

Hypotension

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.

Conclusions


Hot Science

• ROCKET-AF• EMPHISIS-HF • ASCEND-HF • GRAVITAS• RACE-ER• REVEAL• DEFINE

●

Standard-Dose Clopidogrel† clopidogrel 75-mg daily X 6 months

High-Dose Clopidogrel†

clopidogrel 600-mg, thenclopidogrel 150-mg daily X 6 months

Elective or Urgent PCI with DES*

VerifyNow P2Y12 Test 12-24 hours post-PCI

PRU ≥ 230

RR

GRAVITAS Study Design

†placebo-controlled

Primary Efficacy Endpoint: CV Death, Non-Fatal MI, Stent Thrombosis at 6 moKey Safety Endpoint: GUSTO Moderate or Severe Bleeding at 6 mo

Pharmacodynamics: Repeat VerifyNow P2Y12 at 1 and 6 months

All patients received aspirin (81-162mg daily)

*Peri-PCI clopidogrel per protocol-mandated criteria to ensure steady-state at 12-24 hrs*Peri-PCI clopidogrel per protocol-mandated criteria to ensure steady-state at 12-24 hrs

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)

ClopidogrelHigh Dose

N=1109

ClopidogrelStandard Dose

N=1105

GRAVITAS Patient Flow

Pharmacodynamics: Effect of SD vs HD Clopidogrel

500

400

300

200

100

0

PRU value

Post-PCI

High-Dose

30 d 6 mo Post-PCI 30 d 6 mo

Standard-Dose

N=1013 N=940N=1105 N=1012 N=944N=1109

P = 0.98P < 0.001

ITT population

Persistently high reactivity @ 30 days: 62% vs 40%, p<0.001

Persistently high reactivity @ 30 days: 62% vs 40%, p<0.001

Primary Endpoint: CV Death, MI, Stent Thrombosis

Observed event rates are listed; P value by log rank test.

Bleeding Events: Safety Population

P by log rank test; observed event rates listed. HD, high-dose; SD, standard dose

Severe or life-threatening: Fatal bleeding, intracranial hemorrhage, or bleeding that causes hemodynamic compromise requiring blood or fluid replacement, inotropic support, or surgical interventionModerate: Bleeding that leads to transfusion but does not meet criteria for severe bleeding

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.


Hot Science

• ROCKET-AF• EMPHASIS-HF • ASCEND-HF• GRAVITAS• RACE-ER• REVEAL• DEFINE

●

Reperfusion of Acute Myocardial Infarction in Carolina Emergency

Departments – Emergency Response (RACE-ER) Project

on behalf of RACE Coordinators, Nurses, Physicians, Paramedics, and Administrators

Regional approach to overcoming systematic

barriers

1) Increase reperfusion rate

2) Increase speed of reperfusion

RACEPilot

RACE65 hospitals

RACE - ER119 hospitals

2003 2006 2007 2008 20092005

Objectives

Primary PCI (21)

Transfer for Primary PCI (52)Lytics (31)

Mixed (15) (primary PCI if transport readily available

RACE Hospitals by PCI and Reperfusion Designation

Reperfusion StrategyOverall 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


●

A Randomized, Double-blind, A Randomized, Double-blind, Placebo-controlled Trial of Placebo-controlled Trial of

Intravenous Erythropoietin in Intravenous Erythropoietin in Patients with ST-Segment Elevation Patients with ST-Segment Elevation

Myocardial Infarction – Primary Myocardial Infarction – Primary Results of the REVEAL TrialResults of the REVEAL Trial

STEMI n=110STEMI n=110STEMI n=110STEMI n=110

Primary or rescue PCIPrimary or rescue PCITIMI 0-1 flow in IRATIMI 0-1 flow in IRA

Primary or rescue PCIPrimary or rescue PCITIMI 0-1 flow in IRATIMI 0-1 flow in IRA

