Clevidipine Phase III Studies:
Perioperative Hypertension
ESCAPE-1: Pre-operative
ESCAPE-2: Post-operative
Levy JH et al. Anesth Analg. 2007;105:918-925
Singla N et al. Anesth Analg. 2008;107:59-67
ESCAPE Protocol
● Design: two double-blind, randomized, placebo-controlled
trials in cardiac surgery
– ESCAPE-1: preoperative patients with SBP ≥ 160 mm Hg
– ESCAPE-2: postoperative patients with SBP ≥ 140 mm Hg
● Primary endpoint: treatment failure
– Premature and permanent discontinuation of study drug
– Failure to decrease SBP by >15% from baseline within 30 minutes
- Lack of efficacy
- Insufficient efficacy
- Safety
● Secondary endpoints
– Time to target BP
– Change in MAP
– Change in HR
Levy JH et al. Anesth Analg. 2007;105:918-925
Singla N et al. Anesth Analg. 2008;107:59-67
ESCAPE Protocol
● Inclusion Criteria
– Age >18 yrs
– Scheduled for cardiac surgery
- On- or off-pump CABG
- Minimally invasive CABG
- And/or valve replacement or repair
– SPB >140 (post-op) or >160 mm Hg (pre-op)
- ESCAPE-1: Pre-existing hypertension requiring treatment or active
hypertension on admission
- ESCAPE-2: Hypertension within 4 hours of arrival to post-operative
setting
● Exclusion Criteria
–
–
–
–
CVA within 3 months
Pre-existing LBBB or permanent ventricular pacing
Known intolerance to calcium channel blockers
Allergy to soybean oil or egg lecithin
Levy JH et al. Anesth Analg. 2007;105:918-925
Singla N et al. Anesth Analg. 2008;107:59-67
ESCAPE Protocol
● Clevidipine dosing
– 0.4 mcg/kg/min (approximately 2 mg/hr for an 80 kg. patient)
– Dose doubled every 90 seconds until BP decreased by 15% or
more
– Once dose of 3.2 mcg/kg/min reached, could increase by 1.5
mcg/kg/min increments to maximum of 8 mcg/kg/min
● Identical placebo
● Drug continued for at least 30 minutes, up to 1 hour
– D/C at induction of anesthesia for ESCAPE-1
● If target BP not reached at maximal dose, deemed
treatment failure
Levy JH et al. Anesth Analg. 2007;105:918-925
Singla N et al. Anesth Analg. 2008;107:59-67
ESCAPE: Perioperative Efficacy Trials
ESCAPE-1
ESCAPE-2
Pre-operative Hypertension
(SBP >160 mm Hg)
Post-operative Hypertension
(SBP >140 mm Hg)
Placebo
n=52
Placebo
n=49
Levy JH et al. Anesth Analg. 2007;105:918-925
Singla N et al. Anesth Analg. 2008;107:59-67
Clevidipine
n=53
Clevidipine
n=61
ESCAPE Results: Demographics
ESCAPE-1
ESCAPE-2
Clevidipine
Placebo
Clevidipine
Placebo
n=53
N=52
N=61
N=49
65
61.7*
63.8
62.3
62.3
69.8
34.6*
69.2
54.1
77
34.7*
77.6
Stroke (%)
5.7
3.8
6.6
8.2
Hx HTN (%)
100
35.8
30.2
100
48.1
11.5*
83.6
34.4
24.6
83.7
34.7
30.6
Previous CABG (%)
9.4
1.9
1.6
4.1
Angina Pectoris (%)
64.2
57.7
42.6
63.3*
Previous MI (%)
30.2
11.5*
24.6
30.6
Baseline preoperative
SBP (mm Hg), mean
182
177
147.4
150.5
Age, mean (yr)
Age > 65 (%)
Male (%)
Diabetes(%)
Previous MI (%)
Levy JH et al. Anesth Analg. 2007;105:918-925
Singla N et al. Anesth Analg. 2008;107:59-67
* p<0.05
ESCAPE Results: Procedural Characteristics
ESCAPE-1
ESCAPE-2
Clevidipine
Placebo
Clevidipine
Placebo
N=53
