Download clevidipine

Acute Hypertension:
The Need for IV Antihypertensive Therapy
The First Third-Generation Intravenous
Dihydropyridine Calcium Channel Blocker
Cl
Cl
H
CH3OOC
H3C
N
H
Nordlander M, et al. Cardiol Drug Reviews. 2004;22:227-250.
COOCH2OOCC3H7
CH3
The Need for Intravenous (IV)
Antihypertensive Therapy
In acute hypertension, any scenario in which
oral antihypertensive therapy is not feasible or desirable
Hypertensive emergency
– Acute elevations in BP associated with end-organ damage require
immediate BP reduction
Perioperative hypertension
Less critical hypertensive scenarios when oral therapy is not feasible
– Hypertensive urgency: acute elevation of BP without end-organ
damage; requires reduction of BP within a few hours
Calhoun DA. Hypertension: A Companion to Brenner and Recot’s the Kidney. Philadelphia, PA: WB Saunders Co.; 2000:715-718.
Chobanian AV, et al. Hypertension. 2003;42:1206-1252.
Varon J, Marik PE. CHEST. 2000;118:214-227.
Varon J, Marik PE. Crit Care. 2003;7:374-384.
Vaughan CJ, Delanty N. Lancet. 2000;356:411-417.
Vidt DG. Hypertension Primer: The Essentials of High Blood Pressure. Dallas, TX: American Heart Association; 1999:437-440.
3
Acute Hypertension: Epidemiology
Hypertensive emergencies
– Occur in up to 500,000 patients annually
– Affect >25% of patients presenting to the emergency department (ED)
Perioperative hypertension
– Common with cardiovascular surgery (30%–80%)
– 80% incidence following carotid endarterectomy
– Preoperative incidence: 50% of cardiac surgery patients and 25% of
noncardiac surgery patients
– Intraoperative incidence: 50% of patients undergoing cardiac surgery
Biller J et al. Circulation. 1998;97:501-509.
Cheung AT. J Card Surg. 2006;21:S8-S14.
Erstad BL, Barletta JF. Ann Pharmacother. 2000;34:66-79.
Goldman L, et al. N Engl J Med. 1977;297:845-850.
Mansoor GA, Frishman WH. Heart Dis. 2002;4:358-371.
National Center for Health Statistics: 1983-1990 Health Survey. Hyattesville, MD: US Dept of HHS.
Towne JB, Bernhard VM. Surgery. 1980;88:575-580.
Vuylsteke A, et al. J Cardiothorac Vasc Anesth. 2000;14:269-273.
Zampaglione B, et al. Hypertension. 1996;27:144-147.
4
Treatment Goals for Hypertensive
Emergency
Prompt, but smooth reduction in BP
– Reduce MAP by ≤25% during the first minute to 1 hour
– If stable, reduce BP to 160/100–160/110 mm Hg in next 2–6 hours
– Gradual reductions toward normal BP over next 24–48 hours
– Exceptions requiring special care: ischemic stroke, stroke eligible for
thrombolytic agents, aortic dissection
Avoid excessive drops in BP
– May cause renal, cerebral, or coronary ischemia
– Need careful and close monitoring
– Use an arterial catheter for monitoring BP
Choice of pharmacologic agent should be tailored to patient
– Based on risks, comorbidities, and type of end-organ damage
US Department of Heath and Human Services. Bethesda, Md: National Institutes of Health.
NIH Publication No. 04-5230. August 2004.
5
Current IV Antihypertensive Agents
Agent
Onset/
Duration
Elimination
Half-Life
Adverse Events
Cautions/Concerns
Enalaprilat
<15 min/
12–24 h
11 h
Precipitous fall in BP in high-renin
states, headache, cough, renal
failure, hyperkalemia, angioedema
Avoid in acute MI, long duration of action
Esmolol HCl
1–2 min/
10–30 min
2–9 min
Heart block, hypotension, nausea,
bronchospasm, overt heart failure,
cardiogenic shock
Reduces cardiac output, which may
impair organ perfusion
Fenoldopam
mesylate
5–15 min/
30 min–4 h
5 min
Tachycardia, headache, nausea,
dizziness, flushing, hypotension,
increased intraocular pressure
Caution with glaucoma
Hydralazine
HCl
10–20 min/
1–4 h
1h
Marked hypotension, tachycardia,
flushing
Avoid in aortic dissection, MI, severe
renal disease; prolonged and
unpredictable effects; difficult to titrate
Labetalol HCl
<5 min/
3–6 h
5.5 h
Bradycardia (heart block), overt heart
failure, cardiogenic shock, edema,
nausea, vomiting
Avoid in acute heart failure; severe
bradycardia; heart block, asthma
Nicardipine
HCl
5–10 min/
15 min–4 h
44.8 min
Tachycardia, headache, nausea,
flushing, thrombophlebitis,
hypotension, vomiting
Avoid in acute heart failure; caution with
coronary ischemia; long duration of action
Nitroglycerin
2–5 min/
5–10 min
1–4 min
Flushing, headache, vomiting,
Reduction in preload and cardiac output
hypotension, methemoglobinemia, undesirable
in patients with compromised
decreased arterial resistance, reflex
renal
and cerebral perfusion
tachycardia
Sodium
nitroprusside
Immediate/
2–3 min
2–3 min
Nausea, muscle twitching, sweating,
thiocyanate and cyanide intoxication,
hypotension
Increases intracranial pressure; may
reduce coronary perfusion pressure
(coronary “steal”); cyanide toxicity
6
Goals of an Ideal Agent
– Treat underlying pathophysiology
– Rapid onset of action
– Predictable dose response
– Titratable to desired BP
– Minimal dosage adjustments
– Highly vascular selective
– No increase in intracranial pressure
– Rapidly reversible
– Low risk of overshoot hypotension or adverse reaction
– Easy conversion to oral agents
– Acceptable cost–benefit ratio
Levy JH. Anesthesiol Clin North Am. 1988;17:587-678.
Oparil S et al. Am J Hypertens. 1999;12:653-664.
7
The Need for a New IV
Antihypertensive Agent
No one agent meets the goals of an ideal agent
8
Clevidipine: The First Third-Generation
Calcium Channel Blocker
Generic Name
Brand Name
Nifedipine
Procardia®, Adalat®
Nicardipine/Nicardipine I.V.
Amlodipine
Isradipine
Felodipine
Nimodipine/Nimodipine I.V.
(Europe)
Nisoldipine
Cardene®/Cardene I.V.
Norvasc®
DynaCirc®
Plendil®
Nimotop®/Nimotop I.V.
Clevidipine
TBD
First Generation
Second
Generation
Third
Generation
Whiting RL, et al. Angiology. 1990;41:987-991.
Sular®
9
The Clevidipine Molecule
A rationally designed dihydropyridine calcium channel blocker
Cl
Cl
H
CH3OOC
H3C
N
COOCH2OOCC3H7
CH3
H
Nordlander M, et al. Cardiol Drug Reviews. 2004;22:227-250.
10
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
O
Cl
O
*
O
O
Esterases
O
O
Cl
HO
OH
O
O
N
H
Clevidipine
O
+
H
H
+
O
N
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.
11
Clevidipine Clinical Development
Phase I
Phase II
Phase III
N=89
N=300
N=1821
Healthy Volunteers
Patients: Mild to
Moderate Hypertension
N=86
Patients:
Perioperative
N=214
Perioperative
Hypertension
N=1721
Severe
Hypertension
N=100
Tolerability,
Safety, PK
Dose Response
Dose Response:
Clevidipine
vs Placebo
ESCAPE: Efficacy
Clevidipine
vs Placebo
VELOCITY:
Severe Hypertension
PK, Metabolism,
Rates and Routes
of Excretion
PK/BP
Hemodynamics:
Clevidipine vs SNP
ESCAPE: Efficacy
Clevidipine
vs Placebo
PK
PK/PD:
Clevidipine
vs Placebo
BP, HR:
Clevidipine vs SNP
ECLIPSE:
Safety vs NTG
BP, Dose/PK
ECLIPSE:
Safety vs SNP
BP: Clevidipine
vs Placebo
ECLIPSE:
Safety vs NIC
QTc Study
Data on file. The Medicines Company.
12
Clevidipine Pharmacodynamics
Clevidipine: Ultrashort Half-Life
Approximate half-life: 1 min
– T 1/2 (triphasic): alpha, 48 sec; beta, 2.3 min; terminal, 21.7 min
– 85%–90% eliminated in first T 1/2
Triphasic Elimination
Reproduced from Ericsson H, et al. Anesthesiology. 2000;92:993-1001.
