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Critical Challenges Critical Challenges in in Cardiovascular AnesthesiologyCardiovascular Anesthesiology
A Year 2007 Evidence-Based UpdateA Year 2007 Evidence-Based Update
Applying Landmark Trials, Emerging Data, & Expert Applying Landmark Trials, Emerging Data, & Expert Analysis to Management of Severe or Life-Threatening Analysis to Management of Severe or Life-Threatening Blood Pressure Elevations in the Perioperative SettingBlood Pressure Elevations in the Perioperative Setting
Critical Challenges Critical Challenges in in Cardiovascular AnesthesiologyCardiovascular Anesthesiology
A Year 2007 Evidence-Based UpdateA Year 2007 Evidence-Based Update
Applying Landmark Trials, Emerging Data, & Expert Applying Landmark Trials, Emerging Data, & Expert Analysis to Management of Severe or Life-Threatening Analysis to Management of Severe or Life-Threatening Blood Pressure Elevations in the Perioperative SettingBlood Pressure Elevations in the Perioperative Setting
Program Co-ChairmanProgram Co-ChairmanJerrold H. Levy, MDJerrold H. Levy, MD
Professor and Deputy Chair for ResearchProfessor and Deputy Chair for ResearchEmory University School of MedicineEmory University School of Medicine
Director of Cardiothoracic AnesthesiologyDirector of Cardiothoracic AnesthesiologyCardiothoracic Anesthesiology and Critical CareCardiothoracic Anesthesiology and Critical Care
Emory HealthcareEmory HealthcareAtlanta, GeorgiaAtlanta, Georgia
Program Co-ChairmanProgram Co-ChairmanJerrold H. Levy, MDJerrold H. Levy, MD
Professor and Deputy Chair for ResearchProfessor and Deputy Chair for ResearchEmory University School of MedicineEmory University School of Medicine
Director of Cardiothoracic AnesthesiologyDirector of Cardiothoracic AnesthesiologyCardiothoracic Anesthesiology and Critical CareCardiothoracic Anesthesiology and Critical Care
Emory HealthcareEmory HealthcareAtlanta, GeorgiaAtlanta, Georgia
CME-accredited symposium jointly sponsored by University of CME-accredited symposium jointly sponsored by University of Massachusetts Medical Center, office of CME and CMEducation Massachusetts Medical Center, office of CME and CMEducation Resources, LLCResources, LLC
Commercial Support:Commercial Support: Sponsored by an independent educational Sponsored by an independent educational grant from The Medicines Companygrant from The Medicines Company
Mission statement:Mission statement: Improve patient care through evidence-based Improve patient care through evidence-based education, expert analysis, and case study-based managementeducation, expert analysis, and case study-based management
Processes:Processes: Strives for fair balance, clinical relevance, on-label Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and indications for agents discussed, and emerging evidence and information from recent studiesinformation from recent studies
COI:COI: Full faculty disclosures provided in syllabus and at the Full faculty disclosures provided in syllabus and at the beginning of the programbeginning of the program
Welcome and Program OverviewWelcome and Program Overview
Program Educational ObjectivesProgram Educational Objectives
As a result of this session, cardiovascular anesthesiologists, As a result of this session, cardiovascular anesthesiologists, cardiothoracic surgeons, cardiovascular critical care specialists cardiothoracic surgeons, cardiovascular critical care specialists and related specialists will be able to:and related specialists will be able to:
► Identify criteria and management strategies for multiple disease states Identify criteria and management strategies for multiple disease states
and clinical presentations associated with perioperative hypertension, and clinical presentations associated with perioperative hypertension, manifesting as serious and/or life-threatening elevations in systolic and/or manifesting as serious and/or life-threatening elevations in systolic and/or diastolic blood pressure.diastolic blood pressure.
► Learn to manage the hemodynamic derangements and complications of Learn to manage the hemodynamic derangements and complications of serious and/or life-threatening elevations in systolic and/or diastolic serious and/or life-threatening elevations in systolic and/or diastolic blood pressure in the perioperative setting.blood pressure in the perioperative setting.
► Learn evidence-based approaches to prompt and safe lowering of serious Learn evidence-based approaches to prompt and safe lowering of serious elevations in BP in the perioperative setting, using agents that are elevations in BP in the perioperative setting, using agents that are effective and that have an acceptable safety profile.effective and that have an acceptable safety profile.
As a result of this session, cardiovascular anesthesiologists, As a result of this session, cardiovascular anesthesiologists, cardiothoracic surgeons, cardiovascular critical care specialists cardiothoracic surgeons, cardiovascular critical care specialists and related specialists will be able to:and related specialists will be able to:
► Identify criteria and management strategies for multiple disease states Identify criteria and management strategies for multiple disease states
and clinical presentations associated with perioperative hypertension, and clinical presentations associated with perioperative hypertension, manifesting as serious and/or life-threatening elevations in systolic and/or manifesting as serious and/or life-threatening elevations in systolic and/or diastolic blood pressure.diastolic blood pressure.
► Learn to manage the hemodynamic derangements and complications of Learn to manage the hemodynamic derangements and complications of serious and/or life-threatening elevations in systolic and/or diastolic serious and/or life-threatening elevations in systolic and/or diastolic blood pressure in the perioperative setting.blood pressure in the perioperative setting.
► Learn evidence-based approaches to prompt and safe lowering of serious Learn evidence-based approaches to prompt and safe lowering of serious elevations in BP in the perioperative setting, using agents that are elevations in BP in the perioperative setting, using agents that are effective and that have an acceptable safety profile.effective and that have an acceptable safety profile.
Educational ObjectivesEducational Objectives
► Learn how to select among intravenous pharmacologic agents, Learn how to select among intravenous pharmacologic agents, including including calcium channel blockers (dihydropyridines) that offer unique benefits for calcium channel blockers (dihydropyridines) that offer unique benefits for blood pressure control in the setting of cardiothoracic surgeryblood pressure control in the setting of cardiothoracic surgery
► Learn how landmark trials and analyses focusing on BP reduction Learn how landmark trials and analyses focusing on BP reduction may have an impact on current and future strategies for management of BP may have an impact on current and future strategies for management of BP elevations in the setting of cardiovascular surgery.elevations in the setting of cardiovascular surgery.
► Be able to assess the need for and implement optimal BP-lowering Be able to assess the need for and implement optimal BP-lowering strategies for patients with serious and/or life-threatening elevations in strategies for patients with serious and/or life-threatening elevations in systolic and/or diastolic BP in the setting of cardiothoracic surgery.systolic and/or diastolic BP in the setting of cardiothoracic surgery.
► Understand the efficacy and safety profiles of specific pharmacologic Understand the efficacy and safety profiles of specific pharmacologic agents used for anesthesiology-based control of systemic blood pressure.agents used for anesthesiology-based control of systemic blood pressure.
► Be able to discuss the potential impact that new trials are likely to Be able to discuss the potential impact that new trials are likely to have on future management of patients with BP elevation in the have on future management of patients with BP elevation in the perioperative setting.perioperative setting.
► Learn how to select among intravenous pharmacologic agents, Learn how to select among intravenous pharmacologic agents, including including calcium channel blockers (dihydropyridines) that offer unique benefits for calcium channel blockers (dihydropyridines) that offer unique benefits for blood pressure control in the setting of cardiothoracic surgeryblood pressure control in the setting of cardiothoracic surgery
► Learn how landmark trials and analyses focusing on BP reduction Learn how landmark trials and analyses focusing on BP reduction may have an impact on current and future strategies for management of BP may have an impact on current and future strategies for management of BP elevations in the setting of cardiovascular surgery.elevations in the setting of cardiovascular surgery.
► Be able to assess the need for and implement optimal BP-lowering Be able to assess the need for and implement optimal BP-lowering strategies for patients with serious and/or life-threatening elevations in strategies for patients with serious and/or life-threatening elevations in systolic and/or diastolic BP in the setting of cardiothoracic surgery.systolic and/or diastolic BP in the setting of cardiothoracic surgery.
► Understand the efficacy and safety profiles of specific pharmacologic Understand the efficacy and safety profiles of specific pharmacologic agents used for anesthesiology-based control of systemic blood pressure.agents used for anesthesiology-based control of systemic blood pressure.
► Be able to discuss the potential impact that new trials are likely to Be able to discuss the potential impact that new trials are likely to have on future management of patients with BP elevation in the have on future management of patients with BP elevation in the perioperative setting.perioperative setting.