N=52
N=61
N=49
n (%)
n (%)
n (%)
n (%)
42 (79.2)
44 (84.6)
33 (54.1)
35 (71.4)
- Valve repair/replacement
1 (1.9)
2 (3.8)
17 (27.9)
6 (12.2)
- Combined CABG and valve
5 (9.4)
5 (9.6)
8 (13.1)
6 (12.2)
- CABG Only
3 (5.7)
1 (1.9)
0
1 (2)
- Valve repair/replacement
1 (1.9)
0
2 (3.3)
1 (2)
0
0
1 (1.6
0
Primary Surgery
- CABG Only
Repeat Surgery
- Combined CABG and valve
Levy JH et al. Anesth Analg. 2007;105:918-925
Singla N et al. Anesth Analg. 2008;107:59-67
ESCAPE Results: Treatment Success Rate
p<0.0001
% Success
100
92.5
p<0.0001
91.8
80
Clevidipine
60
Placebo
40
20.4
17.3
20
N=53
N=52
N=61
N=49
0
ESCAPE-1
ESCAPE-2
Treatment success = absence of treatment failure
Levy JH et al. Anesth Analg. 2007;105:918-925
Singla N et al. Anesth Analg. 2008;107:59-67
ESCAPE Results:
Clevidipine 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 min; ESCAPE-2 = 5.3 min
ESCAPE-1
Levy JH et al. Anesth Analg. 2007;105:918-925
Singla N et al. Anesth Analg. 2008;107:59-67
ESCAPE-2
ESCAPE Results: Safety
Treatment emergent adverse reactions and the category on “any common
adverse event” in ESCAPE-1 and ESCAPE-2 where the rate on Cleviprex
exceeded the rate on Placebo by at least 5% (common adverse reactions)
ESCAPE-1
Any Common Adverse
Event
Acute Renal Failure
Atrial Fibrillation
Nausea
ESCAPE-2
Clevidipine
Placebo
Clevidipine
Placebo
n=53(%)
N=51(%)
N=61(%)
N=49(%)
27 (51%)
21 (41%)
32 (53%)
24 (49%)
5 (9%)
----
1 (2%)
----
---13 (21%)
---6 (12%)
----
----
13 (21%)
6 (12%)
Clevidipine Product Information August 2008; The Medicines Company
ESCAPE Results: Safety
● 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
Levy JH et al. Anesth Analg. 2007;105:918-925
Singla N et al. Anesth Analg. 2008;107:59-67
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
Aronson S et al. Anesth Analg 2008 (in press)
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
Aronson S et al. Anesth Analg 2008 (in press)
Clevidipine
N=296
Sodium
nitroprusside
N=283
Clevidipine
N=188
Nicardipine
N=193
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: Serum creatinine ≥ 2.0 mg/dL with an
increase of ≥ 0.7 mg/dL from pre- to post-op
● Secondary
– SAEs through day 7
– BP control during the first 24 h
* Blinded CEC adjudication of all primary measures
Aronson S et al. Anesth Analg 2008 (in press)
Inclusion Criteria
● Pre-randomization
– ≥ 18 years of age
– Planned CABG and/or valve repair/replacement
surgery
● Post-randomization
– Require treatment for perioperative
hypertension per investigator decision
Aronson S et al. Anesth Analg 2008 (in press)
Exclusion Criteria
● 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
● Women of child bearing potential
Aronson S et al. Anesth Analg 2008 (in press)
Treatment Protocol
● Clevidipine
– Initiated at 0.4 mcg/kg/min in pre-op, intra-op, or post-op setting
– Titrated every 90 seconds in doubling increments up to 3.2 mcg/kg/min;
infusion rates above 3.2 mcg/kg/min guided by patient response and
permitted in serial increments of 1.5 mcg/kg/min.
