Critical Challenges in

Cardiovascular Anesthesiology
A Year 2007 Evidence-Based Update

Applying Landmark Trials, Emerging Data, & Expert

Analysis to Management of Severe or Life-Threatening
Blood Pressure Elevations in the Perioperative Setting

Program Co-Chairman
Jerrold H. Levy, MD
Professor
Professor and
and Deputy
Deputy Chair
Chair for
for Research
Research
Emory
Emory University
University School of Medicine
Director
Director of
of Cardiothoracic
Cardiothoracic Anesthesiology
Anesthesiology
Cardiothoracic
Cardiothoracic Anesthesiology
Anesthesiology and
and Critical
Critical Care
Emory Healthcare
Atlanta,
Atlanta, Georgia
Georgia
 Welcome and Program Overview

CME-accredited symposium jointly sponsored by University of

Massachusetts Medical Center, office of CME 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
 Program Educational Objectives

As a result of this session, cardiovascular anesthesiologists,

cardiothoracic surgeons, cardiovascular critical care specialists
and related specialists will be able to:

► Identify
Identify criteria
criteria and
and management strategies for multiple disease states
and
and clinical
clinical presentations
presentations associated with perioperative hypertension,
manifesting
manifesting asas serious
serious and/or
and/or life-threatening
life-threatening elevations
elevations in systolic and/or
diastolic
diastolic blood
blood pressure.
pressure.

► Learn
Learn to
to manage
manage thethe hemodynamic
hemodynamic derangements
derangements andand complications
complications of
of
serious
serious and/or
and/or life-threatening
life-threatening elevations
elevations in
in systolic
systolic and/or diastolic
blood
blood pressure
pressure in the perioperative
perioperative setting.
setting.

► Learn
Learn evidence-based
evidence-based approaches
approaches to
to prompt
prompt and
and safe
safe lowering
lowering of
of serious
serious
elevations
elevations in BP in the perioperative setting, using agents that are
effective
effective and
and that
that have
have an
an acceptable
acceptable safety profile.
 Educational Objectives
► Learn
Learn how
how to
to select
select among
among intravenous
intravenous pharmacologic
pharmacologic agents,
agents, including
calcium channel blockers (dihydropyridines)
(dihydropyridines) that
that offer
offer unique
unique benefits for
blood pressure control
control in
in the
the setting
setting of cardiothoracic surgery

► Learn
Learn how
how landmark
landmark trials
trials and
and analyses focusing on BP reduction
may have
have an
an impact
impact on
on current
current and future strategies for management of BP
elevations
elevations in
in the setting of cardiovascular
cardiovascular surgery.
surgery.

► Be
Be able to assess the need
need for
for and
and implement
implement optimal
optimal BP-lowering
strategies
strategies for
for patients
patients with
with serious
serious and/or
and/or life-threatening
life-threatening elevations
elevations in
in
systolic and/or
and/or diastolic
diastolic BP
BP in
in the
the setting
setting of
of cardiothoracic
cardiothoracic surgery.
surgery.

► Understand
Understand the
the efficacy
efficacy and
and safety
safety profiles
profiles of
of specific
specific pharmacologic
pharmacologic
agents used for anesthesiology-based
anesthesiology-based control
control of
of systemic
systemic blood
blood pressure.
pressure.

► Be
Be able to discuss the potential impact that new trials are likely to
have on future
future management
management ofof patients
patients with BP elevation in the
perioperative
perioperative setting.
setting.
 Program Faculty

Solomon Aronson, MD, Kevin A. Stierer Sr., MD

FACC. FCCP, FAHA, FASE Chief
Chief Cardiac
Cardiac Anesthesia
Associate
Associate Director
Director Cardiac
Program Co-Chairman
Co-Chairman
Surgery
Surgery ICU
Professor
Professor
The
The Heart
Heart Institute
Institute
Duke University Medical
Medical Center
Center
St.
St. Joseph
Joseph Medical
Medical Center
Center
Executive Vice Chair
Towson,
Towson, MD
MD
Department
Department of
of Anesthesiology
Anesthesiology
Durham, NC

Jerrold H. Levy, MD
Program Co-Chairman
Co-Chairman
Professor
Professor and
and Deputy
Deputy Chair
Chair for Research
Emory University
University School
School of
of Medicine
Medicine
Director of
of Cardiothoracic
Cardiothoracic Anesthesiology
Anesthesiology
Cardiothoracic Anesthesiology
and Critical
Critical Care
Care
Emory Healthcare
Healthcare
Atlanta, Georgia
Georgia
 Faculty COI Financial Disclosures

Solomon Aronson, MD
Grant/Research Support: Abbott
Consultant: The Medicines Company
Speaker’s Bureau: Baxter
Major Shareholder: Medwave

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

Kevin A. Stierer Sr., MD

Nothing to report
 Off-Label Discussion and Information

NOTE
There will be off-label discussions—both indications
and dosing—during this CME symposium, and
speakers will note such off-label information. This
information does not imply or constitute endorsement
of such strategies, which must be evaluated on the
basis of evidence and expert analysis.
Management of Perioperative
Hypertension in the
Cardiac Surgery Patient
A New Look at an Old Problem

Solomon Aronson, M.D.