Program FacultyProgram Faculty
Solomon Aronson, MD,Solomon Aronson, MD,FACC. FCCP, FAHA, FASEFACC. FCCP, FAHA, FASEProgram Co-ChairmanProgram Co-ChairmanProfessorProfessorDuke University Medical CenterDuke University Medical CenterExecutive Vice ChairExecutive Vice ChairDepartment of AnesthesiologyDepartment of AnesthesiologyDurham, NCDurham, NC
Jerrold H. Levy, MDJerrold H. Levy, MDProgram Co-ChairmanProgram Co-ChairmanProfessor and Deputy Chair for ResearchProfessor and Deputy Chair for ResearchEmory University School of MedicineEmory University School of MedicineDirector of Cardiothoracic AnesthesiologyDirector of Cardiothoracic AnesthesiologyCardiothoracic AnesthesiologyCardiothoracic Anesthesiology and Critical Careand Critical CareEmory HealthcareEmory HealthcareAtlanta, GeorgiaAtlanta, Georgia
Solomon Aronson, MD,Solomon Aronson, MD,FACC. FCCP, FAHA, FASEFACC. FCCP, FAHA, FASEProgram Co-ChairmanProgram Co-ChairmanProfessorProfessorDuke University Medical CenterDuke University Medical CenterExecutive Vice ChairExecutive Vice ChairDepartment of AnesthesiologyDepartment of AnesthesiologyDurham, NCDurham, NC
Jerrold H. Levy, MDJerrold H. Levy, MDProgram Co-ChairmanProgram Co-ChairmanProfessor and Deputy Chair for ResearchProfessor and Deputy Chair for ResearchEmory University School of MedicineEmory University School of MedicineDirector of Cardiothoracic AnesthesiologyDirector of Cardiothoracic AnesthesiologyCardiothoracic AnesthesiologyCardiothoracic Anesthesiology and Critical Careand Critical CareEmory HealthcareEmory HealthcareAtlanta, GeorgiaAtlanta, Georgia
Kevin A. Stierer Sr., MDKevin A. Stierer Sr., MDChief Cardiac AnesthesiaChief Cardiac AnesthesiaAssociate Director Cardiac Associate Director Cardiac Surgery ICUSurgery ICUThe Heart InstituteThe Heart InstituteSt. Joseph Medical CenterSt. Joseph Medical CenterTowson, MDTowson, MD
Kevin A. Stierer Sr., MDKevin A. Stierer Sr., MDChief Cardiac AnesthesiaChief Cardiac AnesthesiaAssociate Director Cardiac Associate Director Cardiac Surgery ICUSurgery ICUThe Heart InstituteThe Heart InstituteSt. Joseph Medical CenterSt. Joseph Medical CenterTowson, MDTowson, MD
Faculty COI Financial DisclosuresFaculty COI Financial Disclosures
Solomon Aronson, MDSolomon Aronson, MDGrant/Research Support: AbbottGrant/Research Support: AbbottConsultant: The Medicines CompanyConsultant: The Medicines CompanySpeaker’s Bureau: BaxterSpeaker’s Bureau: BaxterMajor Shareholder: MedwaveMajor Shareholder: Medwave
Jerrold H. Levy, MDJerrold H. Levy, MDGrant/Research Support: Alexion Grant/Research Support: Alexion Consultant: Bayer HealthCare, Dyax, Novo Nordisk, Consultant: Bayer HealthCare, Dyax, Novo Nordisk, and Organonand Organon
Kevin A. Stierer Sr., MDKevin A. Stierer Sr., MDNothing to reportNothing to report
Solomon Aronson, MDSolomon Aronson, MDGrant/Research Support: AbbottGrant/Research Support: AbbottConsultant: The Medicines CompanyConsultant: The Medicines CompanySpeaker’s Bureau: BaxterSpeaker’s Bureau: BaxterMajor Shareholder: MedwaveMajor Shareholder: Medwave
Jerrold H. Levy, MDJerrold H. Levy, MDGrant/Research Support: Alexion Grant/Research Support: Alexion Consultant: Bayer HealthCare, Dyax, Novo Nordisk, Consultant: Bayer HealthCare, Dyax, Novo Nordisk, and Organonand Organon
Kevin A. Stierer Sr., MDKevin A. Stierer Sr., MDNothing to reportNothing to report
NOTENOTE
There will be off-label discussions—both indications There will be off-label discussions—both indications and dosing—during this CME symposium, and and dosing—during this CME symposium, and speakers will note such off-label information. This speakers will note such off-label information. This information does not imply or constitute information does not imply or constitute endorsement of such strategies, which must be endorsement of such strategies, which must be evaluated on the basis of evidence and expert evaluated on the basis of evidence and expert analysis.analysis.
Off-Label Discussion and InformationOff-Label Discussion and Information
Management of Perioperative Management of Perioperative Hypertension in theHypertension in the
Cardiac Surgery PatientCardiac Surgery PatientA New Look at an Old ProblemA New Look at an Old Problem
Solomon Aronson, M.D.Solomon Aronson, M.D.FACC, FCCP, FAHA, FASEFACC, FCCP, FAHA, FASE
Professor and Executive Vice ChairmanProfessor and Executive Vice ChairmanDepartment of AnesthesiologyDepartment of AnesthesiologyDuke University Health System Duke University Health System
““A man is as old as his arteries”A man is as old as his arteries”
Sir William Osler
0
20
40
60
80
1990 2000 2010 2020 2030 2040 2050
The Aging PopulationThe Aging PopulationP
op
ula
tion
(in
m
illion
s)
30 35 40 45 50 55 60 70 65 75
Age (Years)
0
2
4
6
8
10
Per
cen
t1976-19801988-1991
CHF mortality
National Health & Nutrition Examination Survey II 1976-1980 and 1988-1991National Health & Nutrition Examination Survey II 1976-1980 and 1988-1991
Risk Risk >> 115/75 115/75 90% pts 90% pts >> 55 years of 55 years of
ageage• Pre-HTN > 115/75 < 140/90• Average in Europe: 136/83; USA & Canada: 127/77• # 1 cause of HD death, #3 cause of stroke death• $63.5 B direct & indirect costs• 50 M (25% population)• 30 M “high normal”,• 20-35% (“white coat”) Joint National Committee (JNC-6 & 7)
On Prevention, Detection, Evaluation, & Treatment of Hypertension:Arch Int Med 157; 2413-46,1997JAMA 289; 2560-72,2003
Hypertension: Costs and ConsequencesHypertension: Costs and Consequences
Pre-Hypertension Pre-Hypertension ((>120/80 <140/90)>120/80 <140/90)
Pre-Hypertension is common: 40%Pre-Hypertension is common: 40%Associated with increased risk:Associated with increased risk:
OROR CI CI
CV death CV death 1.58 1.58 1.12-2.211.12-2.21
MI MI 1.76 1.76 1.40-2.221.40-2.22
Stroke Stroke 1.931.93 1.49-2.501.49-2.50
CHF CHF 1.36 1.36 1.05-1.771.05-1.77
Circulation 115;855-60, 2007Circulation 115;855-60, 2007
JACC 40;119-25,2002JACC 40;119-25,2002
Mu
scle
sym
pat
het
ic n
erv
e a
ctiv
ity
Bar
ore
cep
tor
sen
siti
vity
““White Coat” HypertensionWhite Coat” Hypertension
EssentialEssential
SecondarySecondary
Endocrine, Renal, ICP, coarctation, contraceptives, pregnancy, etc.
NE release (stress)
Thickened arterial wall
Altered vasomotor
DBP, SBP, MAP, PP Orthostatic BP changes
Hypertension: Types and MechanismHypertension: Types and Mechanism
CategoryCategory Systolic Systolic mmHgmmHg Diastolic Diastolic mmHgmmHg
OptimalOptimal < 120< 120 and and < 75 < 75
NormalNormal < 130 < 130 andand < 85 < 85
Mild HTNMild HTN 140-159 140-159 or or 90-99 90-99
ModerateModerate 160-179 160-179 oror 100-109 100-109
SevereSevere > 180> 180 oror > 110 > 110
Isolated SBP HTNIsolated SBP HTN > 140 > 140 andand < 90 < 90
Pulse PressurePulse Pressure > 65mmHg > 65mmHg
Orthostatic changesOrthostatic changes Hyper response > 20 mmHg Hyper response > 20 mmHg
Hypo response < 20 mmHGHypo response < 20 mmHG
ClassificationClassification
Physiology: Perioperative HTNPhysiology: Perioperative HTN
► Increase SVR , increase preloadIncrease SVR , increase preload► Rapid intravascular volume shiftsRapid intravascular volume shifts► Renin angiotensin activationRenin angiotensin activation► Adrenergic stimulation (cardiac & neural)Adrenergic stimulation (cardiac & neural)► Serotonergic overproductionSerotonergic overproduction► Baroreceptor denervationBaroreceptor denervation► Altered cardiac reflexesAltered cardiac reflexes► Depth anesthesia inadeqDepth anesthesia inadeq► Cross clampCross clamp
• • Historically, the most important factorHistorically, the most important factor
• • Benchmark measure for trialsBenchmark measure for trials
• • Index of MicrocirculationIndex of Microcirculation
• • Perioperative risk defined by this indexPerioperative risk defined by this index
Diastolic Blood PressureDiastolic Blood Pressure
Historical PerspectiveHistorical Perspective
Decade StudyDecade Study Comment Comment
