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 ChairmanDept of Anesthesiology

Duke University Health System

2

Disclosures

► Abbott (Research Support)

► Baxter (Speaker)

► Medwave (Director)

► Regado Biosciences (Consultant)

► The Medicines Company (Consultant)

3

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

4

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

5

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 J. Anesthesiology 2002;96:1086-94

2Levy J. Anesth Analg 2006 (in press)

6

Objectives

Primary

► Investigate the safety of Clevidipine in peri-operative HTN

Secondary

► Evaluate adverse events

► Examine blood pressure control

7

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

8

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

9

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

10

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

11

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

12

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

3701

150

201

351060

280

13

Baseline Characteristics

Clevidipinen=752

Comparators n=754

Age, median (range) 65 (24-87) 66 (19-89)

Male 72% 74%

Caucasian 82% 83%

Hx HTN 88% 85%

CHF 19% 18%

Insulin dependent diabetes 11% 11%

COPD 14% 15%

Recent MI (< 6 mos) 17% 18%

Prior CABG 3% 6%

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Procedural Characteristics

Clevidipinen=752

Comparators n=754

Surgery duration, median hrs 3.32 3.23

Procedure CABG Valve replacement/repair CABG & Valve replacement/repair Other

77%14%9%

0.3%

77%12%11%0.1%

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Primary Endpoint

2.8%2.3%

1.1%

7.9%

3.8%

2.4%1.7%

7.9%

0%

2%

4%

6%

8%

10%

Clevidipine

Comparators

Death

30-D

ay E

vent

s (%

)

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

MI Stroke RenalDysfunction

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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

Clevidipinen=752

Comparatorsn=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%

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ECLIPSE Secondary Endpoint: Systolic Blood Pressure Control Over 24 Hours

Time (hours)

SBP

Lower

Upper

0 6 12 2418

Lower

19

Cumulative AUC at Targeted BP Ranges

3.8 6.6

23.1

87.7

7.812.5

33.1

111.5

0

20

40

60

80

100

120

Clevidipine

Comparators

n=751

n=756

p=0.0004p<0.0001

p<0.0001

p=0.0002

mm

Hg

x m

in/h

specified +10 +20 +30

20

Pre-specified SBP Range: AUC by Treatment Comparison

4.14 4.37

1.76

8.87

10.50

1.69

0

2

4

6

8

10

12

ECLIPSENTG

ECLIPSESNP

ECLIPSENIC

mm

Hg

x m

in/h

p = 0.0006

p = 0.0027

p = 0.8508

Clevidipinen=269

NTGn=278

Clevidipinen=295

SNPn=284

Clevidipinen=187

NICn=194

Range = Pre-/post-op SBP 75-145, Intra-op SBP 65-135

21

Elevated SBP Range: AUC by Treatment Comparison

83.74

100.17

76.95

108.57

127.87

101.59

0

20

40

60

80

100

120

140

ECLIPSENTG

ECLIPSESNP

ECLIPSENIC

mm

Hg

x m

in/h

p = 0.0556

p = 0.0068

p = 0.0231

Clevidipinen=269

NTGn=278

Clevidipinen=295

SNPn=284

Clevidipinen=187

NICn=194

Range = Pre-/post-op SBP 105-145, Intra-op SBP 95-135

22

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