Clevidipine Effectively and Rapidly Controls Blood

Pressure Preoperatively in Cardiac Surgery Patients:

The Results of the Randomized, Placebo-Controlled
Efficacy Study of Clevidipine Assessing Its Preoperative
Antihypertensive Effect in Cardiac Surgery-1
Jerrold H. Levy, MD*
Miguel Y. Mancao, MD†
Richard Gitter, MD‡
Dean J. Kereiakes, MD, FACC§㛳
Alina M. Grigore, MD¶
Solomon Aronson, MD, FACC,
FCCP, FAHA#
Mark F. Newman, MD#
BACKGROUND: Clevidipine is an ultrashort-acting, third-generation IV dihydropyri-
dine calcium channel blocker that exerts rapid and titratable arterial blood pressure
reduction, with fast termination of effect due to metabolism by blood and tissue
esterases. As an arterial-selective vasodilator, clevidipine reduces peripheral vas-
cular resistance directly, without dilating the venous capacitance bed. In this
randomized, double-blind, placebo-controlled multicenter trial we evaluated the
efficacy and tolerability of clevidipine in treating preoperative hypertension.
METHODS: One-hundred-fifty-two patients scheduled for cardiac surgery with cur-
rent or recent hypertension were randomized to receive clevidipine or placebo
preoperatively. One-hundred-five patients met postrandomization entrance crite-
ria (systolic blood pressure [SBP] ⱖ160 mm Hg after inserting an arterial catheter)
for reduction by ⱖ15% from baseline in SBP. The patients thus received infusions
of clevidipine (0.4 – 8.0 ␮g 䡠 kg⫺1 䡠 min⫺1) or 20% lipid emulsion (placebo) for at
least 30 min. Treatment failure was defined as failure to reduce SBP by ⱖ15% from
baseline or discontinuance of drug for any reason.
RESULTS: Patients treated with clevidipine demonstrated a 92.5% rate of treatment
success and a significantly lower rate of treatment failure (7.5%, 4 of 53) than
patients receiving placebo (82.7%, 43 of 52; P ⬍ 0.0001). Clevidipine achieved target
blood pressures (SBP reduced by ⱖ15%) at a median of 6.0 min (95% confidence
interval 6 – 8 min). A modest increase in heart rate from baseline occurred during
clevidipine administration. Adverse events for each treatment group were similar.
CONCLUSIONS: Clevidipine was effective in rapidly decreasing blood pressure pre-
operatively to targeted blood pressure levels and was well tolerated in patients
scheduled for cardiac surgery.
(Anesth Analg 2007;105:918 –25)

A cute hypertension in patients undergoing cardiac

surgery contributes directly and indirectly to postopera-
tive morbidity, including myocardial ischemia due to
increased myocardial oxygen demand, bleeding due to
From the *Cardiothoracic Anesthesiology and Critical Care,
Emory University Hospital, Atlanta, Georgia; †Sacred Heart Health
System, Pensacola, Florida; ‡Birmingham Baptist Medical Center
Montclair, Birmingham, Alabama; §Lindner Research Center and
㛳Christ Hospital Heart and Vascular Center, The Linder Research
Center, Cincinnati, Ohio; ¶Mayo Clinic Hospital, Department of
Anesthesiology, Phoenix, Arizona; and #Department of Anesthesi-
ology, Duke University Medical Center, Durham, North Carolina.
Accepted for publication June 18, 2007.
Dr. Jerrold Levy, Section Editor for Hemostasis and Transfusion
Medicine, was recused from all editorial decisions related to this
manuscript.
Sponsored by The Medicines Company.
Drs. Mancao, Gitter, and Grigore have no financial disclosures.
Dr. Newman has received financial support from Duke University
for work contracted by The Medicines Company. Drs. Aronson and
Levy have received consultant fees from The Medicines Company.
Dr. Kereiakes has received honoraria related to advisory activities
and the development of educational materials from Conor Medsys-
tems, Cordis, Core Valve, Eli Lilly and CO, Guidant Corporation,
possible disruption of arterial suture lines, and neuro-
logic complications (1– 6). It is generally accepted that the
rapid, controlled treatment of increases in arterial blood
pressure is important for minimizing the risk of postop-
erative morbidity and associated mortality (7). As many
as half of cardiac surgery patients may need intervention
with IV therapy for acute perioperative increases in
arterial blood pressure (8).
Perioperative hypertension is primarily caused by
increased sympathetic discharge with systemic vasocon-
striction, and is often treated with IV therapy to induce
vasodilation (3–5,8,9). However, IV antihypertensive
Boston Scientific, and Medtronic, and has received grant support
related to research activities from Pfizer, Conor Medsystems, Cor-
dis, Boston Scientific and Medtronic.
Address correspondence and reprint requests to Jerrold H. Levy,
MD, Cardiothoracic Anesthesiology and Critical Care, Emory Uni-
versity Hospital, 1364 Clifton Road, NE, Atlanta, GA 30322. Address
e-mail to jerrold.levy@emoryhealthcare.org.
Copyright © 2007 International Anesthesia Research Society
DOI: 10.1213/01.ane.0000281443.13712.b9

