The Science and Medicine of

Circulatory Dysfunction and

Acute Pressure Syndromes
From Threat to Therapy
The Cardiovascular Specialists Perspective
Investigation Innovation Application
Jerrold H. Levy, MD
Program Co-Chairman

Christopher B. Granger, MD
Program 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
CME-accredited symposium jointly sponsored by the University of
Massachusetts Medical School and CMEducation Resources, LLC

Commercial Support: Sponsored by an independent educational grant
from The Medicines Company

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

Processes: Strives for fair balance, clinical relevance, on-label
indications for agents discussed, and emerging evidence and
information from recent studies

COI: Full faculty disclosures provided in syllabus and at the beginning
of the program
Welcome and Program Overview
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.
Program Faculty
Program Chairman
Christopher B. Granger, MD
Professor
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, FACP
Physician-in-Chief and Chairman
Department of Medicine
Sir 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 University
Montreal, PQ, Canada




Jerrold H. Levy, MD
Professor 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, FAAEM
Chairman, Department of Emergency Medicine
Pennsylvania Hospital
Professor of Emergency Medicine
University of Pennsylvania
School of Medicine
Philadelphia, Pennsylvania


Faculty COI Disclosures



Christopher B. Granger, MD
Educational Grants and/or Research Support: Alexion, Astra Zeneca, Procter and
Gamble, 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 for
Innovation, Merck-Frosst, Pfizer Cardiovascular AwardConsultant : Boehringer-
Ingelheim, Bristol-Myers Squibb, Forest Pharmaceuticals, Novartis

Jerrold H. Levy, MD
Grant/Research Support: Alexion
Consultant: Bayer HealthCare, Dyax, Novo Nordisk, and Organon

Charles V. Pollack Jr, MA, MD, FACEP, FAAEM
Grant/Research Support: GlaxoSmithKline
Consultant: The Medicines Company., Schering-Plough, Sanofi-Aventis, BMS,
Genentech, Speakers Bureau: Schering-Plough, Sanofi-Aventis, BMS, Genentech

Acute Pressure Syndromes
From Threat to Therapy

Characterization, Epidemiology, and Approach to Acute Blood
Pressure Elevations Across the Cardiovascular Disease
Continuum

Giving Acute Hypertension the Hyperattention it Deserves

Investigation Innovation Application
Jerrold H Levy, MD, FAHA
Professor of Anesthesiology
Emory University School of Medicine
Deputy Chairman for Research
Director, Cardiothoracic Anesthesiology
Cardiothoracic Anesthesiology and Critical Care
Emory Healthcare
Acute, Severe Hypertension
Common
Deadly and disabling
Poorly studied
Poorly managed
Evidence that speed and degree of
control relate to outcome
Needs more attention
Observed across multiple settings
Better therapies required
72 million with
hypertension
1-2% with acute
severe hypertension
Severe Hypertension
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+
P
e
r
c
e
n
t

o
f

P
o
p
u
l
a
t
i
o
n
Men Women
Prevalence of Hypertension
NHANES: 1999-2004. Source: NCHS and NHLBI.
Extent of awareness, treatment and control of
high blood pressure by age
52.3
35.8
24.6
62.5
39.8
68.4
74.6
34.3
75.3
0
10
20
30
40
50
60
70
80
Awareness Treatment Controlled
P
e
r
c
e
n
t

o
f

P
o
p
u
l
a
t
i
o
n
20-39 40-59 60+
NHANES: 1999-2004. Source: NCHS and NHLBI.
Hypertension: Awareness and Control

5,026 emergency departments
113.9 million visits in 2003
Presentation with severe hypertension in up to
25% of patients in busy urban EDs
Sullivan AF. Acad Emerg Med 2004;11:454; IOM Emergency Medical Care Report 2006.
Emergency Care of Severe
Blood Pressure Elevation
Short-Term (2 to 6 month) Outcomes:
A Deadly and Morbid Condition
1. OASIS-5 NEJM 2006.
2. GUSTO IIb NEJM 1996.
3. GRACE JAMA 2007.
4. IMPACT-HF J Cardiac Failure 2004.
5. Cline DM. Acad Emerg Med 2006.
Acute Condition Death Rehospitalization
ACS
1,2,3
5-7% 30%
CHF
4
8.5% 26%
Severe
Hypertension
5
5-6% 30%
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
Spectrum of End-Organ Damage
Zampaglione, B. Hypertension 1996;27:144-147.
108 Hypertensive Emergencies*
*All Caucasians
End-Organ
Damage Type
No. 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%
Acute Severe Hypertension
Epidemiology and Mortality
1939: First study of the natural
history of hypertensive
emergencies published
Untreated hypertensive emergencies
had a 1-year mortality rate of 79%, with
median survival of 10.5 months
Varon J. CHEST 2007; 131:19491962.
Risk Factors
History of
hypertension
African Americans
Elderly
Men
Noncompliance

Historical
Study
Messerli F. N Engl J Med 1995;332:1038-1039.
St. Louis Post-Dispatch
April 13, 1945
Blood Pressure of FDR
Messerli F. N Engl J Med 1995;332:1038-1039.
Sokolow & 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 150-200/90-110
BP II 200-250/110-130
BP III Over 250/130
BP III
BP II
BP I
38%
18%
8%
Mortality and Severe Hypertension
Hypertensive Urgency or Emergency
Total 865
Reviews 190
Randomized
Clinical Trials 46
ACS
55,353

3,518
HU or HE
An Evaluation of Pharmacotherapeutic
Regimens Inadequately Studied
Medline 1966-2001
References from above
Experts contacted
Cochrane Library checked
Randomized controlled trials
Systematic review of cohort studies
Individual cohort study
Outcome Research
600 Studies
Identified
Excluded
Non-Human
Blood pressures too low
Safety or Tolerability studies
Case Series or Case Reports
39 Studies
Excluded
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 Med 2002;17:937-945.
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 Pharmacotherapeutic
Regimens Questions Unanswered
J Gen Intern Med 2002;17:937-945.
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 on
Prevention, Detection,
Evaluation, and Treatment of High
Blood Pressure (JNC 7)
National Initiatives Hypertension

Hypertension. 2003;42:12061252.
National Heart, Lung, and Blood Institute
National High Blood Pressure Education Program
Hypertensive Urgencies and Emergencies
Hypertensive Urgencies and Emergencies
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 aortic dissection) require
hospitalization and parenteral drug therapy.

