Aps Slidecast

7/27/2019 Aps Slidecast

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The Science and Medicine ofCirculatory Dysfunction andAcute Pressure Syndromes

From Threat to TherapyThe Cardiovascular Specialists Perspective

Investigation Innovation Application

Jerrold H. Levy, MDProgram Co-Chairman

Christopher B. Granger, MDProgram Chairman

Professor, Department of Medicine I Division of Cardiology | Duke University Medical Center| Co-Director, Clinical Trials | Duke Clinical Research Institute (DCRI) | Durham, North

Carolina


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CME-accredited symposium jointly sponsored by the University ofMassachusetts Medical School and CMEducation Resources, LLC

Commercial Support: Sponsored by an independent educational grantfrom The Medicines Company

Mission statement: Improve patient care through evidence-basededucation, expert analysis, and case study-based management

Processes: Strives for fair balance, clinical relevance, on-labelindications for agents discussed, and emerging evidence and

information from recent studies

COI: Full faculty disclosures provided in syllabus and at the beginningof the program

Welcome and Program Overview


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Program Educational Objectives

As a result of this educational activity, physicians will:

Learn to identify underlying chronic, acute, and perioperative precipitants of

acute elevations in systemic blood pressure and how this syndrome presents

across multiple cardiovascular disease states and patient populations.

Learn about the vascular biology of hypertension and its implications for

clinical practice.

Learn to assess and implement optimal pharmacologic interventions for

patients presenting with manifestations of vascular dysfunction and acute

pressure syndromes.

Learn to characterize, identify, and evaluate myriad, acute CV disease states

producing serious and/or life-threatening elevations in systemic blood

pressure, and optimal approaches for intravenous therapy.


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Program Faculty

Program Chairman

Christopher B. Granger, MDProfessor

Department of Medicine

Division of Cardiology

Duke University Medical Center

Co-Director, Clinical Trials

Duke Clinical Research Institute (DCRI)Durham, North Carolina

Ernesto L. Schiffrin, MD, PhD,

FRSC, FRCPC, FACPPhysician-in-Chief and Chairman

Department of MedicineSir Mortimer B. Davis-Jewish General Hospital

Canada Research Chair and Director

Hypertension and Vascular Research Unit

Lady Davis Institute for Medical Research

Professor and Vice-Chair (Research)

Department of Medicine, McGill UniversityMontreal, PQ, Canada

Jerrold H. Levy, MDProfessor and Deputy Chair for Research

Emory University School of Medicine

Director of Cardiothoracic Anesthesiology

Cardiothoracic Anesthesiology and Critical Care

Emory Healthcare

Atlanta, Georgia

Charles V. Pollack Jr, MS, MD,

FACEP, FAAEMChairman, Department of Emergency Medicine

Pennsylvania Hospital

Professor of Emergency MedicineUniversity of Pennsylvania

School of Medicine

Philadelphia, Pennsylvania


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Faculty COI Disclosures

Christopher B. Granger, MDEducational Grants and/or Research Support: Alexion, Astra Zeneca, Procter andGamble, sanofi-aventis, Novartis, The Medicines Company, Boehringer Ingelheim,

Genentech, and Berlex

Ernesto L. Schiffrin, MD, PhD, FRSC, FRCPC, FACP

Grants/Research: Canadian Institutes of Health Research, Canadian Fund forInnovation, Merck-Frosst, Pfizer Cardiovascular AwardConsultant : Boehringer-

Ingelheim, Bristol-Myers Squibb, Forest Pharmaceuticals, Novartis

Jerrold H. Levy, MDGrant/Research Support: Alexion

Consultant: Bayer HealthCare, Dyax, Novo Nordisk, and Organon

Charles V. Pollack Jr, MA, MD, FACEP, FAAEMGrant/Research Support: GlaxoSmithKlineConsultant: The Medicines Company., Schering-Plough, Sanofi-Aventis, BMS,

Genentech, Speakers Bureau: Schering-Plough, Sanofi-Aventis, BMS, Genentech


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Acute Pressure Syndromes From Threat to Therapy

Characterization, Epidemiology, and Approach to Acute BloodPressure Elevations Across the Cardiovascular Disease

Continuum

Giving Acute Hypertension the Hyperattention it Deserves


Jerrold H Levy, MD, FAHAProfessor of Anesthesiology

Emory University School of MedicineDeputy Chairman for Research

Director, Cardiothoracic Anesthesiology

Cardiothoracic Anesthesiology and Critical CareEmory Healthcare


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Acute, Severe Hypertension

Common

Deadly and disabling

Poorly studied

Poorly managed

Evidence that speed and degree ofcontrol relate to outcome

Needs more attention Observed across multiple settings

Better therapies required


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72 million with

hypertension

1-2% with acutesevere hypertension

Severe Hypertension


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Prevalence of high blood pressure in adults

by age and sex

11.2

55.4

73.9

23.2

37.5

49.1

63.6

69.5

37.4

6.4

83.8

18.3

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

90.0

20-34 35-44 45-54 55-64 65-74 75+

Percent

ofPopulation

Men Wom en

Prevalence of Hypertension

NHANES: 1999-2004.Source: NCHS and NHLBI.


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Extent of awareness, treatment and control of

high blood pressure by age

52.3

35.8

24.6

62.5

39.8

68.474.6

34.3

75.3

0

10

20

30

40

50

60

70

80

Awareness Treatment Controlled

Percento

fPopulation

20-39 40-59 60+

NHANES: 1999-2004.Source: NCHS and NHLBI.

Hypertension: Awareness and Control


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5,026 emergency departments

113.9 million visits in 2003

Presentation with severe hypertension in up to25% of patients in busy urban EDs

Sullivan AF.Acad Emerg Med2004;11:454; IOM Emergency Medical Care Report 2006.

Emergency Care of SevereBlood Pressure Elevation


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Short-Term (2 to 6 month) Outcomes:A Deadly and Morbid Condition

1. OASIS-5 NEJM2006.

2. GUSTO IIb NEJM1996.

3. GRACE JAMA 2007.4. IMPACT-HF J Cardiac Failure 2004.

5. Cline DM.Acad Emerg Med2006.

Acute Condition Death Rehospitalization

ACS1,2,3 5-7% 30%

CHF4 8.5% 26%

Severe

Hypertension5 5-6% 30%


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Terminology and Definitions

Severe Hypertension

JNC VIII > 180/110

End-organ Damage

CHF

ACS/AMI Renal failure

Stroke and ICH

Encephalopathy

Aortic dissection

Pre-eclampsia

Other?

plus

Hypertensive Urgency Hypertensive Emergency


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Spectrum of End-Organ Damage

Zampaglione, B. Hypertension 1996;27:144-147.

108 Hypertensive Emergencies*

*All Caucasians

End-Organ

Damage TypeNo. of Cases %

Cerebral Infarction 26 24.5%

ICH or SAH 5 4.5%

Encephalopathy 18 16.3%

Acute Pulmonary Edema 24 22.5%

Acute CHF 15 14.3%Acute MI 13 12.0%

Aortic Dissection 2 2.0%

Eclampsia 5 4.5%


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Acute Severe HypertensionEpidemiology and Mortality

1939: First study of the natural

history of hypertensiveemergencies published

Untreated hypertensive emergencieshad a 1-year mortality rate of 79%, withmedian survival of 10.5 months

Varon J. CHEST2007; 131:19491962.

Risk Factors

History ofhypertension

African Americans

Elderly

Men

Noncompliance

Historical

Study


17/187Messerli F. N Engl J Med1995;332:1038-1039.

St. Louis Post-DispatchApril 13, 1945


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Blood Pressure of FDR

Messerli F. N Engl J Med1995;332:1038-1039.


19/187Sokolow & Perloff. Circulation 1961;23:697-713.

100

80

60

40

20

0

439 patients total

Cumulative% Mortality

1 2 3 4 5

Time in Years

BP I 150-200/90-110BP II 200-250/110-130

BP III Over 250/130

BP III

BP II

BP I

38%

18%

8%

Mortality and Severe Hypertension


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Hypertensive Urgency or Emergency

Total 865

Reviews 190

Randomized

Clinical Trials 46

ACS

55,353

3,518

HU or HE


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An Evaluation of PharmacotherapeuticRegimens Inadequately Studied

Medline 1966-2001

References from aboveExperts contacted

Cochrane Library checked

Randomized controlled trials

Systematic review of cohort studiesIndividual cohort study

Outcome Research

600 Studies

Identified

Excluded

Non-HumanBlood pressures too low

Safety or Tolerability studies

Case Series or Case Reports

39 StudiesExcluded Did not include a target BP &

thus could not do comparisons

Methodologic Flaws

19 Studies Remained

(8 were Open label or Not blinded)

Only 4 HTN Emergency (236 patients)

Only 15 HTN Urgency (1074 patients)

J Gen Intern Med2002;17:937-945.


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Definitions and Distinctions Emergencies always included end organ damage

Urgencies withoutend organ involvement

Emergency Could NOT determine: Optimal rate to BP Mortality benefit

Urgency Could NOT determine: The optimal BP to define (DBP > 120 most common) How quickly should BP The timing to begin maintenance therapy

If observation is needed during treatment

An Evaluation of PharmacotherapeuticRegimens Questions Unanswered

J Gen Intern Med2002;17:937-945.