19701970 Prys Roberts Prys Roberts Preop severePreop severe(>115mmHg) – risk(>115mmHg) – risk
19801980 Goldman Goldman Preop modPreop mod (< 110 mmHg) – no risk(< 110 mmHg) – no risk
Intraoperative control BP Intraoperative control BP importantimportant
19901990 CharlsonCharlson DefinedDefined intraoperative BP patterns intraoperative BP patterns associated with associated with postoperative postoperative
riskrisk
Adverse events are higher with Adverse events are higher with isolated isolated systolic blood pressuresystolic blood pressure HTN, than with HTN, than with diastolic blood diastolic blood
pressurepressure HTN HTN
Kannel, Framingham Heart Study
Systolic Blood PressureSystolic Blood Pressure
Systolic BP: HTN Risk FactorSystolic BP: HTN Risk Factor
19621962 Insurance industry Insurance industry Mortality = SBP > DBPMortality = SBP > DBP
19651965 London business men London business men SBP predicts events in CADSBP predicts events in CAD
19691969 Framingham Heart Study Framingham Heart Study Challenged DBP as 1Challenged DBP as 100 risk risk
19741974 Old Age Assistance Old Age Assistance SBP > DBPSBP > DBP
19781978 Royal Canadian Air Force Royal Canadian Air Force SBP > DBPSBP > DBP
19821982 Italian Rural populationItalian Rural population SBP > DBPSBP > DBP
19831983 Hawaiian – Japanese Hawaiian – Japanese SBP > DBPSBP > DBP
19851985 British Male Civil ServiceBritish Male Civil Service SBP > DBPSBP > DBP
19871987 Oslo, Norwegian Country Oslo, Norwegian Country No difference of CV RiskNo difference of CV Risk
20022002 McSpi Perioperative SBP HTN predicts adverse McSpi Perioperative SBP HTN predicts adverse outcome during CABGoutcome during CABG
Negative outcome* O.R. 2.1 p=0.01
Anesth Analg 94;1079- 84,2002Anesth Analg 94;1079- 84,2002Anesth Analg 95;273-7,2002Anesth Analg 95;273-7,2002
*LOS > 10 days, or death SBP > 160 mmHg
Renal O.R. 1.3 (1.0-1.9)Stroke 1.7 (1.2-2.3)LV dysfunction 1.3 (1.0-1.6)Combined 1.4 (1.1-1.7)
Intraoperative
Preoperative
Systolic BP: HypertensionSystolic BP: Hypertension
0
10
20
30
20 30 40 50 60 70 80 90
Age
Pre
vale
nce
%
Women
Men
Prevalence of IsolatedPrevalence of IsolatedSystolic HypertensionSystolic Hypertension
Circulation 2006;114:2780-7Circulation 2006;114:2780-7
Determinants of Systolic BPDeterminants of Systolic BP
Stroke Volume*
Rate of Systolic Ejection
Arterial Distensibility
SBP (wave reflections)**
* < 50 yrs** >70 yrs
Risk of CV Events by Type of HTNRisk of CV Events by Type of HTN
Age Adjusted Risk Ratio*Age Adjusted Risk Ratio* 35-64 yrs 65-94 yrs35-64 yrs 65-94 yrs
Men Women Men WomenMen Women Men Women
Isolated diastolicIsolated diastolic 1.8 1.2 1.2 1.61.8 1.2 1.2 1.6
Isolated systolicIsolated systolic 2.4 1.9 1.9 1.42.4 1.9 1.9 1.4
CombinedCombined 2.7 2.2 2.7 2.2 2.2 1.6 2.2 1.6
**Reference groups consist of normotensive personsReference groups consist of normotensive persons
36 Year Follow-Up (Framingham Study According to Age & Sex)
Am Jour of Card; 85, 2000
• • SBP-DBP = Pulse PressureSBP-DBP = Pulse Pressure
• • Traditionally, not in risk assessment Traditionally, not in risk assessment
• • Wide PP = high risk Wide PP = high risk
• • Treatment not understoodTreatment not understood
Pulse PressurePulse Pressure
FLOWFLOW
PRESSUREPRESSURE
HR x SV = CO
*BP/ CO = SVR
CO x MAP = work
MAP = 1/3 PP + DBP
All in the absence of pulsationsAll in the absence of pulsations
(*BP = MAP -RAP)
Pressure/Flow RelationshipsPressure/Flow Relationships
Rate /1,000 Rate /1,000
35-64 yrs 65-94yrs35-64 yrs 65-94yrs
Pulse Pressure Pulse Pressure (mm Hg)(mm Hg) Women Men Women Men Women Men Women Men
2-392-39 9 9 4 4 2 2 17 17
40-4940-49 13 13 6 16 19 6 16 19
50-5950-59 16 7 32 22 16 7 32 22
60-6960-69 22 10 39 25 22 10 39 25
70-18270-182 33 16 58 32 33 16 58 32
Regression 0.024 0.025 0.024 0.014Regression 0.024 0.025 0.024 0.014
Risk factor 0.018 0.019 0.021 0.010Risk factor 0.018 0.019 0.021 0.010
Framingham Study (30 Year Follow-Up)
The American Journal of Cardiology Vol 85, January 15, 2000
Pulse Pressure and Cardiac RiskPulse Pressure and Cardiac Risk
Dependent on;
Ventricular Ejection
Viscoelastic properties: Large arteries
Wave Reflection
Pulse PressurePulse Pressure
Wave PropagationWave Propagation
Proximal Aorta:Proximal Aorta: Compliant Compliant (accepts SV with low SBP)(accepts SV with low SBP)
FemoralFemoral
Brach.Brach. stifferstiffer
RadialRadial
Pulse picks up speed as it moves distally;then wave reflected back at peak PVR
Energy distendingEnergy distendingarterial tree in systole arterial tree in systole returned in diastolereturned in diastole
due to proximal aorta due to proximal aorta elasticityelasticity
Energy distendingEnergy distendingarterial tree in systole arterial tree in systole returned in diastolereturned in diastole
due to proximal aorta due to proximal aorta elasticityelasticity
5450 pts 67% current or past history HTN
Mean Preoperative Pressure SBP - mildly elevated (133 + 18)DBP - minimally reduced (75 + 10) ISH - 5% IDH - 3%
Presenting Pulse Pressure50% between 40-60 mmHg 33% between 60-80 mmHg
8% > 80 mmHg
CT Surgery Renal RiskCT Surgery Renal RiskInfluence of PPHInfluence of PPH
Circulation 115,733-42,2007
Figure 1. Study population
5436 patients enrolled in EPI 2 study
371 patients withdrew from the study
5065 patients
- 256 patients with other cardiac or non-cardiac surgery
- 7 patients with incomplete BP recording, 2 patients with questionable BP recording
4801 patients (Study Population)
Derivation set: 2381 patients
Validation set: 2420 patients
• • Cerebral (5.5 % vs. 2.8 %; P = 0.004) Cerebral (5.5 % vs. 2.8 %; P = 0.004) • • Renal (8.6 % vs. 4.5 %; P = 0.0003)Renal (8.6 % vs. 4.5 %; P = 0.0003)• • CHF (12.8 % vs. 7.8 %; P = 0.003)CHF (12.8 % vs. 7.8 %; P = 0.003)• • Cardiac death (4.7 % vs. 2.4 %; P = 0.0001 Cardiac death (4.7 % vs. 2.4 %; P = 0.0001 • • Overall mortality (5.8 % vs. 2.8 %; P = Overall mortality (5.8 % vs. 2.8 %; P = 0.0018)0.0018)
Each Pulse Pressure (PP) Increment of Each Pulse Pressure (PP) Increment of 10 mm Hg Increases Risk10 mm Hg Increases Risk
PP > 80 mm HgPP > 80 mm Hg Associated with Associated with 2X 2X Ischemic EventsIschemic Events
__________________________________________________________
►Each 20 mmHg increaseEach 20 mmHg increase > 40mmHg> 40mmHg Additive risk [OR 1.49; CI, 1.17-1.89 (P = 0.001)]Additive risk [OR 1.49; CI, 1.17-1.89 (P = 0.001)]
►PPH > 80 mmHg assoc 3X renal-related PPH > 80 mmHg assoc 3X renal-related deathdeath [3.7% vs. 1.1%][3.7% vs. 1.1%]
►Renal injury doubled if PP > 80mmHgRenal injury doubled if PP > 80mmHg [8.6 % vs. 4.5 %; P = 0.0003][8.6 % vs. 4.5 %; P = 0.0003] Renal dysfunction [5 % vs. 3 %; P = 0.0004] Renal dysfunction [5 % vs. 3 %; P = 0.0004] Renal failure [5.5 % vs. 2.5 %; P = 0.001]Renal failure [5.5 % vs. 2.5 %; P = 0.001]
Renal RISK INDEX and Renal RISK INDEX and PULSE PRESSUREPULSE PRESSURE
Circulation 115,733-42,2007Circulation 115,733-42,2007
• Brain (96% increase in composite cerebral events)• Heart (61% increase in CHF)• Kidneys (91% increase in composite renal injury)
PPH & Ischemic Complications PPH & Ischemic Complications
0.5
0.6
0.7
0.8
0.9
1.0
0 5 10 15 20 25 30
Days after Revascularization
Su
rviv
al D
istr
ibu
tio
n F
un
ctio
n
No Renal Composite
Renal Composite
0
P < 0.001
PPH accelerates ischemic processes causing fatal & nonfatal complications over hours to days rather than years
Increased Pulse Pressure Is Associated With Increased Pulse Pressure Is Associated With
Decreased Long-term Survival After CABG SurgeryDecreased Long-term Survival After CABG Surgery
SCA Montréal 2007
Mean Arterial Pressure (MAP)Mean Arterial Pressure (MAP)
DeterminantsDeterminants
• • Ventricular EjectionVentricular Ejection
• • Peripheral Vascular Peripheral Vascular Resistance (PVR)Resistance (PVR)
Blood Pressure ComponentsBlood Pressure Components
• • Steady Component (MAP)Steady Component (MAP)