Patients with markedly elevated BP but without
acute TOD usually do not require hospitalization,
but should receive immediate combination oral
antihypertensive therapy.
Hypertensive Urgencies and Emergencies
Proposed Strategies

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
Hypertensive EmergencyProblematic
Brooks, et al. Am J Health Syst Pharm. Dec 15, 2007;64(24):2579-82
Primary and Secondary Endpoints
a
MAP = mean arterial pressure.
b
p < 0.05, nicardipine group versus all patients.

Brooks, et al. Am J Health Syst Pharm. Dec 15, 2007;64(24):2579-82
Outcome
a
All Patients
(n=47)
Nicardipine
Group (n=21)
Nitroprusside
Group (n=18)
Primary
No (%) patients with
appropriate MAP
reduction at 2 hr
15 (32) 4 (19) 7 (39)
No. (%) patients with
excessive MAP
reduction at 2 hr
b
27 (57) 16 (76) 9 (50)
No. (5) treatment
failures at 2 hr
5 (11) 1 (5) 2 (11)
Primary and Secondary Endpoints
a
MAP = mean arterial pressure.
b
p < 0.05, nicardipine group versus all patients.
c
p < 0.05, nicardipine group versus nitroprusside group.
d
One patient was excluded from the analysis. Brooks, et al. Am J Health Syst Pharm. Dec 15, 2007;64(24):2579-82
Outcome
a
All
Patients
(n=47)
Nicardipine
Group
(n=21)
Nitroprusside
Group
(n=18)
Secondary
No. (%) of patients with appropriate
blood-pressure reduction at 6 hr
6 (13) 1 (5) 4 (22)
Mean no. (range) of additional p.r.n.
antihypertensive doses per patient
c
4 (0-33) 6 (0-33)
d
2 (0-5)
Mean length of stay (range), days
c
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 oral
antihypertensives were started, hr
14 (0-72) 16 (0-48) 10 (0-72)
No. (%) of patients meeting 2- or 6-hour
goal
b,c
26 (28) 5 (12) 11 (31)
Treatment-Related Adverse Events
*
p < 0.05, nicardipine group versus nitroprusside group; p < 0.05, nitroprusside group versus all patients.
Brooks, et al. Am J Health Syst Pharm. Dec 15, 2007;64(24):2579-82
No. (%)
Adverse
Event
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 Renal
Failure
2 (4) 1 (5) 1 (6)
Major Ischemia 2 (4) 1 (5) 1 (6)
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
Rigid Pipes or Living Vessels

A Primer of Vascular Biology of Hypertension
for 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
Relationships of Blood Vessels
120
100
80
60
40
20
0
B
l
o
o
d

p
r
e
s
s
u
r
e

(
m
m
H
g
)

10
3
200 100 3 100 10
3
Lumen diameter (mm)
VP
Davis et al., 1986
Remodeling of Large Arteries
Normal
Remodeled
Outward hypertrophic remodeling
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)
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 <PWV < 12.27 m/s
PWV > 12.27 m/s
Duration of follow-up (months)
0 35 70 105 140
1
0.75
0.5
0.25
0
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
Gluteal subcutaneous biopsy
Peripheral resistance artery
(150 ~350 m)
Dissection
isometric
isobaric
Methodology for Study of Human
Resistance Arteries
Subcutaneous fat
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
E
v
e
n
t
-
F
r
e
e

S
u
r
v
i
v
a
l

M/L > 0.11
M/L < 0.11
1
0.8
0.6
0.4
0.2
0
R
a
t
e

o
f

C
V

e
v
e
n
t
s

x

1
0
0

p
a
t
i
e
n
t
s
/
y
e
a
r

M/L > 0.11 M/L < 0.11
**
Normal Remodeled
Remodeling of Small Arteries in Mild
Essential Hypertension
Inward eutrophic remodeling
WKY
Confocal microscopy, antibodies against
o-actin-collagen I/III
SHR
Small Artery Composition in
Hypertensive 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 <0.05
Intengan, Deng, Li & Schiffrin, Hypertension 1999;33:366
Deng LY, Li JS, Schiffrin EL
Clin Sci 1995;88:611-622.
Endothelium-Dependent Relaxation of
Small Arteries in Hypertension
- Log Conc. Acetycholine (mol/l)
R
e
l
a
x
a
t
i
o
n

(
%
)

9 8 7 6 5
0
50
100
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.
Mechanisms of Remodeling
Intengan HD, Schiffrin EL.
Hypertension. 2001;38:581
Lumen Diameter of Resistance Arteries in
Organoid 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
L
u
m
e
n

d
i
a
m
e
t
e
r

(
u
m
)

Wesselman JPM et al.
J Vasc Res 2004:41:277290

Relationship of Tissue Transglutaminase
to Inward Arterial Remodeling
Langille LB, Dajnowiec D. Circ Res 2005;96 9-11
Angiotensin II, Endothelin, Oxidative
Stressand Vascular Damage
LDL
ox-LDL
Endothelial damage
ET-1
ET
A
Receptor
Inflammation
Atherogenesis
ET-1 production
Contraction
Dilatation
MCP-1
VCAM-1
ICAM-1
PAI-1
Smooth muscle
ONOO-
-
O
2
-
-
O
2
-
NO-
NO
-
Endothelium
Platelet aggregation and adhesion
Monocyte adherence
NOS III
ET-1



ICAM-1
VCAM-1
NADH/
NADPH
oxidase
Contraction
Growth
Migration
Fibrosis
TGF|
1

-
O
2
-
ET-1
Adhesion molecules
NFkB, AP-1
Cytokines
Foam cells
Pressure
Angiotensin II
Vasopressin
Cytokines
ox-LDL
Angiotensin II
AT
1
R
AT
1
R
Angiotensin II
NADH/
NADPH
oxidase
ox-LDL
LOX-1
Schiffrin EL. Am J Hypertens 2004;17:1192-1200.
From Oxidative Stress to Inflammation to
Remodeling and Hypertrophy
Ang II or ET-1
p22
p47
p67
p40
Cytokines: IL, TNFo
Chemokines: MCP-1
CAM: selectins, ICAM, VCAM, PECAM
Growth factors: ET-1, TGF|, CTGF
ECM proteins: collagen, fibronectin
TIMP/MMP
Inflammatory response Cell growth and fibrosis
MAP kinases
Tyrosine
kinases
RhoA/
Rho kinase
NAD(P)H
Oxidase
Gp91/
Nox1/
Nox4
2O
2
2O
2
-
H
2
O
2