Successful PCISuccessful PCISuccessful PCISuccessful PCI

IV EPOIV EPOIV EPOIV EPO Matching salineMatching saline

placeboplacebo

Matching salineMatching saline

placeboplacebo

Infarct size in IRA territory

2-6

days

by cMRI

Infarct size in IRA territory

2-6

days

by cMRI

- Randomize

- Study drug within 4 hrs

Results: Primary endpointResults: Primary endpointMean (SE) infarct size at 2-6 days after study drug adminMean (SE) infarct size at 2-6 days after study drug admin

EPO vs. placebo

15.8% vs. 15.0%, P=NS

P-value adjusted for age, infarct location,

enrollment phase

EPO Placebo

Infa

rct

Siz

e (%

LV)

0

5

10

15

20

25

ConclusionsConclusions

These data, coupled with the lack of efficacy These data, coupled with the lack of efficacy seen in other STEMI trials involving EPO seen in other STEMI trials involving EPO (REVIVAL-3(REVIVAL-311, HEBE III, HEBE III22), do not support the ), do not support the hypothesis that EPO favorably impacts outcome hypothesis that EPO favorably impacts outcome after reperfusion for STEMIafter reperfusion for STEMI

Whether earlier administration or alternate Whether earlier administration or alternate dosing provides a cardioprotective effect of dosing provides a cardioprotective effect of EPO in humans remains to be determinedEPO in humans remains to be determined

1Ott I, et. al. Circ:CV Intv 2010

2Voors AA, et. al. EHJ 2010


Hot Science


●

Background: CETP Background: CETP inhibitioninhibition

HDLHDL

LDL / LDL / VLDLVLDL

LiverLiver

BileBile

CECE

LDL-RLDL-R

FCFC

FCFC

LCATLCAT

CETPCETP

CECE

SR-B1SR-B1

X X inhibitioninhibition

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.

Free Cholesterol (FC) Free Cholesterol (FC) in Extrahepatic tissuesin Extrahepatic tissues

Anacetrapib Anacetrapib

Orally active, potent, selective CETP inhibitor Orally active, potent, selective CETP inhibitor

Robust lipid efficacy in Phase I-II studiesRobust lipid efficacy in Phase I-II studies

No effects on blood pressure, electrolytes, and No effects on blood pressure, electrolytes, and aldosterone in preclinical and Phase I-II clinical studies aldosterone in preclinical and Phase I-II clinical studies

In vitroIn vitro HDL functional assays: HDL particles isolated HDL functional assays: HDL particles isolated from anacetrapib-treated patients demonstrate preserved from anacetrapib-treated patients demonstrate preserved (and possibly enhanced) cholesterol efflux properties (and possibly enhanced) cholesterol efflux properties

Dose of 100 mg selected based on PK/PD modeling: Dose of 100 mg selected based on PK/PD modeling: minimal dose to achieve maximal effects on HDL and LDLminimal dose to achieve maximal effects on HDL and LDL

Study DesignStudy Design

• Age: 18-80 years

• LDL-C @ NCEP ATPIII goal < 100 mg/dL

• Statin ± other 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

ScreeningPlacebo

Run-inTreatment Phase

Stable dose-regimen of lipid-modifying therapy

R 12 week follow-up

Anacetrapib 100 mg n=750

Placebo n=750

Randomization

1:1 Ratio

Reversibility

Phase

Study drug stopped ifLDL-C<25mg/dL during

treatment

Effects on LDL-C and HDL-Effects on LDL-C and HDL-CC

HDL-C

Study Week

BaselineWk 6Wk 12Wk 18Wk 24Wk 30 Wk 46 Wk 62 Wk 76

HD

L-C

(m

g/d

L) (

SE

)

0

20

40

60

80

100

120

AnacetrapibPlacebo

Anacetrapib n =Anacetrapib n = 776 757 718 687 647 607 572 543

Placebo n =Placebo n = 766 761 741 744 736 711 691 666

LDL-C

Study Week

BaselineWk 6Wk 12Wk 18Wk 24Wk 30 Wk 46 Wk 62 Wk 76

LDL-

C (

mg/

dL)