• • Pulsatile Component (Pulse Pulsatile Component (Pulse Pressure)Pressure)
Hypertension and Perioperative RiskHypertension and Perioperative Risk
End organ involvementEnd organ involvement
Type of surgeryType of surgery
Type of HTNType of HTN
Treatment effectivenessTreatment effectiveness
Pulsatile flowPulsatile flowEndothelial cell dysfunctionEndothelial cell dysfunctionSmooth Muscle cell hypertrophySmooth Muscle cell hypertrophy
HTN VASC DISEASEHTN VASC DISEASE
BaselineBaselineDBP CategoryDBP Category 7676 8484 9191 9898 105 mmHg105 mmHg
11 22 33 44 55
0.250.25
1.001.00
0.500.50
2.002.00
4.004.00
Relative RiskRelative RiskCHD,CHD, StrokeStroke
Approximate Mean Usual DBPApproximate Mean Usual DBP
Coronary Heart Disease andCoronary Heart Disease andDiastolic Blood PressureDiastolic Blood Pressure
x
x
x
x
x
Lancet. 1990;335,765-74Lancet. 1990;335,765-74
Hypertension,1999;34:375-80Hypertension,1999;34:375-80
• • Each 10 mm Hg increase in PP:Each 10 mm Hg increase in PP: 11% increase in stroke11% increase in stroke
MAP, SBP and PPMAP, SBP and PP Independent Predictors of Risk Independent Predictors of Risk
• • Each 10 mm Hg rise in MAP:Each 10 mm Hg rise in MAP: 20% increase in stroke20% increase in stroke
• • Each 10 mm Hg increase in PP:Each 10 mm Hg increase in PP: 16% increase 16% increase in death and 12% increase in recurrent MIin death and 12% increase in recurrent MI
Cardiac mass associated with SPBCardiac mass associated with SPB Work to drive blood = SBPWork to drive blood = SBP despite MAP & SVRdespite MAP & SVR
Increase PP associated with decreased coronary BFIncrease PP associated with decreased coronary BF
J – Curve HypothesisJ – Curve Hypothesis
Lowering DBP (too much) increases risk for Lowering DBP (too much) increases risk for coronary events esp in patients CAD & wide coronary events esp in patients CAD & wide pulse pressures (> 60 mmHg)pulse pressures (> 60 mmHg)
Farnett et al. JAMA, 265:489-95, 1991Farnett et al. JAMA, 265:489-95, 1991
J – Curve HypothesisJ – Curve Hypothesis
-40
-30
-20
-10
0
10
Esmolol
Nitroprusside
Gray Rj. Am J Cardiol 1985;56:49F-56FGray Rj. Am J Cardiol 1985;56:49F-56FGray Rj. Am J Cardiol 1985;56:49F-56FGray Rj. Am J Cardiol 1985;56:49F-56F
*P < 0.05 vs baseline*P < 0.05 vs baseline
+P < 0.05 vs. esmolol+P < 0.05 vs. esmolol
*P < 0.05 vs baseline*P < 0.05 vs baseline
+P < 0.05 vs. esmolol+P < 0.05 vs. esmolol
PercentPercentChangeChangePercentPercentChangeChange
HRHR SBPSBP DBPDBP PaOPaO22HRHR SBPSBP DBPDBP PaOPaO22
ECLIPSE Secondary Endpoint ECLIPSE Secondary Endpoint Systolic Blood Pressure Control Over 24 HoursSystolic Blood Pressure Control Over 24 Hours
Time (hours)
SBP
Lower
Upper
0 6 12 2418
Lower
ECLIPSE Trial; Presented at ACC, March 27, 2007ECLIPSE Trial; Presented at ACC, March 27, 2007
Logistic Regression Results: Logistic Regression Results: Predictors of MortalityPredictors of Mortality
P-ValueP-Value Odds Odds RatioRatio
95% CI95% CI [Lower Limit, [Lower Limit, Upper Limit]Upper Limit]
Surgery Duration (hour)Surgery Duration (hour) <0.0001<0.0001 1.5171.517 [1.240, 1.856][1.240, 1.856]
Age (year)Age (year) 0.00030.0003 1.0701.070 [1.031, 1.110][1.031, 1.110]
Pre-op Creatinine Pre-op Creatinine ≥ ≥ 1.2 mg/dL1.2 mg/dL 0.00310.0031 2.6702.670 [1.392, 5.122][1.392, 5.122]
AUC (area outside the range)AUC (area outside the range) 0.00690.0069 1.0031.003 [1.001, 1.004][1.001, 1.004]
Additional surgical proceduresAdditional surgical procedures 0.00890.0089 2.4092.409 [1.246, 4.655][1.246, 4.655]
Pre-op Hgb (g/dL)Pre-op Hgb (g/dL) 0.01350.0135 0.8240.824 [0.707, 0.961][0.707, 0.961]
Pre-op SBP >160 or DBP > Pre-op SBP >160 or DBP > 105105 0.02280.0228 2.3862.386 [1.147, 4.963][1.147, 4.963]
History of COPDHistory of COPD 0.02280.0228 2.3262.326 [1.125, 4.812][1.125, 4.812]
History of recent MI History of recent MI (<6 months prior)(<6 months prior) 0.03120.0312 2.1972.197 [1.073, 4.497] [1.073, 4.497]
I mmHg x 60 min
2 mmHg x 60 min
3 mmHg x 60 min
4 mmHg x 60 min
5 mmHg x 60 min
30 Day Mortality 30 Day Mortality by Magnitude of AUCby Magnitude of AUC
Odds Ratio
95% CI [Lower Limit, Upper Limit]
1.201.20 [1.06, 1.27][1.06, 1.27]
1.431.43 [1.13, 1.61][1.13, 1.61]
1.711.71 [1.20, 2.05][1.20, 2.05]
2.052.05 [1.27, 2.61][1.27, 2.61]
2.462.46 [1.35, 3.31][1.35, 3.31]
Adverse Events & BP ControlAdverse Events & BP Control
AUC AUC QuartileQuartile
All agents* All agents* n/N (%)n/N (%)
DeathDeath 1st1st 7/380 (1.8)7/380 (1.8)
4th4th 16/378 (4.2)16/378 (4.2)
MIMI 1st1st 6/380 (1.6)6/380 (1.6)
4th4th 11/378 (2.9)11/378 (2.9)
StrokeStroke 1st1st 4/380 (1.1)4/380 (1.1)
4th4th 6/378 (1.6)6/378 (1.6)
RenalRenal 1st1st 24/380 (6.3)24/380 (6.3)
4th4th 39/378 (10.3)39/378 (10.3)
*ECLIPSE clinical trials, N=1512 SBP range of 75 – 145 (pre & post-op), 65-135 (intra-op)
Cumulative AUC at TargetedCumulative AUC at TargetedBP Ranges 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
6575
8595
95105
7585
Intra-op SBP (mmHg)Pre/post SBP (mmHg)
BP Control : Clevidipine vs SNPBP Control : Clevidipine vs SNP
4.48.9
23.6
100.2
10.517.3
41.5
127.9
0
20
40
60
80
100
120
140
Clevidipine
SNP
n=295
n=284
P=0.0027P=0.0009
P=0.0003
P=0.0068
mm
Hg
x m
in/h
specified +10 +20 +30
BP Control : Clevidipine vs NTGBP Control : Clevidipine vs NTG
4.1 6.0
23.4
83.7
8.914.9
34.2
108.6
0
20
40
60
80
100
120
Clevidipine
NTG
n=269
n=278
P=0.0006P=0.0002
P=0.0016
P=0.0556
mm
Hg
x m
in/h
specified +10 +20 +30
BP Control : Clevidipine vs NICBP Control : Clevidipine vs NIC
1.8 5.3
21.6
77.0
1.75.7
22.8
101.6
0
20
40
60
80
100
120
Clevidipine
NICn=187
n=194
P=0.8508P=0.8949
P=0.3086
P=0.0231
mm
Hg
x m
in/h
specified +10 +20 +30
RISK AND AGERISK AND AGERelationship to Blood Pressure IndexRelationship to Blood Pressure Index
Age (years)Age (years) Pressure Index Pressure Index
________________________________________________________________
< 50< 50 DBP DBP
50-5950-59 SBP, DBP, MAP SBP, DBP, MAP
> 60> 60 PP PP
• • Baseline preoperative value & class Baseline preoperative value & class importantimportant
• • 20% tolerance treatment threshold20% tolerance treatment threshold
• • In chronic HTN* higher BP needed In chronic HTN* higher BP needed (e.g.“sweet spot”)(e.g.“sweet spot”)
* shift in autoregulatory curve, non compliant vasculature, etc.
Conclusions and CaveatsConclusions and Caveats
Advancing Management of Acute and Serious Advancing Management of Acute and Serious Elevations in Blood Pressure – Elevations in Blood Pressure –
A Critical, Comparative, and Clinical Examination of the A Critical, Comparative, and Clinical Examination of the Available Pharmacologic Armamentarium for Cardiothoracic Available Pharmacologic Armamentarium for Cardiothoracic
SurgerySurgery
Jerrold H Levy, MDJerrold H Levy, MDProfessor of AnesthesiologyProfessor of Anesthesiology
Emory University School of MedicineEmory University School of MedicineDeputy Chairman for ResearchDeputy Chairman for Research
Director, Cardiothoracic Anesthesiology Director, Cardiothoracic Anesthesiology Emory HealthcareEmory HealthcareAtlanta, GeorgiaAtlanta, Georgia
““Doctors pour drugs of which Doctors pour drugs of which they know little for disorders of they know little for disorders of
which they know less into which they know less into patients of which they know patients of which they know
nothingnothing.”.”
VoltaireVoltaire
Wisdom for ThoughtWisdom for Thought
VASOACTIVE THERAPYVASOACTIVE THERAPY
VasoconstrictorsVasoconstrictors
BPBP = SVR X CO = SVR X CO
VasodilatorsVasodilators
(SV x HR)(SV x HR)
InotropesInotropes
Beta BlockersBeta Blockers Other agentsOther agents
Beta Adrenergic BlockersBeta Adrenergic Blockers
► Beta blockers represent first line agents for Beta blockers represent first line agents for hypertension and tachycardia; especially in hypertension and tachycardia; especially in patients with ischemic heart disease.patients with ischemic heart disease.