SOD
e
-
NAD(P)H NAD(P)+H
+
Transcription factors:
NF-kB, AP-1, HIF-1
p
PKC, PLD
c-Src, PI3K

Cell Membrane
Touyz RM & Schiffrin EL. 2005
NADPH
Oxidase
NADPH
Oxidase/Nox1/Nox4
NADPH
Oxidase
ROS
All Vascular Layers Generate ROS
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<0.05, **p<0.01 vs Normotensives
+p<0.05, ++p<0.01 vs Ang counterpart
Touyz RM, Schiffrin EL. J Hypertension 2001;19:1245-1254.
NAD(P)H Oxidase Activation
Rap1
Rac2
p67
2 O
2
2 O
2
-
NADPH
NADP
+
+ H
+
Rap1
2 O
2
+ NAD(P)H
2 O
2
-
+ NAD(P)
+
+ H
+
gp91
gp91
p22
p22
Rac2
p40
p67
p47
p47
p40
Touyz RM et al. Circ Res 2002;90:1205-1213.
Confocal microscopy shows effect of NADPH oxidase
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
ET-1
ET
B
NO
PGI
2
Ang II, AVP, NE, insulin
Thrombin, TGF|, cytokines
Shear stress, hypoxia
ET-1
ET-1
ET
A
ET
B
Relaxation Contraction
growth
Endothelium
VSMC
Schiffrin et al. J. Hypert. 1997
G
Transgene Construction
human preproET-1 HA beta-globin Tie-2
638 bp 900 bp
Transgenic mice characteristics
C57BL/6, male
8-10 weeks old
Low litter number
Amiri F, Schiffrin EL. Circulation 2004
Immunohistochemistry for ET-1 in Aorta of
Endothelium-restricted ET-1 Transgenic Mice
WT
TG
Amiri F, Schiffrin EL. Circulation 2004
WT TG

* p < 0.05
p < 0.01
Vascular Morphology in Endothelium-
Restricted ET-1 Transgenic Mice
Growth index = 34%
WT TG
*
Amiri F, Schiffrin EL. Circulation 2004
0
3000
6000
9000
12000
15000
18000
M
e
d
i
a
/
L
u
m
e
n

(
%
)

0
2
4
6
8
10
M
e
d
i
a

C
S
A

(

m
2

Immunostaining for MMP-9 and MMP-2 is Increased in
Endothelium and Media of Vessels Cultured at
150 mmHg Compared with 80 mmHg
Lehoux S et al. Circulation. 2004;109:1041-1047.

RxR
RxR
PPAR
Lipid storage & adipose
tissue differentiation
(adipose tissue)
Insulin sensitivity (skeletal
muscle)
PPARo
Fatty Acid Oxidation
(liver, heart, kidney, skeletal muscle)
Cardiovascular
Anti-inflammatory
Anti-fibrotic
Anti-hypertrophic
PPARb/d
Lipid metabolism?
(ubiquitous)
RxR
Fatty Acids
Fibrates
Thiazolidinediones
(rosiglitazone,
pioglitazone,
troglitazone)
Cell membrane
Fatty Acids
15d-PGJ2
Prostacyclin
Leukotriene B4
gene regulation
Nucleus
PPRE
PPAR|/o
PPAR o
PPAR
Vascular Structure of Ang II-infused
Rats PPAR- Activators
M
e
d
i
a
/
l
u
m
e
n

r
a
t
i
o

(
%
)

*
*
*
Diep et al, Circulation 2002
0
2
4
6
8
10
12
14
16
DNA Synthesis in Blood Vessels
of Ang II-infused Rats PPAR- Activators
T
h
y
m
i
d
i
n
e

i
n
c
o
r
p
o
r
a
t
i
o
n

(
%

o
f

c
o
n
t
r
o
l
)

CTR ANG A+PIO A+ROS PIO ROS
*
*
*
*
*
Diep et al, Circulation 2002
0
40
80
120
160
200
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
Resistance Arteries
*** p< 0.001 vs Cnt ; ** p< 0.01 vs Cnt; * p< 0.05 vs Cnt
Cnt Ang II

m

Lumen
+/+ op/+ op/op
***

m

Media thickness
+/+ op/+ op/op
***
*
%

Media/Lumen
+/+ op/+ op/op
***
***
x
1
0
3
,

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
0
2
4
6
8
10
12
14
16
18
AT
1
R
-
Tyrosine Kinases
c-Src -
O
2
O
2
-
H
2
O
2
H
2
O+O
2



EGFR
PDGFR
IGF - 1R
ROS
NAD(P)H
Oxidase
Vascular Structural
and Functional Changes
EGFR
PDGFR
IGF - 1R
ET-1
Ang II
Vascular remodeling
Adhesion molecules
Chemokines /cytokines
(IL6, MCP - 1, PAI)
NF k B
AP - 1
HIF - 1
MMPs
Hyperplasia
Hypertrophy
Cell survival
Apoptosis/ Anoikis
Collagen synthesis
ECM proteins
-
MAP Kinases
p38MAPK, JNK
ERK5, ERK1/2
-
+
Modified from Schiffrin & Touyz Am J Physiol Heart Circ 2005
Vascular inflammation
Some Pathways Mediating
Vascular Structural Changes
ET-1
Ang II
The Cardiorenal Pathophysiological
Continuum
Angina
Fibrosis And
Muscle Loss
Heart Failure
Death
Sudden Death
Myocardial
Ischemia
P
GC

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 TGF|
NO
Unstable Angina
Myocardial Infarction
Coronary Artery Disease
Plaque Rupture
Altered
Extracellular 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

Acute Blood Pressure Elevations in
the Cardiovascular Surgery and
Cardiac Critical Care Setting

The Good News and Bad News About
Current Treatment OptionsImplications of Landmark Trials
for Perioperative and Cardiac Critical Care

Jerrold H Levy, MD, FAHA
Professor of Anesthesiology
Emory University School of Medicine
Deputy Chairman for Research
Director, Cardiothoracic Anesthesiology
Cardiothoracic Anesthesiology and Critical Care
Emory Healthcare
Atlanta, Georgia
Investigation Innovation Application
Critically Ill Patients Presenting to
CCUs, ICUs, and Postoperative Care
Changing demographics and increasing use
of stenting and platelet inhibitors
Older patients with comorbidities presenting to
ICUs and CCUs with endothelial dysfunction
due to multiple causes
Endothelial and vascular dysfunction common
across this cardiac, neurological, and critically
ill patient populationsacute and chronic
disease
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 Hypertension
The Cardiothoracic Surgery Setting
Patients with preoperative hypertension are at increased
risk for perioperative complications
1