FACC, FCCP, FAHA, FASE
Professor and Executive Vice Chairman
Department of Anesthesiology
Duke University Health System
“A man is as old as his arteries”

Sir William Osler

 The Aging Population
80
10
1988-1991
1976-1980
Population (in

8
60
CHF mortality
Percent
millions)

40
4

2
20
0
30 35 40 45 50 55 60 65 70 75

0 Age (Years)
1990 2000 2010 2020 2030 2040 2050
National Health & Nutrition Examination Survey II 1976-1980 and 1988-1991
 Hypertension: Costs and Consequences

Risk > 115/75

90% pts > 55 years of
age
• Pre-HTN > 115/75 < 140/90
• Average in Europe: 136/83; USA & Canada: 127/77
• # 1 cause of HD death, #3 cause of stroke death
• $63.5 B direct & indirect costs
• 50 M (25% population)
• 30 M “high normal”,
• 20-35% (“white coat”) Joint National Committee (JNC-6 & 7)
On Prevention, Detection, Evaluation, &
Treatment of Hypertension:
Arch Int Med 157; 2413-46,1997
JAMA 289; 2560-72,2003
 Pre-Hypertension
(>120/80 <140/90)

Pre-Hypertension is common: 40%

Associated with increased risk:

OR CI
CV death 1.58 1.12-2.21
MI 1.76 1.40-2.22
Stroke 1.93 1.49-2.50
CHF 1.36 1.05-1.77
Circulation 115;855-60, 2007
 Muscle sympathetic nerve activity

JACC 40;119-25,2002
Baroreceptor sensitivity
“White Coat” Hypertension
 Hypertension: Types and Mechanism

NE release
(stress)
Thickened arterial Essential Endocrine,
wall Renal, ICP,
Altered Secondary coarctation,
contraceptive
vasomotor
s, pregnancy,
etc.

DBP, SBP, MAP, PP

Orthostatic BP changes
 Classification
Category Systolic mmHg Diastolic mmHg
Optimal < 120 and < 75
Normal < 130 and < 85
Mild HTN 140-159 or 90-99
Moderate 160-179 or 100-109
Severe > 180 or > 110
Isolated SBP HTN > 140 and < 90
Pulse Pressure > 65mmHg
Orthostatic changes Hyper response > 20 mmHg
Hypo response < 20 mmHG
 Physiology: Perioperative HTN

► Increase SVR , increase preload

► Rapid intravascular volume shifts
► Renin angiotensin activation
► Adrenergic stimulation (cardiac & neural)
► Serotonergic overproduction
► Baroreceptor denervation
► Altered cardiac reflexes
► Depth anesthesia inadeq
► Cross clamp
 Diastolic Blood Pressure

• Historically, the most important factor

• Benchmark measure for trials
• Index of Microcirculation
• Perioperative risk defined by this index
 Historical Perspective
Decade Study Comment

1970 Prys Roberts Preop severe(>115mmHg) – risk

1980 Goldman Preop mod (< 110 mmHg) – no risk

Intraoperative control BP important

1990 Charlson Defined intraoperative BP patterns

associated with postoperative risk
 Systolic Blood Pressure

Adverse events are higher with

isolated systolic blood pressure
HTN, than with diastolic blood
pressure HTN

Kannel, Framingham Heart Study

 Systolic BP: HTN Risk Factor

1962 Insurance industry Mortality = SBP > DBP

1965 London business men SBP predicts events in CAD
1969 Framingham Heart Study Challenged DBP as 10 risk
1974 Old Age Assistance SBP > DBP
1978 Royal Canadian Air Force SBP > DBP
1982 Italian Rural population SBP > DBP
1983 Hawaiian – Japanese SBP > DBP
1985 British Male Civil Service SBP > DBP
1987 Oslo, Norwegian Country No difference of CV Risk
2002 McSpi Perioperative SBP HTN predicts adverse
outcome during CABG
 Systolic BP: Hypertension
Preoperative
Renal O.R. 1.3 (1.0-1.9)
Stroke 1.7 (1.2-2.3)
LV dysfunction 1.3 (1.0-1.6)
Combined 1.4 (1.1-1.7)
Intraoperative
Negative outcome* O.R. 2.1 p=0.01
*LOS > 10 days, or death
SBP > 160 mmHg

Anesth Analg 94;1079- 84,2002

Anesth Analg 95;273-7,2002
 Prevalence of Isolated
Systolic Hypertension

30
Women
Prevalence %

20

10
Men
0

20 30 40 50 60 70 80 90
Age
Circulation 2006;114:2780-7
 Determinants of Systolic BP

Stroke Volume*
Rate of Systolic Ejection
Arterial Distensibility
SBP (wave reflections)**

* < 50 yrs
** >70 yrs
 Risk of CV Events by Type of HTN
36 Year Follow-Up (Framingham Study According to Age
& Sex)

Age Adjusted Risk Ratio*

35-64 yrs 65-94 yrs
Men Women Men Women
Isolated diastolic 1.8 1.2 1.2 1.6
Isolated systolic 2.4 1.9 1.9 1.4
Combined 2.7 2.2 2.2 1.6

*
Reference groups consist of normotensive persons

AmJourof Card; 85, 2000

 Pulse Pressure

• SBP-DBP = Pulse Pressure

• Traditionally, not in risk assessment
• Wide PP = high risk
• Treatment not understood
Pressure/Flow Relationships