918 Vol. 105, No. 4, October 2007

drugs that do not act selectively on resistance vessels
may induce precipitous hypotension in a patient
population vulnerable to cardiovascular insult and
potentially hypovolemia (4,9). Among currently avail-
able drugs, none provides the ideal combination of
vascular selectivity, rapid onset and offset for precise
titratability, and nontoxicity needed for tight arterial
blood pressure control in patients at risk (4,8 –10).
Clevidipine, the first third-generation IV dihydro-
pyridine calcium channel blocker, exerts arterial-
specific vasodilating effects and is characterized by an
ultrafast onset and offset of effect in decreasing blood
pressure (11,12). After IV administration, clevidipine
is quickly cleared from the blood by nonspecific blood
and tissue esterases, resulting in rapid elimination
with a half-life of approximately 1 min (12–14). In
healthy volunteers, arterial blood pressure and heart
rate (HR) returned to baseline within 10 –15 min after
discontinuation of a short infusion (14). Rapid elimi-
nation of clevidipine is maintained after stopping
either long (24 h) or short infusions (11,15).
Dose-finding and pharmacodynamic studies of cle-
vidipine have demonstrated dose-dependent arterial
blood pressure reduction without changes in cardiac
filling pressures (11,12,16,17). To clearly demonstrate
efficacy against placebo response before cardiac sur-
gery, and to evaluate the time to achieve target arterial
blood pressure in this high-risk patient population,
the Phase III Efficacy Study of Clevidipine Assessing
its Preoperative Antihypertensive Effect in Cardiac
Surgery-1 (ESCAPE-1) trial was performed. The pur-
pose of this randomized, double-blind, placebo-
controlled trial was to determine the efficacy of IV
clevidipine versus placebo as treatment for preopera-
tive hypertension in cardiac surgery patients.
METHODS
The study was conducted at 12 study sites. At each
site, the study was approved by an independent ethics
committee or IRB. All patients provided written in-
formed consent before initiation of any study-related
procedures.
Patient Selection
For inclusion in the trial, patients ⱖ18 yr old and
scheduled for cardiac surgery (including on-pump,
off-pump or minimally invasive coronary artery by-
pass graft [CABG] surgery and/or cardiac valve re-
pair or valve replacement surgery) were required to
meet prerandomization inclusion criteria of hyperten-
sion within the past 6 mo needing treatment with
antihypertensive medication, or active hypertension
upon hospital admission. Patients were randomized to
clevidipine or placebo groups based on a computer-
generated randomization scheme (constructed using
SAS software, version 8, SAS Institute, Cary, NC) and
stratified by site in blocks of four in the order that the
patients qualified. An interactive voice response sys-
tem was used to randomize patients to treatment
Vol. 105, No. 4, October 2007
groups and to assign study medication. Patients were
randomized on the day of surgery after meeting the
prerandomization inclusion criteria; each successive
patient per site was assigned a unique identification
number. Patients were excluded from randomization
if they had cerebrovascular accident within the past 3
mo; preexisting left bundle branch block or permanent
ventricular pacing; known intolerance to calcium
channel blockers; allergy to soybean oil or egg lecithin,
or any other components of the lipid vehicle for
clevidipine; or any other disease or condition exposing
them to undue risk if they participated in the trial.
Patients were also excluded if they had participated in
another therapeutic drug or therapeutic device trial
within 30 days of starting this study. Women of
childbearing age were randomized only if they had a
negative urine or serum pregnancy test.
After insertion of an arterial catheter, patients were
treated with an IV infusion of clevidipine or placebo if
they met prespecified postrandomization criteria: 1)
systolic blood pressure (SBP) ⱖ160 mm Hg and 2)
clinically assessed as needing a reduction in SBP by at
least 15% from baseline. A threshold of 160 mm Hg
was chosen to be high enough for a reduction by
ⱖ15% to be clinically indicated in patients who were
subsequently to receive induction of anesthesia. A
reduction of ⱖ15% was thought to be a large enough
change in SBP to exclude random, background fluc-
tuations in arterial blood pressure, yet was low
enough to be consistent with clinical practice and any
safety concerns. Clinical assessment included the de-
termination that the patient’s SBP was stable at ⱖ160
mm Hg and that reduction by ⱖ15% was medically
indicated and safe.
Study Medications and Patient Treatment
Clevidipine or placebo was administered via pe-
ripheral vein or central venous infusion, using either a
syringe or volumetric pump. The use of sedation for
the purpose of inserting a central venous catheter was
permitted. The use of sedatives, ␤ blockers or vasodi-
lators before and during study drug administration
was recorded. During the first 30 min of study drug
administration, the use of other medications and pro-
cedures specifically for the treatment of hypertension
was prohibited for patients participating in the trial,
unless treatment failure occurred. Drugs with antihy-
pertensive properties were permitted during study
drug administration only if used for another purpose
besides treating hypertension (for example, nitroglyc-
erin for managing ischemia or esmolol for managing
tachycardia).
Patients received either IV clevidipine 0.5 mg/mL in
a 20% lipid solution or placebo. Placebo was a 20% lipid
emulsion identical to the clevidipine lipid vehicle. Both
were supplied as sterile, white, opaque liquids in 100-mL
single-use glass bottles. Blinded study drug infusion was
started at 0.4 ␮g 䡠 kg⫺1 䡠 min⫺1 (which is equivalent to
approximately 2 mg/h in an 80 kg patient) and titrated
© 2007 International Anesthesia Research Society 919
to effect as tolerated by the patient in doubling incre-
ments approximately every 90 s up to a rate of 3.2
␮g 䡠 kg⫺1 䡠 min⫺1. More than 3.2 ␮g 䡠 kg⫺1 䡠 min⫺1, study