– Infusion rates between 4.4-8.0 mcg/kg/min were administered for no longer
than 2 hours
– Titration to higher infusion rates up to the maximal infusion rate of 8.0
mcg/kg/min was required before switching to or adding alternative
antihypertensive drugs.
– May continue through discharge from ICU
● Target blood pressure – as deemed appropriate by the study
physician
● Comparators – dosed as per institutional practice
– Nitroglycerin
– Sodium nitroprusside
– Nicardipine (post-operative only)
Aronson S et al. Anesth Analg 2008 (in press)
Methods
● Descriptive analytical methods
– Prespecified safety analysis by treatment received
– Pooled data for clevidipine and all comparator arms
– Prespecified analyses of clevidipine versus each comparator
● BP Control assessed as the summation of integrated
SBP vs time curve excursions
– SBP plotted versus time from study drug initiation to arterial line
removed or 24 hours, whichever came first
– Pre-determined target SBP range
- 65-135 mm Hg intra-operatively
- 75-145 mm Hg pre- and post-operatively
– AUC = magnitude (mm Hg) x duration (minutes) of SBP outside
range
– AUC normalized per hour and expressed as mm Hg x min/hr
Aronson S et al. Anesth Analg 2008 (in press)
Patient Disposition
Clevidipine
NTG
Clevidipine
SNP
Clevidipine
NIC
Patients randomized
312
316
363
376
296
301
Patients meeting postrandomization
criteria (mITT)
270
278
297
284
188
195
Patients not receiving
study medication a
2
0
1
1
1
1
Patients who received
study medication
(safety population)
268
278
296
283
188
193
Total Safety Population
a
546
579
381
Two patients in the CLV/NIC group did not receive study medication and were excluded from the safety
population. In addition, one patient in the same treatment was randomized to NIC but received CLV
instead. This patient was excluded from the NIC safety population and included in the CLV safety
population
Aronson S et al. Anesth Analg 2008 (in press)
Baseline Characteristics (Safety Population)
Clevidipine
NTG
Clevidipine
SNP
Clevidipine
NIC
n=268
n=278
n=296
n=283
n=188
n=193
Age, median
64.4
63.9
64.2
65.3
66.1
66.1
Male (%)
79.9
74.5
68.9
76.3
67.0
71.5
Stroke (%)
8.6
7.2
7.1
6.4
8.5
6.2
Hx HTN (%)
83.6
86.3
85.5
80.6
96.3*
87.6
8.6
10.8
12.2
10.2
10.6
10.9
COPD (%)
14.2
10.4
12.8
18.4
13.8
17.1
Recent MI (< 6mos) (%)
17.2
18.3
15.5
15.9
20.7
21.8
Baseline SBP (mm Hg)
142.9
139.1
142.1
141.8
144.2
144.0
Baseline DBP (mm Hg)
71.9
71.3
70.7
70.7
69.2
68.4
Insulin dependent
diabetes(%)
*p<0.05, CLV vs. NIC
Aronson S et al. Anesth Analg 2008 (in press)
Results: Procedural Characteristics (Safety
Population)
Aronson S et al. Anesth Analg 2008 (in press)
ECLIPSE NTG: Drug Administration (Safety
Population)
Clevidipine
N=268
Nitroglycerin
N=278
Initiated Pre-op n (%)
92 (34.3)
119 (42.8)
Initiated Intra-op n (%)
145 (54.1)
132 (47.5)
Initiated Post-op n (%)
31 (11.6)
27 (9.7)
Dosed During Pre-op n (%)
92 (34.3)
119 (42.8)
Dosed During Intra-op n (%)
229 (85.4)
245 (88.1)
Dosed During Post-op n (%)
187 (69.8)
226 (81.3)
6.4 h
12.0 h
Average Infusion Rate (Median)
6.2 mL/hr