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U.S. Department

of Health and

Human Services

National

Institutes

of Health

National Heart,

Lung, and Blood

Institute

The Seventh Report of the

Joint National Committee onPrevention, Detection,

Evaluation, and Treatment of High

Blood Pressure (JNC 7)

National Initiatives Hypertension

Hypertension. 2003;42:12061252.

National Heart, Lung, and Blood InstituteNational High Blood Pressure Education Program


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Hypertensive Urgencies and Emergencies


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Patients with marked BP elevations and target

organ damage (e.g., encephalopathy, myocardial

infarction, unstable angina, pulmonary edema,

eclampsia, stroke, head trauma, life-threateningarterial bleeding, or aortic dissection) require

hospitalization and parenteral drug therapy.

Patients with markedly elevated BP but withoutacute TOD usually do not require hospitalization,

but should receive immediate combination oral

antihypertensive therapy.


Proposed Strategies


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Inadequate treatment strategies

Failure to meet goals in acute pressure syndromes

Some agents better than others

We overshoot and/or undertreat

We need to do better

Hypertensive Emergency

How Well Are We Doing?

Blood Pressure Management in Acute


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Blood Pressure Management in Acute

Hypertensive EmergencyProblematic

Brooks, et al.Am J Health Syst Pharm. Dec 15, 2007;64(24):2579-82


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Primary and Secondary Endpoints

aMAP = mean arterial pressure.bp < 0.05, nicardipine group versus all patients.


OutcomeaAll Patients

(n=47)Nicardipine

Group (n=21)NitroprussideGroup (n=18)

Primary

No (%) patients with

appropriate MAPreduction at 2 hr

15 (32) 4 (19) 7 (39)

No. (%) patients withexcessive MAP

reduction at 2 hrb27 (57) 16 (76) 9 (50)

No. (5) treatmentfailures at 2 hr

5 (11) 1 (5) 2 (11)


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Primary and Secondary Endpoints

aMAP = mean arterial pressure.bp < 0.05, nicardipine group versus all patients.

cp < 0.05, nicardipine group versus nitroprusside group.dOne patient was excluded from the analysis.Brooks, et al.Am J Health Syst Pharm. Dec 15, 2007;64(24):2579-82

Outcomea

All

Patients(n=47)

Nicardipine

Group(n=21)

Nitroprusside

Group(n=18)

Secondary

No. (%) of patients with appropriateblood-pressure reduction at 6 hr

6 (13) 1 (5) 4 (22)

Mean no. (range) of additional p.r.n.antihypertensive doses per patientc

4 (0-33) 6 (0-33)d 2 (0-5)

Mean length of stay (range), daysc 9 (2-41) 13 (2-41)d 7 (2-14)

Mean duration (range) of i.v. therapy, hr 20 (1-74) 21 (3-74)d 16 (1-67)

Mean time (range) until scheduled oralantihypertensives were started, hr

14 (0-72) 16 (0-48) 10 (0-72)

No. (%) of patients meeting 2- or 6-hourgoalb,c

26 (28) 5 (12) 11 (31)


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Treatment-Related Adverse Events

*p < 0.05, nicardipine group versus nitroprusside group;p < 0.05, nitroprusside group versus all patients.


No. (%)

AdverseEvent

All Patients(n=47)

Nicardipine(n=21)

Nitroprusside(n=18)

Hypotension* 42 (89) 21 (100) 14 (78)

Tachycardia 15 (32) 9 (43) 5 (28)

Bradycardia 9 (19) 2 (10) 4 (22)

Acute RenalFailure

2 (4) 1 (5) 1 (6)

Major Ischemia 2 (4) 1 (5) 1 (6)

A New Registry to Study Conditions and IV


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The Goal

Improve understanding of clinical conditions

characterized by acute severe hypertension,managed in a critical care setting, and treated

with IV antihypertensive drugs

A New Registry to Study Conditions and IV

Treatment of Severe Hypertension

New Dimensions and
http://www.uihealthcare.com/topics/medicaldepartments/ophthalmology/iih/images/7_iih.jpg


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Rigid Pipes or Living Vessels

A Primer of Vascular Biology of Hypertensionfor the Cardiologist

Ernesto L. Schiffrin MD, PhD, FRSC, FRCPC, FACP

Canada Research Chair in Hypertension and Vascular Research,

Lady Davis Institute for Medical Research and Department of Medicine,

Sir Mortimer B. Davis-Jewish General Hospital, McGill University.

New Dimensions and

Landmark Practice Advances

Blood Pressure and Inside Diameter


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Blood Pressure and Inside DiameterRelationships of Blood Vessels

120

100

80

60

40

20

0

Bloodpressure(mmHg)

103 200 100 3 100 103

Lumen diameter (mm)

VP

Davis et al., 1986


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Remodeling of Large Arteries

Normal Remodeled

Outward hypertrophic remodeling

Pressure Waves in the Ascending Aorta and Radial Artery


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Pressure Waves in the Ascending Aorta and Radial Artery

of a Young Adult (A) and Older Human Subject (B)

ORourke MF et al. Am J Hypertens 2002;15:426-444

A B

Probability of Event Free Survival (Cardiovascular)


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Probability of Event-Free Survival (Cardiovascular)

According to the Level of Aortic PWV Divided in Tertiles

London GM et al. Hypertension 2001;38 :434.

Probability of event-free survival

PWV < 9.55 m/S

9.55 12.27 m/s

Duration of follow-up (months)

0 35 70 105 140

1

0.75

0.5

0.25

0

Classification of Genes Differentially Expressed


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Cell Growth, 4%

,Gene Expression

19%

Metabolism, 12%

Cytoskeleton, 12%

Matrix, 10%

Integrin, etc., 7%

Defense, 8%Signaling/

Communication,

28%

Durier S et al. Circulation. 2003;108:1845

47%29%

Classification of Genes Differentially Expressed

Between Stiff and Distensible Vessels

Methodology for Study of Human


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Gluteal subcutaneous biopsy

Peripheral resistance artery

(150 ~350 m)

Dissection

isometric

isobaric

Methodology for Study of Human

Resistance Arteries

Subcutaneous fat

Event-free Survival of Hypertensive Subjects


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0

2

4

6

8

10

Rizzoni D. et al. Circulation 2003;108:2230-2235.

Event free Survival of Hypertensive Subjects

According to Degree of Remodeling of Small Arteries

0 1000 2000 3000 4000

Days

Event-FreeSurvival

M/L > 0.11

M/L < 0.11

1

0.8

0.6

0.4

0.2

0Ra

teofCVeventsx

100patients/year

M/L > 0.11M/L < 0.11

**

Remodeling of Small Arteries in Mild


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Normal Remodeled

Remodeling of Small Arteries in Mild

Essential Hypertension

Inward eutrophic remodeling

Confocal microscopy antibodies against


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WKY

Confocal microscopy, antibodies against

a-actin-collagen I/III

SHR

Small Artery Composition in


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Small Artery Composition inHypertensive Subjects

Parameter Normotensives Hypertensives p

Number of SMC layers 3.640.34 4.240.13 NS

Volume density of SMC (%) 68.63.0 62.03.0 NS

Volume density of collagen (%) 16.31.9 23.32.5 =0.08

Volume density of elastin (%) 12.21.1 10.21.1 NS

Collagen/elastin 1.430.25 2.500.33


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Deng LY, Li JS, Schiffrin ELClin Sci 1995;88:611-622.

do e u epe de e a a o o

Small Arteries in Hypertension

- Log Conc. Acetycholine (mol/l)

Relaxation(%)

9 8 7 6 5

0

50

100

Prevalence of Target Organ Damage


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Normotensives

Hypertensives

M/L Ach LVH M/L Ach LVH

100

80

60

40

20

0

100

80

60

40

20

0

m+1SD m+2SD

20

97

10

58

10

47

0

63

0

34

0

26

(%) (%)

Prevalence of Target Organ Damage

in Mild Hypertension

Park JB, Schiffrin EL. J Hypertension 2001;19:921-930.


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Mechanisms of Remodeling

Intengan HD, Schiffrin EL.Hypertension. 2001;38:581

Lumen Diameter of Resistance Arteries in


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Lumen Diameter of Resistance Arteries inOrganoid Culture: Effect of Vasoconstriction

Bakker ENTP et al. J Vasc Res 2002;39:1220

0

50

100

150

200

0 1 2 3

FCS ALB + ET-1

FCS + papaverin FCS + verapamil

FCS + low p

Days in Culture

Lumendiameter(um)


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Wesselman JPM et al.