PRESSURE
HR x SV = CO
*BP/ CO = SVR
CO x MAP = work
MAP = 1/3 PP + DBP

All in the absence of pulsations

FLOW
(*BP = MAP -RAP)
 Pulse Pressure and Cardiac Risk
Framingham Study (30 Year Follow-
Up) Rate /1,000
35-64 yrs 65-94yrs
Pulse Pressure (mm Hg) Women Men Women Men
2-39 9 4 2 17
40-49 13 6 16 19
50-59 16 7 32 22
60-69 22 10 39 25
70-182 33 16 58 32

Regression 0.024 0.025 0.024 0.014

Risk factor 0.018 0.019 0.021 0.010

TheAmericanJournal ofCardiologyVol 85, January15, 2000

 Pulse Pressure
Dependent on;
Ventricular Ejection
Viscoelastic properties: Large arteries
Wave Reflection
 Wave Propagation

Pulse picks up speed as it moves distally;

then wave reflected back at peak PVR
Proximal Aorta: Compliant (accepts SV with low SBP)
Femoral
Brach. stiffer
Radial

Energy distending
distending
arterial
arterial tree
tree in systole
returned
returned inin diastole
diastole
due
due to proximal
proximal aorta
aorta
elasticity
elasticity
 CT Surgery Renal Risk
Influence of PPH

5450 pts Figure 1.Stud

5436 patients enrolled
in EPI 2 study
67% current or past history HTN
371 patients withdrew
from the study

Mean Preoperative Pressure 5065 patients

SBP - mildly elevated (133 + 18) - 256 patients with other cardiac or
non-cardiac surgery
DBP - minimally reduced (75 + 10) - 7 patients with incomplete BP
recording, 2 patients with

ISH - 5% questionable BP recording

IDH - 3% 4801 patients

(Study Population)

Presenting Pulse Pressure Derivation set: Validation set:

50% between 40-60 mmHg 2381 patients 2420 patients

33% between 60-80 mmHg

8% > 80 mmHg
Circulation 115,733-42,2007
 Each Pulse Pressure (PP) Increment of
10 mm Hg Increases Risk

PP > 80 mm Hg Associated with 2X

Ischemic Events
_____________________________

• Cerebral (5.5 % vs. 2.8 %; P = 0.004)

• Renal (8.6 % vs. 4.5 %; P = 0.0003)
• CHF (12.8 % vs. 7.8 %; P = 0.003)
• Cardiac death (4.7 % vs. 2.4 %; P = 0.0001
• Overall mortality (5.8 % vs. 2.8 %; P =
0.0018)
 Renal RISK INDEX and
PULSE PRESSURE

►Each 20 mmHg increase > 40mmHg

Additive risk [OR 1.49; CI, 1.17-1.89 (P = 0.001)]

►Renal injury doubled if PP > 80mmHg

[8.6 % vs. 4.5 %; P = 0.0003]
Renal dysfunction [5 % vs. 3 %; P = 0.0004]
Renal failure [5.5 % vs. 2.5 %; P = 0.001]

►PPH > 80 mmHg assoc 3X renal-related

death
[3.7% vs. 1.1%]

Circulation 115,733-42,2007
 PPH & Ischemic Complications

• Brain (96% increase in composite cerebral

events)
• Heart (61% increase in CHF)
• Kidneys (91% increase in composite renal
injury)
1.0

Survival Distribution Function

No Renal Composite
PPH accelerates ischemic 0.9

processes causing fatal & 0.8

nonfatal complications over 0.7

Renal Composite
hours to days rather than 0.6 P < 0.001

0
years 0.5
0 5 10 15 20 25 30
Days after Revascularization
 Increased Pulse Pressure Is Associated With
Decreased Long-term Survival After CABG Surgery

SCA Montréal 2007

 Mean Arterial Pressure (MAP)

Determinants

• Ventricular Ejection
• Peripheral Vascular
Resistance (PVR)
 Blood Pressure Components

• Steady Component (MAP)

• Pulsatile Component (Pulse
Pressure)
 Hypertension and Perioperative Risk

End organ involvement

Type of surgery
HTN VASC DISEASE
Pulsatile flow
Type of HTN Endothelial cell dysfunction
Smooth Muscle cell hypertrophy

Treatment effectiveness
 Coronary Heart Disease and
Diastolic Blood Pressure
4.00 x

2.00 x

1.00
Relative Risk x
CHD, Stroke
0.50
x

0.25 x
1 2 3 4 5
Baseline
DBP Category 76 84 91 98 105 mmHg
Lancet. 1990;335,765-74 Approximate Mean Usual DBP
 MAP, SBP and PP
Independent Predictors of Risk
• Each 10 mm Hg increase in PP:
11% increase in stroke

• Each 10 mm Hg rise in MAP:

20% increase in stroke
• Each 10 mm Hg increase in PP: 16% increase
in death and 12% increase in recurrent MI

Cardiac mass associated with SPB

Work to drive blood = SBP despite MAP & SVR

Increase PP associated with decreased coronary BF

Hypertension,1999;34:375-80
 J – Curve Hypothesis

Lowering DBP (too much) increases risk for

coronary events esp in patients CAD & wide
pulse pressures (> 60 mmHg)

Farnett et al. JAMA, 265:489-95, 1991

 J – Curve Hypothesis
10

-10
Percent
Percent Esmolol
Change
Nitroprusside
-20

-30
HR
HR SBP
SBP DBP PaO
PaO22

-40
*P
*P << 0.05
0.05 vs
vs baseline
baseline
+P
+P << 0.05
0.05 vs.
vs. esmolol
esmolol
Gray
Gray Rj.
Rj. Am
Am JJ Cardiol
Cardiol 1985;56:49F-56F
1985;56:49F-56F
 ECLIPSE Secondary Endpoint
Systolic Blood Pressure Control Over 24 Hours

