Transcript Document 7270030

Blood Pressure Control with
Clevidipine Compared with
Nitroglycerin, Sodium Nitroprusside, or
Nicardipine in the Treatment of
Peri-operative Hypertension:
Results of the Three Randomized
ECLIPSE Trials
Solomon Aronson, M.D.
FACC,FCCP,FAHA,FASE
Professor and Executive Vice Chairman
Dept of Anesthesiology
Duke University Health System
Disclosures
► Abbott (Research Support)
► Baxter (Speaker)
► Medwave (Director)
► Regado Biosciences (Consultant)
► The Medicines Company (Consultant)
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Acknowledgements
Cornelius Dyke, MD
Dean Kereiakes, MD
Jerrold H. Levy, MD
Philip Lumb, MD
Albert Cheung, MD
Howard Corwin, MD
Kevin Stierer, MD
Mark Newman, MD
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Background
► Peri-operative HTN is associated with life-threatening
complications1-2
► As many as 56% of cardiac surgery patients experience
acute HTN requiring an IV agent1,3-4
► Current antihypertensive therapies are not without limitations
1Cheung,
A. J Card Surg, 2006, S8
2Aronson,
S. Anesth Analg 2002; 94:1079-84
3Estafanous,
F. Am J Cardiol, 1980, p685;
4Landymore,
R. Can J Surg, 1980
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Rationale
► Clevidipine is a rationally designed IV dihydropyridine
calcium channel blocker with an ultrashort half-life (~1 min)
► Phase I & II studies (300 pts) demonstrated:
 Dose: 2–16 mg/hr effective1
 Rapid onset: BP control in 5 min2
► Phase III safety program required for FDA registration
 Evaluation: Death, MI, Stroke, Renal Dysfunction
 Comparators: Nitroglycerin (NTG), Sodium nitroprusside
(SNP), Nicardipine (NIC)
1Bailey
2Levy
J. Anesthesiology 2002;96:1086-94
J. Anesth Analg 2006 (in press)
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Objectives
Primary
► Investigate the safety of Clevidipine in peri-operative HTN
Secondary
► Evaluate adverse events
► Examine blood pressure control
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Inclusion Criteria
Pre-randomization
► ≥ 18 years of age
► Written informed consent
► Planned CABG, OPCAB, MIDCAB surgery and/or valve
repair/replacement surgery
Post-randomization
► Require treatment for peri-operative HTN
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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
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Treatment
► Clevidipine
 Initiated 2 mg/hr
 Titrated doubling increments Q 90s to 16 mg/hr
 40 mg/hr maximum
► Comparators (NTG, SNP, NIC) admin per institutional practice
► Treatment duration up to discharge from the ICU
► Concomitant anti-hypertensives discouraged
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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 with min absolute ↑ of 0.7
Secondary
► SAEs through day 7
► BP control during the first 24 h
* Blinded CEC adjudication of all primary measures
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Statistical Methods
► Assumptions
 Sample size (1500 pts) recommended by FDA for
safety profile assessment
► Descriptive analytical methods
 Pre-specified safety analysis population (pts according to
actual treatment received)
 Data pooled to provide an overall event rate for
Clevidipine & comparator arms
 Pre-specified analysis of each randomized comparison
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Patient Disposition
Clevidipine
Comparators
Randomized patients
971
993
Met post-randomization criteria
755
757
Safety population
752
754
Completed study
715
719
Did not complete study
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
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Baseline Characteristics
Age, median (range)
Male
Caucasian
Hx HTN
CHF
Insulin dependent diabetes
COPD
Recent MI (< 6 mos)
Prior CABG
Clevidipine
n=752
65 (24-87)
72%
82%
88%
19%
11%
14%
17%
3%
Comparators
n=754
66 (19-89)
74%
83%
85%
18%
11%
15%
18%
6%
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Procedural Characteristics
Surgery duration, median hrs
Procedure
CABG
Valve replacement/repair
CABG & Valve replacement/repair
Other
Clevidipine
n=752
3.32
Comparators
n=754
3.23
77%
14%
9%
0.3%
77%
12%
11%
0.1%
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Primary Endpoint
30-Day Events (%)
10%
8%
Clevidipine
Comparators
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
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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%
* p = 0.045
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Serious Adverse Events
Total
AFIB
Respiratory failure
ARF
Ventricular fibrillation
Cardiac arrest
CVA
Post-procedural hemorrhage
Clevidipine
n=752
Comparators
n=754
17.7%
2.4%
1.1%
2.3%
0.9%
0.5%
0.5%
0.5%
20.0%
2.4%
2.5%
1.7%
1.5%
1.1%
1.1%
1.1%
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ECLIPSE Secondary Endpoint:
Systolic Blood Pressure Control Over 24 Hours
SBP
Upper
Lower
Lower
0
6
12
18
24
Time (hours)
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Cumulative AUC at Targeted BP Ranges
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
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3.8
7.8
23.1
6.6
12.5
0
specified
+10
+20
+30
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Pre-specified SBP Range:
AUC by Treatment Comparison
p = 0.0027
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10.50
p = 0.0006
mm Hg x min/h
10
8.87
8
6
4.14
4.37
p = 0.8508
4
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
Range = Pre-/post-op SBP 75-145, Intra-op SBP 65-135
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Elevated SBP Range:
AUC by Treatment Comparison
p = 0.0068
127.87
140
mm Hg x min/h
120
p = 0.0556
108.57
p = 0.0231
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
Range = Pre-/post-op SBP 105-145, Intra-op SBP 95-135
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Conclusions
►Clevidipine is a safe alternative to therapy with
commonly used antihypertensive agents
►Clevidipine demonstrated superior blood pressure
control as assessed by integral analysis of
excursions outside specified ranges over time
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