drug titration in serial increments of 1.5 ␮g 䡠 kg⫺1 䡠 min⫺1
was permitted as tolerated up to a maximum rate of 8.0
␮g 䡠 kg⫺1 䡠 min⫺1 as defined for this study. The study
drug could be temporarily stopped and restarted to
achieve the desired arterial blood pressure effect. Study
drug was administered for at least 30 min and allowed
up to a maximum of 1 h or anesthesia induction, unless
treatment failure (defined in the following section) oc-
curred. No patients received study drug after anesthesia
induction. Titration up to the maximum infusion rate of
8.0 ␮g 䡠 kg⫺1 䡠 min⫺1 was required before treatment fail-
ure was identified, assuming that each dose was well
tolerated by the patient and no safety issue arose. After
treatment failure, alternative antihypertensive treatment
could be instituted as per institutional practice.
Study Assessments
All patients were assessed for baseline SBP and
diastolic blood pressure and other vital signs within
24 h before randomization. Baseline electrocardio-
gram, hematologic and biochemical laboratory screen-
ing, and medical history were obtained within 14 days
before randomization. Antihypertensive efficacy was
evaluated by comparing the incidence of treatment
failure between the clevidipine and placebo treatment
groups over the 30-min time period from initiation of
study drug. Treatment failure was defined as the
premature and permanent discontinuation of study
drug infusion for any reason, or the failure to decrease
SBP by ⱖ15% from baseline at any time within the
30-min period from study drug initiation. The event
causing each treatment failure was assessed and clas-
sified into one of three predefined categories: lack of
efficacy (no change or an increase in SBP, or failure to
achieve a nominal decrease in SBP by an acceptable
time); insufficient efficacy (inability to achieve at least
15% reduction in SBP before the end of the 30-min
treatment period); or safety reason. The study also
evaluated time to target blood pressure (first reduc-
tion of SBP by ⱖ15% from baseline), change in mean
arterial blood pressure (MAP) from baseline, and
change in HR. SBP was measured via an indwelling
arterial catheter. HR, SBP, and diastolic blood pressure
were assessed every minute during the treatment
period and for at least 30 min after termination of
study drug infusion until these vital signs had stabi-
lized at levels acceptable to the attending physician,
up to the induction of anesthesia. The incidence of
adverse events (AEs) occurring from study drug ini-
tiation until hospital discharge or 7 days, whichever
came first, regardless of physician-assessed causal
relationship with study drug, was recorded.
Statistical Analysis
Study sample size was determined based on the
assumption that clevidipine would be more effective
920 Clevidipine in Preoperative Hypertension
in decreasing SBP than placebo. Assuming a treatment
success rate of 40% for patients treated with clevidip-
ine and 12% for patients receiving placebo, it was
calculated that 50 patients per treatment group would
be required to demonstrate a difference between the
two groups with 85% power at a two-sided signifi-
cance level of 0.05. Efficacy results from this study
were based on analysis of the modified intent-to-treat
(MITT) population, defined as all patients who were
randomized and met the prespecified postrandomiza-
tion inclusion criteria immediately before treatment
initiation. Comparisons were performed according to
the randomized treatment assignment, regardless of
the actual treatment received. Safety results were
based on analysis of the safety population, defined as
all randomized patients treated with study drug ac-
cording to the actual treatment received. The inci-
dence of treatment failure between treatment groups
and other categorical parameters was analyzed using
the ␹2 test. Continuous parameters were calculated
using an analysis of covariance (ANCOVA) model for
absolute change from baseline with treatment as a
factor and baseline as a covariate, and an analysis of
variance (ANOVA) model for percentage change from
baseline with treatment as a factor. Time to target
arterial blood pressure was analyzed as a time-to-
event parameter, using the log-rank test and Kaplan–
Meier survival curves. All statistical comparisons were
made using two-sided tests at the ␣ ⫽ 0.05 significance
level.
RESULTS
One-hundred-fifty-two patients were enrolled into
the study (76 in each treatment group) based on
meeting prerandomization entrance criteria. Of this
group, 105 patients met postrandomization treatment
criteria of SBP ⱖ160 mm Hg, thus qualifying for
treatment and inclusion into the MITT population.
The MITT population consisted of 53 patients in the
clevidipine group and 52 patients in the placebo group
(Fig. 1). The number of MITT patients enrolled across
the 12 study sites varied, with no single site contrib-
uting more than 11 patients. One patient in the MITT
placebo group did not receive treatment because be-
fore administration, the assigned study medication
was found to be frozen. Thus, the safety population
consisted of 53 clevidipine patients and 51 placebo
patients.
Baseline Comparison of Treatment Groups
Baseline demographic variables and medical risk
factors were similar between the clevidipine and pla-
cebo treatment groups (MITT population) except for
age distribution, history of myocardial infarction (MI),
and family history of coronary artery disease (Table 1).
More clevidipine patients were ⱖ65-yr-old and had a
medical history of MI compared with placebo patients,
whereas more placebo patients reported a family
history of coronary artery disease.
ANESTHESIA & ANALGESIA
Figure 1. Patient populations analyzed:
53 clevidipine patients and 52 placebo
patients met postrandomization criteria
for treatment of preoperative hyperten-
sion (MITT population); 53 clevidipine
and 51 placebo patients received study
drug (safety population) and were
evaluated according to actual treat-
ment received. MITT ⫽ modified
intent-to-treat population, consisting
of randomized patients who quali-
fied for study treatment according to
prespecified study criteria for preop-
erative hypertension.