11.3 mL/hr
Total Infusion Volume (Median)
21.8 mL
74.8 mL
Overall Infusion Duration
including periods when
infusion stopped (Median)
Aronson S et al. Anesth Analg 2008 (in press)
ECLIPSE SNP: Drug Administration (Safety
Population)
Clevidipine
Initiated Pre-op n (%)
Initiated Intra-op n (%)
Initiated Post-op n (%)
Dosed During Pre-op n (%)
Dosed During Intra-op n (%)
Dosed During Post-op n (%)
Overall Infusion Duration including
periods when infusion stopped
(Median)
Average Infusion Rate (Median)
Total Infusion Volume (Median)
Aronson S et al. Anesth Analg 2008 (in press)
SNP
N=283
N=296
52 (17.6)
161 (54.4)
83 (28.0)
52 (17.6)
209 (70.6)
219 (74.0)
34 (12.0)
158 (55.8)
90 (31.8)
34 (12.0)
185 (65.4)
204 (72.1)
6.7 h
5.4 h
6.4 mL/hr
26.5 mL
8.5 mL/hr
25.6 mL
ECLIPSE NIC: Drug Administration (Safety
Population)
Clevidipine
N=188
Nicardipine
N=193
188(100)
193(100)
5.6 h
4.6 h
Average Infusion Rate
(Median)
7.9 mL/hr
33.6 mL/hr
Total Infusion Volume
(Median)
56.4 mL
163.8 mL
Dosed During Post-op n (%)
Overall Infusion Duration
Including Periods When
Infusion Stopped (Median)
Aronson S et al. Anesth Analg 2008 (in press)
Results: Primary Endpoint (Safety Population)
p=NS for all
30-Day Events (%)
10%
Clevidipine (n=752)
Comparators (n=754)
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
Aronson S et al. Anesth Analg 2008 (in press)
ECLIPSE NTG: Primary Endpoint (Safety
Population)
Clevidipine
n/N (%)
N=268
Nitroglycerin
n/N (%)
N=278
P Value
Death
7/252 (2.8)
9/266 (3.4)
0.69
MI
8/246 (3.3)
9/260 (3.5)
0.90
Stroke
4/245 (1.6)
6/260 (2.3)
0.59
Renal Dysfunction
17/248 (6.9)
21/260 (8.1)
0.60
Aronson S et al. Anesth Analg 2008 (in press)
ECLIPSE SNP: Primary Endpoint (Safety
Population)
Clevidipine
n/N (%)
N=296
Nitroprusside
n/N (%)
N=283
P Value
Death
5/286 (1.7)
13/274 (4.7)
0.04
MI
4/281 (1.4)
6/264 (2.3)
0.46
Stroke
3/282 (1.1)
4/262 (1.5)
0.63
Renal Dysfunction
24/284 (8.5)
24/265 (9.1)
0.80
Aronson S et al. Anesth Analg 2008 (in press)
ECLIPSE NIC: Primary Endpoint (Safety
Population)
Clevidipine
n/N (%)
N=188
Nicardipine
n/N (%)
N=193
P Value
Death
8/181 (4.4)
6/189 (3.2)
0.53
MI
4/173 (2.3)
2/183 (1.1)
0.37
Stroke
1/173 (0.6)
2/183 (1.1)
0.60
Renal Dysfunction
15/180 (8.3)
11/185 (5.9)
0.38
Aronson S et al. Anesth Analg 2008 (in press)
ECLIPSE Secondary Endpoint:
SBP Control Within Predefined Range Over 24 Hours
SBP
145
75
Time (24 hrs)
• Schematic illustration for an individual patient
• Prespecified SBP ranges of 75–145 (pre and post-op); 65–135 (intra-op)
ECLIPSE Secondary Endpoint AUC:
Schematic Illustration for an Individual Patient
SBP
Upper
Lower
0
6
12
Time (hours)
Aronson S et al. Anesth Analg 2008 (in press)
18
24
ECLIPSE: Blood Pressure Control
Clevidipine
Comparators
AUC
AUC
(mm Hg X min/h) (mm Hg X min/h) P Value
Median
Median
ECLIPSE–NTG
4.14
8.87
0.0006
ECLIPSE–SNP
4.37
10.5
0.0027
ECLIPSE–NIC
1.76
1.69
NS
3.79
7.79
0.0004
ECLIPSE-All
Comparators
Aronson S et al. Anesth Analg 2008 (in press)
Post-Hoc Analysis:
Total AUC Outside Targeted BP Range
Median AUC
p=0.0002
111.5
mm Hg x min/h
120
100