Approximately 30% to 56% of patients undergoing routine
cardiac surgery experience acute rises in blood pressure
that require administration of a parenteral
antihypertensive agent
2

Antihypertensive therapy is often needed to manage life-
threatening arterial bleeding, myocardial ischemia, or
cardiac failure
3

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 BP
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 Antihypertensive
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 Arterial
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 Scand 1993; 37(S):20-25.
Treatment Options
Hypertension in Surgical Patients (1)
Patients who are normotensive may become
hypertensive
Most blood pressure changes develop acutely
and require rapid intervention with IV agents
Characterized by systemic vasoconstriction with
intravascular hypovolemia
Patients may have preoperative biventricular
dysfunction

Levy JH: Management of systemic and pulmonary hypertension. Tex Heart Inst J 2005;32:467-471.
Principles and Practice Considerations
BP may be maintained at lower levels to avoid
graft/suture line disruption
Patients are being Fast Tracked
Mechanical manipulation, suturing with potential
risk for vascular spasm
Ventricular dysfunction is common in patients
with normal preop function due to stunning/
reperfusion injury
Hypertension in Surgical Patients (2)
Levy JH: Management of systemic and pulmonary hypertension. Tex Heart Inst J 2005;32:467-471.
Principles and Practice Considerations
Nitrovasodilators

Na
+
CN

NO
+
CN

Fe
++
CN

CN

CN

Na
+
Sodium Nitroprusside
Nitroprusside Therapy
Potent venodilator/arterial vasodilator
Cardiac output is often affected due to
venodilation
Volume replacement is often required for
venodilation
Levy JH: Management of systemic and pulmonary hypertension. Tex Heart Inst J 2005;32:467-471.
Principles and Practice Considerations
IV DHP Calcium Channel Blockers
1st Generation: Nifedipine

2nd Generation: Nicardipine, isradipine

3rd Generation: Clevidipine
Evolution of Therapeutic Options
Properties of Dihydropyridines
Arterial vasodilator
1
Decreases SVR
2-6
More selective for vascular smooth
muscle than cardiac muscle
1
No significant increase in ICP
7
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 al Am 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
Lambert CR: Am J Cardiol 1993;71:420.
Control Nicardipine
HR 71 13 70 14
MAP 107 14 80 9
PAOP 9 4 8 3
MPAP 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


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 Dysfunction
Studies
Salmenperra MT: Effects of PDE inhibitors on the human IMA. Anesth
Analg 1996; 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.
Anesthesiology 1998;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 Analg 2001;93:1453-1459.
Sato N: Vasodilatory effects of hydralazine, nicardipine, nitroglycerin and
fenoldopam in the human umbilical artery. Anesth Analg 2003;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

Nitroglycerin is the most potent; but
nitrate tolerance occur
Milrinone, dihydropyridines, PGE1,
were also effective at therapeutically
used doses
Huraux: Anesthesiology 1998;88:1654.
A Comparative Evaluation of the Effects of
Multiple Vasodilators on Human IMA
Vasodilator Effects of
Clevidipine on Human IMA
Clevidipine was effective
anti-vasospasm agent at
therapeutically
used doses
Huraux C, Makita T, Szlam F, Nordlander M, Levy JH: Anesth Analg 1997; 85: 1000-1004.
Simulated Drug Level Curves
=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
Therapeutic
Concentration
Range
P
l
a
s
m
a

D
r
u
g

L
e
v
e
l

Cl
Cl
H
CH
3
OOC
H
3
C
COOCH
2
OOCC
3
H
7
CH
3
N
H
The Clevidipine Molecule
Clevidipine is the first ultrashort acting dihydropyridine
intravenous calcium channel blocker
Clevidipine Metabolized by
Plasma and Tissue Esterases
Clevidipine is rapidly metabolized by esterases in blood and
extravascular tissue to an inactive carboxylic acid metabolite
+
O H
O
H
H
O
Clevidipine
Cl
O
O
O
O
N
H
Cl
O
O
*
Esterases
+
O
O
N
H
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.
SBP changes for patients receiving clevidipine during a 30-minute treatment period.
10
5
0
5
10
15
20
25
30
0 5 10 15 20 25 30
%

C
h
a
n
g
e

F
r
o
m

B
a
s
e
l
i
n
e

Time (min)
SBP
SBP Changes
Clevidipine Rapid Onset of Action
BP-lowering effects are seen within 23 minutes of
clevidipine infusion
Levy JH, et al. Anesth Analg. 2007;105(4):918 .
*Css = concentration at steady state; median blood concentration of clevidipine obtained
during the last 10 minutes of infusion.
Clevidipine Linear Pharmacokinetics
At steady state, there is a linear relationship between dosage
and arterial blood concentrations
Linear relationship maintained for dosages as high as 21.9
mcg/kg/min
120
100
80
60
40
20
0
0 5 10 15 20 35
C
l
e
v
i
d
i
p
i
n
e

C
o
n
c
e
n
t
r
a
t
i
o
n


a
t

C
s
s

(
n
m
o
l
/
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
After discontinuation of clevidipine infusion, there
was rapid clearance
BP returned to baseline in <10 minutes in healthy
volunteers
Reproduced from Ericsson H, et al. Anesthesiology. 2000;92:993-1001.
100
90
80
70
60
50
40
5 0 5 10 15 20 35
M
A
P

(
m
m

H
g
)

a
n
d


H
R

(
b
e
a
t
s
/
m
i
n
)

Time (min)
25 30
Clevidipine Infusion
MAP
Reproduced from Ericsson H, et al. Anesthesiology. 2000;92:993-1001.
Clevidipine Ultrashort Half-Life
Clinically relevant half-life: Approximately 1
minute
Arterial and venous clevidipine blood samples
*P<0.05, P<0.001, P<0.01, control vs 0.375, 0.75, 1.5, and 3.0 mcg/kg
/
min
1
and post-drug control.
Values are mean SEM.
12
m
m