SBP

Upper

Lower
Lower

0 6 12 18 24
Time (hours)
ECLIPSE Trial; Presented at ACC,
March 27, 2007
 Logistic Regression Results:
Predictors of Mortality

P-Value Odds 95% CI

Ratio [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 0.0312 2.197 [1.073, 4.497]
(<6 months prior)
 30 Day Mortality
by Magnitude of AUC
Odds 95% CI
Ratio [Lower Limit,
Upper Limit]

1.20 [1.06, 1.27]

I mmHg x 60 min
1.43 [1.13, 1.61]
2 mmHg x 60 min
1.71 [1.20, 2.05]
3 mmHg x 60 min
2.05 [1.27, 2.61]
4 mmHg x 60 min
2.46 [1.35, 3.31]
5 mmHg x 60 min
 Adverse Events & BP Control

AUC Quartile All agents* n/N

(%)
Death 1st 7/380 (1.8)
4th 16/378 (4.2)
MI 1st 6/380 (1.6)
4th 11/378 (2.9)
Stroke 1st 4/380 (1.1)
4th 6/378 (1.6)
Renal 1st 24/380 (6.3)
4th 39/378 (10.3)

*ECLIPSE clinical trials, N=1512

SBP range of 75 – 145 (pre & post-op), 65-135 (intra-op)
 Cumulative AUC at Targeted
BP Ranges

p=0.0002
120 111.5

Clevidipine n=751
100
mm Hg x min/h

n=756 87.7
Comparators
80

60 p<0.0001

40 p<0.0001 33.1
p=0.0004
23.1
20 12.5
7.8 6.6
3.8
0
Intra-op SBP (mmHg) 65 75 85 95
Pre/post SBP (mmHg) 75 85 95 105
 BP Control : Clevidipine vs SNP

P=0.0068
140
127.9
120 Clevidipinen=295
mm Hg x min/h

SNP n=284 100.2

100

80
P=0.0003
60
P=0.0009 41.5
40 P=0.0027
23.6
17.3
20 10.5 8.9
4.4
0 specified +10 +20 +30
 BP Control : Clevidipine vs NTG

P=0.0556
120
108.6

100
Clevidipine n=269
mm Hg x min/h

n=278
NTG 83.7
80

60 P=0.0016

P=0.0002
40 P=0.0006 34.2
23.4
20 14.9
8.9 6.0
4.1
0 specified +10 +20 +30
 BP Control : Clevidipine vs NIC

120 P=0.0231
101.6
100
Clevidipinen=187
mm Hg x min/h

NIC n=194
77.0
80

60 P=0.3086

40 P=0.8949
P=0.8508
21.6 22.8
20
5.3 5.7
1.8 1.7
0 specified +10 +20 +30
 RISK AND AGE
Relationship to Blood Pressure Index

Age (years) Pressure Index

________________________________

< 50 DBP
50-59 SBP, DBP, MAP
> 60 PP
 Conclusions and Caveats

• Baseline preoperative value & class

important

• 20% tolerance treatment threshold

• In chronic HTN* higher BP needed

(e.g.“sweet spot”)

* shift in autoregulatory curve, non compliant vasculature, etc.

Advancing Management of Acute and Serious
Elevations in Blood Pressure –
A Critical, Comparative, and Clinical Examination of the
Available Pharmacologic Armamentarium for Cardiothoracic
Surgery

Jerrold H Levy, MD
Professor of Anesthesiology
Emory University School of Medicine
Deputy Chairman for Research
Director, Cardiothoracic Anesthesiology
Emory Healthcare
Atlanta, Georgia
 Wisdom for Thought

“Doctors pour drugs of which

they know little for disorders of
which they know less into
patients of which they know
nothing.”

Voltaire
 VASOACTIVE THERAPY

Vasodilators Beta Blockers

Other agents

BP = SVR X CO
(SV x HR)

Vasoconstrictors
Inotropes
 Beta Adrenergic Blockers

► Beta blockers represent first line agents for

hypertension and tachycardia; especially in
patients with ischemic heart disease.
► Beta blockers produce negative inotropic
effects and conduction defects, and should
be used cautiously in patients with reactive
airways disease and ventricular
dysfunction.
► Beta blockers have “ceiling effects” as
antihypertensive agents, and effects are
limited by heart rate.
Kass DA Ann Intern Med. 1993;119:466-73.
 Vascular Endothelium

Huraux C et al: Circulation 1999;99:53-59.

 Vascular Regulation

Landry NEJM 2001; 345: 588.