Table 1. Baseline Patient Demographics/Medical History (Modified Intent-to-Treat Population)

Clevidipine Placebo
Characteristic (N ⫽ 53) (N ⫽ 52) P
Age (yr), mean (sd) 65.8 (10.0) 61.7 (10.3) 0.04
Age ⱖ65 yr 33 (62.3) 18 (34.6) 0.0046
Male patients 37 (69.8) 36 (69.2) 0.95
Weight (kg), mean (sd) 89.1 (19.0) 89.5 (22.8) 0.92
Height (cm), mean (sd) 171 (11) 172 (10) 0.54
Baseline preoperative SBP (mm Hg), mean (sd) 182 (22) 177 (19) 0.23
Previous myocardial infarction 16 (30.2) 6 (11.5) 0.02
Previous PCI 13 (24.5) 11 (21.2) 0.68
Previous CABG 5 (9.4) 1 (1.9) 0.10
Family history of CAD 27 (50.9) 40 (76.9) 0.0056
Hypertension 53 (100.0) 52 (100.0) NA
Congestive heart failure 6 (11.3) 6 (11.5) 0.97
Dyslipidemia 32 (60.4) 34 (65.4) 0.60
Diabetes 19 (35.8) 25 (48.1) 0.20
Cigarette smoker 11 (20.8) 11 (21.2) 0.78
Transient ischemic attack 7 (13.2) 3 (5.8) 0.19
Stroke 3 (5.7) 2 (3.8) 0.66
Angina pectoris 34 (64.2) 30 (57.7) 0.50
Peripheral vascular disease 8 (15.1) 13 (25.0) 0.20
P values based on t-test for continuous variables, and ␹2 test for categorical variables.
Table data expressed as number (percentage) unless otherwise noted.
The modified intent-to-treat population consisted of randomized patients who qualified for study treatment according to prespecified study criteria for preoperative hypertension.
SD ⫽ standard deviation; SBP ⫽ systolic blood pressure; mm Hg ⫽ millimeters of mercury; PCI ⫽ percutaneous coronary intervention; CABG ⫽ coronary artery bypass grafting; CAD ⫽ coronary
artery disease; NA ⫽ not applicable.

Procedural Characteristics and seven placebo-treated patients. During study drug

Previous/Concomitant Medications
Most patients in both the clevidipine and placebo
treatment groups underwent primary CABG as the
index procedure (Table 2). On the day of surgery,
about a third of patients were premedicated for sur-
gery before study drug administration, most often
with midazolam (Table 3). Seven clevidipine-treated
patients received a ␤ blocker on the day of surgery
before study drug administration, compared with
administration, more placebo patients than clevidip-
ine patients received nitroglycerin, probably because
of the increased incidence of treatment failure in the
placebo group.
Efficacy
Clevidipine was effective in reducing increased
arterial blood pressure to target levels, with a statisti-
cally significantly lower rate of treatment failure

Vol. 105, No. 4, October 2007 © 2007 International Anesthesia Research Society 921
Table 2. Procedural Characteristics (Modified Table 4. Efficacy Results (Modified Intent-to-Treat Population)
Intent-to-Treat Population)
Clevidipine Placebo
Clevidipine Placebo Parameter (N ⫽ 53) (N ⫽ 52) P
(N ⫽ 53)a (N ⫽ 52) Treatment failure, a
4 (7.5) 43 (82.7) ⬍0.0001
Procedure n (%) n (%) all-cause
Primary surgery Lack of efficacy 0 (0.0) 18 (34.6) ⬍0.0001
CABG only 42 (79.2) 44 (84.6) Insufficient efficacy 4 (7.5) 25 (48.1) ⬍0.0001
Valve repair or 1 (1.9) 2 (3.8) Safety 0 (0.0) 0 (0.0) NA
replacement only Treatment success 49 (92.5) 9 (17.3) ⬍0.0001
Combined CABG and 5 (9.4) 5 (9.6) Time to target 6 (6, 8) NEc NA
valve surgery SBPb (min),
Repeat surgery median (95% CI)
CABG only 3 (5.7) 1 (1.9) P values based on ␹2 test. Table data expressed as number (percentage) unless otherwise
Valve repair or 1 (1.9) 0 (0.0) noted.
replacement only The modified intent-to-treat population consisted of randomized patients who qualified for
Combined CABG and 0 (0.0) 0 (0.0) study treatment according to prespecified study criteria for preoperative hypertension.
valve surgery SBP ⫽ systolic blood pressure; CI ⫽ confidence interval; NA ⫽ not applicable; NE ⫽ not
estimable.
CABG ⫽ coronary artery bypass grafting. a
Treatment failure was the premature and permanent discontinuation of study drug infusion
a
For one of the 53 clevidipine patients in the modified intent-to-treat population, the for any reason, or the failure to decrease SBP by ⱖ15% from baseline at any time during the
scheduled surgical procedure was not completed because of difficulty in accessing the left 30-min treatment period. Three categories of reasons for treatment failure were predefined:
anterior descending coronary artery. The modified intent-to-treat population consisted of lack of efficacy (increase, no change, or failure to achieve nominal reduction in SBP);
randomized patients who qualified for study treatment according to prespecified study criteria insufficient efficacy (inability to decrease SBP by at least 15% from baseline); or safety
for preoperative hypertension. reason.
b
Defined as time to first reduction of SBP by at least 15% from baseline.
c
Not estimable due to too few patients in the placebo group achieving the prespecified SBP
among patients treated with clevidipine versus pa- target.
tients receiving placebo (7.5% vs 82.7%, P ⬍ 0.0001).
Clevidipine-treated patients demonstrated a 92.5% baseline) at a median time of 6 min (95% confidence
rate of treatment success (Table 4). In most patients interval 6 – 8 min). The median time for placebo was
with treatment failure, the reason was identified as not estimable because too few patients in the placebo
insufficient efficacy. No patients in the clevidipine group reached the prespecified target of a 15% reduc-
group had treatment failure for lack of efficacy, and no tion in SBP relative to baseline. Clevidipine demon-
patients in either group had treatment failure for strated a greater decrease in MAP from baseline
safety reasons. compared with placebo that was statistically signifi-
Clevidipine-treated patients reached target arterial cant at the 5-min time point and for every 5 min
blood pressures (first reduction of SBP by ⱖ15% from thereafter to the end of the 30-min treatment period.