14
Clevidipine: Linear Pharmacokinetics
At steady state, there is a linear relationship between dosage and
arterial blood concentrations
Clevidipine Concentration
at Css (nmol/L)*
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
Dose Rate (nmol/kg/min)
25
30
35
*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.
15
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
Responders (%)
90
n=9
80
n=6
70
60
50
n=4
40
30
20
10
n=1
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.
16
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
MAP
MAP (mm Hg) and
HR (beats/min)
90
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.
17
Clevidipine: Rapid Onset
BP-lowering effects seen within 1–2 minutes of clevidipine infusion
SBP Changes
% Change From Baseline
10
5
0
–5
–10
–15
–20
SBP
–25
–30
0
5
10
15
20
Time (min)
SBP changes for patients receiving clevidipine during a 30-minute treatment period.
Levy JH, et al. Anesthesiology. 2005;103:A354.
25
30
18
Clevidipine Selectivity/Hemodynamics
Selectivity of Calcium Channel
Antagonists
Cl
O
O
O
H3C
O
Cl
O
H
N
CH3
O
CH3
O
*
O
Nicardipine
Clevidipine
Clevidipine
Nicardipine
Diltiazem
Verapamil
NO2
NO2
N
H
IV Agent
CH3
COCH3
CH3OC
COCH2CH2NCH2
H3COC
O
H3C
O
H
N
Nifedipine
Vasodilation
Myocardial
Depression
SA Node
Suppression
AV Node
Suppression
5
5
3
4
0
0
2
4
0
0
5
5
0
0
4
5
*The chiral center of clevidipine.
SA = sinoatrial; AV = atrioventricular.
Kerins DM, et al. In: Goodman and Gilman’s Pharmacological Basis of Therapeutics. 2001:843-870.
Massie BM. Am J CardioI. 1997;80:23I-32I.
20
Clevidipine: Vascular Selectivity
Clevidipine is selective for vascular as opposed to myocardial smooth
muscle therefore has no negative inotopic or chonotropic effects as
opposed to other calcium channel blockers (e.g.diltiazem and
verapamil)
Nordlander M, et al. Cardiol Drug Reviews. 2004;22:227-250.
Data on file. The Medicines Company.
21
Clevidipine:
Additional Findings
Animal and Ex Vivo Data
Clevidipine: Evaluation of
Cardioprotection
Study hypothesis: clevidipine may provide a cardioprotective
effect during myocardial ischemia and reperfusion
– Rationale: probable mechanism related to blocking action of
calcium channel
Study design: pig ischemia model
– Local administration of clevidipine into left anterior descending
coronary artery (LAD) during late ischemia and early perfusion
– Pigs subjected to 45-minute ligation of LAD followed by 4 hours
of reperfusion
– Five groups received either vehicle, synthase inhibitor, clevidipine,
clevidipine in combination with an NO synthase inhibitor, or
clevidipine
in combination with an NO synthase inhibitor and an NO precursor
Gourine AV, et al. Cardiovasc Res. 2001;51:100-107.
Gourine AV, et al. J Cardiovasc Pharmacol. 2002;40:564-570.
Nordlander M, et al. Cardiol Drug Reviews. 2004;22:227-250.
23
Clevidipine: Evaluation of
Cardioprotection
Study results: clevidipine reduced infarct size and preserved coronary
endothelial function
– Endothelium-dependent coronary vasodilation induced by
substance P
was significantly larger in the clevidipine group
– Coronary endothelial function was preserved
Infarct Size
Clevidipine Reduced Infarct Size Compared With Vehicle (P<0.001)
100
90
80
70
60
50
40
30
20
10
0
86 +2%
59 +3%
Vehicle Group
Gourine A, et al. Cardiovasc Res. 2001;51:100-107.
Clevidipine Group
24
Clevidipine: Evaluation of Renal
Protection
Study hypothesis: clevidipine may provide protection of renal function
in ischemia/reperfusion
– Rationale: calcium channel blockers have proven efficacy in providing
organ protection in experimental models
Study design: a rat model was used to evaluate the efficacy of
clevidipine vs fenoldopam in protecting renal function
– Experimental model of ischemia/reperfusion-induced acute renal failure
– Renal failure induced by occlusion of the left renal artery for 40 minutes
followed by release
– Four groups received either saline, clevidipine, fenoldopam, or high-dose
fenoldopam
– Agent infused for 60 minutes, beginning 10 minutes before release
of occlusion
Stephens CT, Jandhyala BS. Exp Hypertens. 2002;24:301-313.
25
Clevidipine: Evaluation of Renal
Protection
Study results: renal protection observed with clevidipine therapy
in a rat model of ischemic renal failure
– Both agents were potent diuretics and natriuretics
– Clevidipine infusion caused:
– No change in renal blood blow
– Fenoldopam infusion caused:
– Increased renal blood flow
– Following ischemia reperfusion injury:
– Clevidipine markedly improved tubular function, while
fenoldopam did not
Conclusion: protection may be related to reduced calcium-mediated
cellular injury and reduced oxygen free radical–mediated injury
Stephens CT, Jandhyala BS. Exp Hypertens. 2002;24:301-313.
26
Clevidipine: Evaluation of Splanchnic
Protection
Hypothesis: clevidipine may provide splanchnic protection through
increased vascular resistance
Study design: in a rat model, clevidipine was infused into occluded,
ischemic mesenteric arteries prior to reperfusion
Study results: clevidipine prevented intense increases in mesenteric
vascular resistance resulting from induced ischemia
– Facilitated significant recovery of mesenteric blood flow
– Prevented deterioration of mesenteric circulation during
reperfusion
Conclusion: behavior consistent with the action of calcium channel
blockers, believed to be linked to their mechanism of action
Goyal M, Jandhyala B. FASEB J. 1997;11:A285. Abstract 1654.
27
Clevidipine: Evaluation of Vasospasm
Prevention
Study hypothesis: clevidipine may offer an alternative to nitroglycerin
for the prevention of vasospasm during CABG surgery
– Spasm of of arterial grafts is common and may compromise
myocardial perfusion
– Resistance to nitroglycerin may limit its effectiveness in patients
with
long-term exposure to this agent
Study design: ex vivo model
– Human internal mammary artery (IMA) segments obtained during
CABG surgery were precontracted with a thromboxane A2 analog
– Clevidipine and nitroglycerin were added to segments to assess
their effect on vasoconstriction
– Clevidipine was tested in segments with and without intact
endothelium
Huraux C, et al. Anesth Analg. 1997;85:1000-1004.
28
Clevidipine: Evaluation of Vasospasm
Prevention
Study result: both clevidipine and
nitroglycerin reversed vasospasm
Clevidipine Response
– Vasoconstricted IMAs relaxed
with clevidipine in the presence
or absence of endothelium
25
% Relaxation
Conclusion: clevidipine may be a
good alternative to nitroglycerin
0
50
75
Endothelium +
Endothelium –
100
9
8
7
6
5
– log (mol/L)
4
Mean Clevidipine
Concentration
Reproduced from Huraux C, et al. Anesth Analg. 1997;85:1000-1004.
29
Clevidipine: Effect on Systemic
and Coronary Arterial Resistance
Study objective: to compare the acute systemic and coronary
hemodynamic effects of clevidipine with those of sodium
nitroprusside (SNP) and nitroglycerin (NTG)
Study design: normal anesthetized pig model
– Crossover design with a total of 8 pigs
– SNP > washout > clevidipine
– Clevidipine > washout > SNP
– NTG > washout > clevidipine
– Clevidipine > washout > NTG
– Hemodynamic and perfusion measurements taken in multiple
stages
– Standard hemodynamics with flow probes, pressure monitors
– Microsphere technique for pre-capillary perfusion
Data on file. The Medicines Company.
30
Data on file. The Medicines Company.
Stop
Infusion
MAOP – 30%
MAOP – 15%
Washout
Colored
Microsphere
Colored
Microsphere
MAOP –30%
MAOP –15%
Microsphere
Analysis
Euthanasia
Surgical
Instrumentation
Drug I Infusion
Re-stable
Hemodynamics
Stop
Infusion
Colored
Microsphere
Colored
Microsphere
Baseline
Hemodynamics
Effect on Systemic and Coronary Arterial
Resistance: Experimental Design
Drug II Infusion
31
Effect on Systemic and Coronary Arterial
Resistance: Mean Aortic Pressure
% Change From Baseline
Mean Aortic Pressure
0
–10
NTG
SNP
Clevidipine
–20
–30
0
Dose 1
Dose 2
Mean ± SE; n = 8 in clevidipine group; n = 4 in SNP group; n = 4 in NTG group.
Data on file. The Medicines Company.