 Vasodilators (1)
► ACE inhibitors
► Adenosine

► A-II
antagonists
► Alpha-1-adrenergic antagonists

► Alpha-2-adrenergic agonists
► ANP (nesiritide)
► Beta-2-adrenergic agonists
 Vasodilators (2)
► Calciumchannel blockers
► Dopamine-1-agonists

► Hydralazine

► Nitrovasodilators

► Phosphodiesterase inhibitors
► Prostaglandins
 Therapeutic Approaches
To Vasodilation
► ACE inhibition
► Alpha-1 adrenergic blockade
► Calcium channel blockade
► Dopamine-1 stimulation
► Ganglionic blockade
► Cyclic nucleotide stimulation
► PDE inhibition
► Potassium channel modulation
►
Novel agents

Levy JH: The ideal agent for perioperative hypertension. Acta Anaesth Scand 1993; 37(S):20-25.
 Vascular Smooth Muscle

H
=O
HC-O- N= Enzymatic
O H
Glutathione H
H
C - O - N=O
H C-O- N=O =O

=O
=O
S-Transfers:
HC-O- N= C - O - N==
O Product is nitrate. H C - O - N==
O
+ NO 2

O H
O Activity O
O
O increased by H C - O - N==
O H C-O- N== O
HC-O- N== H
O excess GSH H

H O

Nonenzymatic Enzymatic
cysteine Unknown pathway. Likely
dithiothreitol requires glutathione. Less active
N-acetylcysteine in coronary microvessels <100 µm
mercaptosuccinic acid (Possibly secondary to decreased
thiosallcylic acid availability of glutathione)
methylthiolsalicylic acid
others
(large concentrations)
N=0 Guanylate
Cyclase
N=0
 Mechanisms of Nitrate Tolerance

► Decreased bioconversion to NO 1

► Depletion of sulfhydryl groups 2,3

► Neurohumoral adaptations 4

► Superoxide anion production 5

► Upregulation of endothelin 1 6

1. Münzel T. Am J Cardiol. 1996;77:24C-30C.

2. Parker JD, Parker JO. N Engl J Med. 1998;338:520-531.
3. Needleman P, Johnson EMJ. J Pharmacol Exp Ther. 1973;184:709-715.
4. Münzel T, et al. J Am Coll Cardiol. 1996;27:297-303.
5. Münzel T, et al. J Clin Invest. 1995;95:187-194.
6. Münzel T, et al. Proc Natl Acad Sci. 1995;92:5244-5248.
 Hemodynamic effects of Inhaled NO in
Patients with Heart Failure (n=19)

Room Air NO P
HR, bpm 90 ± 3 93 ± 3 NS
MAP, mmHg 79 ± 3 81 ± 3 NS
SVR, dyne –s-cm-5 1102 ± 104 1041 ± 97 NS
PA, mmHg 35 ± 4 37 ± 4 NS
PAWP, mmHg 25 ± 3 31 ± 4 <.001
LVEDP, mmHg: n=10 28 ± 4 34 ± 5 .02
PVR, dyne – s cm-5 226 ± 30 119 ± 13 <.001
PA-PAWP, mmHG 11 ± 1 6 ± 0.5 <.001
SVI, mL/m2 226 ± 30 24 ± ±2 .03
CI, L-min-1 m-2 2.3 ± 0.2 2.1 ± 0.2 .03
Loh E. Cardiovascular effects of iNO in patients with LV dysfunction. Circulation. 1994;90:2780.
 Hypertension In Cardiac
Surgical Patients (1)

► Patients normotensive may become

hypertensive.
► Most BP changes develop acutely and
require rapid intervention.

► Characterized by systemic vasoconstriction

with intravascular hypovolemia.

► Patients may have preop biventricular

dysfunction.
 Hypertension In Cardiac
Surgical Patients (2)

► BPmay be maintained at lower levels to

avoid graft/suture line disruption.
► Patients are being “Fast Tracked.”

► Mechanical manipulation, suturing with

potential risk for coronary/IMA spasm.
► Ventriculardysfunction is common in
patients with normal preop function due to
stunning/reperfusion injury.
 Nitrovasodilators
Sodium Nitroprusside

NO+

CN

CN
Na+ CN

Fe++

CN
Na
+

CN
 Venodilation Occurs with
Nitroprusside Therapy

► Nitroprusside is potent venous and

arterial vasodilator
► Venodilation:

● Affects cardiac output

● Often requires compensatory
volume replacement

Kerins DM, et al. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological Basis
of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 1997:843-870.
 IV Dihydropyridines
Calcium Channel Blockers

► 1st Generation CCB: Nifedipine

► 2nd Generation CCB: Nicardipine, isradipine

► 3rd Generation CCB: Clevidipine

 Nicardipine
► Only IV dihydropyridine CCB
available in the United States
► Arterial vasodilator1
► Decreases SVR2-6
► More selective for vascular smooth
muscle 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 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

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

Lambert CR: Am J Cardiol 1993;71:420.

 Hemodynamic Effects Of Isradipine

Variable Baseline 30 Minutes

SBP 150 ± 20 -30 ± 30‡
DBP 75 ± 9 -18 ± 8.0‡
MAP 101 ± 10 -23 ± 11.0‡
HR 89 ± 12 4 ± 12*
CI 2.7 ± 0.6 0.4 ± 0.6‡
SVR 1470 ± 417 -478 ± 281‡
SVI 0.0310 ± 0.006 0.004 ± 0.006†
PADP 13.4 ± 3.9 0.2 ± 3.2
PCW 11.7 ± 4.3 -0.0 ± 3.0
PVR 1.25 ± 0.9 -0.05 ± 0.47

Leslie: Circulation. 1994 Nov;90(5 Pt 2):II256.

 Nicardipine Pharmacokinetics
and Metabolism

► Redistribution phase after IV bolus

● Half-life=2.7 minutes

► Intermediate phase
● Half-life=44 minutes

► Terminal half-life after long-term

infusion
● Half-life=14.4 hours

Cardene IV [package insert].