Clevidipine
Comparators
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
Aronson S et al. Anesth Analg 2008 (in press)
85-145 pre-/post-op
75-135 intra-op
95-145 pre-/post-op 105-145 pre-/post-op
95-135 intra-op
85-135 intra-op
Post-hoc Analysis:
Perioperative BP Control - Clevidipine vs SNP
Median AUC
P=0.0068
mm Hg x min/h
140
127.9
Clevidipine
120
n=295
Sodium Nitroprusside
100
n=284
100.2
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
Aronson S et al. Anesth Analg 2008 (in press)
85-145 pre-/post-op
75-135 intra-op
95-145 pre-/post-op 105-145 pre-/post-op
95-135 intra-op
85-135 intra-op
Post-hoc Analysis:
Perioperative BP Control - Clevidipine vs NTG
Median AUC
P=0.0556
mm Hg x min/h
120
108.6
Clevidipine
Nitroglycerin
100
n=269
n=278
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:
75-145 pre-/post-op
65-135 intra-op
Aronson S et al. Anesth Analg 2008 (in press)
85-145 pre-/post-op
75-135 intra-op
95-145 pre-/post-op 105-145 pre-/post-op
95-135 intra-op
85-135 intra-op
Post-hoc Analysis:
Postoperative BP Control - Clevidipine vs NIC
Median AUC
mm Hg x min/h
120
P=0.0231
101.6
Clevidipine n=187
Nicardipine n=194
100
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:
75-145 post-op
Aronson S et al. Anesth Analg 2008 (in press)
85-145 post-op
95-145 post-op
105-145 post-op
Post-Hoc 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 (1 mm Hg * 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 mm Hg
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]
Aronson S et al. American College of Cardiology 56th Annual Scientific Session. March 2007. New Orleans, LA
Post-hoc Analysis:
30-Day Mortality by Magnitude of AUC
Odds
Ratio
95% CI
[Lower
Limit,
Upper Limit]
I mm Hg x 60 min
1.20
[1.06, 1.27]
2 mm Hg x 60 min
1.43
[1.13, 1.61]
3 mm Hg x 60 min
1.71
[1.20, 2.05]
4 mm Hg x 60 min
2.05
[1.27, 2.61]
5 mm Hg x 60 min
2.46
[1.35, 3.31]
0
1
2
3
4
Aronson S et al. American College of Cardiology 56th Annual Scientific Session. March 2007. New Orleans, LA
Post-Hoc Logistic Regression Results:
Predictors of 30-day Renal Dysfunction
P-Value
Odds
Ratio
95% CI
[Lower Limit,
Upper Limit]
Pre-op serum Cr ≥1.2 mg/dl
<0.0001
5.466
3.506, 8.521
Pre-op hemoglobin (g/dL)
Body mass index
Surgery duration (hour)
<0.0001
0.0074
0.0077
0.785
1.049
1.292
0.699, 0.881
1.013, 1.087
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. American College of Cardiology 56th Annual Scientific Session. March 2007. New Orleans, LA
Serious Adverse Events
Clevidipine
n=752
Comparators
n=754
Total
17.7%
22.7%
AFIB
2.4%
2.5%
Respiratory failure
1.1%
2.5%
ARF
2.3%
1.9%
Ventricular fibrillation
0.9%
1.5%
Cardiac arrest
0.5%
1.7%
CVA
0.5%
1.1%
Post-procedural hemorrhage
0.5%
1.2%
Atrial Fibrillation
reported as ANY
Adverse Event (%)
Clevidipine
NTG
Clevidipine
SNP
Clevidipine
NIC
33.6
32.0
36.1
32.2
35.6
35.2
Aronson S et al. Anesth Analg 2008 (in press)
Primary Endpoint Conclusions
● Clevidipine demonstrated similar 30 day outcomes (Death,
MI, Stroke, Renal Dysfunction) in a pooled analysis with
comparator treatments (NTG, SNP, NIC).