► Beta blockers produce negative inotropic Beta blockers produce negative inotropic effects and conduction defects, and should effects and conduction defects, and should be used cautiously in patients with reactive be used cautiously in patients with reactive airways disease and ventricular airways disease and ventricular dysfunction.dysfunction.
► Beta blockers have “ceiling effects” as Beta blockers have “ceiling effects” as antihypertensive agents, and effects are antihypertensive agents, and effects are limited by heart rate.limited by heart rate.
Kass DA Ann Intern Med. 1993;119:466-73.
Vascular EndotheliumVascular Endothelium
Huraux C et al: Circulation 1999;99:53-59.Huraux C et al: Circulation 1999;99:53-59.
Vascular RegulationVascular Regulation
Landry NEJM 2001; 345: 588. Landry NEJM 2001; 345: 588.
Vasodilators (1)Vasodilators (1)
► ACE inhibitorsACE inhibitors► AdenosineAdenosine► A-II antagonistsA-II antagonists► Alpha-1-adrenergic antagonistsAlpha-1-adrenergic antagonists► Alpha-2-adrenergic agonistsAlpha-2-adrenergic agonists► ANP (nesiritide)ANP (nesiritide)► Beta-2-adrenergic agonistsBeta-2-adrenergic agonists
Vasodilators (2)Vasodilators (2)
► Calcium channel blockers Calcium channel blockers ► Dopamine-1-agonists Dopamine-1-agonists ► HydralazineHydralazine► NitrovasodilatorsNitrovasodilators► Phosphodiesterase inhibitorsPhosphodiesterase inhibitors► ProstaglandinsProstaglandins
Therapeutic Approaches Therapeutic Approaches To VasodilationTo Vasodilation
► ACE inhibition ACE inhibition
► Alpha-1 adrenergic blockadeAlpha-1 adrenergic blockade
► Calcium channel blockadeCalcium channel blockade
► Dopamine-1 stimulationDopamine-1 stimulation
► Ganglionic blockadeGanglionic blockade
► Cyclic nucleotide stimulationCyclic nucleotide stimulation
► PDE inhibitionPDE inhibition
► Potassium channel modulationPotassium channel modulation
► Novel agentsNovel agents
Levy JH: The ideal agent for perioperative hypertension. Acta Anaesth Scand 1993; 37(S):20-25. Levy JH: The ideal agent for perioperative hypertension. Acta Anaesth Scand 1993; 37(S):20-25.
Vascular Smooth MuscleVascular Smooth Muscle
C - O - N
C - O - N
C - O - N
H
H
H
H
H
= O= O
= O= O
= O= O
Nonenzymaticcysteine
dithiothreitolN-acetylcysteine
mercaptosuccinic acidthiosallcylic acid
methylthiolsalicylic acidothers
(large concentrations)
C - O - N
C - O - N
C - O - N
H
H
H
H
H
= O
= O
= O
= O
= O
= O
C - O - N
C - O - N
C - O - N
H
H
H
H
H
= O
= O
= O
= O
= O
= O
EnzymaticUnknown pathway. Likely
requires glutathione. Less activein coronary microvessels <100 µm(Possibly secondary to decreased
availability of glutathione)
N = 0
N = 0 GuanylateCyclase
NO2+
EnzymaticGlutathioneS-Transfers:
Product is nitrate.Activity
increased byexcess GSH
Mechanisms of Nitrate ToleranceMechanisms of Nitrate Tolerance
► Decreased bioconversion to NODecreased bioconversion to NO11
► Depletion of sulfhydryl groupsDepletion of sulfhydryl groups2,32,3
► Neurohumoral adaptationsNeurohumoral adaptations44
► Superoxide anion productionSuperoxide anion production55
► Upregulation of endothelin 1Upregulation of endothelin 166
1.1. MMüünzel T. nzel T. Am J CardiolAm J Cardiol. 1996;77:24C-30C. . 1996;77:24C-30C. 2.2. Parker JD, Parker JO. Parker JD, Parker JO. N Engl J MedN Engl J Med. 1998;338:520-531. . 1998;338:520-531. 3.3. Needleman P, Johnson EMJ. Needleman P, Johnson EMJ. J Pharmacol Exp TherJ Pharmacol Exp Ther. 1973;184:709-715. . 1973;184:709-715. 4.4. MMüünzel T, et al. nzel T, et al. J Am Coll CardiolJ Am Coll Cardiol. 1996;27:297-303. . 1996;27:297-303. 5.5. MMünzel T, et al. ünzel T, et al. J Clin InvestJ Clin Invest. 1995;95:187-194. . 1995;95:187-194. 6.6. MMüünzel T, et al. nzel T, et al. Proc Natl Acad SciProc Natl Acad Sci. 1995;92:5244-5248.. 1995;92:5244-5248.
Hemodynamic effects of Inhaled NO in Hemodynamic effects of Inhaled NO in Patients with Heart Failure (n=19)Patients with Heart Failure (n=19)
Room AirRoom Air NONO PP
HR, bpmHR, bpm 90 90 ±± 3 3 93 93 ±± 3 3 NSNS
MAP, mmHgMAP, mmHg 79 79 ±± 3 3 81 81 ±± 3 3 NSNS
SVR, dyne –s-cmSVR, dyne –s-cm-5-5 1102 1102 ±± 104 104 1041 1041 ±± 97 97 NSNS
PA, mmHgPA, mmHg 35 35 ±± 4 4 37 37 ±± 4 4 NSNS
PAWP, mmHgPAWP, mmHg 25 25 ±± 3 3 31 31 ±± 4 4 <.001<.001
LVEDP, mmHg: n=10LVEDP, mmHg: n=10 28 28 ±± 4 4 34 34 ±± 5 5 .02.02
PVR, dyne – s cmPVR, dyne – s cm-5-5 226 226 ±± 30 30 119 119 ±± 13 13 <.001<.001
PA-PAWP, mmHGPA-PAWP, mmHG 11 11 ±± 1 1 6 6 ±± 0.5 0.5 <.001<.001
SVI, mL/mSVI, mL/m22 226 226 ±± 30 30 24 24 ±± ±±22 .03.03
CI, L-min-1 mCI, L-min-1 m-2-2 2.3 2.3 ±± 0.2 0.2 2.1 2.1 ±± 0.2 0.2 .03.03
Loh E. Cardiovascular effects of iNO in patients with LV dysfunction. Loh E. Cardiovascular effects of iNO in patients with LV dysfunction. CirculationCirculation. 1994;90:2780.. 1994;90:2780.
Hypertension In CardiacHypertension In CardiacSurgical Patients (1)Surgical Patients (1)
► Patients normotensive may become Patients normotensive may become hypertensive.hypertensive.
► Most BP changes develop acutely and Most BP changes develop acutely and require rapid intervention.require rapid intervention.
► Characterized by systemic vasoconstriction Characterized by systemic vasoconstriction with intravascular hypovolemia.with intravascular hypovolemia.
► Patients may have preop biventricular Patients may have preop biventricular dysfunction.dysfunction.
Hypertension In CardiacHypertension In CardiacSurgical Patients (2)Surgical Patients (2)
► BP may be maintained at lower levels to BP may be maintained at lower levels to avoid graft/suture line disruption.avoid graft/suture line disruption.
► Patients are being “Fast Tracked.”Patients are being “Fast Tracked.”
► Mechanical manipulation, suturing with Mechanical manipulation, suturing with potential risk for coronary/IMA spasm.potential risk for coronary/IMA spasm.
► Ventricular dysfunction is common in Ventricular dysfunction is common in patients with normal preop function due to patients with normal preop function due to stunning/reperfusion injury.stunning/reperfusion injury.
NitrovasodilatorsNitrovasodilatorsSodiumSodium NitroprussideNitroprusside
Na+
CN
NO+
CN
Fe++
CN
CN
CNNa+
Venodilation Occurs withVenodilation Occurs withNitroprusside TherapyNitroprusside Therapy
► Nitroprusside is potent venous and Nitroprusside is potent venous and arterial vasodilatorarterial vasodilator
► Venodilation:Venodilation: Affects cardiac output Affects cardiac output Often requires compensatory Often requires compensatory
volume replacementvolume replacement
Kerins DM, et al. In: Hardman JG, Limbird LE, eds. Kerins DM, et al. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological Basis Goodman and Gilman’s Pharmacological Basis of Therapeuticsof Therapeutics. 10th ed. New York, NY: McGraw-Hill; 1997:843-870.. 10th ed. New York, NY: McGraw-Hill; 1997:843-870.