 Nicardipine: Pharmacokinetics of IV
Bolus Administration
10
150

Change in MAP (mm Hg)

Plasma nicardipine concentration (ng/mL)

-10

-20
100 -30

-40

-50
0 20 40 60 80 100 120 140
50 Nicardipine concentration (ng/mL)

Group 1: 0.25 mg
Group 2: 0.5 mg
Group 3: 1.0 mg
Group 4: 2.0 mg

0
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Time after drug administration (h)

Adapted from Cheung AT, et al. Anesth Analg. 1999;89:1116.

 Clevidipine In CABG
A Dose-finding Study

► Clevidipine decreased MAP and SVR, without

changes in heart rate, CVP, PAOP, or CI at
increasing doses.
► The early phase of drug disposition had a half-life
of 0.6 min. The context-sensitive half-time <2 min
for up to 12 hours of administration.
►

► CONCLUSION: Clevidipine is a CCB that lowers

BP without changing heart rate, CI, or cardiac
filling pressures.

Bailey
Bailey JM
JM et
et al:Anesthesiology
al:Anesthesiology 2002;96:1086.
2002;96:1086.
 Clevidipine Effectively and Rapidly Controls Blood
Pressure Preoperatively in Cardiac Surgery

Results of the Randomized, Placebo-

Controlled Efficacy Study of Clevidipine
Assessing its Preoperative antihypertensive
Effect in Cardiac Surgery-(ESCAPE-1) Trial

Levy JH: Anesth Analg, In Press.

 Arterial Spasm
► Loss of endothelial function via
vascular injury and platelet activation
is potential mechanism, but other
mechanisms include NO scavenging
by hemoglobin.

► Thromboxane, a potent constrictor,

has been implicated.

► Only certain drugs will completely

reverse arterial spasm.
 Vasospasm: Body of Literature

► 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.
 In Vitro Effects Of Phosphodiesterase
Inhibitors On Human IMA Relaxation

0 A =amrinone
E =enoximone
20
M=milrinone
% Relaxation

P =papaverine
40

60

80 E
A
M P
100
0.1 1 10 100 1000
Concentration (microM)

Salmenpera M, Levy, JH. Anesth Analg. 1996;82:954-957.

 A Comparative Evaluation of the Effects of
Multiple Vasodilators on Human IMA

► Nitroglycerin was most

potent for thromboxane
A2 inhibitor

► Milrinone,dihydropyridines
, PGE1, and papaverine
were also effective at
therapeutically used doses

Huraux C et al. Anesthesiology. 1998;88:1654-1659.

 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.
 Comparative Study of Calcium
Antagonists On Human Radial Artery

He GW: JTCVS 2000;119:94

 Simulated Drug Level Curves

“Full” loading dose = [Cp] x Vdss

Smaller loading dose = [Cp] x Vc
No loading dose
60
Plasma Drug Level

50

40 Therapeutic
Concentration
30 Range
20

10

0
0 1 2 3 4 5 6

Time (Half-life)
 Fenoldopam (Corlopam)
► Selective vascular DA1 agonist
► Produces arterial vasodilation,
increases renal perfusion, and
naturesis
► Short duration of action/half life

► Approved in June 1997

► Expense, potency, reflex tachycardia

are major issues
 Summary (1)
► Multiple pharmacologic agents produce
vasodilation via different mechanisms.
► Beta-blockers are important in hypertension

and tachycardia, but effects are limited by

heart rate.
► Arterial vasoconstriction is characteristic of

perioperative hypertension with intravascular

hypovolemia.
► Nitrate tolerance is important to consider in

critically ill patients.

 Summary (2)
► Nitrovasodilators decrease both preload and
resistance vessels.

► DHP CCBs produce arterial selective

vasodilation, controlling BP without producing
venodilation or negative inotropic and
conduction effects, and reverses vasospasm in
the IMA and other vascular beds.

► Large clinical trials regarding DHP CCBs will

contribute to our understanding of their
perioperative and other indications.
VasoactiveTherapy.com
Emerging Agents for Blood Pressure
Control in Cardiac Surgery
Results of the ECLIPSE Trials Comparing Clevidipine
with Available Agents in Perioperative Hypertension

Kevin A. Stierer Sr., M.D.

Chief Division of Cardiac and Thoracic Anesthesia
Associate Director Cardiac Surgery ICU
The Heart Institute at St. Joseph Medical Center
Towson, Maryland
 Acknowledgements

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.
 Perioperative Hypertension

► Patients with preoperative hypertension are at an

increased risk for perioperative complications1
► Approximately 30% to 56% of patients undergoing
routine cardiac surgery experience acute rises in blood
pressure that require administration of a parenteral
antihypertensive agent2
► Antihypertensive therapy is often needed to manage life-
threatening arterial bleeding, myocardial ischemia, or
cardiac 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.
 Considerations for Perioperative BP
Control During Cardiac Surgery

► INTRAOPERATIVE
● Induction
● Cannulation
● Protamine and hemostasis
(aortotomy/suture lines)
● Chest closure
● Transport
► POSTOPERATIVE
● 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.
 Clevidipine: The First Third-
Generation Calcium Channel Blocker
Generic Name Brand Name
First Nifedipine Procardia®, Adalat®
Generation
Second Nicardipine/ (I.V.) Cardene®/Cardene I.V.
Generation Amlodipine Norvasc®
Isradipine DynaCirc®
Felodipine Plendil®
Nimodipine/ (I.V.) Nimotop®/Nimotop I.V.