H
g

8
4
0
0 0.375 0.75 1.5 3 0
10
6
2
mcg/kg/min
Central Venous Pressure
Clevidipine and Arterial Selectivity
1400
U
n
i
t
s
1200
1000
0
C1 0.375 0.75 1.5 3 C2
Systemic Vascular Resistance




mcg/kg/min
C2

Mean Arterial Pressure
90
80
70
*


C1 0.375 0.75 1.5 3
mcg/kg/min
m
m

H
g

Kieler-Jensen N, et al. Acta Anaesthesiol Scand. 2000;44:186-193.
SVR = systemic vascular resistance; RVEDV = right ventricular end-diastolic volume.
Clevidipine Hemodynamic Effects
In postoperative patients
Increased stroke volume, cardiac output
No reflex increase in HR or changes in cardiac preload
Lower SVR, higher cardiac filling pressures and
RVEDV vs SNP
Data from Kieler-Jensen N, et al. Acta Anaesthesiol Scand. 2000;44:186-193.
C2
75
m
L
/
b
e
a
t

70
65
0
C1 0.375 0.75 1.5 3
Stroke Volume

*
L

m
i
n

1

Cardiac Output
0
1
2
3
4
5
6
C1 0.375 0.75 1.5 3 C2
Infusion Rate (g kg
1
min
1
) Infusion Rate (g kg
1
min
1
)
*P<0.05
P<0.001
Preoperative HR Changes
in Non-Anesthetized Patients
Postoperative HR Changes
in Anesthetized Patients

Clevidipine:
Minimal Effect on Heart Rate
10
5
0
5
0 5 10 15 20 25 30
%

C
h
a
n
g
e

F
r
o
m

B
a
s
e
l
i
n
e

Time (min)
HR
HR changes for patients during the
30-minute treatment period
5
0
5
0 5 10 15 20 25 30
%

C
h
a
n
g
e

F
r
o
m

B
a
s
e
l
i
n
e

Time (min)
HR
HR changes for patients during the
30-minute treatment period

Levy JH, et al. Anesth Analg. 2007;105(4):918.
Singla N, et al. Anesthesiology. 2005;103:A292.
Clevidipine Clinical Development
Tolerability,
Safety, PK
Dose 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 Study
ECLIPSE:
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 I
N=89
Phase II
N=300
Healthy Volunteers
Patients: Mild to
Moderate Hypertension
N=86
Phase III
N=1821
Perioperative
Hypertension
N=1721
Severe
Hypertension
N=100
Patients:
Perioperative
N=214
Data on file. The Medicines Company.
Acknowledgements ECLIPSE Trial
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, who
first presented much of this material as a Late Breaker at
ACC 2007 Scientific Assembly on March 27, 2007
ECLIPSE Rationale
Clevidipine is an IV dihydropyridine calcium channel
blocker with an ultrashort half-life (~1 min)
Phase I and II studies (300 pts) demonstrated:
Dose: 216 mg/hr effective
1
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 min
2
1
Bailey J. Anesthesiology 2002;96:1086-94.
2
Levy J. Anesth Analg. 2007;105(4):918.
ECLIPSE

Randomized (1:1), open-label, parallel group with
active comparators: nitroglycerin (NTG), sodium
nitroprusside (SNP), or nicardipine (NIC)
NTG and SNP studies are perioperative and NIC is
postoperative
Treatment with study drug allowed until discharge from
ICU
Patients undergoing cardiac surgery; CABG, OPCAB,
Valve, MIDCAB






Data on file. The Medicines Company.
Protocols
ECLIPSE: Trial Design
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
Data on file. The Medicines Company.
Treatment Protocol
Clevidipine
Initiated 2 mg/hr
Titrated doubling increments Q 90s to 16 mg/hr
40 mg/hr maximum
Comparators (NTG, SNP, NIC) administered
per institutional practice
Treatment duration up to discharge from the
ICU
Concomitant antihypertensives discouraged
Outcome Endpoints
Primary End Points* (Cumulative rate of clinical
outcomes at 30 days):
Death
MI: Symptomatic presentation, enzyme release, and/or
new ECG changes
Stroke: Hemorrhagic or ischemic
Renal Dysfunction: Cr >2.0 with min absolute change
of 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
Populations Clevidipine Comparators
Randomized patients 971 993
Met post-randomization criteria 755 757
Safety population 752 754
Completed study 715 719
Did not complete study
Withdrew consent
Physician decision
Lost to follow up
Adverse experience
Patient death
Other
37
0
1
15
0
20
1
35
1
0
6
0
28
0
Baseline Characteristics
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
Procedural Characteristics
Clevidipine
n=752
Comparators
n=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
Timing and Duration
Clevidipine
N=268
Nitroglycerin
N=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
Data on file. The Medicines Company.
ECLIPSE SNP: Drug Administration
Timing and Duration
Clevidipine
N=296
Nitroprusside
N=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
Data on file. The Medicines Company.
ECLIPSE NIC: Drug Administration
Timing and Duration
Clevidipine
N=188
Nicardipine
N=193
Dosed During
Post-Op
188 (100) 193 (100)
Overall Infusion
Duration (median)
5.55 hr 5.12 hr
Data on file. The Medicines Company.
RESULTS Primary Endpoint
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
3
0
-
D
a
y

E
v
e
n
t
s

(
%
)

n=729 n=700 n=707 n=700 n=705 n=712 n=710 n=719
MI Stroke Renal
Dysfunction
Primary End Points by
Treatment Comparison
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
Serious Adverse Events
Clevidipine
n=752
Comparators
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
Arrhythmia
CLV
n/N (%)
NTG
n/N (%)
SNP
n/N (%)
NIC
n/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/A
70/172
(40.7)
55/143
(38.5)
ECLIPSE was put on hold due to higher AF rates in clevidipine in
March 2004 and restarted in December 2005

No statistically significant differences in any of the arms or in overall
comparison
.