Table 3. Previous/Concomitant Medications (Modified Intent-to-Treat Population)

Before study drug During study drug
administration administration

Clevidipine Placebo Clevidipine Placebo

(N ⫽ 53) (N ⫽ 52) (N ⫽ 53) (N ⫽ 52)
Medication n (%) n (%) n (%) n (%)
Sedatives before surgery
All patients receiving at least one sedative 17 (32.1) 20 (38.5) 9 (17.0) 7 (13.5)
Midazolam 12 (22.6) 13 (25.0) 3 (5.7) 7 (13.5)
Fentanyl 1 (1.9) 2 (3.8) 2 (3.8) 1 (1.9)
Morphine 9 (17.0) 8 (15.4) 2 (3.8) 0 (0.0)
Othera 1 (1.9) 6 (11.5) 2 (3.8) 0 (0.0)
␤ blockers/vasodilators
All patients receiving at least one beta 14 (26.4) 12 (23.1) 2 (3.8) 10 (19.2)
blocker or vasodilator
Esmolol 0 (0.0) 0 (0.0) 1 (1.9) 0 (0.0)
Metoprolol 6 (11.3) 3 (5.8) 1 (1.9) 0 (0.0)
Other selective ␤ blockers 1 (1.9) 3 (5.8) 0 (0.0) 0 (0.0)
␣ and ␤ blockers 0 (0.0) 1 (1.9) 0 (0.0) 0 (0.0)
Nicardipine 0 (0.0) 0 (0.0) 0 (0.0) 1 (1.9)
Nitroglycerin 7 (13.2) 2 (3.8) 1 (1.9) 9 (17.3)
Otherb 3 (5.7) 8 (15.4) 0 (0.0) 0 (0.0)
The modified intent-to-treat population consisted of randomized patients who qualified for study treatment according to prespecified study criteria for preoperative hypertension.
a
Including angiotensin-converting enzyme (ACE) inhibitors, aminoalkyl ethers, angiotensin II antagonists and diuretics, barbiturates, benzodiazepine derivatives and related drugs, and other
general anesthetics.
b
Including ACE inhibitors, ␣-adrenoreceptor antagonists, angiotensin II antagonists, benzothiazepine derivatives, imidazoline receptor agonists, organic nitrates, low-ceiling diuretics, and
sulfonamide.

922 Clevidipine in Preoperative Hypertension ANESTHESIA & ANALGESIA

Table 5. Study Drug Titrations (Safety Population)
ⱖ15% SBP reduction
from baselinea Highest titration rate

Clevidipine Placebo Clevidipine Placebo

Study drug titrated up to doses (N ⫽ 53) (N ⫽ 51) (N ⫽ 53) (N ⫽ 51)
(␮g 䡠 kg⫺1 䡠 min⫺1) n (%) n (%) n (%) n (%)
⬎0–0.4 8 (15.1) 3 (5.9) 1 (1.9) 1 (2.0)
⬎0.4–0.8 5 (9.4) 1 (2.0) 2 (3.8) 0 (0.0)
⬎0.8–1.6 8 (15.1) 2 (3.9) 10 (18.9) 1 (2.0)
⬎1.6–3.2 11 (20.8) 1 (2.0) 12 (22.6) 0 (0.0)
⬎3.2–4.7 9 (17.0) 2 (3.9) 11 (20.8) 4 (7.8)
⬎3.2–6.2 5 (9.4) 0 (0.0) 6 (11.3) 3 (5.9)
⬎6.2–7.7 1 (1.9) 1 (2.0) 4 (7.5) 5 (9.8)
up to 8.0 3 (5.7) 0 (0.0) 7 (13.2) 37 (72.5)
SBP ⫽ systolic blood pressure.
a
Fifty of 53 patients in the clevidipine group and 10 of 51 patients in the placebo group (safety population) achieved ⱖ15% reduction of SBP from baseline. Note that because ⱖ15% reduction
of SBP from baseline was achieved at 31min for one of the clevidipine patients, this patient is not included in the number of patients considered to have achieved treatment success.