J Vasc Res 2004:41:277290

Relationship of Tissue Transglutaminase


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Relationship of Tissue Transglutaminaseto Inward Arterial Remodeling

Langille LB, Dajnowiec D. Circ Res 2005;96 9-11

Angiotensin II, Endothelin, Oxidative


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g , ,

Stressand Vascular Damage

LDL

ox-LDL

Endothelial damage

ET-1

ETA ReceptorInflammation

Atherogenesis

ET-1 production

Contraction

Dilatation

MCP-1

VCAM-1ICAM-1PAI-1

Smooth muscle

ONOO

O2-

O2-

NO

NO

Endothelium

Platelet aggregation and adhesion

Monocyte adherence

NOS III

ET-1

ICAM-1

VCAM-1

NADH/

NADPH

oxidase

Contraction

GrowthMigration

FibrosisTGF1

O2-

ET-1

Adhesion moleculesNFB, AP-1Cytokines

Foam cells

Pressure

Angiotensin II

Vasopressin

Cytokines

ox-LDL

Angiotensin II

AT1R

AT1R

Angiotensin II

NADH/NADPH

oxidase

ox-LDLLOX-1

Schiffrin EL. Am J Hypertens 2004;17:1192-1200.

From Oxidative Stress to Inflammation to


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Remodeling and Hypertrophy

Ang II or ET-1

p22

p47 p67

p40

Cytokines: IL, TNFaChemokines: MCP-1

CAM: selectins, ICAM, VCAM, PECAM

Growth factors: ET-1, TGF, CTGFECM proteins: collagen, fibronectin

TIMP/MMP

Inflammatory response Cell growth and fibrosis

MAP kinasesTyrosine

kinases

RhoA/

Rho kinase

NAD(P)H

OxidaseGp91/

Nox1/

Nox4

2O2 2O2- H2O2

SODe-

NAD(P)H NAD(P)+H+

Transcription factors:

NF-B, AP-1, HIF-1

pPKC, PLD

c-Src, PI3K

Cell Membrane

Touyz RM & Schiffrin EL. 2005

All Vasc lar La ers Generate ROS


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NADPHOxidase

NADPH

Oxidase/Nox1/Nox4

NADPH

Oxidase

ROS

All Vascular Layers Generate ROS

DPI Attenuates Ang II-induced Generation


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DPI Attenuates Ang II induced Generation

of ROS in Human VSMCs.

0

20

40

60

80

100

10-12 10-10 10-8 10-6

Ang II concentration (mol/L)

**

**

**

++++

++

++ ++

+

Normotensive, Ang II

Hypertensive, Ang II

Normotensive, Ang II+DPI

Hypertensive, Ang II+DPI

*p


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NAD(P)H Oxidase Activation

Rap1

Rac2

p67

2 O2 2 O2-NADPH

NADP+ + H+

Rap1

2 O2 + NAD(P)H 2 O2- + NAD(P)+ + H+

gp91gp91 p22p22

Rac2

p40

p67 p47

p47

p40

Touyz RM et al. Circ Res 2002;90:1205-1213.

Confocal microscopy shows effect of NADPH oxidasei hibiti ith i ll d iti i th


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inhibition with apocynin on collagen deposition in the

media of mesenteric arteries of Ang II-infused mice

Smooth muscle actin

Collagen type I/III

Virdis A. et al.J Hypertension 2004.

Vascular Effects of ET 1 and its Receptors


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Vascular Effects of ET-1 and its Receptors

ET-1

ETB

NO

PGI2

Ang II, AVP, NE, insulin

Thrombin, TGF, cytokines Shear stress, hypoxia

ET-1

ET-1

ETA

ETB

Relaxation Contraction

growth

Endothelium

VSMC


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Schiffrin et al. J. Hypert. 1997

G

Transgene Construction


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Transgene Construction

human preproET-1 HA beta-globinTie-2

638 bp 900 bp

Transgenic mice characteristicsC57BL/6, male

8-10 weeks old Low litter number

Amiri F, Schiffrin EL. Circulation 2004

Immunohistochemistry for ET-1 in Aorta of


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Endothelium-restricted ET-1 Transgenic Mice

WT TG

Amiri F Schiffrin EL. Circulation 2004

Vascular Morphology in Endothelium-


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WT TG

* p < 0.05

p < 0.01

Restricted ET-1 Transgenic Mice

Growth index = 34%

WT TG

*

Amiri F, Schiffrin EL. Circulation 2004

0

3000

6000

9000

12000

15000

18000

Media/Lum

en(%)

0

2

4

6

8

10

MediaCSA(m2

Immunostaining for MMP-9 and MMP-2 is Increased inEndothelium and Media of Vessels Cultured at


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Endothelium and Media of Vessels Cultured at150 mmHg Compared with 80 mmHg

Lehoux S et al. Circulation. 2004;109:1041-1047.

Fatty AcidsThiazolidinediones

(rosiglitazone,Cell membrane


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RxR

RxR

PPARLipid storage & adipose

tissue differentiation

(adipose tissue)

Insulin sensitivity (skeletal

muscle)

PPARaFatty Acid Oxidation(liver, heart, kidney, skeletal muscle)

CardiovascularAnti-inflammatory

Anti-fibrotic

Anti-hypertrophic

PPARb/dLipid metabolism?

(ubiquitous)

RxR

Fibrates( g ,

pioglitazone,

troglitazone)Fatty Acids

15d-PGJ2Prostacyclin

Leukotriene B4

gene regulation

Nucleus

PPRE

PPAR/PPAR a

PPAR

Vascular Structure of Ang II-infused


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Rats PPAR- Activators

M

edia/lumenratio

(%)

* *

*

Diep et al, Circulation 2002

0

2

4

6

8

10

12

14

16

DNA Synthesis in Blood Vessels


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of Ang II-infused Rats PPAR- Activators

Thym

idineincorporation

(%o

fcontrol)

CTR ANG A+PIO A+ROS PIO ROS

**

**

*

Diep et al, Circulation 2002

0

40

80

120

160

200

Osteopetrotic Mice (op mice)


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Defect in osteoclast development and deficiency in number of monocytes

and macrophages.

Characterized by skeletal sclerosis due to a failure of bone resorption and

remodeling.

Absence of incisors, small body, domed skull and absence of tooth

eruption.

+/+ +/ op/op

++ +/ op/op

Osteopetrotic Mice (op mice)

Vascular Structural Parameters


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Resistance Arteries

*** p< 0.001 vs Cnt ; ** p< 0.01 vs Cnt; * p< 0.05 vs CntCnt Ang II

m

Lumen

+/+ op/+ op/op

***

m

Media thickness

+/+ op/+ op/op

****

%

Media/Lumen

+/+ op/+ op/op

******

x103,m

Media Cross Sectional Area

+/+ op/+ op/op

**

0

2000

4000

6000

8000

10000

12000

14000

0

2

4

6

8

10

0

50

100

150

200

250

300

02

4

6

8

10

12

1416

18

Some Pathways Mediating


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AT1R

-TyrosineKinases c-Src-

O2 O2- H2O2 H2O+O2

EGFR

PDGFRIGF-1R

ROS

NAD(P)HOxidase

Vascular Structural

and Functional Changes

EGFR

PDGFRIGF-1R

ET-1

Ang II

Vascular remodeling

Adhesion moleculesChemokines/cytokines(IL6, MCP-1, PAI)

NFBAP-1HIF-1

MMPs

HyperplasiaHypertrophyCell survivalApoptosis/AnoikisCollagen synthesis

ECM proteins

-

MAP Kinasesp38MAPK, JNKERK5, ERK1/2

-+

Modified from Schiffrin & Touyz Am J Physiol Heart Circ 2005

Vascular inflammation

Vascular Structural Changes

ET-1

Ang II

The Cardiorenal PathophysiologicalC ti


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Continuum

Angina

Fibrosis And

Muscle Loss

Heart Failure

Death

Sudden DeathMyocardial

Ischemia

PGC

Glomerular Sclerosis

Hypertension

Diabetes

Insulin Resistance

Dyslipidemia

Endothelial

Dysfunction

ROS

Inflammation

Cell Injury

Angiotensin II

Aldosterone

Endothelin-1

Glycosylated Proteins

Release of ET-1

Production of TGFNO

Unstable Angina

Myocardial Infarction

Coronary Artery Disease

Plaque Rupture

AlteredExtracellular Matrix

(mesangium)

Atherosclerosis

Tubulointerstitial Damage

Albumin Shunting

Through

Membrane Pores Oxidative Stress

Inflammation

Schiffrin EL. Am J Hypertens 2004;17(12):1192-1200

Calcification

Renal Failure

Endothelial

Dysfunction



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Acute Blood Pressure Elevations in

the Cardiovascular Surgery andCardiac Critical Care Setting

The Good News and Bad News About

Current Treatment OptionsImplications of Landmark Trialsfor Perioperative and Cardiac Critical Care

Jerrold H Levy, MD, FAHAProfessor of Anesthesiology

Emory University School of MedicineDeputy Chairman for Research

Director, Cardiothoracic AnesthesiologyCardiothoracic Anesthesiology and Critical Care

Emory Healthcare

Atlanta, Georgia


Critically Ill Patients Presenting toCCU ICU d P i C


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CCUs, ICUs, and Postoperative Care

Changing demographics and increasing useof stenting and platelet inhibitors

Older patients with comorbidities presenting toICUs and CCUs with endothelial dysfunctiondue to multiple causes

Endothelial and vascular dysfunction common

across this cardiac, neurological, and criticallyill patient populationsacute and chronicdisease

Estafanous FG, et al.Ann Thorac Surg. 1998;65:383-389.

Fontana GP. Chest Surg Clin N Am. 1998;8:871-890.Verrier ED. J Am Coll Surg. 1999;188:104-110.