IV DihydropyridinesIV Dihydropyridines
Calcium Channel BlockersCalcium Channel Blockers
► 1st Generation CCB:1st Generation CCB: Nifedipine Nifedipine
► 2nd Generation CCB:2nd Generation CCB: Nicardipine, isradipine Nicardipine, isradipine
► 3rd Generation CCB:3rd Generation CCB: Clevidipine Clevidipine
NicardipineNicardipine
► Only IV dihydropyridine CCB Only IV dihydropyridine CCB available in the United Statesavailable in the United States
► Arterial vasodilatorArterial vasodilator11
► Decreases SVRDecreases SVR2-62-6
► More selective for vascular smooth More selective for vascular smooth muscle than cardiac musclemuscle than cardiac muscle11
► No significant increase in ICPNo significant increase in ICP77
1.1. Clarke B, et al. Clarke B, et al. Br J PharmacolBr J Pharmacol. 1983;79:333P. . 1983;79:333P. 2.2. Lambert CR, et al. Lambert CR, et al. Am J CardiolAm J Cardiol. 1987;60:471-476. . 1987;60:471-476. 3.3. Silke B, et al. Silke B, et al. Br J Clin PharmacolBr J Clin Pharmacol. 1985;20:169S-176S. . 1985;20:169S-176S. 4.4. Lambert CR, et al Lambert CR, et al Am J CardiolAm J Cardiol. 1985;55:652-656. . 1985;55:652-656. 5.5. Visser CA, et al. Visser CA, et al. Postgrad Med JPostgrad Med J. 1984;60:17-20. . 1984;60:17-20. 6.6. Silke B, et al. Silke B, et al. Br J Clin PharmacolBr J Clin Pharmacol. 1985;20:169S-176S. . 1985;20:169S-176S. 77.. Nishiyama MT, et al. Nishiyama MT, et al. Can J Anaesth.Can J Anaesth. 2000;47:1196-1201. 2000;47:1196-1201.
Hemodynamic Effects Of NicardipineHemodynamic Effects Of Nicardipine
ControlControl Nicardipine NicardipineHRHR 71 71 ± ± 1313 70 70 ±± 14 14
MAPMAP 107 107 ±± 14 14 80 80 ±± 9 9
PAOPPAOP 9 9 ±± 4 4 8 8 ±± 3 3
MPAPMPAP 15 15 ±± 3 3 16 16 ±± 4 4
RAPRAP 8 8 ±± 3 3 8 8 ±± 2 2
CICI 2.2 2.2 ±± 0.3 0.3 2.8 2.8 ±± 0.4 0.4
LVLVdP/dTdP/dT 1509 1509 ±± 376 376 1680 1680 ±± 485 485
LVEFLVEF %% 57 57 ±± 9 9 68 68 ±± 7 7
Lambert CR: Am J Cardiol 1993;71:420.Lambert CR: Am J Cardiol 1993;71:420.
Hemodynamic Effects Of IsradipineHemodynamic Effects Of Isradipine
VariableVariable BaselineBaseline 30 Minutes30 MinutesSBPSBP 150 150 ± ± 20 20 -30 -30 ±± 30 30‡‡
DBPDBP 75 75 ±± 9 9 -18 -18 ±± 8.0 8.0‡‡
MAPMAP 101 101 ±± 10 10 -23 -23 ±± 11.0 11.0‡‡
HRHR 89 89 ±± 12 12 4 4 ±± 12* 12*
CICI 2.7 2.7 ±± 0.6 0.6 0.4 0.4 ±± 0.6 0.6‡‡
SVRSVR 1470 1470 ±± 417 417 -478 -478 ±± 281 281‡‡
SVISVI 0.0310 0.0310 ±± 0.006 0.006 0.004 0.004 ±± 0.006 0.006††
PADPPADP 13.4 13.4 ±± 3.9 3.9 0.2 0.2 ±± 3.2 3.2
PCWPCW 11.7 11.7 ±± 4.3 4.3 -0.0 -0.0 ±± 3.0 3.0
PVRPVR 1.25 1.25 ±± 0.9 0.9 -0.05 -0.05 ±± 0.47 0.47
Leslie: Circulation. 1994 Nov;90(5 Pt 2):II256.Leslie: Circulation. 1994 Nov;90(5 Pt 2):II256.
Nicardipine PharmacokineticsNicardipine Pharmacokineticsand Metabolismand Metabolism
► Redistribution phase after IV bolusRedistribution phase after IV bolus Half-life=2.7 minutesHalf-life=2.7 minutes
► Intermediate phaseIntermediate phase Half-life=44 minutesHalf-life=44 minutes
► Terminal half-life after long-term Terminal half-life after long-term infusioninfusion Half-life=14.4 hoursHalf-life=14.4 hours
CardeneCardene IV [ IV [package insert].package insert].
Nicardipine: Pharmacokinetics of IV Nicardipine: Pharmacokinetics of IV Bolus AdministrationBolus Administration
Adapted from Cheung AT, et al. Adapted from Cheung AT, et al. Anesth Analg.Anesth Analg. 1999;89:1116. 1999;89:1116.
0
50
100
150
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5Time after drug administration (h)
-50
-40
-30
-20
-10
0
10
0 20 40 60 80 100
Ch
ang
e i
n M
AP
(m
m H
g)
Nicardipine concentration (ng/mL)
120 140
Pla
sma
nic
ard
ipin
e co
nce
ntr
atio
n (
ng
/mL
)
Group 1: 0.25 mgGroup 2: 0.5 mgGroup 3: 1.0 mgGroup 4: 2.0 mg
Clevidipine In CABGClevidipine In CABGA Dose-finding StudyA Dose-finding Study
► Clevidipine decreased MAP and SVR, without Clevidipine decreased MAP and SVR, without changes in heart rate, CVP, PAOP, or CI at changes in heart rate, CVP, PAOP, or CI at increasing doses. increasing doses.
► The early phase of drug disposition had a half-The early phase of drug disposition had a half-life of 0.6 min. The context-sensitive half-time <2 life of 0.6 min. The context-sensitive half-time <2 min for up to 12 hours of administration.min for up to 12 hours of administration.
►
► CONCLUSION:CONCLUSION: Clevidipine is a CCB that lowers Clevidipine is a CCB that lowers BP without changing heart rate, CI, or cardiac BP without changing heart rate, CI, or cardiac filling pressures.filling pressures.
Bailey JM et al:Anesthesiology 2002;96:1086.Bailey JM et al:Anesthesiology 2002;96:1086.Bailey JM et al:Anesthesiology 2002;96:1086.Bailey JM et al:Anesthesiology 2002;96:1086.
Clevidipine Effectively and Rapidly Controls Blood Clevidipine Effectively and Rapidly Controls Blood Pressure Preoperatively in Cardiac SurgeryPressure Preoperatively in Cardiac Surgery
Results of the Randomized, Placebo-Controlled Efficacy Study of Clevidipine Assessing its Preoperative antihypertensive Effect in Cardiac Surgery-(ESCAPE-1) Trial
Levy JH: Anesth Analg, In Press.Levy JH: Anesth Analg, In Press.
Arterial SpasmArterial Spasm
► Loss of endothelial function via vascular injury and platelet activation is potential mechanism, but other mechanisms include NO scavenging by hemoglobin.
► Thromboxane, a potent constrictor, has been implicated.
► Only certain drugs will completely reverse arterial spasm.
Vasospasm: Body of LiteratureVasospasm: Body of Literature
► Salmenperra MT: Effects of PDE inhibitors on the human Salmenperra MT: Effects of PDE inhibitors on the human IMA. Anesth Analg 1996; 82: 954-957.IMA. Anesth Analg 1996; 82: 954-957.
► Huraux C: Vasodilator effects of clevidipine on human Huraux C: Vasodilator effects of clevidipine on human IMA. Anesth Analg 1997; 85: 1000-1004.IMA. Anesth Analg 1997; 85: 1000-1004.
► Huraux C: A comparative eval of multiple vasodilators on Huraux C: A comparative eval of multiple vasodilators on human IMA. Anesthesiology 1998;88:1654-1659.human IMA. Anesthesiology 1998;88:1654-1659.
► Huraux C: Superoxide production, risk factors, and Huraux C: Superoxide production, risk factors, and EDRF relaxations in human IMAs. Circulation EDRF relaxations in human IMAs. Circulation 1999;99:53-59. 1999;99:53-59.
► Tsuda A: Reversal of histamine-induced vasodilation in Tsuda A: Reversal of histamine-induced vasodilation in the human IMA. Anesth Analg 2001;93:1453-1459.the human IMA. Anesth Analg 2001;93:1453-1459.
► Sato N: Vasodilatory effects of hydralazine, nicardipine, Sato N: Vasodilatory effects of hydralazine, nicardipine, nitroglycerin and fenoldopam in the human umbilical nitroglycerin and fenoldopam in the human umbilical artery. Anesth Analg 2003;96:539-544.artery. Anesth Analg 2003;96:539-544.
► Tanaka KA: In vitro effects of antihypertensive drugs on Tanaka KA: In vitro effects of antihypertensive drugs on TxA2 (U46619)-induced vasoconstriction in human IMA. TxA2 (U46619)-induced vasoconstriction in human IMA. Br J Anaesth 2004;93:257-262.Br J Anaesth 2004;93:257-262.
A Comparative Evaluation of the Effects of A Comparative Evaluation of the Effects of Multiple Vasodilators on Human IMAMultiple Vasodilators on Human IMA
► Nitroglycerin was most Nitroglycerin was most potent for thromboxanepotent for thromboxane
A2 inhibitorA2 inhibitor
► Milrinone,dihydropyridinesMilrinone,dihydropyridines, PGE1, and papaverine , PGE1, and papaverine were also effective at were also effective at therapeutically used dosestherapeutically used doses
Huraux C et al. Huraux C et al. Anesthesiology.Anesthesiology. 1998;88:1654-1659. 1998;88:1654-1659.
Vasodilator Effects of Vasodilator Effects of Clevidipine on Human IMA Clevidipine on Human IMA
► Clevidipine was effective Clevidipine was effective anti-vasospasm agent at anti-vasospasm agent at therapeutically used therapeutically used dosesdoses
Huraux C, Makita T, Szlam F, Nordlander M, Levy JH: Anesth Analg 1997; 85: 1000-1004. Huraux C, Makita T, Szlam F, Nordlander M, Levy JH: Anesth Analg 1997; 85: 1000-1004.