Nisoldipine Sular®

Third Clevidipine TBD

Generation

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

 The Clevidipine Molecule

Cl

Cl
H
CH3OOC COOCH2OOCC3H7

H3C N CH3

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
Cl
Cl

O Cl
O O Cl O
O O HO
O Esterases + +
O * O
OH
H H
O
O
N
H N
H

Clevidipine 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

► BP-lowering effects are seen within 2–3 minutes of

clevidipine infusion
10 SBP Changes
5
% Change From Baseline

–5

–10

–15

–20
SBP
–25

–30
0 5 10 15 20 25 30
Time (min)
SBP changes for patients receiving clevidipine during a 30-minute treatment period.

Levy JH, et al. Anesthesiology. 2005;103:A354.

 Clevidipine: Linear Dose Response

► Linear dose response in postoperative cardiac

surgery patients
► Effective in 95% of patients at ≤3.2 mcg/kg/min
n=19
100
90
n=9
Responders (%)

80
70 n=6
60
50
40 n=4
30
20 n=1
10 n=0
0
0 0.05 0.18 0.32 1.37 3.19
Infusion Rate (mcg/kg/min)

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.

 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
Clevidipine Concentration

100
at Css (nmol/L)*

80

60

40

20

0
0 5
10 15 20 25 30 35
Dose Rate (nmol/kg/min)
*Css = concentration at steady state; median blood concentration of clevidipine obtained during the last 10 minutes of infusion.

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: Ultrashort Half-Life

► Clinically relevant half-life: approximately 1 minute

Arterial and venous clevidipine

blood samples

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

 Clevidipine: Metabolized by Plasma
and Tissue Esterases

► Clevidipine is rapidly metabolized by esterases

in blood and extravascular tissue to an inactive
carboxylic acid metabolite
Cl
Cl

O Cl
O O Cl O
O O HO
O Esterases + +
O * O
OH
H H
O
O
N
H N
H

Clevidipine 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 Offset

► After discontinuation of clevidipine infusion, there was a

rapid clearance
► BP returned to baseline in <10 minutes in healthy volunteers
100
Clevidipine Infusion
90 MAP
MAP (mm Hg) and
HR (beats/min)

80

70

60

50

40
–5 0 5 10 15 20 25 30 35
Time (min)

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

 Clevidipine: Arterial Selectivity
Mean Arterial Pressure
Pressure Central Venous
90
12
* 10
mm Hg

80 † 8

mm Hg
†
† 6
70 4
2
0
C1 0.375 0.75 1.5 3 C2 Systemic Vascular Resistance 0 0.375 0.75 1.5 3 0
mcg/kg/min 1400 mcg/kg/min

1200 ‡
Units

†
†
1000 †

0
C1 0.375 0.75 1.5 3 C2
mcg/kg/min

*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.

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

 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
Cardiac Output Stroke Volume

†
6 75 *
5
70
L • min–1

mL/beat
4
3
65
2
1
*P<0.05
0 0
C1 0.375 0.75 1.5 3 C2 †P<0.001 C1 0.375 0.75 1.5 3 C2

Infusion Rate (µg • kg–1 • min–1 ) Infusion Rate (µg • kg–1 • min–1 )

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

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

 Clevidipine
Minimal Effect on Heart Rate

Preoperative HR Changes Postoperative HR Changes

in Non-Anesthetized Patients in Anesthetized Patients

% Change From Baseline

% Change From Baseline

10
5 5
HR
0 0
HR
–5 –5

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

Levy JH, et al. Anesthesiology. 2005;103:A354.

Singla N, et al. Anesthesiology. 2005;103:A292.
 Clevidipine Clinical Development

Phase I Phase II Phase III

N=89 N=300 N=1821

Patients: Mild to Patients: Perioperative Severe

Healthy Volunteers Moderate Hypertension Perioperative Hypertension Hypertension
N=86 N=214 N=1721 N=100

Dose Response: ESCAPE: Efficacy

Tolerability, VELOCITY:
Dose Response Clevidipine Clevidipine
Safety, PK Severe Hypertension
vs Placebo vs Placebo

PK, Metabolism, ESCAPE: Efficacy

Hemodynamics:
Rates and Routes PK/BP Clevidipine
Clevidipine vs SNP
of Excretion vs Placebo

PK/PD:
BP, HR: ECLIPSE:
PK Clevidipine
Clevidipine vs SNP Safety vs NTG
vs Placebo

ECLIPSE:
QTc Study BP, Dose/PK
Safety vs SNP

BP: Clevidipine ECLIPSE:

vs Placebo Safety vs NIC

Data on file. The Medicines Company.

 ECLIPSE: Rationale
► Clevidipine is an IV dihydropyridine calcium
channel blocker with an ultrashort half-life (~1 min)
► Phase I & II studies (300 pts) demonstrated:
● Dose: 2–16 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

Bailey J. Anesthesiology 2002;96:1086-94.

1

Levy J. Anesth Analg 2006 (in press).

2
 ECLIPSE 1, 2, and 3
Blood Pressure Control with
Clevidipine Compared with
Nitroglycerin, Sodium Nitroprusside, or
Nicardipine in the Treatment of
Peri-operative Hypertension:
Eclipse - NTG
Eclipse - SNP
Eclipse - NIC
 Objectives of ECLIPSE Trial

Primary
► Investigate the safety of clevidipine in
perioperative HTN

Secondary
► Evaluate adverse events
► Examine blood pressure control
 ECLIPSE: Protocols
► 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
► Patients undergoing cardiac surgery; CABG,
OPCAB, Valve, MIDCAB
► Treatment with study drug allowed until discharge
from ICU

Data on file. The Medicines Company.