● Clevidipine demonstrated similar 30 day outcomes when
compared individually with NTG and NIC in all
components of the primary endpoint
● When compared with SNP, Clevidipine demonstrated a
significant mortality advantage, with similar outcomes in
the remaining endpoint components
● In post hoc analyses, clevidipine demonstrated improved
blood pressure control compared to NTG and SNP as
measured by 24 hour median AUC
● BP control with clevidipine was comparable to nicardipine
Post-Hoc Analyses Conclusions
● Clevidipine demonstrated improved blood pressure control
compared to NTG and SNP as measured by 24 hour
median AUC
● BP control with clevidipine was comparable to nicardipine
as measured by AUC
● Excursions outside a targeted BP range are correlated
with 30-day mortality and renal dysfunction
– Future analysis of this post-hoc finding is warranted
Annals of Emergency Medicine - 06 June 2008
(10.1016/j.annemergmed.2008.04.025)
VELOCITY:
Rationale
Common Hypertensive Emergencies1,2
● Acute coronary syndromes
● Heart failure, pulmonary edema
● Acute cerebrovascular syndromes (Stroke)
– subarachnoid hemorrhage
– cerebral bleeding
– cerebral infarction
● Hypertensive encephalopathy and retinopathy
● Renal Crisis
1. Varon J, Marik PE. Chest. 2000;118:214-227.
2. Mansoor GA, Frishman WH. Heart Dis. 2002;4:358-371.
VELOCITY:
Rationale
Treatment Goals for Hypertensive Emergency
● Prompt, but smooth reduction in BP
–
–
–
–
Reduce BP by ≤ 25% during the first minute to 1 hour
If stable, reduce BP 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 of an arterial catheter for monitoring BP routinely required
● Choice of pharmacologic agent should be tailored to patient
– Based on risks, comorbidities and type of end-organ damage
Chobanian AV, et al. Hypertension. 2003;42:1206-1252.
VELOCITY:
Objective
● To assess the safety and efficacy of IV clevidipine
for the treatment of acute, severe hypertension:
– A predetermined, patient-specific SBP target range (TR)
– Prespecified, non-weight-based titration dosing
– Continuous maintenance infusion for 18 hours or longer
Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)
VELOCITY:
Design and Methods
● Prospective, open-label, single-arm evaluation
● Population: patients 18 years or older presenting to ED or
ICU with severe hypertension (SBP >180 mm Hg or DBP
>115 mm Hg) assessed at 2 successive occasions 15 min
apart at baseline
● Selection of SBP Target Range (TR) was determined prior
to the initiation of clevidipine for each individual patient,
with a range of 20-40 mm Hg from upper to lower limit
● Dosing: clevidipine was initiated at 2 mg/hr and titrated to
achieve TR:
– during initial 30 min in doubling increments every 3 min to a
maximum of 32 mg/hr
– continued for a total duration of 18-96 hrs.