Dose 3
Dose 4
32
Effect on Systemic and Coronary Arterial
Resistance: Total Peripheral Resistance
% Change From Baseline
Total Peripheral Resistance
0
–10
NTG
SNP
Clevidipine
–20
–30
0
Dose 1
Dose 2
Mean ± SE; n = 8 in clevidipine group; n = 4 in SNP group; n = 4 in NTG group.
Data on file. The Medicines Company.
Dose 3
Dose 4
33
% Change in MAOP, CBF, CAR
Clevidipine
50
25
MAOP
CBF
0
–25
–50
Dose 0
0.35
0.7
1.4
2.8
% Change in MAOP, CBF, CAR
% Change in MAOP, CBF, and CAR
Effect on Systemic and Coronary Arterial
Resistance: Epicardial Coronary
Hemodynamics
NTG
50
25
MAOP
CBF
0
–25
–50
Dose 0
0.625
1.25
2.5
5
50
SNP 1
25
MAOP
CBF
0
–25
–50
Dose 0
0.35
0.7
1.4
Data on file. The Medicines Company.
2.8
34
Clevidipine  Washout  SNP
Whole Layer Myocardial Perfusion (Epi + Endo)
3
Flow (mL/min•g)
2.5
2
1.5
Baseline
Clevidipine
Re-stable
SNP
1
0.5
0
0
8
Data on file. The Medicines Company.
16
24
32
40
35
NTG  Washout  Clevidipine
Whole Layer Myocardial Perfusion (Epi + Endo)
3
Baseline
NTG
Flow (mL/min•g)
2.5
Re-stable
Clevidipine
2
1.5
1
0.5
0
0
8
Data on file. The Medicines Company.
16
24
32
40
36
Clevidipine: Summary
– The first third-generation IV dihydropyridine calcium channel
blocker
– Rapid onset: BP-lowering effects seen within 1–2 minutes of
infusion
– Ultrashort half-life with rapid offset: BP returned to baseline in <10
minutes
– Specific for vascular smooth muscle: no chronotropic or inotropic
effects
– Lowered BP in >90% of patients with perioperative hypertension
– Well tolerated in extensive safety trials
– In animal model, demonstrated a cardioprotective effect during
myocardial ischemia and reperfusion
37
Clevidipine Phase III Studies:
Perioperative Hypertension
ESCAPE-1: Preoperative
ESCAPE-2: Postoperative
ESCAPE: Perioperative Efficacy Trials
ESCAPE-1
ESCAPE-2
Preoperative Hypertension
(SBP >160 mm Hg)
Postoperative Hypertension
(SBP >140 mm Hg)
Placebo
n=52
Placebo
n=49
Clevidipine
n=53
Clevidipine
n=61
Levy JH et al. Anesth Analg. 2007;105:918-925.
Data on file. The Medicines Company.
39
ESCAPE Protocol
Design: two double-blind, randomized, placebo-controlled trials
– ESCAPE-1: 100 preoperative patients with SBP ≥160 mm Hg
– ESCAPE-2: 100 postoperative patients with SBP ≥140 mm Hg
Primary endpoint: need for alternative hypertensive agent due to lack
of efficacy (either no BP reduction or reduction by a minimum of 15%
from the baseline) or a safety issue
Data on file. The Medicines Company.
40
ESCAPE Results: Onset and
Time-to-Target Effect
Onset of BP-lowering effect: within 1–2 minutes of infusion
Time to target BP (15% reduction): ESCAPE-1 = 6.0 min*; ESCAPE-2
= 5.3 min†
ESCAPE-2
% Change From Baseline
% Change From Baseline
ESCAPE-1
10
5
0
–5
–10
–15
–20
SBP
–25
–30
0
5
10 15 20
Time (min)
25
30
SBP Changes
5
0
–5
–10
–15
SBP
–20
–25
–30
0
5
10 15 20
Time (min)
25
30
SBP Changes
Levy JH et al. Anesth Analg. 2007;105:918-925.
Data on file, The Medicines Company.
*Reproduced from Levy JH, et al. Anesthesiology. 2005;103:A354.
†Reproduced from Singla N, et al. Anesthesiology. 2005;103:A292.
41
ESCAPE Results: Success Rate
Clevidipine was successful in lowering BP to target in >90% of patients
with preoperative or postoperative hypertension*†
% Success
100
92.5
n=53
91.8
n=61
80
Clevidipine
60
40
20
17.3
n=52
20.4
n=49
Placebo
0
ESCAPE-1
ESCAPE-2
*Dose of 0.4–8.0 mcg/kg/min in preoperative and postoperative coronary and/or valve surgery patients.
†Treatment success defined by the absence of bailout (discontinuation of clevidipine or failure to reduce SBP by ≥15%).
Levy JH et al. Anesth Analg. 2007;105:918-925.
Singla N, et al. Anesthesiology. 2005;103:A292.
42
ESCAPE Results: Safety
In ESCAPE-1 and ESCAPE-2 trials*
– Clevidipine was well tolerated
– AEs were similar between clevidipine- and placebo-treated
patients
– AEs were as expected for a cardiac surgery population
– Three AEs considered related to clevidipine treatment: atrial
fibrillation, thrombophlebitis, and insomnia (1 patient each)
– No clinically relevant reflex tachycardia
*Modified intent-to-treat population; total of 215 randomized pre- and post-surgery patients.
Data on file. The Medicines Company.
Levy JH et al. Anesth Analg. 2007;105:918-925.
Singla N, et al. Anesthesiology. 2005;103:A292.
43
Blood Pressure Control with Clevidipine Compared with
Nitroglycerin, Sodium Nitroprusside, or Nicardipine in the
Treatment of Perioperative Hypertension:
Results of the Three Randomized ECLIPSE Trials
Solomon Aronson, MD,FACC,FCCP,FAHA,FASE
Professor and Executive Vice Chairman, Dept of Anesthesiology
Duke University Health System
Background
Perioperative hypertension may be associated with life-threatening
complications1-2
Over 50% of cardiac surgery patients experience acute perioperative
hypertension requiring an IV agent1,3-4
Current intravenous antihypertensive therapies have limitations
1Cheung,
2Aronson,
A. J Card Surg, 2006, S8
S. Anesth Analg 2002; 94:1079-84
3Estafanous,
F. Am J Cardiol, 1980, p685;
4Landymore,
R. Can J Surg, 1980
45
Rationale
Clevidipine is a rationally designed IV dihydropyridine calcium channel
blocker with an ultrashort half-life (~1 min)
Phase I & II studies (300 patients) demonstrated:
– Dose: 2–16 mg/h effective in controlling BP1
– Rapid onset: BP control within 5 min2
Phase III safety program
– Endpoints: death, MI, stroke, renal dysfunction
– Comparative agents: nitroglycerin (NTG), sodium nitroprusside
(SNP), nicardipine (NIC)
1Bailey
2Levy
J. Anesthesiology 2002;96:1086-94
JH et al. Anesth Analg. 2007;105:918-925.
46
Objectives
Primary
– Safety of Clevidipine in perioperative hypertension in cardiac
surgery patients (Death, MI, Stroke, Renal Dysfunction)
Secondary
– Other adverse events
– Blood pressure control
Aronson S et al. Abstract 1020-169. American College of Cardiology Annual Meeting; March 24-27 2007; New Orleans, LA.
Data of file, The Medicines Company.
47
Inclusion Criteria
Pre-randomization
– ≥ 18 years of age
– Written informed consent
– Planned CABG and/or valve repair/replacement surgery
Post-randomization
– Require treatment for perioperative hypertension per investigator
decision
Data of file, The Medicines Company.
48
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
Data of file, The Medicines Company.
49
Treatment
Clevidipine
– Initiated at 2 mg/h either pre-op, intra-op, post-op
– Titrated every 90 seconds in doubling increments until lowering of
BP achieved or maximum dose of 16 mg/h
– 40 mg/h maximum
Comparators (NTG, SNP, NIC) as per institutional practice
Treatment duration until ICU discharge
Concomitant antihypertensive administered per investigator choice, but
discouraged
Data of file, The Medicines Company.
50
ECLIPSE: Trial Design
Perioperative
Perioperative
Postoperative
Clevidipine
vs nitroglycerin
Clevidipine
vs sodium
nitroprusside
Clevidipine
vs nicardipine
1:1
1:1
1:1
Clevidipine
N=268
Nitroglycerin
N=278
Data on file. The Medicines Company.
Clevidipine
N=296
Sodium
nitroprusside
N=283
Clevidipine
N=188
Nicardipine
N=193
51
Endpoints
Primary* (Cumulative rate of clinical outcomes at 30 days):
– Death
– MI: symptomatic presentation, enzyme release, &/or new ECG
changes
– Stroke: Hemorrhagic or ischemic
– Renal Dysfunction: Cr >2.0 mg/dL with increase ≥ 0.7 mg/dL
Secondary
– SAEs through day 7
– BP control during the first 24 h
* Blinded CEC adjudication of all primary measures
Aronson S et al. Abstract 1020-169. American College of Cardiology Annual Meeting; March 24-27 2007; New Orleans, LA.