 ECLIPSE: Trial Design

Perioperative Perioperative Postoperative

Clevidipine
Clevidipine Clevidipine
vs sodium
vs nitroglycerin vs nicardipine
nitroprusside

1:1 1:1 1:1

Nitroglycerin Sodium
Clevidipine Clevidipine Clevidipine Nicardipine
N=278 nitroprusside
N=268 N=296 N=188 N=193
N=283

Data on file. The Medicines Company.

 Inclusion Criteria

Pre-randomization
► ≥ 18 years of age
► Written informed consent
► Planned CABG, OPCAB, MIDCAB surgery and/or valve
repair/replacement surgery
Post-randomization
► Require treatment for perioperative HTN
 Exclusion Criteria
► Women of child bearing potential
► CVA ≤ 3 months of randomization
► Intolerance to calcium channel blockers
► Hypersensitivity to NTG, SNP or NIC
► Allergy to the lipid vehicle
► Permanent ventricular pacing
► Any disease/condition that would put the
patient at risk
► Participation in another trial within 30 days
 Treatment

► Clevidipine
● Initiated 2 mg/hr

● Titrated doubling increments Q 90s to 16 mg/hr

● 40 mg/hr maximum

► Comparators (NTG, SNP, NIC) admin per institutional

practice

► Treatment duration up to discharge from the ICU

► Concomitant anti-hypertensives discouraged

 Outcome Endpoints

Primary* (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
► SAEs through day 7
► BP control during the first 24 h

* Blinded CEC adjudication of all primary measures

 Statistical Methods

► Assumptions
● Sample size (1500 pts) recommended by FDA
for safety profile assessment
► Descriptive analytical methods
● Pre-specified safety analysis population (pts
according to actual treatment received)
● Data pooled to provide an overall event rate
for Clevidipine & comparator arms
● Pre-specified analysis of each randomized
comparison
 Patient Disposition
Clevidipine Comparators

Randomized patients 971 993

Met post-randomization criteria 755 757
Safety population 752 754
Completed study 715 719
Did not complete study 37 35
Withdrew consent 0 1
Physician decision 1 0
Lost to follow up 15 6
Adverse experience 0 0
Patient death 20 28
Other 1 0
 Baseline Characteristics

Clevidipine Comparators
n=752 n=754
Age, median (range) 65 (24-87) 66 (19-89)
Male 72% 74%
Caucasian 82% 83%
Hx HTN 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

Clevidipine Comparators
n=752 n=754
Surgery duration, median hrs 3.32 3.23
Procedure
CABG 77% 77%
Valve replacement/repair 14% 12%
CABG & Valve replacement/repair 9% 11%
Other 0.3% 0.1%
 ECLIPSE NTG: Drug Administration

Clevidipine Nitroglycerin
N=268 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 3.35 hr 8.13 hr
Duration (median)

Data on file. The Medicines Company.

 ECLIPSE SNP: Drug Administration

Clevidipine Nitroprusside
N=296 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 4.03 hr 3.25 hr
Duration (median)

Data on file. The Medicines Company.

 ECLIPSE NIC: Drug Administration

Clevidipine Nicardipine
N=188 N=193
Dosed During 188 (100) 193 (100)
Post-Op
Overall Infusion 5.55 hr 5.12 hr
Duration (median)

Data on file. The Medicines Company.

 Primary Endpoint
10%

Clevidipine 7.9% 7.9%

8%
30-Day Events (%)

Comparators
6%

3.8%
4%
2.8%
2.3% 2.4%
2% 1.7%
1.1%

0% n=719 n=729 n=700 n=707 n=700 n=705 n=712 n=710

Death MI Stroke Renal

Dysfunction
 Primary Endpoint by
Treatment Comparison

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

Dysfunction

* p = 0.045
 Serious Adverse Events

Clevidipine Comparators
n=752 n=754
Total 17.7% 20.0%
AFIB 2.4% 2.4%
Respiratory failure 1.1% 2.5%
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

CLV NTG SNP NIC

n/N (%) n/N (%) n/N (%) n/N (%)
Afib (total) 275/752 91/278 95/283 71/193
(36.6) (32.7) (33.6) (36.8)
Afib 108/296 91/278 25/111 16/50
(before March (36.5) (32.7) (22.5) (32.0)
25, 2005)
Afib 67/188 N/A 70/172 55/143
(after March 25, (35.6) (40.7) (38.5)
2005)

► 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

Data on file. The Medicines Company.

 ECLIPSE Secondary Endpoint:
SBP Control Within Predefined Range Over 24 Hours

Upper
SBP

Lower

Time (24hrs)
Prespecified SBP ranges of 75 – 145 (pre and post-op), 65-135 (intra-op)
 ECLIPSE: Summary

► Largest safety program to ever be performed with

an intravenous antihypertensive (n=1,512)
► Balanced demographics and baseline
characteristics
► Met primary endpoints with adverse event rates
comparable across groups
► Atrial fibrillation rates are equivalent
► AUC data suggests better overall BP control
compared with SNP and NTG

Data on file. The Medicines Company.

 Conclusions

► Clevidipine is a safe alternative to

therapy with commonly used
antihypertensive agents

► Clevidipine demonstrated superior blood

pressure control as assessed by integral
analysis of excursions outside specified
ranges over time