– If TR not achieved in first 30 min, use of additional IV antihypertensives permitted
Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)
VELOCITY:
Methods – Transition to Oral Therapy
● Transition to an oral antihypertensive agent could be
initiated after 18 hours of clevidipine infusion, starting 1 hr
prior to stopping the infusion
● During transition to oral therapy:
– 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 after stopping the infusion,
additional oral therapy may have been added or clevidipine infusion
may have been restarted
● Successful transition to oral therapy was defined as
transition with SBP remaining within the last identified TR
within 6 hours of stopping the clevidipine infusion
Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)
VELOCITY:
Outcome Measures – Efficacy
● Primary: percentage of patients in whom
SBP decreased to within the SBP target
range within 30 min of initiating infusion
● Secondary: Time to achieve SBP target
range within the initial 30 minute treatment
period
Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)
VELOCITY:
Outcome Measures – SAFETY
● Primary: percentage of patients in whom SBP decreased
below the lower limit of the initial SBP target range within
3 min of initiating infusion
● Secondary
– Change in pulse rate during initial 30 min treatment
period
– Dose of clevidipine during treatment period
– Percentage of patients meeting criteria of “successful
transition to oral antihypertensive”
- In TR of last specified SBP 6 hrs after cessation of
clevidipine infusion
Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)
VELOCITY:
Enrollment Criteria
Inclusion Criteria
● Age 18 years and older
● Systolic BP >180 mm Hg
and/or diastolic BP >115 mm
Hg, assessed on 2 successive
occasions, 15 minutes apart
● Provide written informed
consent before initiation of
any study-related procedures
Exclusion Criteria
● SBP ≤180 mm Hg and DBP ≤115 mm Hg
● Expectation that the patient will not tolerate
IV antihypertensive therapy for a minimum of
18 hrs
● Known or suspected aortic dissection, liver
failure or cirrhosis
● Acute hypertension precipitated by the use or
withdrawal from alcohol, illicit drugs, or by
intentional overdose
● Positive pregnancy test result
● Intolerance/allergy to Ca channel blockers,
soybean oil, or egg lecithin
● Any antihypertensive drug within 2 hrs before
enrollment
● Participation in another study in previous 30
days
Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)
VELOCITY:
Patient Disposition
N=131
Patients enrolled (ITT)
N=14
SBP ≤upper limit of
target range
N=5
Did not receive
clevidipine
N=117
mITT Population
N=126
Safety Population
N=9
Received <18 hr
treatment
N=117
Patients who
received long-term
clevidipine
Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)
VELOCITY:
Patient Demographics (Safety Population, n=126)
Parameter
Age (yrs)
Gender (%)
Male
Female
BMI (kg/m2)
Race (%)
African American
White
Hispanic or Latino
Asian
SBP (mm Hg)
DBP (mm Hg)
TR (high, low)
Value
53.5 ± 15.2
48.4
51.6
30 ± 7.6
77.0
15.9
6.3
0.8
202.1 ± 21.8
111.0 ± 21.0
174.7, 142.9
No statistically significant differences in demographics between patients with (n=102) or without (n=24) end-organ injury
Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)
VELOCITY:
Medical History (Safety Population, n=126)
Medical History
End organ injury
Myocardial infarction
Renal disease
Dialysis dependent
Coronary artery disease
Hypertension
Previous hospitalization for hypertension
Congestive heart failure
Dyslipidemia
Current Smoker
Former Smoker
Diabetes
Stroke
Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)
Percent (%)
81
4.8
25.4
11.1
27.8
96.8
31.0
17.5
36.5
38.9
20.6
31.0
11.1
VELOCITY:
Clevidipine Infusion (Safety Population)
Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)
VELOCITY:
Primary Outcome Measure (mITT)
Probability of Having Attained SBP Initial
Target Range Within 30 Minutes
Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)
VELOCITY:
Primary Outcome Measures
● 88.9% of patients (ITT) achieved prespecified TR within 30
min
– Only 2.6% of patients failed to reach TR during or after initial 30 min
treatment period.