Data of file, The Medicines Company.
52
Statistical Methods
Assumptions
– Sample size 1500 patients recommended by FDA for safety profile
assessment
Descriptive analytical methods
– Prespecified safety analysis by treatment received
– Pooled data for clevidipine and all comparator arms
– Prespecified analyses of clevidipine versus each comparator
Data of file, The Medicines Company.
53
Study Completion
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
Data on file, The Medicines Company.
54
Baseline Characteristics
Clevidipine
n=752
Comparators
n=754
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%
Age, median (range)
Data on file, The Medicines Company.
55
Procedural Characteristics
Clevidipine
n=752
Comparators
n=754
3.32
3.23
– CABG
77%
77%
– Valve replacement/repair
14%
12%
– CABG & Valve replacement/repair
9%
11%
0.3%
0.1%
Surgery duration, median hrs
Procedure
– Other
Data on file, The Medicines Company.
56
Primary Endpoint
30-Day Events (%)
10%
Clevidipine
Comparators
8%
7.9% 7.9%
6%
3.8%
4%
2.8%
2.3% 2.4%
1.7%
2%
1.1%
0%
n=719 n=729
n=700 n=707
n=700 n=705
n=712 n=710
Death
MI
Stroke
Renal
Dysfunction
Data on file, The Medicines Company.
57
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
Dysfunction
6.9%
8.1%
8.5%
9.1%
8.3%
5.9%
Perioperative
* p=0.045
Perioperative
Postoperative
Only
Aronson S et al. Abstract 1020-169. American College of Cardiology Annual Meeting; March 24-27 2007; New Orleans, LA.
Data of file, The Medicines Company.
58
ECLIPSE NTG: Primary Endpoint
Clevidipine
n/N (%)
N=270
Nitroglycerin
n/N (%)
N=278
P Value
Death
7/254 (2.8)
9/266 (3.4)
0.67
MI
8/248 (3.2)
8/260 (3.1)
0.92
Stroke
4/247 (1.6)
6/260 (2.3)
0.57
Renal Dysfunction
17/250 (6.8)
21/260 (8.1)
0.58
• MI defined as symptomatic presentation, cardiac enzyme determinations, and/or
new ECG changes
• Stroke: hemorrhagic or ischemic
• Renal dysfunction defined as creatinine of >2 mg/dL with minimum of
absolute increase ≥ 0.7 mg/dL
Aronson S et al. Abstract 1020-169. American College of Cardiology Annual Meeting; March 24-27 2007; New Orleans, LA.
Data of file, The Medicines Company.
59
ECLIPSE SNP: Primary Endpoint
Clevidipine
n/N (%)
N=293
Nitroprusside
n/N (%)
N=283
P Value
Death
5/286 (1.7)
13/274 (4.7)
0.045
MI
4/281 (1.4)
6/264 (2.3)
0.460
Stroke
3/281 (1.1)
4/262 (1.5)
0.632
Renal Dysfunction
24/284 (8.5)
24/265 (9.1)
0.802
• MI defined as symptomatic presentation, cardiac enzyme determinations, and/or
new ECG changes
• Stroke: hemorrhagic or ischemic
• Renal dysfunction defined as creatinine of >2 mg/dL with minimum of
absolute increase ≥ 0.7 mg/dL
Data on file. The Medicines Company.
60
ECLIPSE NIC: Primary Endpoint
Clevidipine
n/N (%)
N=188
Nicardipine
n/N (%)
N=193
P Value
Death
8/181 (4.4)
6/189 (3.2)
0.530
MI
3/173 (2.3)
2/183 (1.1)
0.372
Stroke
1/173 (0.6)
2/183 (1.1)
0.595
Renal Dysfunction
15/180 (8.3)
11/185 (5.9)
0.375
• MI defined as symptomatic presentation, cardiac enzyme determinations, and/or
new ECG changes
• Stroke: hemorrhagic or ischemic
• Renal dysfunction defined as creatinine of >2 mg/dL with minimum of
absolute increase ≥ 0.7 mg/dL
Data on file. The Medicines Company.
61
ECLIPSE: Blood Pressure Control
Clevidipine
AUC
(mm Hg X min/h)
Comparators
AUC
(mm Hg X min/h)
P Value
ECLIPSE–NTG
4.14
8.87
<0.001
ECLIPSE–SNP
4.37
10.50
0.003
ECLIPSE–NIC
1.76
1.69
0.851
Data on file. The Medicines Company.
62
ECLIPSE Secondary Endpoint:
SBP Control Within Predefined Range Over 24 Hours
SBP
145
75
Time (24 hrs)
• Prespecified SBP ranges of 75–145 (pre and post-op); 65–135 (intra-op)
Data on file. The Medicines Company.
63
ECLIPSE Secondary Endpoint AUC:
Systolic Blood Pressure Control Over 24 Hours
SBP
Upper
Lower
Lower
0
6
12
18
24
Time (hours)
Data on file, The Medicines Company.
64
Blood Pressure AUC by Treatment Group
50
p = 0.0006
p = NS
p = 0.0004
44.48
45
Mean AUC (mmHg x min/h)
Median value in Italics
p = 0.0027
40.40
39.51
40
35.84
35
28.02
30
24.33
25
20
22.37
16.30
15
5
0
10.50
8.87
10
7.79
4.37
4.14
3.79
1.76
Clevidipine
n=269
NTG
n=278
ECLIPSE
NTG
Data on file, The Medicines Company.
Clevidipine
n=295
SNP
n=284
ECLIPSE
SNP
Clevidipine
n=187
1.69
NIC
n=194
ECLIPSE
NIC
Clevidipine All Comparators
n=751 n=756
ECLIPSE
NTG/SNP/NIC
65
Total AUC Outside Targeted BP Range
p=0.0002
111.5
mm Hg x min/h
120
Clevidipine
Comparators
100
n=751
87.7
n=756
80
60
p<0.0001
40
33.1
p<0.0001
p=0.0004
20
3.8
7.8
23.1
6.6
12.5
0
SBP Ranges:
75-145 pre-/post-op
65-135 intra-op
85-145 pre-/post-op
75-135 intra-op
95-145 pre-/post-op
85-135 intra-op
105-145 pre-/post-op
95-135 intra-op
Median AUC
Data on file, The Medicines Company.
66
Total AUC Outside Targeted BP Range by Treatment
Perioperative
Postoperative
Only
p = 0.0027
12
10.50
p = 0.0006
mm Hg x min/h
10
8.87
8
6
4.14
4.37
4
p = 0.8508
1.76
2
1.69
0
Clevidipine NTG
n=269
n=278
ECLIPSE
NTG
Clevidipine SNP
n=295
n=284
ECLIPSE
SNP
Clevidipine NIC
n=187
n=194
ECLIPSE
NIC
Median AUC
Range = Pre-/post-op SBP 75-145, Intra-op SBP 65-135
Data of file, The Medicines Company.
67
Total AUC Outside Narrowed BP Range by Treatment
Perioperative
140
p = 0.0556
mm Hg x min/h
120
Postoperative
Only
p = 0.0068
127.87
p = 0.0231
108.57
101.59
100.17
100
83.74
76.95
80
60
40
20
0
Clevidipine NTG
n=269
n=278
ECLIPSE
NTG
Clevidipine SNP
n=295
n=284
ECLIPSE
SNP
Clevidipine NIC
n=187
n=194
ECLIPSE
NIC
Median AUC
Range = Pre-/post-op SBP 105-145, Intra-op SBP 95-135
Data of file, The Medicines Company.
68
Perioperative BP Control : Clevidipine vs SNP
P=0.0068
140
127.9
Clevidipine n=295
Sodium Nitroprusside
mm Hg x min/h
120
100
100.2
n=284
80
P=0.0003
60
40
P=0.0027
20
4.4
10.5
41.5
P=0.0009
17.3
23.6
8.9
0
SBP Ranges:
75-145 pre-/post-op
65-135 intra-op
Median AUC
85-145 pre-/post-op
75-135 intra-op
95-145 pre-/post-op
85-135 intra-op
105-145 pre-/post-op
95-135 intra-op
Data on file. The Medicines Company.
69
Perioperative BP Control : Clevidipine vs NTG
P=0.0556
mm Hg x min/h
120
108.6
Clevidipine n=269
Nitroglycerin n=278
100
83.7
80
60
P=0.0016
40
34.2
P=0.0002
P=0.0006
20
4.1
8.9
23.4
14.9
6.0
0
SBP Ranges:
Median AUC
75-145 pre-/post-op
65-135 intra-op
85-145 pre-/post-op
75-135 intra-op
95-145 pre-/post-op
85-135 intra-op
105-145 pre-/post-op
95-135 intra-op
Data on file. The Medicines Company.