Trends and Observations

Perioperative HypertensionTh C di th i S S tti


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The Cardiothoracic Surgery Setting

Patients with preoperative hypertension are at increasedrisk for perioperative complications1

Approximately 30% to 56% of patients undergoing routinecardiac surgery experience acute rises in blood pressurethat require administration of a parenteralantihypertensive agent2

Antihypertensive therapy is often needed to manage life-threatening arterial bleeding, myocardial ischemia, orcardiac failure3

1. Sladen, IARS Rev Course Lectures, 2002, p100; DeQuattro, J Cardiovasc Pharmacol Ther, 1997.

2. Cheung, J Card Surg, 2006, S8; Estafanous,Am J Cardiol, 1980, p685; Landymore, Can J Surg, 1980.3. Cheung, J Card Surg, 2006, S8.

The Problems

Considerations for Perioperative BPC t l D i C di S


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Control During Cardiac Surgery

Acute, Severe Elevations in Blood Pressure are

Triggered by Multiple Perioperative Events

Intraoperative Events Induction

Cannulation Protamine and hemostasis (aortotomy/suture lines)

Chest closure

Transport

Postoperative Events Temperature management (warming and shivering)

Emergence

Weaning and extubation

Volume status

Goals for an Ideal AntihypertensiveA t i S tti f C di S


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Agent in Setting of Cardiac Surgery

Rapid onset of action

Predictable dose response

Titratable to desired BP Highly vascular selective

Maintain stroke volume and cardiac output

Rapidly reversible

Low risk of overshoot hypotension

Low risk of adverse reactions

Levy JH.Anesthesiol Clin North Am. 1988;17:587-678.Oparil S et al.Am J Hypertens. 1999;12:653-664.

Desirable Properties for Intravenous Agent

Therapeutic Approaches to ArterialVasodilation: Armamentarium


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Vasodilation: Armamentarium

ACE inhibition

Alpha-1 adrenergic blockade

Calcium channel blockade Dopamine-1 stimulation

Ganglionic blockade

Cyclic nucleotide stimulation PDE inhibition

Potassium channel modulation

Levy JH: The ideal agent for perioperative hypertension.Acta Anaesth Scand1993; 37(S):20-25.

Treatment Options

Hypertension in Surgical Patients (1)


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Patients who are normotensive may becomehypertensive

Most blood pressure changes develop acutelyand require rapid intervention with IV agents

Characterized by systemic vasoconstriction withintravascular hypovolemia

Patients may have preoperative biventriculardysfunction

Levy JH: Management of systemic and pulmonary hypertension. Tex Heart Inst J2005;32:467-471.

Principles and Practice Considerations



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BP may be maintained at lower levels to avoidgraft/suture line disruption

Patients are being Fast Tracked

Mechanical manipulation, suturing with potentialrisk for vascular spasm

Ventricular dysfunction is common in patientswith normal preop function due to stunning/reperfusion injury




Nitrovasodilators


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Na+

CN

NO+

CN

Fe++

CN

CN

CN

Na+

SodiumNitroprusside

Nitroprusside Therapy


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p py

Potent venodilator/arterial vasodilator

Cardiac output is often affected due tovenodilation

Volume replacement is often required for

venodilation



IV DHP Calcium Channel Blockers


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IV DHP Calcium Channel Blockers

1st Generation: Nifedipine

2nd Generation: Nicardipine, isradipine

3rd Generation: Clevidipine

Evolution of Therapeutic Options

Properties of Dihydropyridines


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Properties of Dihydropyridines

Arterial vasodilator1

Decreases SVR2-6

More selective for vascular smoothmuscle than cardiac muscle1

No significant increase in ICP7

1. Clarke B, et al. Br J Pharmacol. 1983;79:333P.

2. Lambert CR, et al.Am J Cardiol. 1987;60:471-476.

3. Silke B, et al. Br J Clin Pharmacol. 1985;20:169S-176S.

4. Lambert CR, et alAm J Cardiol. 1985;55:652-656.

5. Visser CA, et al. Postgrad Med J. 1984;60:17-20.

6. Silke B, et al. Br J Clin Pharmacol. 1985;20:169S-176S.7. Nishiyama MT, et al. Can J Anaesth. 2000;47:1196-1201.

Hemodynamic Effects of Nicardipine


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y p

Lambert CR:Am J Cardiol1993;71:420.

Control Nicardipine

HR 71 13 70 14

MAP 107 14 80 9

PAOP 9 4 8 3MPAP 15 3 16 4

RAP 8 3 8 2

CI 2.2 0.3 2.8 0.4

LVdP/dT 1509 376 1680 485

LVEF % 57 9 68 7

Arterial Spasm


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Arterial Spasm

Loss of endothelial function via vascular injury

and platelet activation is potential mechanism

Other mechanisms include NO scavenging by

hemoglobin

Thromboxane, a potent constrictor, has been

implicated

Only certain drugs will completely reverse arterial

spasm

Mechanism

Vasospasm/Vascular DysfunctionStudies


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Studies

Salmenperra MT: Effects of PDE inhibitors on the human IMA. AnesthAnalg1996; 82: 954-957.

Huraux C: Vasodilator effects of clevidipine on human IMA. Anesth Analg

1997; 85: 1000-1004.

Huraux C: A comparative eval of multiple vasodilators on human IMA.

Anesthesiology1998;88:1654-1659. Huraux C: Superoxide production, risk factors, and EDRF relaxations in

human IMAs. Circulation 1999;99:53-59.

Tsuda A: Reversal of histamine-induced vasodilation in the human IMA.

Anesth Analg2001;93:1453-1459.

Sato N: Vasodilatory effects of hydralazine, nicardipine, nitroglycerin andfenoldopam in the human umbilical artery. Anesth Analg2003;96:539-544.

Tanaka KA: In vitro effects of antihypertensive drugs on TxA2 (U46619)-

induced vasoconstriction in human IMA. Br J Anaesth 2004;93:257-262.

Studies on Arteriolar Vasodilators


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Nitroglycerin is the most potent; butnitrate tolerance occur

Milrinone, dihydropyridines, PGE1,

were also effective at therapeuticallyused doses

Huraux:Anesthesiology1998;88:1654.

A Comparative Evaluation of the Effects ofMultiple Vasodilators on Human IMA

Vasodilator Effects ofClevidipine on Human IMA


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Clevidipine on Human IMA

Clevidipine was effectiveanti-vasospasm agent attherapeuticallyused doses

Huraux C, Makita T, Szlam F, Nordlander M, Levy JH: Anesth Analg1997; 85: 1000-1004.

Simulated Drug Level Curves


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g

=Full loading dose = [Cp] x Vdss

= Smaller loading dose =[Cp] x Vc= No loading dose

Time (Half-life)

0

10

20

30

40

50

60

0 1 2 3 4 5 6

TherapeuticConcentration

Range

PlasmaDrugLevel

The Clevidipine Molecule


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Cl

Cl

HCH3OOC

H3C

COOCH2OOCC3H7

CH3N

H

Clevidipine is the first ultrashort acting dihydropyridine

intravenous calcium channel blocker

Clevidipine Metabolized byPlasma and Tissue Esterases


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Plasma and Tissue Esterases

Clevidipine is rapidly metabolized by esterases in blood andextravascular tissue to an inactive carboxylic acid metabolite

+OH

OHH

O

Clevidipine

Cl

OO

O

O

NH

Cl

O

O

*Esterases +O

O

NH

Cl

O

O

Cl

H

Primary metabolite

*The chiral center of clevidipine.

Reproduced from Ericsson H, et al. Eur J Clin Pharmacol. 1999;55:61-67.

Bailey JM, et al.Anesthesiology. 2002;96:1086-1094.

Ericsson H, et al. Drug Metab Dispos. 1999;27:558-564.

Ericsson H et al. Eur J Clin Pharmacol. 1999;55:61-67.Ericsson H, et al. Eur J Pharm Sci. 1999;8:29-37.

Clevidipine Rapid Onset of Action


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SBP changes for patients receiving clevidipine during a 30-minute treatment period.

10

5

0

5

10

15

20

25

300 5 10 15 20 25 30

%

ChangeFromBase

line

Time (min)

SBP

SBP Changes

BP-lowering effects are seen within 23 minutes ofclevidipine infusion

Levy JH, et al.Anesth Analg. 2007;105(4):918.

Clevidipine Linear Pharmacokinetics


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*Css = concentration at steady state; median blood concentration of clevidipine obtained

during the last 10 minutes of infusion.

At steady state, there is a linear relationship between dosage

and arterial blood concentrations

Linear relationship maintained for dosages as high as 21.9mcg/kg/min

120

100

80

60

40

20

0

0 5 10 15 20 35

ClevidipineConcentr

ation

atCss(nmol/L)*

Dose Rate (nmol/kg/min)25 30

Reproduced from Ericsson H, et al.Anesthesiology. 2000;92:993-1001.

Ericsson H, et al.Anesthesiology. 2000;92:993-1001.Ericsson H, et al. Br J Clin Pharmacol. 1999;47:531-538.

Clevidipine Rapid Offset


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After discontinuation of clevidipine infusion, there

was rapid clearance BP returned to baseline in


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Reproduced from Ericsson H, et al.Anesthesiology. 2000;92:993-1001.