ECLIPSE Secondary Endpoint
Systolic Blood Pressure Control Over 24 Hours
Time (hours)
SBP
Lower
Upper
0 6 12 24 18
Lower
ECLIPSE Trial; Presented at ACC, March 27, 2007.
Logistic Regression Results
Predictors of Mortality
Mortality Predictors P-Value
Odds
Ratio
95% CI
[Lower Limit,
Upper Limit]
Surgery Duration (hour) <0.0001 1.517 [1.240, 1.856]
Age (year) 0.0003 1.070 [1.031, 1.110]
Pre-op Creatinine 1.2 mg/dL 0.0031 2.670 [1.392, 5.122]
AUC (area outside the range) 0.0069 1.003 [1.001, 1.004]
Additional surgical procedures 0.0089 2.409 [1.246, 4.655]
Pre-op Hgb (g/dL) 0.0135 0.824 [0.707, 0.961]
Pre-op SBP >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
(<6 months prior)
0.0312 2.197 [1.073, 4.497]
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
30-Day Mortality by Magnitude of AUC
Odds
Ratio
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
Largest safety program ever performed with an
intravenous 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 rates
comparable across groups
Atrial fibrillation rates are equivalent
AUC data suggests better overall BP control with
clevidipine compared with SNP and NTG

Summary
ECLIPSE Trial
Clevidipine appears to be a safe alternative to
commonly used antihypertensive agents in the
cardiovascular surgery setting, and demonstrated
superior blood pressure control as assessed by
integral analysis of excursions outside specified
ranges over time
Data supports importance of precise blood
pressure control in a critically ill patient population
Clevidipine represents the first potential
nitroprusside replacement for clinicians
Conclusions
Acute Severe Hypertension
Evolving Strategies and New Dimensions of
Emergency Cardiovascular Care
Charles V. Pollack, Jr., M.A., M.D., FACEP
Professor and Chairman, Emergency Medicine
Pennsylvania Hospital
University of Pennsylvania Health System
Philadelphia
Investigation Innovation Application
Hypertension
Affects at least 72 million Americans

Affects at least 1 BILLION individuals worldwide

Most current (2003) evidence basis for management
The Seventh Report of the Joint National Committee
on the Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure Hypertension (JNC
7)lacks guidance on acute management of patients
presenting to an ED with hypertension
JNC 7, JAMA 2003; 289:2560-2572.
Hypertensive Urgencies
and Emergencies What We Know
Epidemiologic data are largely lacking

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

In a single-center Italian study, HU or HE accounted
for 3% of all medicine admissions and 27.5% of all
medical emergencies
HU:HE 3:1 in that study
Patients with HU much more likely to be unaware of their
htn dx than those with HE
Zampaglione et al, Hypertension 1996;27:144.
Acute Pressure Syndromes Management
Considerations
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 Therapy
of Hypertensive Crises
HU can generally be managed with oral medications and
requires BP lowering over 24-48 hours
Important to prevent too-rapid lowering due to autoregulation of flow
by 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-organ
system is affected and on comorbidities

JNC 7, JAMA 2003; 289:2560-2572.
Why Are We Here Today?
Severe hypertension is increasingly prevalent as
population ages and obesity and diabetes become
more common

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

Advancements in therapy are possible

There is a new agent on the horizon that has been
tested specifically in the ED
Therapeutic Agents Currently Used
ACE Inhibitors
Diazoxide
Esmolol
Hydralazine
Nicardipine
Nitroglycerin
Clonidine
Diuretics
Fenoldopam
Labetalol
Nifedipine
Nitroprusside
Rynn et al, J Pharm Pract 2005;18:363-76.
Armamentarium
Esmolol
Blocks -1 receptors of heart and vasculature
Given IV, onset of action is 6-10min after bolus,
and activity persists 20 minutes after infusion is
discontinued; must be carefully titrated
May cause bradycardia and hypotension,
bronchospasm, seizures, and pulmonary edema
Chest pain may occur after abrupt withdrawal
Rynn et al, J Pharm Pract 2005;18:363-76.
Principles of Use
Fenoldopam
Selective dopamine-1 receptor agonist,
decreasing PVR while increasing RBF, natriuresis,
and diuresis
Six times more potent than dopamine in producing
renal vasodilation
Given IV and titrated; onset of action 10 minutes
and effects persist for an hour after
discontinuation
May cause T-wave flattening, angina, atrial
fib/flutter, and reflex tachycardia
Rynn et al, J Pharm Pract 2005;18:363-76.
Principles of Use
Labetalol
Decreases PVR by blocking -1 receptors and
prevents reflex tachycardia by blocking -1 receptors,
resulting in a BP
Given as repeated IV boluses and can be carefully
given as a short-term infusion
Optimally used when a gradual in BP is needed
with 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
Rynn et al, J Pharm Pract 2005;18:363-76.
Principles of Use
Nicardipine
As a CCB, nicardipine relaxes arteriolar smooth
muscle and decreases PVR through baroreceptor-
mediated sympathetic discharge
Seems to be selective for L-type, voltage-sensitive
calcium channels of the heart, and works by
decreasing afterload
Given by IV infusion with careful titration
May cause tachycardia, flushing, headache,
dizziness, hypotension, and digital dysesthesias
Rynn et al, J Pharm Pract 2005;18:363-76.
Principles of Use
Nicardipine
Onset to effect is about 10 minutes, and lasts 2-6
hours after discontinuation

Abrupt withdrawal can cause rebound angina and
hypertension

In at least one head-to-head trial, better tolerated
than nitroprusside
Neutel et al, Am J Hypertens 1994;7:623-8.
Principles of Use
Nitroprusside
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
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
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 direct
artery pressure monitoring

So Whats New for Emergency
Medicine-Based Therapy of Acute,
Severe Blood Pressure Elevations in
the Setting of Cardiovascular or
Cerebrovascular Disease?

Acute Pressure Syndromes
Clevidipine: The First Third-Generation
Calcium Channel Blocker
Generic Name Brand Name
First
Generation
Nifedipine Procardia

, Adalat

Second
Generation

Nicardipine/Nicardipine I.V.
Amlodipine
Isradipine
Felodipine
Nisoldipine
Cardene

/Cardene I.V.
Norvasc

DynaCirc

Plendil

Sular

Third
Generation

Clevidipine Cleviprex

Whiting RL, et al. Angiology. 1990;41:987-991.
Metabolism by Plasma
and Tissue Esterases
Clevidipine is rapidly metabolized by esterases
in blood and extravascular tissue to an inactive
carboxylic acid metabolite, independent of
renal or hepatic function!
+
O H
O
H
H
O
Clevidipine
Cl
O
O
O
O
N
H
Cl
O
O
*
Esterases
+
O
O
N
H
Cl
O
O
Cl
H
Primary metabolite
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
Linear dose response in postoperative cardiac surgery
patients
Effective in 95% of patients at 3.2 mcg/kg/min (16 mg/hr)
n=19
Infusion Rate (mcg/kg/min)
0
10
20
30
40
50
60
70
80
90
100
0 0.05 0.18 0.32 1.37 3.19
R
e
s
p
o
n
d
e
r
s

(
%
)

n=0
n=1
n=4
n=6
n=9
Selectivity of Calcium Channel Antagonists
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
O
O
O
O
N
H
Cl
O
O
*
COCH
2
CH
2
NCH
2
NO
2
CH
3
O