70
Postoperative BP Control : Clevidipine vs NIC
120
P=0.0231
Clevidipine
Nicardipine
mm Hg x min/h
100
101.6
n=187
n=194
77.0
80
60
P=0.3086
40
P=0.8949
P=0.8508
21.6
22.8
20
1.8
1.7
5.3
5.7
0
SBP Ranges:
Median AUC
75-145 post-op
85-145 post-op
95-145 post-op
105-145 post-op
Data on file. The Medicines Company.
71
Serious Adverse Events
Clevidipine
n=752
Comparators
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%
Data on file. The Medicines Company.
72
Use of Concomitant Antihypertensive Agents
Clevidipine vs. NTG
Clevidipine vs. SNP
156 (57.8) 158 (56.8)
Clevidipine vs. NIC
127 (42.8) 150 (52.8)
76 (40.4) 77 (39.5)
Clevidipine vs Comparators
(Pooled Data)
359 (47.5) 385 (50.9)
Data on file. The Medicines Company.
73
ECLIPSE NTG: Drug Administration
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)
Dosed During Pre-op
92 (34.3)
119 (42.8)
Dosed During Intra-op
229 (85.4)
245 (88.1)
Dosed During Post-op
187 (69.8)
226 (81.3)
3.35 h
8.13 h
21.8 mL
74.8 mL
Overall Infusion Duration (Median)
Total Infusion Volume (Median)
Data on file. The Medicines Company.
74
ECLIPSE SNP: Drug Administration
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)
Dosed During Pre-op
52 (17.6)
34 (12.0)
Dosed During Intra-op
209 (70.6)
185 (65.4)
Dosed During Post-op
219 (74.0)
204 (72.1)
4.03 h
3.25 h
26.5 mL
25.6 mL
Overall Infusion Duration (Median)
Total Infusion Volume (Median)
Data on file. The Medicines Company.
75
ECLIPSE NIC: Drug Administration
Dosed During Post-op
Overall Infusion Duration (Median)
Total Infusion Volume (Median)
Data on file. The Medicines Company.
Clevidipine
N=188
Nicardipine
N=193
188(100)
193(100)
5.55 h
5.12 h
56.4 mL
163.8 mL
76
ECLIPSE: Demographics, Baseline
Characteristics
Clevidipine
Nitroglycerin
Age (median)
65.0
64.0
Male Sex (%)
79.9
74.5
Hx HTN (%)
83.6
86.3
Age (median)
64.0
65.0
Male Sex (%)
70.2
76.1
Hx HTN (%)
85.5
80.6
Age (median)
66.5
67.0
Male Sex (%)
67.0
71.5
Hx HTN (%)
96.3
87.6
Data on file. The Medicines Company.
Nitroprusside
Nicardipine
77
ECLIPSE: Adverse Events and BP
Control
AUC Quartile
Death
MI
Stroke
Renal
Data on file. The Medicines Company.
1st
2nd
3rd
4th
1st
2nd
3rd
4th
1st
2nd
3rd
4th
1st
2nd
3rd
4th
All Agents Combined
(N=1512)
n/N (%)
7/380 (1.8)
14/375 (3.7)
11/374 (2.9)
16/378 (4.2)
6/380 (1.6)
9/375 (2.4)
7/374 (1.9)
11/378 (2.9)
4/380 (1.1)
4/375 (1.1)
6/374 (1.6)
6/378 (1.6)
24/380 (6.3)
24/375 (6.4)
25/374 (6.7)
39/378 (10.3)
78
ECLIPSE: Summary of Adverse Events
Clevidipine
n/N (%)
Nitroglycerin
n/N (%)
Pts with at
least one AE
267/268
278/278
(99.6)
(100)
Pts with at
least one SAE
43/268
51/283
(16.0)
(18.3)
Pts with at
least one AE
296/296
283/283
(100)
(100)
Pts with at
least one SAE
57/296
66/283
(19.3)
(23.3)
Pts with at
least one AE
187/188
193/193
(100)
(100)
Pts with at
least one SAE
33/188
34/193
(17.6)
(17.6)
Data on file. The Medicines Company.
Nitroprusside
n/N (%)
Nicardipine
n/N (%)
79
ECLIPSE: Atrial Fibrillation
Afib (total)
CLV
n/N (%)
NTG
n/N (%)
SNP
n/N (%)
NIC
n/N (%)
275/752
(36.6)
91/278 (32.7)
95/283 (33.6)
71/193 (36.8)
• No statistically significant differences in any of the arms or in overall comparison
Data on file. The Medicines Company.
80
Conclusions
Clevidipine is a safe alternative to currently available intravenous
antihypertensive agents
Clevidipine demonstrated superior efficacy in blood pressure control as
compared to currently available intravenous antihypertensive agents
over the first 24 hours of therapy
Aronson S et al. Abstract 1020-169. American College of Cardiology Annual Meeting; March 24-27 2007; New Orleans, LA.
Data of file, The Medicines Company.
81
Blood Pressure Control is an Independent Predictor of
Short-term Mortality in Cardiac Surgery Patients:
Analysis from the Three Randomized ECLIPSE Trials
Solomon Aronson, MD,FACC,FCCP,FAHA,FASE
Professor and Executive Vice Chairman, Dept of Anesthesiology
Duke University Health System
Statistical Analysis
Data pooled for 1512 patients
A multiple logistic regression analysis was performed to determine the
association of BP control with 30-day mortality
BP control was expressed as the cumulative area under the curve
(AUC) outside specified SBP ranges
AUC was analyzed as a continuous variable
Data on file, The Medicines Company.
83
SBP Control Within Predefined Range Over 24 Hours
SBP
145
75
Time (24 hrs)
• Prespecified SBP ranges of 75–145 (pre and post-op); 65–135 (intra-op)
Data on file. The Medicines Company.
84
Logistic Regression Model Selection
Candidate variables included:
– Demographics
– Baseline characteristics
– Medical history
– Treatment group
– AUC
– Procedural characteristics
p<0.05 required for inclusion in final output
Data on file, The Medicines Company.
85
Logistic Regression Results: Predictors
of Mortality
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 (1mmHg*min)
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]
Data on file, The Medicines Company.
86
30-Day Mortality by Magnitude of AUC
Odds
Ratio
95% CI
[Lower Limit,
Upper Limit]
I mmHg x 60 min
1.20
[1.06, 1.27]
2 mmHg x 60 min
1.43
[1.13, 1.61]
3 mmHg x 60 min
1.71
[1.20, 2.05]
4 mmHg x 60 min
2.05
[1.27, 2.61]
5 mmHg x 60 min
2.46
[1.35, 3.31]
0
Data on file, The Medicines Company.
1
2
3
4
87
Conclusions
Excursions outside a targeted BP range are correlated with 30-day
mortality
This relationship is direct and proportionate to the magnitude of
excursions outside the BP range
These data suggest that great attention should be given to precise
peri-operative BP control
Future analysis of this finding is warranted
Data on file, The Medicines Company.
88
Clevidipine: Arterial Selectivity
Systemic Vascular
Resistance
Mean Arterial
Pressure
†
†
†
70
Units
mm Hg
*
1200
1000
0
C1 0.375 0.75 1.5 3 C2
mcg/kg/min
‡
†
†
†
mm Hg
1400
90
80
Central Venous
Pressure
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.
12
10
8
6
4
2
0
0 0.375 0.75 1.5 3
0
mcg/kg/min
89
Clevidipine: Coronary 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
6
5
4
3
2
1
0
Stroke Volume
*
75
mL/beat
L • min–1
Cardiac Output
C1 0.375 0.75
1.5
3
C2
†
70
65
0
C1
Infusion Rate
(µg • kg–1 • min–1)
*P<0.05.
†P<0.001.
SVR = systemic vascular resistance; RVEDV = right ventricular end-diastolic volume.
Data from Kieler-Jensen N, et al. Acta Anaesthesiol Scand. 2000;44:186-193.
0.375 0.75 1.5
3
Infusion Rate
(µg • kg–1 • min–1)
C2
90
Clevidipine: Minimal Effect on Heart
Rate
10
5
HR
0
–5
0
5
10 15 20
Time (min)
Postoperative HR Changes
in Anesthetized Patients
% Change From Baseline
% Change From Baseline
Preoperative HR Changes
in Non-Anesthetized Patients
25
30
HR changes for patients during the
30-minute treatment period
5
0
HR
–5
0
5
10 15 20
Time (min)
25
30
HR changes for patients during the
30-minute treatment period
Levy JH et al. Anesth Analg. 2007;105:918-925.