Comparative Study of Calcium Comparative Study of Calcium Antagonists On Human Radial ArteryAntagonists On Human Radial Artery
He GW: He GW: JTCVSJTCVS 2000;119:942000;119:94
Simulated Drug Level CurvesSimulated Drug Level Curves
““Full” loading dose = [Cp] x VdssFull” loading dose = [Cp] x VdssSmaller loading dose = [Cp] x VcSmaller loading dose = [Cp] x VcNo loading doseNo loading dose
Time (Half-life)
0
10
20
30
40
50
60
0 1 2 3 4 5 6
TherapeuticConcentration
Range
Pla
sma
Dru
g Le
vel
Fenoldopam (Corlopam)Fenoldopam (Corlopam)
► Selective vascular DA1 agonistSelective vascular DA1 agonist► Produces arterial vasodilation, Produces arterial vasodilation,
increases renal perfusion, and increases renal perfusion, and naturesisnaturesis
► Short duration of action/half lifeShort duration of action/half life► Approved in June 1997Approved in June 1997► Expense, potency, reflex tachycardia Expense, potency, reflex tachycardia
are major issuesare major issues
Summary (1)Summary (1)
► Multiple pharmacologic agents produce Multiple pharmacologic agents produce vasodilation via different mechanisms.vasodilation via different mechanisms.
► Beta-blockers are important in hypertension Beta-blockers are important in hypertension and tachycardia, but effects are limited by and tachycardia, but effects are limited by heart rate.heart rate.
► Arterial vasoconstriction is characteristic of Arterial vasoconstriction is characteristic of perioperative hypertension with intravascular perioperative hypertension with intravascular hypovolemia.hypovolemia.
► Nitrate tolerance is important to consider in Nitrate tolerance is important to consider in critically ill patients.critically ill patients.
Summary (2)Summary (2)
► Nitrovasodilators decrease both preload and Nitrovasodilators decrease both preload and resistance vessels. resistance vessels.
► DHP CCBs produce arterial selective DHP CCBs produce arterial selective vasodilation, controlling BP without vasodilation, controlling BP without producing venodilation or negative inotropic producing venodilation or negative inotropic and conduction effects, and reverses and conduction effects, and reverses vasospasm in the IMA and other vascular vasospasm in the IMA and other vascular beds.beds.
► Large clinical trials regarding DHP CCBs will Large clinical trials regarding DHP CCBs will contribute to our understanding of their contribute to our understanding of their perioperative and other indications.perioperative and other indications.
VasoactiveTherapy.comVasoactiveTherapy.com
Emerging Agents for Blood Pressure Emerging Agents for Blood Pressure Control in Cardiac SurgeryControl in Cardiac Surgery
Results of the ECLIPSE Trials Comparing ClevidipineResults of the ECLIPSE Trials Comparing Clevidipinewith Available Agents in Perioperative Hypertensionwith Available Agents in Perioperative Hypertension
Kevin A. Stierer Sr., M.DKevin A. Stierer Sr., M.D..Chief Division of Cardiac and Thoracic AnesthesiaChief Division of Cardiac and Thoracic Anesthesia
Associate Director Cardiac Surgery ICUAssociate Director Cardiac Surgery ICUThe Heart Institute at St. Joseph Medical CenterThe Heart Institute at St. Joseph Medical Center
Towson, Maryland Towson, Maryland
AcknowledgementsAcknowledgements
Cornelius Dyke, MDCornelius Dyke, MD Dean Kereiakes, MDDean Kereiakes, MD
Jerrold H. Levy, MDJerrold H. Levy, MD Philip Lumb, MDPhilip Lumb, MD
Albert Cheung, MDAlbert Cheung, MD Howard Corwin, MDHoward Corwin, MD
Solomon Aronson, MD*Solomon Aronson, MD* Mark Newman, MDMark Newman, MD
*Acknowledgement and thanks to Dr. Solomon Aronson, who*Acknowledgement and thanks to Dr. Solomon Aronson, whofirst presented much of this material as a Late Breaker at first presented much of this material as a Late Breaker at ACC 2007 Scientific Assembly on March 27, 2007.ACC 2007 Scientific Assembly on March 27, 2007.
Perioperative Hypertension Perioperative Hypertension
► Patients with preoperative hypertension are at an Patients with preoperative hypertension are at an increased risk for perioperative complicationsincreased risk for perioperative complications11
► Approximately 30% to 56% of patients undergoing Approximately 30% to 56% of patients undergoing routine cardiac surgery experience acute rises in routine cardiac surgery experience acute rises in blood pressure that require administration of a blood pressure that require administration of a parenteral antihypertensive agentparenteral antihypertensive agent22
► Antihypertensive therapy is often needed to manage Antihypertensive therapy is often needed to manage life-threatening arterial bleeding, myocardial life-threatening arterial bleeding, myocardial ischemia, or cardiac failureischemia, or cardiac failure33
1. Sladen, 1. Sladen, IARS Rev Course Lectures,IARS Rev Course Lectures, 2002, p100; DeQuattro, 2002, p100; DeQuattro, J Cardiovasc Pharmacol Ther,J Cardiovasc Pharmacol Ther, 1997. 1997.2. Cheung, 2. Cheung, J Card SurgJ Card Surg, 2006, S8; Estafanous, , 2006, S8; Estafanous, Am J CardiolAm J Cardiol, 1980, p685; Landymore, , 1980, p685; Landymore, Can J SurgCan J Surg, 1980., 1980.3. Cheung, 3. Cheung, J Card SurgJ Card Surg, 2006, S8., 2006, S8.
Considerations for Perioperative BP Considerations for Perioperative BP Control During Cardiac SurgeryControl During Cardiac Surgery
► INTRAOPERATIVEINTRAOPERATIVE InductionInduction CannulationCannulation Protamine and hemostasisProtamine and hemostasis
(aortotomy/suture lines)(aortotomy/suture lines) Chest closureChest closure TransportTransport
► POSTOPERATIVEPOSTOPERATIVE Temperature management (warming and shivering)Temperature management (warming and shivering) EmergenceEmergence Weaning and extubationWeaning and extubation Volume statusVolume status
Goals for an Ideal Antihypertensive Goals for an Ideal Antihypertensive Agent in Setting of Cardiac SurgeryAgent in Setting of Cardiac Surgery
► Rapid onset of actionRapid onset of action
► Predictable dose responsePredictable dose response
► Titratable to desired BPTitratable to desired BP
► Highly vascular selectiveHighly vascular selective
► Maintain stroke volume and cardiac outputMaintain stroke volume and cardiac output
► Rapidly reversibleRapidly reversible
► Low risk of overshoot hypotension Low risk of overshoot hypotension
► Low risk of adverse reactionsLow risk of adverse reactions
Levy JH. Levy JH. Anesthesiol Clin North Am.Anesthesiol Clin North Am. 1988;17:587-678. 1988;17:587-678.
Oparil S et al. Oparil S et al. Am J Hypertens. Am J Hypertens. 1999;12:653-664.1999;12:653-664.
Clevidipine: The First Third-Clevidipine: The First Third-Generation Calcium Channel BlockerGeneration Calcium Channel Blocker
Generic NameGeneric Name Brand NameBrand Name
First First GenerationGeneration NifedipineNifedipine ProcardiaProcardia®®, Adalat, Adalat®®
Second Second GenerationGeneration
Nicardipine/ (I.V.)Nicardipine/ (I.V.)AmlodipineAmlodipineIsradipineIsradipineFelodipineFelodipine
Nimodipine/ (I.V.)Nimodipine/ (I.V.)
NisoldipineNisoldipine
CardeneCardene®®/Cardene /Cardene I.V.I.V.
NorvascNorvasc®®
DynaCircDynaCirc®®
PlendilPlendil®®
NimotopNimotop®®/Nimotop /Nimotop I.V.I.V.
SularSular®®
Third Third GenerationGeneration ClevidipineClevidipine TBDTBD
Whiting RL, et al. Whiting RL, et al. Angiology.Angiology. 1990;41:987-991. 1990;41:987-991.
Cl
ClH
CH3OOC
H3C
COOCH2OOCC3H7
CH3N
H
The Clevidipine MoleculeThe Clevidipine Molecule
Clevidipine is the first ultrashort acting Clevidipine is the first ultrashort acting dihydropyridine intravenous calcium channel blockerdihydropyridine intravenous calcium channel blocker
Clevidipine: Metabolized by Plasma Clevidipine: Metabolized by Plasma and Tissue Esterasesand Tissue Esterases
► Clevidipine is rapidly metabolized by esterases in Clevidipine is rapidly metabolized by esterases in blood and extravascular tissue to an inactive blood and extravascular tissue to an inactive carboxylic acid metabolitecarboxylic acid metabolite
+OH
OHH
O
Clevidipine
Cl
OO
O
O
NH
Cl
O
O
*Esterases +O
O
NH
Cl
O
O
Cl
H
Primary metabolite
*The chiral center of clevidipine.*The chiral center of clevidipine.Reproduced from Ericsson H, et al. Reproduced from Ericsson H, et al. Eur J Clin PharmacolEur J Clin Pharmacol. 1999;55:61-67.. 1999;55:61-67.Bailey JM, et al. Bailey JM, et al. Anesthesiology.Anesthesiology. 2002;96:1086-1094. 2002;96:1086-1094.Ericsson H, et al. Ericsson H, et al. Drug Metab Dispos. Drug Metab Dispos. 1999;27:558-564.1999;27:558-564.Ericsson H et al. Ericsson H et al. Eur J Clin PharmacolEur J Clin Pharmacol. 1999;55:61-67.. 1999;55:61-67.Ericsson H, et al. Ericsson H, et al. Eur J Pharm Sci.Eur J Pharm Sci. 1999;8:29-37. 1999;8:29-37.