● 2 patients (1.6%) fell below the lower TR limit within first 3
min
– One patient had narrower than specified TR (205-195 mm Hg),
SBP was 15 mm Hg below the lower limit
– One patient exceeded the lower SBP limit (160 mm Hg) by 4 mm Hg
– Both patients continued clevidipine infusion beyond 18 hours without
AEs
– No hypotensive events were reported
Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)
VELOCITY:
Secondary Outcome Measure (mITT, n=117)
Mean Percentage Change in SBP from Baseline
During First 30 Minutes of Clevidipine Infusion
Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)
VELOCITY:
Secondary Outcome Measure (mITT, n=117)
Mean Percentage Change in SBP from Baseline
During 18 hours of Clevidipine Infusion
Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)
VELOCITY:
Secondary Outcome Measures
● Median time to first achievement of Target Range (TR) was
10.9 min (95% CI 9.0-15.0)
– Median percentage decrease in SBP necessary to achieve upper limit
of TR was 14.2%
– Median time for patients to achieve 15% reduction in SBP was 9.5 min
– Mean decrease in SBP of 21.1% at 30 min
● Among all patients who achieved their SBP TR within or past
the 30 min period (n=112), the average mean infusion rate to
achieve TR was 5.71 + 4.9 mg/hr
● Median percentage increase in pulse rate did not exceed
13.2% (10 bpm) at any point during the first 30 min period
– Pulse rate continued to remain stable during 18 hrs of continuous
clevidipine infusion
Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)
VELOCITY:
Secondary Outcome Measures
● Overall, transition to oral antihypertensive therapy was
successful in 91.3% of patients
● Of the 118 patients eligible for transition, 97.5% did so within
6 hours
● Most common oral agents:
–
–
–
–
Imidazoline receptor agonists (33%)
ACE inhibitors (29%)
Dihydropyridine calcium channel blockers (24%)
Beta-blockers (21%)
Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)
VELOCITY:
Adverse Events (Safety Population)
● 39.7% of patients experienced one adverse event
– Related to clevidipine treatment (30.2%)
– Unrelated to clevidipine treatment (9.5%)
● Most common:
–
–
–
–
Headache 6.3% (8/126)
Nausea 4.8% (6/126)
Chest discomfort 3.2% (4/126)
Vomiting 3.2% (4/126)
● 8.7% of patients experienced one serious adverse event
– 1 patient experienced chest discomfort that was assessed as possibly
related to treatment
– All other serious AE’s, including 3 deaths, were assessed as unrelated or
unlikely to be related to clevidipine
Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)
VELOCITY:
Limitations
● Open label study
– However, the study was designed to permit use of
concomitant IV therapy at any time if needed.
● Definition of severe HTN (SBP>180, DBP>115
mm Hg) was developed according to clinical
experience
● Patient population was a mixture of hypertensive
urgencies and emergencies.
Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)
VELOCITY:
Conclusions
● Initial non-weight-based dose of 2 mg/hr of
clevidipine is appropriate in the ED setting
● 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
● Transition from clevidipine to oral antihypertensive
therapy was successful
Annals of Emergency Medicine - 06 June 2008 (10.1016/j.annemergmed.2008.04.025)
IMPORTANT SAFETY INFORMATION
● Cleviprex is intended for intravenous use. Titrate drug depending on the
response of the individual patient to achieve the desired blood pressure
reduction. Monitor blood pressure and heart rate continually during
infusion, and then until vital signs are stable. Patients who receive
prolonged Cleviprex infusions and are not transitioned to other
antihypertensive therapies should be monitored for the possibility of
rebound hypertension for at least 8 hours after the infusion is stopped.
● Cleviprex is contraindicated in patients with allergies to soybeans, soy
products, eggs, or egg products; defective lipid metabolism such as
pathologic hyperlipemia, lipoid nephrosis, or acute pancreatitis if it is
accompanied by hyperlipidemia; and in patients with severe aortic stenosis.
● Hypotension and reflex tachycardia are potential consequences of rapid
upward titration of Cleviprex. Dihydropyridine calcium channel blockers can
produce negative inotropic effects and exacerbate heart failure. Monitor
heart failure patients carefully. Cleviprex gives no protection against the
effects of abrupt beta-blocker withdrawal.
Cleviprex is a diydropyridine calcium channel blocker indicated for the reduction of blood pressure
when oral therapy is not feasible or not desirable. Please see full prescribing information.
Clevidipine Product Information August 2008; The Medicines Company
IMPORTANT SAFETY INFORMATION:
continued
● Most common adverse reactions (> 2%) are headache, nausea, and
vomiting.
● Cleviprex should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
● Maintain aseptic technique while handling Cleviprex. Cleviprex contains
phospholipids and can support microbial growth. Do not use if
contamination is suspected. Once the stopper is punctured, use and
discard within 4 hours.
Cleviprex is a diydropyridine calcium channel blocker indicated for the reduction of blood pressure
when oral therapy is not feasible or not desirable. Please see full prescribing information.
Clevidipine Product Information August 2008; The Medicines Company