Levy JH et al. Anesthesiology. 2005;103:A354.
Singla N et al. Anesthesiology. 2005;103:A292.
91
92
What is VELOCITY?
Multi-center, Phase III, open-label, single-arm, study to
confirm the safety of IV clevidipine for patients who present
to the ED (or ICU) with severe hypertension requiring parenteral
treatment for at least 18 h
Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American
College of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA.
93
VELOCITY:
Rationale
Clevidipine is a rationally designed IV dihydropyridine calcium
channel blocker with an ultrashort half-life (~1 min)
Phase I & II studies (300 patients) demonstrated:
– Dose: 2–16 mg/h effective1
– Rapid onset: BP control in 5 min2
Clevidipine’s quick onset/offset, good safety profile,
predictable dose-response effect, good hemodynamic
properties, and easy titration make it a good
candidate for treatment of severe hypertension in acute
care settings
1Bailey
2Levy
J. Anesthesiology. 2002;96:1086-1094.
JH et al. Anesth Analg. 2007;105:918-925.
94
VELOCITY:
Rationale (cont.)
Phase III safety and efficacy study
– Evaluation: to confirm the safety and efficacy of clevidipine
in patients with severe HTN using a predefined, non-weight
based dosing algorithm
– Population: patients presenting in the Emergency Department
with severe HTN (SBP >180 mmHg or DBP >115 mmHg)
assessed at 2 successive occasions 15 min apart at baseline
Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American
College of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA.
95
VELOCITY:
Objectives
Primary
Confirm the safety of a titration dosing regimen of an IV infusion of
clevidipine for the treatment of severe HTN
– Efficacy: percentage of patients in whom SBP fell within the
initial 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
Data on file. The Medicines Company.
96
VELOCITY:
Objectives (cont.)
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)
Data on file. The Medicines Company.
97
VELOCITY:
Enrollment Criteria
Inclusion Criteria
– Age 18 years and older
– Systolic BP >180 mmHg and/or diastolic BP >115 mmHg
assessed on 2 successive occasions, 15 min 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 hr
– Known or suspected aortic dissection
Data on file. The Medicines Company.
98
VELOCITY:
Treatment
Clevidipine
– Selection of Initial Target Range (ITR) was determined
prior to the initiation of clevidipine
– ITR was determined for each individual patient
– The difference between the upper and lower ITR was
between 20 mmHg and 40 mmHg
Data on file. The Medicines Company.
99
VELOCITY:
Treatment (cont.)
Clevidipine initiated at 2 mg/hr via
peripheral vein
Titrated in doubling increments Q3 min,
not to exceed 32 mg/hr, to achieve
pre-specified ITR
Infusion rate could have been decreased
at the investigators discretion in order to
achieve the target SBP
Infusion was maintained or further titrated after the first 30 min
to achieve the desired long-term reduction in SBP
Treatment duration for at least 18 hr and not exceeding 96 hr
BP monitoring was done with a BP cuff
Data on file. The Medicines Company.
100
VELOCITY:
Treatment – Transition to Oral Therapy
If transition to an oral antihypertensive agent was required,
the agent could be given 1 hr prior to the anticipated cessation
of clevidipine infusion but not before the 18 hr time point
At any time following the administration of the oral agent,
the clevidipine infusion could have been down-titrated or
terminated in order to achieve the desired BP level
If the BP rose to an undesirable level upon cessation of the infusion,
additional oral therapy may have been added or clevidipine infusion
may have been restarted
Data on file. The Medicines Company.
101
VELOCITY:
Sites
Data on file. The Medicines Company.
102
VELOCITY Study ‘Statistics’
No of sites:
No of enrolling sites:
Enrollment period (FPI to LPI):
Highest enrollers:
14
12
4th Sept 06 to 28th Jan 07 (146
days) ~5 mths
Dr Garrison/Mary Jones: 40
patients
Dr Varon/Michelle Bunch/Carliss
Ramos: 39 patients
Database lock: (LPO to DB Lock): 11 days
Data on file. The Medicines Company.
103
VELOCITY:
Patient Demographics
Parameter
Value
Age (yrs)
53.5 ± 15
Gender (%)
Male
48
Female
52
BMI (kg/m2)
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
Safety Population, N=126.
Mean ± SD
Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American
College of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA.
104
VELOCITY:
Results – Medical History, Comorbidity, and EndOrgan 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 hypertension
31
Congestive heart failure
18
Dyslipidemia
37
Smoker
Current / Former
39 / 21
Diabetes
31
Stroke
11
Safety Population, N=126.
Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American
College of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA.
105
VELOCITY:
Patient Disposition
ITT (patients enrolled)
N=131
SBP ≤UL of target
range
n=14
mITT (patients with
SBP >UL of target range)
N=117
No
clevidipine
n=5
Safety (patients who
received at least 1 dose)
N=126
<18 hr treatment
n=9
DNC
n=12
Completed
Patients
n=105
≥18 hr continuous
infusion
n=117
DNC
n=7
Completed
Patients
n=114
DNC=did not complete.
Data on file, The Medicines Company.
Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral
therapy. Poster presented at the American College of Emergency Physicians Annual Meeting;
October 8-11, 2007; Seattle, WA.
Completed
Patients
n=110
106
In VELOCITY…
“End-organ damage” is inclusive of acute and
chronic findings readily apparent in the ED:
– Hypertensive changes on funduscopy
– LVH on ECG
– Renal dysfunction
– Serum creatinine (above the normal lab limits)
– Calculated creatinine clearance < 90 mL/min
– > Trace proteinuria
– > Trace hematuria
– Acute heart failure
– Acute focal neurologic abnormalities
– Objective evidence of ACS
– Ischemic ST-segment changes
– Positive biomarkers of myocardial necrosis
Data on file. The Medicines Company.
107
VELOCITY:
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 4 mg/hr (max 11 mg/hr)
mITT population
Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American
College of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA.
108
VELOCITY:
Results
89% of patients achieved pre-specified ITR within 30 min
– An additional 7% of patients achieved ITR after 30 min
– 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 min
– Median infusion rate 6 mg/h (max 15 mg/h)
Time to a 15% drop in blood pressure 9.5 min
Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American
College of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA.
109
VELOCITY:
Results
Only 2 patients (1.6%) fell below the lower ITR limit
within first 3 min
– One patient had 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 hypotensive events were reported
mITT population
Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American
College of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA.
Data on file. The Medicines Company.
110
Percent of Patients
VELOCITY:
Probability of Having Attained Initial SBP Range
100
90
80
70
60
50
40
30
20
10
0
91%
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Minutes
K-M Analysis
Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American
College of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA.
111
% Reduction from Baseline SBP
(Mean ± SE)
VELOCITY:
Results – Change in BP (30 min)
0
-5
-6%
-10
-15
-21%
-16.5%
-20
-25
3
6
9
12 15 18
21
24 27 30
Time after start of infusion (min.)
mITT population
Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American College
of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA.
112
% Reduction from Baseline SBP
(Mean ± SE)
VELOCITY:
Results – Change in BP (18 hour)
0
-5
-10
-15
-20
-25
-30
0
3
6
9
12
15
18
Time after start of infusion (hours)
Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American
College of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA.
113
VELOCITY:
Results – Safety TEAEs by Organ
System Class, >5%
End Organ Injury
Yes
(N=102)
No
(N=24)
All Patient
s
(N=126)
n (%)
n (%)
n (%)
Number of patients with at least one TEAE 41 (40.2)
9 (37.5)
50 (39.7)
Nervous system disorders
12 (11.8)
5 (20.8)
17 (13.5)
General disorders and administration site
conditions
9 (8.8)
3 (12.5)
12 (9.5)
Gastrointestinal disorders
7 (6.9)
2 (8.3)
9 (7.1)
Investigations
9 (8.8)
0 (0.0)
9 (7.1)
Cardiac disorders
7 (6.9)
1 (4.2)
8 (6.3)
Respiratory, thoracic, and mediastinal
disorders
6 (5.9)
1 (4.2)
7 (5.6)
System Organ Class
TEAE=treatment-emergent adverse events.
Data on file. The Medicines Company.
114
VELOCITY:
Results – Transition to Oral
Antihypertensives
Transition to oral antihypertensive therapy was
successful in 91.3% of patients
Of the 11 not transitioning to oral therapy within 6 h of
IV termination:
– 2.4% could not be converted from clevidipine
– 3.2% did not reach the 18-h end point for transition eligibility
– 3.2% had contraindications to oral transition
– Contraindications included 3 patients having severe medical
events preventing the initiation of oral therapy and 1 patient
receiving another IV therapy
Of the 118 patients eligible for transition, 97.5% did so within 6 h
Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American College
of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA.