CH
3
N

H

O

H
3
C
H
3
COC
Nifedipine
NO
2
COCH
3
CH
3
O

N

H

O

H
3
C
CH
3
OC
Nicardipine
Multi-center, Phase III, open-label, single-arm, study to confirm
the safety of IV clevidipine for patients who present to the
emergency department (ED) or intensive care unit (ICU) with
acute, severe hypertension requiring parenteral treatment for
at least 18 hours
New Dimensions and Advances
Pollack, ACEP, October, 2007; Varon, ACCP, October, 2007.
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 Annual
Conference, Oct 23, 2007: Varon J
New Dimensions and Advances
Pollack, ACEP, October, 2007; Varon, ACCP, October, 2007.
VELOCITY Rationale
Multi-center, Phase III, open-label, single-arm,
study to confirm the safety of IV clevidipine for
patients with acute hypertension requiring
parenteral treatment for at least 18 hours
Phase III safety and efficacy study
Evaluation: to confirm the safety and efficacy
of clevidipine in patients with acute
hypertension using a predefined, non-weight
based dosing algorithm
Population: patients with acute hypertension
(SBP >180 mmHg or DBP >115 mmHg)
assessed at 2 successive occasions 15 min
apart at baseline
Pollack, ACEP, October, 2007; Varon, ACCP, October, 2007.
VELOCITY Objectives
Primary
Confirm the safety of a titration dosing regimen of
an IV infusion of clevidipine for the treatment of
acute hypertension
Efficacy: Percentage of patients in whom SBP
fell within the SBP target range within 30 min of
initiating infusion
Safety: Percentage of patients in whom SBP
fell below the lower limit of the initial SBP target
range within 3 min of initiating infusion
Pollack, ACEP, October, 2007; Varon, ACCP, October, 2007.
VELOCITY Objectives
Secondary
Efficacy:
Time to attainment of 30-min SBP target range
Safety:
Change in heart rate during the 30-min period from
initiation of infusion
Dose of clevidipine during the treatment period
Of the patients converted to oral antihypertensive
therapy, the proportion of those with successful
transition, defined as SBP within the last specified target
range at 6 hr after cessation of clevidipine infusion
Safety of prolonged infusion of clevidipine (18 hr)
Pollack, ACEP, October, 2007; Varon, ACCP, October, 2007.
VELOCITY Criteria
Inclusion Criteria
Age 18 years and older
Systolic BP >180 mmHg and/or diastolic BP >115
mmHg 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
Pollack, ACEP, October, 2007; Varon, ACCP, October, 2007.
VELOCITY Treatment
Clevidipine

Selection of Initial Target Range (ITR) for
systolic blood pressure determined prior
to the initiation of clevidipine for each
individual patient

Difference between the upper and lower
ITR was 20-40 mmHg
VELOCITY Treatment
Clevidipine initiated at 2 mg/h via
peripheral vein
Titrated up to 32 mg/h in doubling
increments Q3 min to achieve
pre-specified ITR
Infusion rate could be decreased
if needed
Infusion maintained or further titrated after the first 30
min to reach ITR
Treatment duration for at least 18 h, up to 96 h
BP monitoring with BP cuff

VELOCITY Transition to Oral Therapy
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, clevidipine
could be down-titrated or terminated
If the BP rose to an undesirable level upon
cessation of the infusion, additional oral therapy
or restarting of clevidipine infusion were options

VELOCITY Patient Demographics
Parameter Value
Age (yrs) 53.5 15
Gender (%)
Male 48
Female 52
BMI (kg/m
2
) 30 7.6
Race (%)
African American 77
White 16
Hispanic 6
Asian 1
SBP (mmHg) 202 22
DBP (mmHg) 111 21
ITR (high, low) 175, 143
Mean SD Safety Population, N=126. Pollack, ACEP, October, 2007; Varon, ACCP, October, 2007.

Medical History, Comorbidity, and
End-Organ Dysfunction
Medical History Percent (%)
End organ injury 81
Myocardial 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
DNC=did not complete.
mITT Population
(patients with
SBP >UL of target range)
N=117
Total patients enrolled
N=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 continuous
infusion
n=117
<18 hr treatment
n=9
Pollack, ACEP, October, 2007; Varon, ACCP, October, 2007.
VELOCITY Efficacy Results
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 population Pollack, ACEP, October, 2007; Varon, ACCP, October, 2007.
VELOCITY Efficacy Results
89% of patients achieved pre-specified ITR within
30 minutes
An additional 7% of patients achieved ITR after
30 minutes
Of the 96% of patients who did not have
protocol 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

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

K-M Analysis
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
0
10
20
30
40
50
60
70
80
90
100
91%
Minutes
P
e
r
c
e
n
t

o
f


P
a
t
i
e
n
t
s

Probability of Having Attained SBP
Initial Target Range
Pollack, ACEP, October, 2007; Varon, ACCP, October, 2007.
VELOCITY
Efficacy Results
mITT population
Time after start of infusion (min.)
%

R
e
d
u
c
t
i
o
n

f
r
o
m

B
a
s
e
l
i
n
e

S
B
P

(
M
e
a
n

S
E
)

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)
Pollack, ACEP, October, 2007; Varon, ACCP, October, 2007.
VELOCITY
Results
92.9% of patients were administered clevidipine
for 18 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% (-55
mmHg) from baseline
Patients were maintained on a steady
infusion of clevidipine without evidence of
tachyphylaxis or drug accumulation

Long-Term Infusion
Pollack, ACEP, October, 2007; Varon, ACCP, October, 2007.
VELOCITY
Efficacy Results
Time after start of infusion (hours)
%

S
B
P

R
e
d
u
c
t
i
o
n

f
r
o
m

B
a
s
e
l
i
n
e

(
M
e
a
n

S
E
)

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)
Pollack, ACEP, October, 2007; Varon, ACCP, October, 2007.
VELOCITY
Results
92.3% of all patients were maintained on
clevidipine monotherapy without the need for
additional IV antihypertensive therapy
Clevidipine was well tolerated for a median
duration 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
Pollack, ACEP, October, 2007; Varon, ACCP, October, 2007.
VELOCITY
Safety Results
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 clevidipine
were reported throughout the study
mITT population Pollack, ACEP, October, 2007; Varon, ACCP, October, 2007.
VELOCITY
Transition to Oral Therapy
Transition successful in 91.3% of patients

Of the 11 not transitioning to oral therapy
within 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