Clinically relevant half-life: Approximately 1minute

Arterial and venous clevidipine blood samples

Clevidipine and Arterial Selectivity


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*P


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SVR = systemic vascular resistance; RVEDV = right ventricular end-diastolic volume.

In postoperative patients

Increased stroke volume, cardiac output No reflex increase in HR or changes in cardiac preload

Lower SVR, higher cardiac filling pressures andRVEDV vs SNP

Data from Kieler-Jensen N, et al.Acta Anaesthesiol Scand. 2000;44:186-193.

C2

75

mL/beat 70

65

0

C1 0.375 0.75 1.5 3

Stroke Volume

*

Lmin1

Cardiac Output

0

1

2

3

4

5

6

C1 0.375 0.75 1.5 3 C2

Infusion Rate (g kg1 min1) Infusion Rate (g kg1 min1)

*P


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Preoperative HR Changesin Non-Anesthetized Patients

Postoperative HR Changesin Anesthetized Patients

Minimal Effect on Heart Rate

10

5

0

5

0 5 10 15 20 25 30

%C

hangeFromBaseline

Time (min)

HR

HR changes for patients during the30-minute treatment period

5

0

5

0 5 10 15 20 25 30

%C

hangeFromBaseline

Time (min)

HR

HR changes for patients during the30-minute treatment period

Levy JH, et al.Anesth Analg. 2007;105(4):918.Singla N, et al.Anesthesiology. 2005;103:A292.

Clevidipine Clinical Development


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Tolerability,

Safety, PKDose Response

ESCAPE: Efficacy

Clevidipine

vs Placebo

VELOCITY

Severe Hypertension

PK, Metabolism,

Rates and Routes

of Excretion

PK/BP

ESCAPE: Efficacy

Clevidipine

vs Placebo

PK

PK/PD:

Clevidipine

vs Placebo

ECLIPSE:

Safety vs NTG

QTc StudyECLIPSE:

Safety vs SNP

ECLIPSE:

Safety vs NIC

Dose Response:

Clevidipine

vs Placebo

Hemodynamics:

Clevidipine vs SNP

BP, HR:

Clevidipine vs SNP

BP, Dose/PK

BP: Clevidipine

vs Placebo

Phase IN=89

Phase IIN=300

Healthy Volunteers

Patients: Mild to

Moderate Hypertension

N=86

Phase IIIN=1821

Perioperative

Hypertension

N=1721

Severe

Hypertension

N=100

Patients:

Perioperative

N=214

Data on file. The Medicines Company.

Acknowledgements ECLIPSE Trial


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Cornelius Dyke, MD Dean Kereiakes, MD

Jerrold H. Levy, MD Philip Lumb, MD

Albert Cheung, MD Howard Corwin, MD

Solomon Aronson, MD* Mark Newman, MD

*Acknowledgement and thanks to Dr. Solomon Aronson, whofirst presented much of this material as a Late Breaker at

ACC 2007 Scientific Assembly on March 27, 2007

ECLIPSE Rationale


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Clevidipine is an IV dihydropyridine calcium channelblocker with an ultrashort half-life (~1 min)

Phase I and II studies (300 pts) demonstrated:

Dose: 216 mg/hr effective1

Phase III safety program required for FDA registration

Evaluation: Death, MI, Stroke, Renal Dysfunction

Comparators: Nitroglycerin (NTG), Sodium nitroprusside (SNP),

Nicardipine (NIC)

Rapid onset: BP control in 5 min2

1Bailey J.Anesthesiology2002;96:1086-94.2Levy J.Anesth Analg. 2007;105(4):918.

ECLIPSE


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Randomized (1:1), open-label, parallel group withactive comparators: nitroglycerin (NTG), sodiumnitroprusside (SNP), or nicardipine (NIC)

NTG and SNP studies are perioperative and NIC ispostoperative

Treatment with study drug allowed until discharge fromICU

Patients undergoing cardiac surgery; CABG, OPCAB,Valve, MIDCAB


Protocols

ECLIPSE: Trial Design


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Clevidipine

vs nitroglycerin

Clevidipine

vs sodium

nitroprusside

Clevidipine

vs nicardipine

Perioperative Perioperative Postoperative

Clevidipine

N=268

Nitroglycerin

N=278

Clevidipine

N=296

Sodium

nitroprusside

N=283

Clevidipine

N=188

Nicardipine

N=193

1:1 1:1 1:1


Treatment Protocol


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Clevidipine Initiated 2 mg/hr

Titrated doubling increments Q 90s to 16 mg/hr

40 mg/hr maximum

Comparators (NTG, SNP, NIC) administeredper institutional practice

Treatment duration up to discharge from the

ICU Concomitant antihypertensives discouraged

Outcome Endpoints


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Primary End Points*(Cumulative rate of clinicaloutcomes at 30 days):

Death

MI: Symptomatic presentation, enzyme release, and/ornew ECG changes

Stroke: Hemorrhagic or ischemic

Renal Dysfunction: Cr >2.0 with min absolute changeof 0.7

Secondary End Points SAEs through day 7

BP control during the first 24 h

* Blinded CEC adjudication of all primary measures

Patient Disposition


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Populations Clevidipine Comparators

Randomized patients 971 993

Met post-randomization criteria 755 757

Safety population 752 754

Completed study 715 719

Did not complete studyWithdrew consentPhysician decision

Lost to follow upAdverse experiencePatient deathOther

3701

150

201

3510

60

280

Baseline Characteristics


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Historical Features Clevidipine

n=752

Comparators

n=754

Age, median (range) 65 (24-87) 66 (19-89)

Male 72% 74%

Caucasian 82% 83%

History of Hypertension 88% 85%

CHF 19% 18%

Insulin dependent diabetes 11% 11%

COPD 14% 15%

Recent MI (< 6 mos) 17% 18%

Prior CABG 3% 6%

Procedural Characteristics


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Procedural Characteristics Clevidipinen=752

Comparatorsn=754

Surgery Duration: Median Hours 3.32 3.23

Procedure

CABG

Valve replacement/repair

CABG & Valve replacement/repair

Other

77%

14%

9%

0.3%

77%

12%

11%

0.1%

ECLIPSE NTG Drug Administration


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Timing and Duration ClevidipineN=268

NitroglycerinN=278

Initiated Pre-Op 92 (34.3) 119 (42.8)

Initiated Intra-Op 145 (54.1) 132 (47.5)

Initiated Post-Op 31 (11.6) 27 (9.7)

Overall Infusion

Duration (median) 3.35 hr 8.13 hr


ECLIPSE SNP: Drug Administration


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Timing and DurationClevidipine

N=296

NitroprussideN=283

Initiated Pre-Op 52 (17.6) 34 (12.0)

Initiated Intra-Op 161 (54.4) 158 (55.8)

Initiated Post-Op 83 (28.0) 90 (31.8)

Overall Infusion

Duration (median)4.03 hr 3.25 hr


ECLIPSE NIC: Drug Administration


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Timing and Duration ClevidipineN=188 NicardipineN=193

Dosed DuringPost-Op

188 (100) 193 (100)

Overall Infusion

Duration (median)

5.55 hr 5.12 hr


RESULTS Primary Endpoint


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2.8%2.3%

1.1%

7.9%

3.8%

2.4%

1.7%

7.9%

0%

2%

4%

6%

8%

10%

Clevidipine

Comparators

Death

30-DayEvents(%)

n=729 n=700 n=707 n=700 n=705 n=712 n=710n=719

MI Stroke RenalDysfunction

Primary End Points byTreatment Comparison


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p

End Points Clevidipine NTG Clevidipine SNP Clevidipine NIC

Death 2.8% 3.4% 1.7% 4.7%* 4.4% 3.2%

MI 3.3% 3.5% 1.4% 2.3% 2.3% 1.1%

Stroke 1.6% 2.3% 1.1% 1.5% 0.6% 1.1%

Renal

Dysfunction

6.9% 8.1% 8.5% 9.1% 8.3% 5.9%

* p = 0.045

Serious Adverse Events


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Serious Adverse EventsClevidipine

n=752Comparators

n=754

Total 17.7% 20.0%

Atrial fibrillation (AF) 2.4% 2.4%

Respiratory failure 1.1% 2.5%

Acute renal failure (ARF) 2.3% 1.7%Ventricular fibrillation 0.9% 1.5%

Cardiac arrest 0.5% 1.1%

CVA 0.5% 1.1%

Post-procedural hemorrhage 0.5% 1.1%

ECLIPSE: Atrial Fibrillation


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Arrhythmia CLVn/N (%) NTGn/N (%) SNPn/N (%) NICn/N (%)

Atrial fibrillation(Total)

275/752(36.6)

91/278(32.7)

95/283(33.6)

71/193(36.8)

Atrial fibrillation(before March 25,

2005)

108/296

(36.5)

91/278

(32.7)

25/111

(22.5)

16/50

(32.0)

Atrial fibrillation(after March

25, 2005)

67/188(35.6)

N/A70/172(40.7)

55/143(38.5)

ECLIPSE was put on hold due to higher AF rates in clevidipine inMarch 2004 and restarted in December 2005

No statistically significant differences in any of the arms or in overallcomparison

.