(SE

)

0

20

40

60

80

100

AnacetrapibPlacebo

Anacetrapib n = 804 771 716 687 646 604 568 540

Placebo n = 803 759 741 743 735 711 691 666

-39.8% (p<0.001) +138.1% (p<0.001)

Lipid ParametersLipid 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 Anacetrapib had no effect on BPon BP

SBP

DBP

Sy

sto

lic

blo

od

pre

ss

ure

S

ys

toli

c b

loo

d p

res

su

re

(mm

Hg

)(m

mH

g)

Dia

sto

lic

blo

od

pre

ss

ure

D

ias

toli

c b

loo

d p

res

su

re

(mm

Hg

)(m

mH

g)

Baseline 6 12 18 24 30 38 46 5 4 62 70 76

0

20

40

60

80

100

120

140

160

180

200

220

A= A nac etrapibB= Placebo

0

20

40

60

80

100

120

140

A= AnacetrapibB= Placebo

Week

Baseline 6 12 18 24 30 38 46 5 4 62 70 76

Week

L

L

Anacetrapib treatment had robust effects on HDL-C, LDL-C, non HDL-Anacetrapib treatment had robust effects on HDL-C, LDL-C, non HDL-C and Lp(a) with sustained effects over 18 months.C and Lp(a) with sustained effects over 18 months.

Anacetrapib had an acceptable side-effect profile with no effects on Anacetrapib had an acceptable side-effect profile with no effects on blood pressure, electrolytes or aldosterone. blood pressure, electrolytes or aldosterone.

Within the power of the study, anacetrapib did not exhibit adverse Within the power of the study, anacetrapib did not exhibit adverse cardiovascular effects seen with a prior CETP inhibitorcardiovascular effects seen with a prior CETP inhibitor

The long term safety and efficacy of anacetrapib will now be tested in The long term safety and efficacy of anacetrapib will now be tested in a large clinical outcomes trial. 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


●

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

EGFR Phosphorylation Src Activity

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.

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.

β2AR stable HEK-293 cells

PI3K is Required for 2AR-EGFR Complex Formation

Fluorescence Resonance Energy Transfer (FRET)

PI3K Inhibition

Grow two populations of HEK-293 cells expressing HA-Src and β2AR

“Light” medium “Heavy” medium

LY + ISO

L-Arg L-Lys HCl

[13C6, 15N2 ]-L-Lys HCl (+8) [13C6, 15N4]-L-Arg (+10)

ISO

Mix, IP, trypsin digest, and IMAC phosphopeptide enrichment

Phosphopeptide analysis by LC-MS

Re

lativ

e A

bu

nd

an

ceR

ela

tive

Ab

un

da

nce

00

100100

pept

ide

Ape

ptid

e B

pept

ide

Cpe

ptid

e D

pept

ide

Epe

ptid

e F Extracted Ion

Chromatogram(XIC)

Light

Heavy

Quantification of Src Phosphorylation Using Stable Isotope Labelling with Amino Acids in

Cell Culture (SILAC)

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 transactivation1. Formation of PIP3

2. Src phosphorylation


Agenda



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

Best of AHA Specialty Conferences Poster Session: QCOR 2010

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


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


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”

SponsorsDuke Heart CenterDuke Division of CardiologyDuke Clinical Research Institute

NetworkingCurrent Faculty & FellowsHeart Center, Division, DCRI StaffFormer FellowsAcademic & Industry Collaborators


Agenda



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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. 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. 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. 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: ARandomized Placebo Controlled Trial of Intravenous Erythropoietin to Reduce Infarct SizeAfter 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 MemosFrom 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

John H. Alexander, MD

Director, Heart Center SBR

Co-Director, DCRI CV Research

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

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