was 71 bpm (minimum–maximum [min–max]: 48 –120,

Figure 2. Mean percent change in heart rate and systolic
blood pressure versus time during the efficacy evaluation
period (clevidipine-treated patients only), demonstrating a
modest increase in heart rate and rapid onset of arterial
blood pressure-lowering effect. HR ⫽ heart rate; SBP ⫽
systolic blood pressure.
For the lowest MAP assessed during the 30-min
treatment period, the mean change from baseline was
⫺34.8 mm Hg (⫺31.2%) in the clevidipine group,
compared with ⫺12.5 mm Hg (⫺11.2%) in the placebo
group (P ⬍ 0.0001).
Study Drug Titration and Dose Response
More than half of patients in the clevidipine group
(60%) demonstrated a reduction in SBP of ⱖ15% from
baseline in response to study drug titration to infusion
rates ⱕ3.2 ␮g 䡠 kg⫺1 䡠 min⫺1, and 47.2% received ⱕ3.2
␮g 䡠 kg⫺1 䡠 min⫺1 as their highest titrated infusion rate
(Table 5, safety population). Patients receiving placebo
had more up-titrations of study drug than clevidipine-
treated patients, as indicated by a higher mean total
infusion amount (20.7 vs 16.6 mL, respectively) and
lower mean infusion duration (25.5 vs 32.1 min). These
results are consistent with the higher rate of treatment
failure among placebo patients.
Safety
An increase in HR was observed during clevidipine
administration (Fig. 2). The median HR at baseline
n ⫽ 50) for clevidipine patients compared with 76 bpm
(min–max: 53–126, n ⫽ 49) for placebo patients. The
maximum HRs reported for the 30-min treatment
period were median 84 bpm (min–max: 57–132) for
clevidipine patients compared with 84 bpm (min-
–max: 57–133) for placebo patients. Among patients
receiving clevidipine, HR changes were not observed
after discontinuation of infusion. No clinically impor-
tant differences between treatment groups with re-
spect to other vital signs or laboratory results were
observed at baseline or postbaseline during the
study.
The types and rates of AEs were similar for each
treatment group. The most often reported AEs for
clevidipine versus placebo patients were pyrexia (fe-
ver), 18.9% (10 of 53) vs 13.7% (7 of 51); atrial fibrilla-
tion, 13.2% (7 of 53) vs 11.8% (6 of 51); acute renal
insufficiency/failure, 9.4% (5 of 53) vs 2.0% (1 of 51);
and nausea, 5.7% (3 of 53) vs 9.8% (5 of 51). None of
these differences in AE rates was statistically signifi-
cant. Other AEs occurred with a frequency of ⱕ5.7%
in the clevidipine group. Overall, 5 (9.4%) clevidipine
patients and 2 (3.9%) placebo patients were assessed
by investigators as having possibly treatment-related
AEs, each of which was unique.
Treatment failure for safety reasons did not occur
in either treatment group during the 30-min treat-
ment period. Two patients were withdrawn from
the study because of an AE: one from the placebo
group because of exacerbation of hypertension, and
one from the clevidipine group because of de-
creased hemoglobin, which was evaluated as unre-
lated to the study drug. Two patients in the placebo
group were reported as having had an MI, com-
pared with no patients in the clevidipine group. One
patient death was reported during the study period.
The patient was in the clevidipine group and died
on postoperative day 1 as a result of a mediastinal
hemorrhage, which was not considered to be related
to the study drug.