ECLIPSE Secondary EndpointSystolic Blood Pressure Control Over 24 Hours


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Time (hours)

SBP

Lower

Upper

0 6 12 2418

Lower

ECLIPSE Trial; Presented at ACC, March 27, 2007.

Logistic Regression ResultsPredictors of Mortality


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Mortality Predictors P-Value OddsRatio

95% CI[Lower Limit,Upper Limit]

Surgery Duration (hour) 160 or DBP > 105 0.0228 2.386 [1.147, 4.963]

History of COPD 0.0228 2.326 [1.125, 4.812]

History of recent MI(


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I mmHg x 60 min

2 mmHg x 60 min

3 mmHg x 60 min

4 mmHg x 60 min

5 mmHg x 60 min

OddsRatio

95% CI[Lower Limit,Upper Limit]

1.20 [1.06, 1.27]

1.43 [1.13, 1.61]

1.71 [1.20, 2.05]

2.05 [1.27, 2.61]

2.46 [1.35, 3.31]

0 1 2 3 4

ECLIPSE Trial


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Largest safety program ever performed with anintravenous antihypertensive (n=1,512) agent

Landmark trial examining management of acute,

severe hypertension in the perioperative setting Balanced demographics and baseline characteristics

Met primary end points with adverse event ratescomparable across groups

Atrial fibrillation rates are equivalent

AUC data suggests better overall BP control withclevidipine compared with SNP and NTG

Summary

ECLIPSE Trial


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Clevidipine appears to be a safe alternative tocommonly used antihypertensive agents in the

cardiovascular surgery setting, and demonstratedsuperior blood pressure control as assessed byintegral analysis of excursions outside specifiedranges over time

Data supports importance of precise bloodpressure control in a critically ill patient population

Clevidipine represents the first potentialnitroprusside replacement for clinicians

Conclusions



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Acute Severe HypertensionEvolving Strategies and New Dimensions of

Emergency Cardiovascular Care

Charles V. Pollack, Jr., M.A., M.D., FACEPProfessor and Chairman, Emergency Medicine

Pennsylvania Hospital

University of Pennsylvania Health System

Philadelphia

Hypertension


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Affects at least 72 million Americans

Affects at least 1 BILLION individuals worldwide

Most current (2003) evidence basis for managementThe Seventh Report of the Joint National Committeeon the Prevention, Detection, Evaluation, and

Treatment of High Blood Pressure Hypertension (JNC7)lacks guidance on acute management of patientspresenting to an ED with hypertension

JNC 7, JAMA 2003; 289:2560-2572.

Hypertensive Urgenciesand Emergencies What We Know


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Epidemiologic data are largely lacking

It is thought that ~ 1% of patients with htn willeventually present to the ED in hypertensive crisis

In a single-center Italian study, HU or HE accountedfor 3% of all medicine admissions and 27.5% of allmedical emergencies

HU:HE 3:1 in that study

Patients with HU much more likely to be unaware of theirhtn dx than those with HE

Zampaglione et al, Hypertension 1996;27:144.

Acute Pressure Syndromes ManagementConsiderations


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What is the magnitude of:

Disease risk?

Treatment benefit?

Treatment risk?

How persistent is the benefit?

What improved outcome is there for

the patient?

Goals of Emergency Therapyof Hypertensive Crises


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HU can generally be managed with oral medications andrequires BP lowering over 24-48 hours

Important to prevent too-rapid lowering due to autoregulation of flowby pressure in brain, heart, and kidneys

Goal in hypertensive emergency is to reduce MAP by 10-15% and/or to a DBP of 110 as rapidly as possible

Aortic dissection requires especially rapid lowering

Once initial reduction achieved, transition to oral agents

Dug of choice for initial therapy often depends on which end-organsystem is affected and on comorbidities

JNC 7, JAMA 2003; 289:2560-2572.

Why Are We Here Today?


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Severe hypertension is increasingly prevalent aspopulation ages and obesity and diabetes becomemore common

Currently available agents for the management ofacute severe BP elevation leave much to be desired

Advancements in therapy are possible

There is a new agent on the horizon that has beentested specifically in the ED

Therapeutic Agents Currently Used


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ACE Inhibitors

Diazoxide

Esmolol

Hydralazine

Nicardipine

Nitroglycerin

Clonidine

Diuretics

Fenoldopam

Labetalol

Nifedipine

Nitroprusside

Rynn et al, J Pharm Pract2005;18:363-76.

Armamentarium

Esmolol


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Blocks -1 receptors of heart and vasculature

Given IV, onset of action is 6-10min after bolus,

and activity persists 20 minutes after infusion isdiscontinued; must be carefully titrated

May cause bradycardia and hypotension,bronchospasm, seizures, and pulmonary edema

Chest pain may occur after abrupt withdrawal


Principles of Use

Fenoldopam


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Selective dopamine-1 receptor agonist,decreasing PVR while increasing RBF, natriuresis,and diuresis

Six times more potent than dopamine in producingrenal vasodilation

Given IV and titrated; onset of action 10 minutesand effects persist for an hour afterdiscontinuation

May cause T-wave flattening, angina, atrialfib/flutter, and reflex tachycardia


Principles of Use

Labetalol


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Decreases PVR by blocking -1 receptors andprevents reflex tachycardia by blocking -1 receptors,resulting in a BP

Given as repeated IV boluses and can be carefullygiven as a short-term infusion

Optimally used when a gradual in BP is neededwith minimal effects on HR, and in CVA (labetolol has

minimal effects on cerebral blood flow) Should be avoided in significant asthma/COPD; may

cause bradycardia, AV block, hypotension


Principles of Use

Nicardipine


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As a CCB, nicardipine relaxes arteriolar smoothmuscle and decreases PVR through baroreceptor-mediated sympathetic discharge

Seems to be selective for L-type, voltage-sensitivecalcium channels of the heart, and works bydecreasing afterload

Given by IV infusion with careful titration

May cause tachycardia, flushing, headache,dizziness, hypotension, and digital dysesthesias


Principles of Use

Nicardipine


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Onset to effect is about 10 minutes, and lasts 2-6hours after discontinuation

Abrupt withdrawal can cause rebound angina andhypertension

In at least one head-to-head trial, better toleratedthan nitroprusside

Neutel et al,Am J Hypertens 1994;7:623-8.

Principles of Use

Nitroprusside


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Spontaneously releases nitric oxide (NO)NO activates guanylyl cyclase, increasing cGMP

cGMP activates myosin light chain phosphatase (MLCP)

MLCP dephosphorylates myosin light chains

Leads to relaxation

Mechanism

Nitroprusside


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Arterial and venodilator

Decreases preload and afterload

No chronotropic effect, but HR (baroreceptors)

Onset 1-2 minutes, t 3-4 minutes

Start @ 0.5 g/kg/min, then titrate Average effective dose is 3 g/kg/min (0.5-10

g/kg/min)

The 7th Report of the JNC. JAMA 2003;289:2560-2571

Principles of Use

Nitropusside: Issues and Concerns


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Common Side Effects

BP

May cause N/V, twitching, sweating

Metabolized to CN, then thiocyanate

RF issue

Problematic Aspects Pregnancy

Coronary steal

Dose dependent in CBF Caution with high ICP

Hypoxia ( Va/Q mismatch) Requires special delivery system

Usually requires directartery pressure monitoring

Acute Pressure Syndromes


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So Whats New for EmergencyMedicine-Based Therapy of Acute,

Severe Blood Pressure Elevations inthe Setting of Cardiovascular or

Cerebrovascular Disease?

Clevidipine: The First Third-GenerationCalcium Channel Blocker


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Generic Name Brand Name

FirstGeneration

Nifedipine Procardia, Adalat

SecondGeneration

Nicardipine/Nicardipine I.V.

AmlodipineIsradipine

Felodipine

Nisoldipine

Cardene/Cardene I.V.

NorvascDynaCirc

Plendil

Sular

ThirdGeneration

Clevidipine Cleviprex

Whiting RL, et al.Angiology. 1990;41:987-991.

Metabolism by Plasmaand Tissue Esterases


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Clevidipine is rapidly metabolized by esterases

in blood and extravascular tissue to an inactivecarboxylic acid metabolite, independent ofrenal or hepatic function!

+

OH

OHH

O

Clevidipine

Cl

OO

O

O

N

H

Cl

O

O

*Esterases

+O

O

N

H

Cl

O

O

Cl

H

Primary metabolite

Linear Dose Response


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Responders = treatment success: >10% decrease in MAP or >20% decrease in MAP at each measured concentration.

Bailey JM, et al.Anesthesiology. 2002;96:1086-1094.

Linear dose response in postoperative cardiac surgerypatients

Effective in 95% of patients at 3.2 mcg/kg/min (16 mg/hr)

n=19

Infusion Rate (mcg/kg/min)

0

1020

30

40

50

60

70

80

90

100

0 0.05 0.18 0.32 1.37 3.19

Responders(%)

n=0n=1

n=4

n=6

n=9

Selectivity of Calcium Channel Antagonists


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Myocardial SA Node AV Node

IV Agent Vasodilation Depression Suppression Suppression

Clevidipine 5 0 0 0

Nicardipine 5 0 0 0

Diltiazem 3 2 5 4

Verapamil 4 4 5 5

*The chiral center of clevidipine; SA = sinoatrial; AV = atrioventricular.