Data on file. The Medicines Company.
115
What We Learned From VELOCITY
Reliably lowered BP to pre-specified target range in 90%
of patients within 30 min
Predictably reached target BP without overshoot in a median 10.9 min
Clevidipine was easy to administer and well tolerated
– Peripheral venous administration and BP monitoring via a cuff was
safe and feasible in the ED
Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American College of
Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA.
Data on file. The Medicines Company.
116
Perioperative Blood Pressure Control
Predicts Renal Dysfunction in Cardiac
Surgery Patients
Solomon Aronson, MD,1 Albert Cheung, MD,2 Kevin Stierer, MD,3 Jerrold H.
Levy, MD,4 Philip Lumb, MD5 for the DCRI-GPRO Investigators
1Dept
of Anesthesiology, Duke University Medical Center, Durham, NC;
2Dept of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA;
3Heart Institute at St. Joseph Medical Center, Towson, MD; 4Dept of Anesthesiology, Emory
University School of Medicine, Atlanta, GA;
5Dept of Anesthesiology, Keck School of Medicine, University of Southern California, Los
Angeles, CA
Aronson S et al. Perioperative blood pressure control predicts renal dysfunction in cardiac surgery patients. Presented at the American Society of
Anesthesiologists Annual Meeting. Oct. 15, 2007; San Francisco, CA.
117
Background
As many as 56% of cardiac surgery patients develop perioperative
hypertension requiring IV therapy.1
Perioperative hypertension in cardiac surgery patients is associated
with life-threatening complications,1-2 but evidence that active BP
control improves outcomes is lacking.
The recently completed ECLIPSE trials showed that perioperative BP
control (assessed as integral analysis of SBP excursions outside
specified ranges over time) is associated with treatment protocol.3
In addition, logistic regression analysis of pooled ECLIPSE data
showed that perioperative BP control is a significant predictor of 30-day
mortality4 (p<0.01, OR 1.003 [95% CI 1.001-1.004]).
Further analysis of the ECLIPSE database was performed to evaluate
perioperative BP control as a predictor of renal dysfunction at 30 days.
1. Cheung AT. J Card Surg. 2006;21:S8-S14.
2. Aronson S et al. Circulation. 2007;115:733-742.
3. Aronson S et al. Blood pressure control with clevidipine compared with nitroglycerin, sodium nitroprusside, or nicardipine in the treatment of
perioperative hypertension: results of the three randomized ECLIPSE trials. Am Col Cardiol. March 27, 2007; New Orleans, LA.
4. Aronson S et al. Blood pressure control is an independent predictor of short-term mortality in cardiac surgery patients: Analysis from the
three randomized ECLIPSE trials. Late-breaking clinical trials. Am Coll Cardiol. March 26, 2007; New Orleans, LA.
118
Methods (slide 1 of 2)
The 3 open-label ECLIPSE trials compared clevidipine with NTG, SNP
or NIC for perioperative BP management in cardiac surgery patients.
Clevidipine is an IV dihydropyridine calcium channel blocker with an
ultrashort half-life (~1 min).
Pre-randomization inclusion criteria: ≥18 years old; planned CABG,
OPCAB, or valve surgery.
Post-randomization inclusion criterion: needing treatment for
perioperative hypertension.
Exclusion criteria: CVA ≤3 months of randomization; permanent
ventricular pacing; hypersensitivity, intolerance or allergy to study
drugs; any disease/condition that would put patient at risk.
Clevidipine was initiated at 2 mg/h and titrated in doubling increments
Q 90s up to 16 mg/h (40 mg/h maximum); comparators administered
per institutional practice.
Aronson S et al. Perioperative blood pressure control predicts renal dysfunction in cardiac surgery patients. Presented at the American Society
of Anesthesiologists Annual Meeting. Oct. 15, 2007; San Francisco, CA.
119
Methods (slide 2 of 2)
Patients were treated up to ICU discharge.
Hemodynamics were monitored for 24 h post-study drug initiation.
Multiple logistic regression analysis was performed on pooled data
from all 3 ECLIPSE trials to assess the relationship between BP control
and 30-day renal dysfunction (Cr >2.0 with minimum increase of
0.7 mg/dL).
Blood pressure control was assessed as the cumulative AUC outside
specified SBP ranges; AUC was analyzed as a binary variable.
Aronson S et al. Perioperative blood pressure control predicts renal dysfunction in cardiac surgery patients. Presented at the American Society
of Anesthesiologists Annual Meeting. Oct. 15, 2007; San Francisco, CA.
120
Safety Population
Baseline Characteristics
Patients
N=1506
Age, median (range)
65 (19-89)
Male
73%
Caucasian
83%
History of HTN
86%
CHF
19%
COPD
14%
Recent MI (<6 mos)
18%
Prior CABG
4%
Aronson S et al. Perioperative blood pressure control predicts renal dysfunction in cardiac surgery patients. Presented at the American Society
of Anesthesiologists Annual Meeting. Oct. 15, 2007; San Francisco, CA.
121
Safety Population
Procedural Characteristics
Patients
N=1506
Treatment
Clevidipine
49.9%
NTG
18.5%
SNP
18.8%
NIC
12.8%
Surgery duration, median hrs
3.48
Procedure
CABG
73.9%
Valve repair or replacement
11.7%
CABG & valve surgery
8.4%
Other
0.2%
Aronson S et al. Perioperative blood pressure control predicts renal dysfunction in cardiac surgery patients. Presented at the American Society
of Anesthesiologists Annual Meeting. Oct. 15, 2007; San Francisco, CA.
122
Logistic Regression Model
Multiple logistic regression analysis with model-building processes was
performed to identify variables predicting an increased risk of 30-day
renal dysfunction.
Candidate variables included:
– Demographics
– Baseline characteristics
– Medical history
– Treatment group
– Procedural characteristics
– AUC
For inclusion in final output, p<0.05 was required.
Aronson S et al. Perioperative blood pressure control predicts renal dysfunction in cardiac surgery patients. Presented at the American Society
of Anesthesiologists Annual Meeting. Oct. 15, 2007; San Francisco, CA.
123
Results of Logistic Regression
Predictors of 30-day Renal
Dysfunction
95%
Odds Confidence
P value Ratio
Interval
Pre-op serum Cr ≥1.2 mg/dl <0.0001 5.466 3.506, 8.521
Pre-op hemoglobin (g/dL)
<0.0001 0.785 0.699, 0.881
Body mass index
0.0074
1.049 1.013, 1.087
Surgery duration (hour)
0.0077
1.292 1.070, 1.559
Age (year)
0.0086
1.033 1.008, 1.059
BP (4th quartile of AUC*)
0.0126
1.785 1.132, 2.815
Race (African American)
0.0151
2.164 1.161, 4.035
Primary CABG + valve
0.0165
1.944 1.129, 3.348
*Total AUC of the magnitude and duration of SBP excursions outside the range of 85-145 mmHg pre- and postoperatively, and 75-135 mmHg
intraoperatively; patients with AUC ≥75th percentile analyzed.
Aronson S et al. Perioperative blood pressure control predicts renal dysfunction in cardiac surgery patients. Presented at the American Society
of Anesthesiologists Annual Meeting. Oct. 15, 2007; San Francisco, CA.
124
Results of AUC Comparison by Treatment
Median Total AUC (4th Quartile) of BP
Excursions outside Targeted SBP range
p=0.008
400
354.6
mm Hg x min/h
350
300
n=187
Clevidipine
Comparators n=189
250
p<0.0001
200
150
327.2
p<0.0001
p<0.0001
82.4
100
50.4
161.2
121.9
93.4
64.4
50
0
75-145 pre-/postop 85-145 pre-/postop 95-145 pre-/postop 105-145 pre-/postop
75-135 intraop
95-135 intraop
85-135 intraop
65-135 intraop
Comparison between CLV and all
comparators combined (pooled
data) of total AUC (median) for BP
excursions outside specified SBP
ranges in mmHg
Patients with AUC in ≥75th
percentile (those with greatest
magnitude and duration of BP
excursions outside target SBP
range) analyzed
For the targeted SBP range and
increasingly narrow ranges (lower
limit increased by increments of 10
mmHg), patients treated with CLV
had lower AUC than patients in all
other treatment groups combined
Aronson S et al. Perioperative blood pressure control predicts renal dysfunction in cardiac surgery patients. Presented at the American Society
of Anesthesiologists Annual Meeting. Oct. 15, 2007; San Francisco, CA.
125
Conclusions
Perioperative BP excursions outside a targeted SBP range are
correlated with renal dysfunction at 30 days.
Cardiac surgery patients with the greatest magnitude and/or duration of
BP excursions outside the SBP range (4th quartile AUC) were at risk of
renal dysfunction at 30 days.