Vol. 105, No. 4, October 2007 © 2007 International Anesthesia Research Society 923
DISCUSSION
In this randomized, double-blind, placebo-controlled
trial, IV clevidipine was shown to be effective for
treating preoperative hypertension with a 92.5% suc-
cess rate in decreasing SBP at least 15% from baseline
when titrated to effect in a high-risk patient popula-
tion scheduled for cardiac surgery. This efficacy for
clevidipine compared with placebo occurred against a
background of other preoperative interventions that
could affect hemodynamic response, with a median
time of 6 min for achieving target arterial blood
pressure in the acute preoperative setting. These find-
ings extend what is known of clevidipine’s therapeutic
value from smaller dose-finding and pharmacody-
namic studies, and support its use in a broader
perioperative setting.
There is an unmet need for a rapid-acting, fast-
offset IV antihypertensive drugs providing rapid,
tight arterial blood pressure control in the periopera-
tive setting without the disadvantages of unpredict-
able or prolonged arterial blood pressure reduction,
myocardial depression, adverse drug effects, or drug–
drug interactions (4,8 –10). Clevidipine is a third-
generation dihydropyridine calcium channel blocker
that incorporates an easily hydrolyzable ester group in
its chemical structure as part of rational drug design
(11). As a result, clevidipine is rapidly metabolized by
blood and tissue esterases independent of kidney and
liver function (11,13–15). In addition to fast onset and
offset, esterase-based metabolism may partially ac-
count for the lack of drug toxicity, little to no risk of
cytochrome P450-associated drug interactions (11,18),
and tolerance of clevidipine by a high-risk patient
population with previous cardiovascular disease.
The present study evaluated the efficacy of clevi-
dipine in decreasing SBP to a predetermined target
immediately before anesthesia induction for cardiac
surgery. Preoperative cardiac surgery patients were
chosen as the study population based on their likeli-
hood of developing hypertension and on the high-risk
nature of cardiac surgery (1–3), and because a preop-
erative study design allowed for the safe and ethical
use of placebo. The use of placebo control made it
possible to evaluate clevidipine’s efficacy against fluc-
tuations in arterial blood pressure in the acute care
setting. Placebo was administered during a controlled
treatment period before surgery under a study design
allowing for the use of an alternative parenteral anti-
hypertensive drug for any reason, at any time after
initiation of study drug.
One limitation of the present placebo-controlled
investigation is that it could not be designed to
evaluate clevidipine during surgery for ethical reasons
(i.e., not treating hypertension), and therefore in-
volved a somewhat artificial preoperative treatment
strategy. Adequate premedication and the effects of
anesthesia induction on arterial blood pressure are
924 Clevidipine in Preoperative Hypertension
important considerations before administering antihy-
pertensive treatment during the preoperative period.
Our study, which evaluated the short-term response
to treatment of acutely hypertensive patients with
either a known history of hypertension or active
untreated hypertension, some of whom may have
responded to higher doses of premedication or anes-
thesia induction, does not suggest otherwise. How-
ever, the results of the present study as designed
provide clear evidence of rapid, controlled clevidipine
efficacy in a highly relevant clinical setting. Cardiac
surgery patients in the immediate preoperative period
could be considered representative of other high-risk
patient populations needing urgent IV management of
hypertension in complex acute-care settings.
Another potential study limitation was the influ-
ence of premedication on arterial blood pressure.
Because the present study was designed as an acute
assessment of antihypertensive treatment over 30 min,
and included comparison of active treatment to pla-
cebo, it is unlikely that any effects of premedication on
study results would have gone unnoticed. In any case,
the administration of preoperative sedatives and ␤
blockers/vasodilators (permitted in the present study
if given for another purpose besides hypertension)
was balanced between the clevidipine and the placebo
groups (Table 3), suggesting little to no effect on study
outcome.
In a previous double-blind study of 30 patients after
cardiac surgery (19), clevidipine was compared with
sodium nitroprusside with respect to efficacy and hemo-
dynamic effects. Patients were randomized to clevidip-
ine or sodium nitroprusside after elective CABG and
were treated postoperatively if they became hyperten-
sive (MAP ⬎90 mm Hg for at least 10 min). No statisti-
cally significant difference in efficacy (inversely measured
as area under the MAP-time curve when MAP ex-
ceeded or decreased below the target arterial blood
pressure window) was found between clevidipine and
sodium nitroprusside. A significantly larger increase
in HR (assessed as area under the HR-time curve, P ⬍
0.001) was observed for sodium nitroprusside com-
pared with clevidipine. Clevidipine-treated patients
showed less change in central venous pressure and
less need for fluid replacement than patients treated
with sodium nitroprusside.
In the present study, clevidipine was shown to be
well tolerated with an AE profile similar to that of
placebo and consistent with outcomes expected in
cardiac surgery (20,21). A modest increase in HR was
observed during clevidipine administration, as has
been reported with other IV dihydropyridines (22,23)
and in studies of clevidipine in essential hypertension
and postcardiac surgery (16,19). This finding repre-
sents a positive attribute of clevidipine in patients
susceptible to myocardial ischemia (24).
The results of the present study support the conclu-
sion that clevidipine is an effective treatment for preop-
erative hypertension with a good safety profile when
ANESTHESIA & ANALGESIA
titrated to effect in cardiac surgery patients. Target
arterial blood pressures were achieved with clevidipine
within minutes of initiating IV administration and drug
titration. Current large-scale studies of clevidipine’s
safety compared with nitroglycerin, sodium nitroprus-
side, and nicardipine in cardiac surgery patients, and of
the effects of prolonged clevidipine infusion in severely
hypertensive patients, should further add to our under-
standing of the clinical utility of clevidipine.
APPENDIX
The following institutions, clinical investigators, and re-
search coordinators participated in the conduct of this trial:
Atlanta VA Medical Center, Atlanta, GA—J.H. Levy,
MD, K. Tanaka, MD, K. Egan, RN, S. Chan, S. Bigsby, P.
Patel; Baptist Health Systems Montclair, Birmingham,
AL—R. Gitter, MD, H.W. Knott, MD, C.D. Randleman
Jr, MD, J.B. Casterline, MD, K. Spray, RN; The Christ
Hospital, Cincinnati, OH—D.J. Kereiakes, MD, T.D.
Ivey, MD, D.L. Mitts, MD, G.A. Answini, MD, D.K.
Garza, RN, M.P. Connor, RN; Houston Northwest Medi-
cal Center, Houston, TX—T.C. Osborn, MD, C.M. Kitten,
MD, D.G. Stroud, MD, D.S. Bhatia, MD, M. Bittman;
MacNeal Hospital, Berwyn, IL—S. Aronson, MD, P.
Porcelli; Memorial Hermann Memorial City Hospital,
Houston, TX—H. Minkowitz, MD, J.G. Baerenstecher,
MD, P. Lindley; Regional Medical Center Bayonet Point,
Hudson, FL—R.S. Waters, MD, M. DeSantis, MD, G.
Gunn; Sacred Heart Hospital, Pensacola, FL—M.Y. Man-
cao, MD, C. Yount-Malone; St. Luke’s Episcopal Hospi-
tal, Houston, TX—A.M. Grigore, MD, D. Hirsch, MD,
J.M. Anton, MD, J.R. Cooper, MD, L.Q. Chen, MD, N.A.
Nussmeier, MD, E. Dragon, J. Dean; St. Vincent Medical
Center, Los Angeles, CA—A. Gheissari, MD, R. Gottner,
MD, E. Capouya, MD, S.A. Hillman, MD, J. Barra;
Swedish Medical Center, Seattle, WA—L. Heller, MD, I.
Wright, MD, D. Stout, MD, S. Knapp, MD, B. Lee, MD, J.
Lew, MD, B. Tupper, MD, M. Uppal, MD, R. Woodland,
MD, I. Rasmussen; Wake Forest University School of
Medicine, Winston-Salem, NC—R.C. Prielipp, MD, J.F.
Butterworth IV, MD, R.L. Royster, MD, D.A. Zvara, MD,
L. Groban, MD, N. Pailes, MD, J. Bennett.
REFERENCES
1. Aronson S, Boisvert D, Lapp W. Isolated systolic hypertension is
associated with adverse outcomes from coronary artery bypass
grafting surgery. Anesth Analg 2002;94:1079 – 84
2. Weitz HH. Perioperative cardiac complications. Med Clin North
Am 2001;85:1151– 69
3. Erstad BL, Barletta JF. Treatment of hypertension in the periop-
erative patient. Ann Pharmacother 2000;34:66 –79
4. Leslie JB. Incidence and aetiology of perioperative hypertension.
Acta Anaesthesiol Scand Suppl 1993;99:5–9
5. Weiss SJ, Longnecker DE. Perioperative hypertension: an over-
view. Coron Artery Dis 1993;4:401– 6
6. Estafanous FG, Tarazi RC. Systemic arterial hypertension asso-
ciated with cardiac surgery. Am J Cardiol 1980;46:685–94
7. Vuylsteke A, Feneck RO, Jolin-Mellgård Å, Latimer RD, Levy
JH, Lynch C III, Nordlander ML, Nyström P, Ricksten SE.
Perioperative blood pressure control: a prospective survey of
patient management in cardiac surgery. J Cardiothorac Vasc
Anesth 2000;14:269 –73
Vol. 105, No. 4, October 2007
8. Cheung AT. Exploring an optimum intra/postoperative man-
agement strategy for acute hypertension in the cardiac surgery
patient. J Card Surg 2006;21:S8 –14
9. Levy JH. The ideal agent for perioperative hypertension and
potential cytoprotective effects. Acta Anaesthesiol Scand Suppl
1993;99:20 –5
10. Sladen RN. Perioperative hypertension: what’s new and what’s
useful? In: International Anesthesia Research Society (IARS)
2002 course review lecture. IARS 76th clinical and scientific
congress. San Diego, California: International Anesthesia Re-
search Society, 2002:100 – 8
11. Nordlander M, Sjoquist PO, Ericsson H, Ryden L. Pharmacody-
namic, pharmacokinetic and clinical effects of clevidipine, an
ultrashort-acting calcium antagonist for rapid blood pressure
control. Cardiovasc Drug Rev 2004;22:227–50
12. Kieler-Jensen N, Jolin-Mellgård Å, Nordlander M, Ricksten SE.
Coronary and systemic hemodynamic effects of clevidipine, an
ultra-short-acting calcium antagonist, for treatment of hyperten-
sion after coronary artery surgery. Acta Anaesthesiol Scand
2000;44:186 –93
13. Vuylsteke A, Milner Q, Ericsson H, Mur D, Dunning J, Jolin-
Mellgård Å, Nordlander M, Latimer R. Pharmacokinetics and
pulmonary extraction of clevidipine, a new vasodilating
ultrashort-acting dihydropyridine, during cardiopulmonary by-
pass. Br J Anaesth 2000;85:683–9
14. Ericsson H, Fakt C, Höglund L, Jolin-Mellgård Å, Nordlander
M, Sunzel M, Regårdh CG. Pharmacokinetics and pharmacody-
namics of clevidipine in healthy volunteers after intravenous
infusion. Eur J Clin Pharmacol 1999;55:61–7
15. Ericsson H, Bredberg U, Eriksson U, Jolin-Mellgård Å,
Nordlander M, Regårdh CG. Pharmacokinetics and arterio-
venous differences in clevidipine concentration following a
short- and a long-term intravenous infusion in healthy vol-
unteers. Anesthesiology 2000;92:993–1001
16. Bailey JM, Lu W, Levy JH, Ramsay JG, Shore-Lesserson L, Prielipp
RC, Brister NW, Roach GW, Jolin-Mellgard A, Nordlander M.
Clevidipine in adult cardiac surgical patients: a dose-finding study.
Anesthesiology 2002;96:1086 –94
17. Schwieler JH, Ericsson H, Löfdahl P, Thulin T, Kahan T.
Circulatory effects and pharmacology of clevidipine, a novel
ultra short acting and vascular selective calcium antagonist, in
hypertensive humans. J Cardiovasc Pharmacol 1999;34:268 –74
18. Zhang JG, Dehal SS, Ho T, Johnson J, Chandler C, Blanchard AP,
Clark RJ Jr, Crespi CL, Stresser DM, Wong J. Human cyto-
chrome P450 induction and inhibition potential of clevidipine
and its primary metabolite H152/81. Drug Metab Dispos
2006;34:734 –7
19. Powroznyk AVV, Vuylsteke A, Naughton C, Misso SL, Holloway
J, Jolin-Mellgård Å, Latimer RD, Nordlander M, Feneck RO.
Comparison of clevidipine with sodium nitroprusside in the
control of blood pressure after coronary artery surgery. Eur J
Anaesth 2003;20:697–703
20. Eagle KA, Guyton RA, Davidoff R, Edwards FH, Ewy GA,
Gardner TJ, Hart JC, Herrmann HC, Hillis LD, Hutter AM Jr,
Lytle BW, Marlow RA, Nugent WC, Orszulak TA. ACC/AHA
2004 guideline update for coronary artery bypass graft surgery:
a report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines (Commit-
tee to Update the 1999 Guidelines for Coronary Artery Bypass
Graft Surgery). American College of Cardiology Web site.
Available at: http://circ.ahajournals.org/cgi/reprint/110/14/
e340.pdf
21. Mack MJ, Brown PP, Kugelmass AD, Battaglia SL, Tarkington
LG, Simon AW, Culler SD, Becker ER. Current status and
outcomes of coronary revascularization 1999 to 2002: 148,396
surgical and percutaneous procedures. Ann Thorac Surg
2004;77:761– 8
22. Lambert CR, Hill JA, Nichols WW, Feldman RL, Pepine CJ.
Coronary and systemic hemodynamic effects of nicardipine.
Am J Cardiol 1985;55:652– 6
23. Leslie J, Brister N, Levy JH, Yared JP, Marty A, Martin H, Hines
R, Savino J, Cohen M. Treatment of postoperative hypertension
after coronary artery bypass surgery. Double-blind comparison
of intravenous isradipine and sodium nitroprusside. Circulation
1994;90:II256 – 61
24. Mangano DT; Study of Perioperative Ischemia (SPI) Research
Group. Dynamic predictors of perioperative risk. J Card Surg
1990;5:231– 6
© 2007 International Anesthesia Research Society 925