Kerins DM, et al. In: Goodman and Gilmans Pharmacological Basis of Therapeutics. 2001:843-870.

Massie BM.Am J CardioI. 1997;80:23I-32I.

Clevidipine

Cl

OO

O

O

NH

Cl

O

O

*

COCH2CH2NCH2

NO2

CH3O CH3

N

H

O

H3C

H3COC

Nifedipine

NO2

COCH3

CH3

O

N

H

O

H3C

CH3OC

Nicardipine

New Dimensions and Advances


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Multi-center, Phase III, open-label, single-arm, study to confirm

the safety of IV clevidipine for patients who present to theemergency department (ED) or intensive care unit (ICU) withacute, severe hypertension requiring parenteral treatment for

at least 18 hours

Pollack, ACEP, October, 2007; Varon, ACCP, October, 2007.

New Dimensions and Advances


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Presented in part at American College of Emergency Physicians

Scientific Assembly, Oct 5, 07: Pollack CV and Peacock WF

Presented in part at American College of Chest Physicians AnnualConference, Oct 23, 2007: Varon J


VELOCITY Rationale


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Multi-center, Phase III, open-label, single-arm,study to confirm the safety of IV clevidipine forpatients with acute hypertension requiringparenteral treatment for at least 18 hours

Phase III safety and efficacy study

Evaluation: to confirm the safety and efficacyof clevidipine in patients with acutehypertension using a predefined, non-weightbased dosing algorithm

Population: patients with acute hypertension(SBP >180 mmHg or DBP >115 mmHg)assessed at 2 successive occasions 15 minapart at baseline


VELOCITY Objectives


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Primary

Confirm the safety of a titration dosing regimen ofan IV infusion of clevidipine for the treatment ofacute hypertension

Efficacy: Percentage of patients in whom SBPfell within the SBP target range within 30 min ofinitiating infusion

Safety: Percentage of patients in whom SBPfell below the lower limit of the initial SBP targetrange within 3 min of initiating infusion


VELOCITY Objectives


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Secondary Efficacy:

Time to attainment of 30-min SBP target range

Safety:

Change in heart rate during the 30-min period frominitiation of infusion

Dose of clevidipine during the treatment period

Of the patients converted to oral antihypertensive

therapy, the proportion of those with successfultransition, defined as SBP within the last specified targetrange at 6 hr after cessation of clevidipine infusion

Safety of prolonged infusion of clevidipine (18 hr)


VELOCITY Criteria


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Inclusion Criteria

Age 18 years and older

Systolic BP >180 mmHg and/or diastolic BP >115mmHg assessed on two successive occasions,

15 minutes apart Provide written informed consent before initiation of any

study-related procedures

Exclusion Criteria

SBP 180 mmHg and DBP 115 mmHg Expectation that the patient will not tolerate

IV antihypertensive therapy for a minimum of 18 hourz

Known or suspected aortic dissection


VELOCITY Treatment


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Clevidipine

Selection of Initial Target Range (ITR) for

systolic blood pressure determined priorto the initiation of clevidipine for eachindividual patient

Difference between the upper and lowerITR was 20-40 mmHg

VELOCITY Treatment


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Clevidipine initiated at 2 mg/h via

peripheral vein

Titrated up to 32 mg/h in doublingincrements Q3 min to achievepre-specified ITR

Infusion rate could be decreasedif needed

Infusion maintained or further titrated after the first 30min to reach ITR

Treatment duration for at least 18 h, up to 96 h

BP monitoring with BP cuff

VELOCITY Transition to Oral Therapy


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If transition to an oral antihypertensive agent was

required, the agent could be given after 18h of

clevidipine, starting 1 hr prior to

ending infusion

After administration of the oral agent, clevidipinecould be down-titrated or terminated

If the BP rose to an undesirable level upon

cessation of the infusion, additional oral therapyor restarting of clevidipine infusion were options

VELOCITY Patient Demographics


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Parameter Value

Age (yrs) 53.5 15Gender (%)

Male 48

Female 52

BMI (kg/m

2

) 30 7.6Race (%)

African American 77

White 16

Hispanic 6

Asian 1

SBP (mmHg) 202 22

DBP (mmHg) 111 21

ITR (high, low) 175, 143

Mean SDSafety Population, N=126.Pollack, ACEP, October, 2007; Varon, ACCP, October, 2007.

Medical History, Comorbidity, andEnd-Organ Dysfunction

M di l Hi t P t (%)


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Medical History Percent (%)

End organ injury 81Myocardial infarction 5

Renal disease 25

Dialysis dependent 11

Coronary artery disease 28

Hypertension 97

Previous hospitalization for HBP 31

Congestive heart failure 18

Dyslipidemia 37

Smoker

Current / Former 39 / 21

Diabetes 31

Stroke 11

Safety Population, N=126.Pollack, ACEP, October, 2007; Varon, ACCP, October, 2007.

VELOCITY Patient Disposition


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DNC=did not complete.

mITT Population(patients with

SBP >UL of target range)

N=117

Total patients enrolledN=131

Safety Population(patients who

received at least 1 dose)

N=126

No

clevidipine

n=5

SBP UL of target

range

n=14

18 hr continuousinfusion

n=117


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Initial infusion rate 2 mg/hr (4 mL/hr)

Time to first achievement to Initial Target Range(ITR)

10.9 min (95% CI 9.0, 15.0) Median dose rate 4 mg/hr (mean 6 mg/hr)

mITT populationPollack, ACEP, October, 2007; Varon, ACCP, October, 2007.

VELOCITY Efficacy Results


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89% of patients achieved pre-specified ITR within30 minutes

An additional 7% of patients achieved ITR after30 minutes

Of the 96% of patients who did not haveprotocol violations with selection of ITR, 90%achieved the ITR within 30 min

From drug initiation to 30 minutes Median infusion rate 7 mg/hr (mean 9.5mg/hr)

Time to a 15% drop in blood pressure 9.5 min


VELOCITY


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K-M Analysis

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

0

10

20

30

40

5060

70

80

90

10091%

Minutes

Percentof

Patients

Probability of Having Attained SBP

Initial Target Range


VELOCITYEfficacy Results


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mITT population

Time after start of infusion (min.)

%R

eductionfromB

aselineSBP

(MeanSE)

3 6 9 12 15 18 21 24 27 30-25

-20

-15

-10

-5

0

-6%

-16.5%

-21%

Change in BP (30 minutes)


VELOCITYResults

L T I f i


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92.9% of patients were administered clevidipinefor18 hours

The infusion rate was maintained or further

titrated after 30 min to the desired long-term(18 h) SBP target

SBP reduction at 18 hours was -27% (-55mmHg) from baseline

Patients were maintained on a steadyinfusion of clevidipine without evidence oftachyphylaxis or drug accumulation

Long-Term Infusion


VELOCITYEfficacy Results


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Time after start of infusion (hours)

%SBPReduction

fromBaseline

(Mean

SE)

0 3 6 9 12 15 18

0

-5

-10

-15

-20

-25

-30

Additional Titration

BP Adjustment

and Maintenance

30 min.

Titration to ITR

Change in BP (18 hours)


VELOCITYResults

L T I f i


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92.3% of all patients were maintained on

clevidipine monotherapy without the need for

additional IV antihypertensive therapy

Clevidipine was well tolerated for a medianduration of 21 hours (max 60 hours)

118 patients were eligible for transition to oral

antihypertensive therapy

97.5% did so to a defined target BP within 6

hours of cessation of clevidipine infusion

Long-Term Infusion


VELOCITYSafety Results


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2 patients (1.6%) fell below the lower ITR limit within

first 3 min. of clevidipine infusion One patient had a narrower than specified ITR (205-195

mmHg), SBP was 15 mmHg below the lower limit

One patient lower limit was 160 mmHg and SBP fell

4 mmHg below this Both patients continued clevidipine infusion beyond

18 hr without AEs

No clinical hypotensive events related to clevidipinewere reported throughout the study

mITT populationPollack, ACEP, October, 2007; Varon, ACCP, October, 2007.

VELOCITYTransition to Oral Therapy


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Transition successful in 91.3% of patients

Of the 11 not transitioning to oral therapywithin 6 hr of IV termination:

2.4% could not be converted from clevidipine 3.2% did not reach the 18-hr endpoint for

transition eligibility

3.2% had contraindications to oral transition

Of 118 patients eligible for transition,97.5% did so within 6 hr


VELOCITY Trial: Renal Disease


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RD(Dialysis)

RD (non-Dialysis)

All RD WithoutRD

N 13 11 24 102

Initial Mean SBP SD(mmHg)

206 22 212 18 209 20 201 22

Initial Mean SBP ITR

(mmHg)

145-179 152-182 148-180 142-172

Median Time to ITR(mins) [95%CI]

6.3 [3,15] 16.5 [9,30] 8.5 [7,17] 11 [9,15]

Achieved ITR by 30 min(wthout protocolviolations)

92% 88% 91% 90%

Mean mmHg BPdecrease from baseline(18 hr)

48 (23%) 59 (28%) 54 (25%) 55 (27%)

Median CLV dose(mg/h)

11 11 11 6

Peacock WF, et al. Crit Care Med2007 Vol. 35, No. 12 (Suppl): A82

VELOCITY Trial: Heart Failure


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Clevidipine Safety in Heart Failure (subanalysis)

19 patients with heart failure were identified among 126

VELOCITY enrollees

Target blood pressure was achieved in a median of 11.3

minutes

Target blood pressure was achieved by 94% within 30

minutes.