This result is consistent with the previously reported relationship
between BP control and 30-day mortality.
Patients with the greatest magnitude and/or duration of BP excursions
outside target SBP range (4th quartile AUC) showed improved BP
control with clevidipine.
These findings suggest that treatment to attain more precise
perioperative BP control is important and may be especially significant
in patients who are most at risk for labile perioperative BP.
Further study of the relationship between perioperative BP control and
patient outcomes is warranted.
Aronson S et al. Perioperative blood pressure control predicts renal dysfunction in cardiac surgery patients. Presented at the American Society
of Anesthesiologists Annual Meeting. Oct. 15, 2007; San Francisco, CA.
126
The Pharmacokinetics and
Pharmacodynamics of Clevidipine after
Prolonged Continuous Infusion
in Patients with Essential Hypertension
William B. Smith, MD,1 Thomas C. Marbury, MD,2
Steven F. Komjathy, MD,3 Mark Sumeray, MD4
1New
Orleans Center for Clinical Research, Knoxville, TN;
2Orlando Clinical Research Center, Orlando, FL;
3PRA International Clinical Pharmacology Center, Lenexa, KS;
4The Medicines Company, Parsippany, NJ
Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO.
127
Background
Clevidipine is a novel 3rd-generation dihydropyridine calcium channel
blocker under study as IV treatment for acute and severe
hypertension.1
As an arterioselective vasodilator, clevidipine directly reverses arterial
vasoconstriction, which predominantly underlies hypertension.2,3
Clevidipine is rapidly eliminated through esterase metabolism and
demonstrates an ultrashort half-life of approx 1 min and a fast-on,
fast-off pharmacologic profile4,5
Prior to this study, clinical experience with prolonged clevidipine
infusion was limited
This study evaluated the pharmacology and safety of continuous
prolonged (72 h) clevidipine infusion in patients with mild to moderate
essential hypertension.
1. Nordlander M et al. Cardiovascr Drug Rev. 2004;22(3):227-250.
2. Kieler-Jensen N et al. Acta Anaesthesiol Scand. 2000;44:186-193.
3. Marik PE et al. CHEST 2007;131:1949-1962.
4. Ericsson H et al. Anesthesiol. 2000;92:993-1001.
5. Ericsson H et al. Br J Clin Pharmacol 1999;47:531-538.
128
Methods (slide 1 of 3)
Study Design: randomized, placebo-controlled, single-blind study in
patients with mild to moderate essential hypertension.
Treatment:
– Clevidipine (0.5 mg/mL in 20% lipid emulsion) in dose cohorts of
2.0 mg/h, 4.0 mg/h, 8.0 mg/h, or 16.0 mg/h; or
– Placebo (Intralipid 20% lipid emulsion)
Clevidipine administered IV at initial infusion rate of 2.0 mg/h and
force-titrated by doubling increments every 3 min to target dose.
Placebo administered similarly.
Target dose maintained continuously for 72 hours.
Patients were followed for 7 days from study drug initiation.
Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO.
129
Methods (slide 2 of 3)
Patient Selection: Patients aged 18-80 years old with mild to
moderate essential hypertension (treated or untreated)
Treated patients withdrew from oral anti-HTN medications for 8-14
days prior to study drug administration
While untreated, patients were assessed for systolic blood pressure
(SBP), diastolic blood pressure (DBP) and heart rate (HR) at least
twice, at least 30 min apart, on 3 separate days to confirm study
eligibility
To be eligible, patients had to have:
– SBP ≥140 and <200 mmHg, and/or DBP ≥95 and <115 mmHg; and
– HR <120 bpm
Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO.
130
Methods (slide 3 of 3)
Other inclusion criteria:
– Clinical laboratory results (screening chemistry, hematology,
fasting lipid panel) within normal limits and/or considered clinically
insignificant
– Negative drug / alcohol screening tests
– Negative urine pregnancy test (women of childbearing potential)
Exclusion criteria included:
– Taking 5 or more oral anti-hypertension meds
– Secondary hypertension
– Severe cardiovascular disease such as severe arrhythmia, CHF,
aortic dissection or ischemia requiring nitrates
– MI or CVA within last 6 months
– History of cerebral hemorrhage or intracranial tumor
– Liver failure or cirrhosis
– Unwilling to stop smoking or stop caffeine or alcohol intake during
study
Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO.
131
Results
Patient Population: 61 patients were enrolled; 1 patient in Cohort 3
withdrew prior to PK evaluation; 60 patients completed the study
Intent-to-treat (ITT) and safety populations (N=61):
– Cohort 1 (clevidipine 2.0 mg/h): 10 patients
– Cohort 2 (clevidipine 4.0 mg/h): 10 patients
– Cohort 3 (clevidipine 8.0 mg/h): 18 patients
– Cohort 4 (clevidipine 16.0 mg/h): 10 patients
– Cohort 5 (placebo): 13 patients
Per-protocol population (N=53):
– Cohorts 1-4: 10 patients in each cohort
– Cohort 5: 13 patients
– Defined as all patients who received 72 h treatment at target dose
and had blood samples for PK analysis drawn correctly
– (excludes the 1 patient who withdrew and 7 patients in Cohort 3
whose blood samples were drawn from the clevidipine IV cannula)
Dose cohorts were balanced with respect to baseline characteristics
Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO.
132
Screening Demographics and Medical
History
Clevidipine
Placebo
N=13
2.0 mg/h
N=10
4.0 mg/h
N=10
8.0 mg/h
N=18
16.0 mg/h
N=10
55
56
47
52
56
Mean weight (kg)
88.1
87.4
105.3
93.6
99.9
2
32.1
30.2
34.3
30.6
34.4
Mean age (yr)
Mean BMI (kg/m )
Male
7 (53.8%)
5 (50.0%)
7 (70.0%)
14 (77.8%)
7 (70.0%)
Smoker
3 (23.1%)
2 (20.0%)
2 (20.0%)
2 (11.1%)
0 (0.0%)
Dyslipidemia
2 (15.4%)
5 (50.0%)
1 (10.0%)
3 (16.7%)
2 (20.0%)
Diabetes
(non-insulin-dep)
2 (15.4%)
3 (30.0%)
3 (30.0%)
3 (16.7%)
3 (30.0%)
Diabetes (insulindep)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
Angina pectoris
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
COPD
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
1 (10.0%)
Renal disease
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
Stroke
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
ITT / Safety Population
Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO.
133
Pharmacodynamics
All clevidipine dose cohorts showed a rapid onset of drug effect
(decrease in SBP from baseline)
Clevidipine drug effect was consistent throughout the 72-h treatment
period, with no evidence of diminishing effect (tolerance)
Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO.
134
Mean % Change in SBP from Baseline vs Time Over
the Entire Study Drug Infusion Period (All Cohorts)
PP Population
SBP returned to baseline after drug treatment was stopped, with no
evidence of rebound
Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO.
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Mean % Change in SBP from Baseline vs Time after the
End of Study Drug Infusion
(Cohort 1 vs Placebo)
(Cohort 2 vs Placebo)
(Cohort 3 vs Placebo)
(Cohort 4 vs Placebo)
Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO.
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Pharmacokinetics
Clevidipine was rapidly metabolized throughout the 72-h infusion
period
Clevidipine blood concentrations decreased bi-exponentially following
infusion
The concentration-time profile for clevidipine was similar across all
dose cohorts
Calculated clevidipine mean clearance = ~30 L/min, and was similar
across dose cohorts
Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO.
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Mean Clevidipine Blood Concentrations vs Time
over the 72-h Infusion Time through 60 min PostInfusion (All Cohorts)
Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO.
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Mean Blood Clevidipine Concentrations vs Time from
End of Infusion to 1 h Post-Infusion (All Cohorts)
Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO.
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Safety
No deaths or serious adverse events (AEs) occurred during the study
One patient had AEs (facial pressure, headache and nausea) leading
to clevidipine discontinuation and study withdrawal; all AEs resolved
the same day they occurred
The most commonly reported AEs across treatments and dose levels
were headache and infusion site reaction, swelling, and erythema
No dose- or treatment-related differences in AE incidence, description,
severity or duration were apparent between the clevidipine dose
cohorts
Other clinical safety assessments (ECG, laboratory results) were
unremarkable overall
Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO.
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Conclusions
After prolonged (72 h) continuous clevidipine infusion:
– No drug tolerance developed
– The decrease from baseline in SBP was maintained at relatively
constant levels
– No evidence of rebound HTN was observed upon discontinuation
– A rapid return to baseline SBP was observed after stopping
clevidipine infusion across all dose levels
– Clevidipine PK and PD are consistent with previously reported
findings1
Prolonged (72 h) continuous clevidipine infusion was well tolerated by
patients with essential hypertension.
Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO.
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