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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). - PowerPoint PPT Presentation
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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
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
All Rights Reserved, Duke Medicine 2008
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)
All Rights Reserved, Duke Medicine 2008
Hot Science
• ROCKET-AF• EMPHISIS-HF• ASCEND-HF• GRAVITAS• RACE-ER• REVEAL• DEFINE
●
All Rights Reserved, Duke Medicine 2008
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
Rivaroxaban Warfarin
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
Rivaroxaban Warfarin
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
Rivaroxaban Warfarin
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
All Rights Reserved, Duke Medicine 2008
Hot Science
• ROCKET-AF• EMPHASIS-HF• ASCEND-HF• GRAVITAS• RACE-ER• REVEAL• DEFINE
●
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
All Rights Reserved, Duke Medicine 2008
Hot Science
• ROCKET-AF• EMPHASIS-HF• ASCEND-HF• GRAVITAS• RACE-ER• REVEAL• DEFINE
●
“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
All Rights Reserved, Duke Medicine 2008
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.
All Rights Reserved, Duke Medicine 2008
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
All Rights Reserved, Duke Medicine 2008
Hot Science
• ROCKET-AF• EMPHASIS-HF • ASCEND-HF• GRAVITAS• RACE-ER• REVEAL• DEFINE
●
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
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Hot Science
• ROCKET-AF• EMPHASIS-HF • ASCEND-HF• GRAVITAS• RACE-ER• REVEAL• DEFINE
●
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
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Hot Science
• ROCKET-AF• EMPHASIS-HF • ASCEND-HF• GRAVITAS• RACE-ER• REVEAL• DEFINE
●
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
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Agenda
• Hot Science• Duke at the AHA• Modern Communication
All Rights Reserved, Duke Medicine 2008
Duke At the AHA
• An Award• Presentations• Fellow Presentations• LBCT & LBSS• The Duke Reception
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Award
• Dr. Victor Dzau receives the 2010 Research Achievement Award at the AHA Opening Sessions
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Duke Presentations
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Duke Presentations
• Saturday November 13th 5• Sunday November 14th 23
• Monday November 15th 57• Tuesday November 16th 52• Wednesday November 17th 18• Total 155
All Rights Reserved, Duke Medicine 2008
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
All Rights Reserved, Duke Medicine 2008
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
All Rights Reserved, Duke Medicine 2008
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
All Rights Reserved, Duke Medicine 2008
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
From Acute Thrombotic to Chronically Occluded Coronary Arteries
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
All Rights Reserved, Duke Medicine 2008
Duke LBCT & LBSS
• Late Breaking Clinical Trials– ROCKET-AF– ASCEND-HF
• Late Breaking Sciences Sessions– RACE-ER– REVEAL
All Rights Reserved, Duke Medicine 2008
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
All Rights Reserved, Duke Medicine 2008
All Rights Reserved, Duke Medicine 2008
Agenda
• Hot Science• Duke at the AHA• Modern Communication
All Rights Reserved, Duke Medicine 2008
All Rights Reserved, Duke Medicine 2008
Internet Abuse Shutdown Nov 15 13:55
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44 Shows Broadcast in Real Time
Duke TV Temporarily Shut Down for “Internet Abuse”
All Rights Reserved, Duke Medicine 2008
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.
All Rights Reserved, Duke Medicine 2008
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.
All Rights Reserved, Duke Medicine 2008
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.
All Rights Reserved, Duke Medicine 2008
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.
All Rights Reserved, Duke Medicine 2008
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.
All Rights Reserved, Duke Medicine 2008
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.
All Rights Reserved, Duke Medicine 2008
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.
All Rights Reserved, Duke Medicine 2008
All Rights Reserved, Duke Medicine 2008
Daily Heart Line MemosFrom Chris & Marti
All Rights Reserved, Duke Medicine 2008
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
All Rights Reserved, Duke Medicine 2008
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