No patient experienced hypotension

Peacock WF, et al. Crit Care Med2007 Vol. 35, No. 12 (Suppl): A82

Conclusions


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Clevidipine lowered BP to pre-specified target range in ~90% ofpatients within 30 minutes

Patients reached target BP without overshoot in a median 10.9minutes

Clevidipine was easy to administer and well tolerated

Peripheral venous administration

BP monitoring via a cuff

Non-weight based dosing regimen

Clevidipine was effective and well tolerated after prolongedinfusion and maintained BP in patients with acute and severehypertension

What We Learned From VELOCITY

Summary


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Hypertension is extremely prevalent in US society,and as population ages, hypertensive crises willbecome increasingly common in the ED

Debate over terminology and numerical definitions is too

prevalent in the literature

Choices among available agents often difficult, andnone is ideal across the spectrum

Must balance effective reduction with avoidance of over-reduction and its complications

Summary


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As ED LOS increases, care of BP derangements

will fall ever more in the purview of the emergencyphysician

Even with prompt transfer of HU/HE patients tothe inpatient setting, this is one of the few areaswhere emergency physicians and cardiologistsapproach definitive care in much the same way

Clevidipine may soon afford a novel, safe, andmulti-setting, multidisciplinary approach to acutesevere hypertension



164/187

The Pressure to Improve: Registry TrialsEvaluatingStrategies, Outcomes, and Optimal Intervention for

Acute, Severe Blood Pressure Elevation

What Registries Are Beginning to Teach UsChallengesand The Road to Best Practice for APS

Program Chairman

Christopher B. Granger, MD, FACCProfessor, Department of Medicine

Division of Cardiology

Duke University Medical Center

Co-Director, Clinical Trials

Duke Clinical Research Institute (DCRI)

Durham North Carolina

Short-Term (2 to 6 month) Outcomes:A Deadly and Morbid Condition


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1. OASIS-5 NEJM2006.

2. GUSTO IIb NEJM1996.

3. GRACE JAMA 2007.

4. IMPACT-HF J Cardiac Failure 2004.

5. Cline DM.Acad Emerg Med2006.

6. STAT Re istr SCCM 2008

Acute Condition Death Rehospitalization

ACS1,2,3 5-7% 30%

CHF4 8.5% 26%

SevereHypertension5,6

6.5% 40%

Acute Hypertension, End-OrganDamage, and Comorbidities


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ICH

Aort ic

Dissect ion

Stroke,

Encepha-

lopathy

Myocardial

Infarct ion

Renal

Dysfunct ion

CHF and

Pulmonary

Edema

Acute

HTN

62 year old African American presenting with

Patient Profile


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62 year old African American presenting with

shortness of breath, mild chest discomfort BP 195/120, HR 90

ECG LVH; cardiac biomarkers negative; CXR ?mild pulmonary edema

Creatinine 2.1 (1.5 1 year ago); 2+ blood in urine

How to treat?

PO or IV? Target BP range over what time

period?

Management


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Difficulty in defining acute end-organdysfunction

Consensus that overly rapid BP may result in

cerebral/coronary/renal hypoperfusion Patients have rightward shift of end-organ

autoregulatory curve

Clinical trial data lacking on how rapidly to BP invarious disease states


JNC VII


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Patients with markedly elevated BP butwithout acute

TOD usually do not require hospitalization, but should

receive immediate combination oral antihypertensive

therapy.

Patients with marked BP elevations and target organ

damage (e.g., encephalopathy, myocardial infarction,

unstable angina, pulmonary edema, eclampsia, stroke,

head trauma, life-threatening arterial bleeding, or aorticdissection)require hospitalization and parenteral drug

therapy.

JNC VII


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Goal

Improve our understanding of clinicalconditions of acute severe hypertension

managed in a critical care setting, and treatedwith IV antihypertensive drugs

Granger et al. SCCM February 2008, Crit Care Medicine, 2007; Vol 35, No.12 (supp A-180)

Inclusion Criteria
http://www.uihealthcare.com/topics/medicaldepartments/ophthalmology/iih/images/7_iih.jpg


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>18 years of age

Presenting to the hospital with acute severe HTN

Treated in a critical care setting

Acute severe HTN treated with an IV agent

Severe hypertension

At least one SBP >180 mmHg and/or

At least one DBP >110 mmHg

SAH patients with SBP >140 and/or DBP >90

Granger et al. SCCM February 2008

Primary Objectives

Describe patient characteristics: Who are these


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ppatients?

Describe contemporary practice: How are they treated?

Timing of initiating IV treatment

Medications used (IV and oral transition)

Control of BP Time to achieve control

Describe in-hospital patient outcomes: How do theyfare?

Link practice and patient variations with outcome: Howdoes management relate to outcome?


Sites Participating in STAT (n=21)


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Cleveland, OH

WorcesterMA

Dallas, TX

New York, NY

Philadelphia, PA

Houston, TX

Durham, NC

Sacramento, CA

Columbus, OH

Miami, FL

Boston,MA

Detroit, MI (3)

New Orleans, LA

Chandler, AZ

Royal Oak, MI Stony Brook, NY

Charleston, SC

Winston-Salem, NC

Ann Arbor, MI


Preliminary Results


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982 (of 1500 planned)patients

21 hospitals

79% had IV therapystarted in ED

Median age 58 yrs

Women 49%

Black race 58%

Median initial BP 201/110

90% had HTN history

33% history of kidney

disease 17% drug abuse


Preliminary Results


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Predisposing factors 26% med non-compliance

11% drug use

30% prior admission for

severe HTN

Most common symptoms 29% dyspnea

29% chest pain

HTN

Neuro

ACSCHF

Reason for Admission


Results and Observations


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How were they treated?

Time from Qualifying BPto Initiation of IV Therapy

96.7%100.0%

100%


177/187

45.3%

72.4%

87.4%

0%

20%

40%

60%

80%

100%

Within 1 h Within 3 h Within 6 h Within 12 h Within 24 hn=982

Granger et al SCCM February 2008

First IV Antihypertensive

31.8%Labetolol


178/187

5.9%

7.5%

9.3%

14.7%

14.7%

16.1%

0% 10% 20% 30% 40%

Nipride

Nicardipine

Other

Hydralazine

Nitroglycerin

Metoprolol

n=982


Number of IV Antihypertensives DuringHospitalization According to First Received

One Two Three or more


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24.1%

51.4%

36.8%

45.8%

36.7%

31.1%

32.8%

25.7%

28.5%

41.7%

39.2%

43.6%

43.1%

23.0%

34.7%

12.5%

24.1%

25.3%

Nipride (n=58)

Nicardapine (n=74)

Nitroglycerin (n=144)

Hydralazine (n=144)

Metoprolol (n=158)

Labetolol (n=312)

FirstIVa

ntihyp

ertensive

Percent of patients

One Two Three or more


Systolic BP Control Over 24 h by FirstIV Antihypertensive

0 Enalapril* Hydralazine* Labetolol*


180/187

-40

-30

-20

-10

0

0 2 4 6 8 10 12 14 16 18 20 22 24

Time since IV initiation (h)

Changefrom

qualifying(%

p y

Metoprolol* Nicardapine* Nipride*

Nitroglycerin*

n=982

*MedianGranger et al SCCM February 2008

Systolic BP Control Over 24 h by FirstIV Antihypertensive

0


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-40

-30

-20

-10

0

0 2 4 6 8 10 12 14 16 18 20 22 24

Time since IV initiation (h)

Changefrom

qualifying(%

Enalapril* Nipride*

n=982

*MedianGranger et al SCCM February 2008


182/187

How did they fare?

Patient Outcomes

50%


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40.2%

6.5%8.4%

40.1%

10.4%

0%

10%

20%

30%

40%

New end-organ

damage*

In-hospital

death*

Admit to 90-day

death*

90-day

readmission

90-day

readmission due

to HTN*n=982 (all patients)

n=867 (all patients alive at discharge and with 90-day follow-up)


Preliminary STAT Results


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Median time to SBP of 180 after initial control 4% had iatrogenic hypotension

Median duration of IV therapy was 10.5 hrs

Time to first PO med was 8 hrs




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49% were admitted to an ICU setting

Resources used included ECHO (47%)

Brain Imaging (50%)

Mechanical Ventilation (18%)

Cardiac cath (8%)




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Patients were discharged on median of 2antihypertensive drugs

63% had no scheduled follow-up ormissed their appointment


Summary

STAT provides a contemporary view of


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STAT provides a contemporary view of

hospitalization for acute severe hypertension Recurrent condition

Associated with poor medical adherence

Heterogeneous management: ICU admission,drugs used, BP targets

Alarmingly low rates of follow-up

High mortality and morbidity, with over 40% re-

h it li ti t b 90 d

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