Pollack, ACEP, October, 2007; Varon, ACCP, October, 2007.
RD
(Dialysis)
RD (non-
Dialysis)
All RD Without
RD
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 protocol
violations)
92% 88% 91% 90%
Mean mmHg BP
decrease 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 Med 2007 Vol. 35, No. 12 (Suppl): A82
VELOCITY Trial: Renal Disease
Clevidipine Safety in Heart Failure (subanalysis)

VELOCITY Trial: Heart Failure
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 Med 2007 Vol. 35, No. 12 (Suppl): A82
Conclusions

Clevidipine lowered BP to pre-specified target range in ~90% of
patients within 30 minutes
Patients reached target BP without overshoot in a median 10.9
minutes
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 prolonged
infusion and maintained BP in patients with acute and severe
hypertension

What We Learned From VELOCITY
Summary
Hypertension is extremely prevalent in US society,
and as population ages, hypertensive crises will
become increasingly common in the ED
Debate over terminology and numerical definitions is too
prevalent in the literature

Choices among available agents often difficult, and
none is ideal across the spectrum
Must balance effective reduction with avoidance of over-
reduction and its complications
As ED LOS increases, care of BP derangements
will fall ever more in the purview of the emergency
physician

Even with prompt transfer of HU/HE patients to
the inpatient setting, this is one of the few areas
where emergency physicians and cardiologists
approach definitive care in much the same way

Clevidipine may soon afford a novel, safe, and
multi-setting, multidisciplinary approach to acute
severe hypertension
Summary
The Pressure to Improve: Registry TrialsEvaluating
Strategies, Outcomes, and Optimal Intervention for
Acute, Severe Blood Pressure Elevation
What Registries Are Beginning to Teach UsChallenges
and The Road to Best Practice for APS

Program Chairman
Christopher B. Granger, MD, FACC
Professor, Department of Medicine
Division of Cardiology
Duke University Medical Center
Co-Director, Clinical Trials
Duke Clinical Research Institute (DCRI)
Durham, North Carolina
Investigation Innovation Application
Short-Term (2 to 6 month) Outcomes:
A Deadly and Morbid Condition
1. OASIS-5 NEJM 2006.
2. GUSTO IIb NEJM 1996.
3. GRACE JAMA 2007.
4. IMPACT-HF J Cardiac Failure 2004.
5. Cline DM. Acad Emerg Med 2006.
6. STAT Registry SCCM 2008
Acute Condition Death Rehospitalization
ACS
1,2,3
5-7% 30%
CHF
4
8.5% 26%
Severe
Hypertension
5,6
6.5% 40%
Acute Hypertension, End-Organ
Damage, and Comorbidities
ICH
Aortic
Dissection
Stroke,
Encepha-
lopathy
Myocardial
Infarction
Renal
Dysfunction
CHF and
Pulmonary
Edema
Acute
HTN
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?
Patient Profile
Management
Difficulty in defining acute end-organ
dysfunction

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 in
various disease states

Hypertensive Urgencies and Emergencies
Patients with markedly elevated BP but without 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 aortic
dissection) require hospitalization and parenteral drug
therapy.

JNC VII
Goal
Improve our understanding of clinical
conditions of acute severe hypertension
managed in a critical care setting, and treated
with IV antihypertensive drugs
Granger et al. SCCM February 2008, Crit Care Medicine, 2007; Vol 35, No.12 (supp A-180)
Inclusion Criteria
>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
patients?
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 they
fare?
Link practice and patient variations with outcome: How
does management relate to outcome?
Granger et al. SCCM February 2008
Sites Participating in STAT (n=21)
Cleveland, OH
Worcester
MA
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
Granger et al. SCCM February 2008
Preliminary Results
982 (of 1500 planned)
patients
21 hospitals
79% had IV therapy
started 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
Granger et al. SCCM February 2008
Preliminary Results
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
ACS
CHF
Reason for Admission
Granger et al. SCCM February 2008
How were they treated?
Results and Observations
Time from Qualifying BP
to Initiation of IV Therapy
45.3%
72.4%
87.4%
96.7%
100.0%
0%
20%
40%
60%
80%
100%
Within 1 h Within 3 h Within 6 h Within 12 h Within 24 h
n=982
Granger et al. SCCM February 2008
First IV Antihypertensive
5.9%
7.5%
9.3%
14.7%
14.7%
16.1%
31.8%
0% 10% 20% 30% 40%
Nipride
Nicardipine
Other
Hydralazine
Nitroglycerin
Metoprolol
Labetolol
n=982
Granger et al. SCCM February 2008
Number of IV Antihypertensives During
Hospitalization According to First Received
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)
F
i
r
s
t

I
V

a
n
t
i
h
y
p
e
r
t
e
n
s
i
v
e
Percent of patients
One Two Three or more
Granger et al. SCCM February 2008
Systolic BP Control Over 24 h by First
IV Antihypertensive
-40
-30
-20
-10
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time since IV initiation (h)
C
h
a
n
g
e

f
r
o
m

q
u
a
l
i
f
y
i
n
g

(
%
)
Enalapril* Hydralazine* Labetolol*
Metoprolol* Nicardapine* Nipride*
Nitroglycerin*
n=982

*Median Granger et al. SCCM February 2008
Systolic BP Control Over 24 h by First
IV Antihypertensive
-40
-30
-20
-10
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time since IV initiation (h)
C
h
a
n
g
e

f
r
o
m

q
u
a
l
i
f
y
i
n
g

(
%
)
Enalapril* Nipride*
n=982

*Median Granger et al. SCCM February 2008
How did they fare?
Patient Outcomes
40.2%
6.5%
8.4%
40.1%
10.4%
0%
10%
20%
30%
40%
50%
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)
Granger et al. SCCM February 2008
Preliminary STAT Results
Median time to SBP of <160 mmHg: 4 hrs

BUT:
59% increased to >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
Granger et al. SCCM February 2008
Preliminary STAT Results
49% were admitted to an ICU setting

Resources used included
ECHO (47%)
Brain Imaging (50%)
Mechanical Ventilation (18%)
Cardiac cath (8%)
Granger et al. SCCM February 2008
Preliminary STAT Results
Patients were discharged on median of 2
antihypertensive drugs

63% had no scheduled follow-up or
missed their appointment
Granger et al. SCCM February 2008
Summary
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-
hospitalization rate by 90 days
Major pressure to improve management of this
understudied condition
Granger et al. SCCM February 2008