SBP changes for patients receiving clevidipine during a 30-minute treatment period.
10
5
0
–5
–10
–15
–20
–25
–300 5 10 15 20 25 30
% C
han
ge
Fro
m B
asel
ine
Time (min)
SBP
SBP ChangesSBP Changes
Clevidipine: Rapid OnsetClevidipine: Rapid Onset
► BP-lowering effects are seen within 2–3 minutes of BP-lowering effects are seen within 2–3 minutes of clevidipine infusionclevidipine infusion
Levy JH, et al. Levy JH, et al. Anesthesiology.Anesthesiology. 2005;103:A354. 2005;103:A354.
Responders = treatment success: >10% decrease in MAP or >20% decrease in MAP at each measured concentration.
Clevidipine: Linear Dose ResponseClevidipine: Linear Dose Response
► Linear dose response in postoperative cardiacLinear dose response in postoperative cardiacsurgery patientssurgery patients
► Effective in 95% of patients at ≤3.2 mcg/kg/minEffective in 95% of patients at ≤3.2 mcg/kg/minn=19
Infusion Rate (mcg/kg/min)
0
10
20
30
40
50
60
70
80
90
100
0 0.05 0.18 0.32 1.37 3.19
Res
po
nd
ers
(%)
n=0n=1
n=4
n=6
n=9
Bailey JM, et al. Bailey JM, et al. Anesthesiology.Anesthesiology. 2002;96:1086-1094. 2002;96:1086-1094.
*Css = concentration at steady state; median blood concentration of clevidipine obtained during the last 10 minutes of infusion.
Clevidipine: Linear PharmacokineticsClevidipine: Linear Pharmacokinetics
► At steady state, there is a linear relationship between At steady state, there is a linear relationship between dosage and arterial blood concentrationsdosage and arterial blood concentrations
► Linear relationship maintained for dosages as high asLinear relationship maintained for dosages as high as21.9 mcg/kg/min21.9 mcg/kg/min
120
100
80
60
40
20
0
0 5 10 15 20 35
Cle
vid
ipin
e C
on
ce
ntr
ati
on
at
Cs
s (
nm
ol/
L)*
Dose Rate (nmol/kg/min)25 30
Reproduced from Ericsson H, et al. Reproduced from Ericsson H, et al. AnesthesiologyAnesthesiology. 2000;92:993-1001.. 2000;92:993-1001.Ericsson H, et al. Ericsson H, et al. AnesthesiologyAnesthesiology. 2000;92:993-1001.. 2000;92:993-1001.Ericsson H, et al. Ericsson H, et al. Br J Clin Pharmacol. Br J Clin Pharmacol. 1999;47:531-538.1999;47:531-538.
Reproduced from Ericsson H, et al. Reproduced from Ericsson H, et al. AnesthesiologyAnesthesiology. 2000;92:993-1001.. 2000;92:993-1001.
Clevidipine: Ultrashort Half-LifeClevidipine: Ultrashort Half-Life
► Clinically relevant half-life: approximately 1 minuteClinically relevant half-life: approximately 1 minute
Arterial and venous clevidipine blood samples
Clevidipine: Metabolized by Plasma Clevidipine: Metabolized by Plasma and Tissue Esterasesand Tissue Esterases
► Clevidipine is rapidly metabolized by esterasesClevidipine is rapidly metabolized by esterasesin blood and extravascular tissue to an inactive in blood and extravascular tissue to an inactive carboxylic acid metabolitecarboxylic acid metabolite
+OH
OHH
O
Clevidipine
Cl
OO
O
O
NH
Cl
O
O
*Esterases +O
O
NH
Cl
O
O
Cl
H
Primary metabolite
*The chiral center of clevidipine.
Reproduced from Ericsson H, et al. Reproduced from Ericsson H, et al. Eur J Clin PharmacolEur J Clin Pharmacol. 1999;55:61-67.. 1999;55:61-67.Bailey JM, et al. Bailey JM, et al. Anesthesiology.Anesthesiology. 2002;96:1086-1094. 2002;96:1086-1094.Ericsson H, et al. Ericsson H, et al. Drug Metab Dispos. Drug Metab Dispos. 1999;27:558-564.1999;27:558-564.Ericsson H et al. Ericsson H et al. Eur J Clin PharmacolEur J Clin Pharmacol. 1999;55:61-67.. 1999;55:61-67.Ericsson H, et al. Ericsson H, et al. Eur J Pharm Sci.Eur J Pharm Sci. 1999;8:29-37. 1999;8:29-37.
Clevidipine: Rapid OffsetClevidipine: Rapid Offset
► After discontinuation of clevidipine infusion, there was a After discontinuation of clevidipine infusion, there was a rapid clearancerapid clearance
► BP returned to baseline in <10 minutes in healthy volunteersBP returned to baseline in <10 minutes in healthy volunteers
Reproduced from Ericsson H, et al. Reproduced from Ericsson H, et al. AnesthesiologyAnesthesiology. 2000;92:993-1001.. 2000;92:993-1001.
100
90
80
70
60
50
40–5 0 5 10 15 20 35
MA
P (
mm
Hg
) a
nd
H
R (
be
ats
/min
)
Time (min)
25 30
Clevidipine InfusionClevidipine InfusionMAP
*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.
12
mm
Hg 8
4
00 0.375 0.75 1.5 3 0
10
6
2
mcg/kg/min
Pressure Central Venous
Clevidipine: Arterial SelectivityClevidipine: Arterial Selectivity
1400
Un
its 1200
1000
0C1 0.375 0.75 1.5 3 C2
Systemic Vascular Resistance
‡†
††
mcg/kg/min
C2
†
Mean Arterial Pressure
90
80
70
*†
†
C1 0.375 0.75 1.5 3
mcg/kg/min
mm
Hg
Kieler-Jensen N, et al. Kieler-Jensen N, et al. Acta Anaesthesiol Scand. Acta Anaesthesiol Scand. 2000;44:186-193.2000;44:186-193.
SVR = systemic vascular resistance; RVEDV = right ventricular end-diastolic volume.
Clevidipine: Hemodynamic EffectsClevidipine: Hemodynamic Effects
► In postoperative patientsIn postoperative patients Increased stroke volume, cardiac outputIncreased stroke volume, cardiac output No reflex increase in HR or changes in cardiac preloadNo reflex increase in HR or changes in cardiac preload Lower SVR, higher cardiac filling pressures and Lower SVR, higher cardiac filling pressures and
RVEDV vs SNPRVEDV vs SNP
Data from Data from Kieler-Jensen N, et al. Kieler-Jensen N, et al. Acta Anaesthesiol Scand. Acta Anaesthesiol Scand. 2000;44:186-193.2000;44:186-193.
C2
75
mL
/bea
t 70
65
0
C1 0.375 0.75 1.5 3
Stroke Volume
†*
L •
min
–1
Cardiac Output
0
1
2
3
4
5
6
C1 0.375 0.75 1.5 3 C2
Infusion Rate (µg • kg–1 • min–1) Infusion Rate (µg • kg–1 • min–1)
*P<0.05
†P<0.001
10
5
0
–5
0 5 10 15 20 25 30% C
ha
ng
e F
rom
Ba
se
lin
e
Time (min)
HR5
0
–5
0 5 10 15 20 25 30
% C
ha
ng
e F
rom
Ba
se
lin
eTime (min)
HR
Preoperative HR Changes in Non-Anesthetized Patients
Postoperative HR Changesin Anesthetized Patients
HR changes for patients during the 30-minute treatment period
HR changes for patients during the 30-minute treatment period
Clevidipine Clevidipine Minimal Effect on Heart RateMinimal Effect on Heart Rate
Levy JH, et al. Levy JH, et al. Anesthesiology.Anesthesiology. 2005;103:A354. 2005;103:A354. Singla N, et al. Singla N, et al. Anesthesiology.Anesthesiology. 2005;103:A292. 2005;103:A292.
Clevidipine Clinical DevelopmentClevidipine Clinical Development
Tolerability, Safety, PK
Dose ResponseESCAPE: Efficacy
Clevidipine vs Placebo
VELOCITY: Severe Hypertension
PK, Metabolism, Rates and Routes
of ExcretionPK/BP
ESCAPE: EfficacyClevidipine vs Placebo
PKPK/PD:
Clevidipine vs Placebo
ECLIPSE: Safety vs NTG
QTc StudyECLIPSE:
Safety vs SNP
ECLIPSE: Safety vs NIC
Dose Response:Clevidipine vs Placebo
Hemodynamics:Clevidipine vs SNP
BP, HR:Clevidipine vs SNP
BP, Dose/PK
BP: Clevidipine vs Placebo
Phase IN=89
Phase II N=300
Healthy VolunteersPatients: Mild to
Moderate HypertensionN=86
Phase III N=1821
Perioperative Hypertension
N=1721
SevereHypertension
N=100
Patients: Perioperative
N=214
Data on file. The Medicines Company. Data on file. The Medicines Company.
ECLIPSE: RationaleECLIPSE: Rationale
► Clevidipine is an IV dihydropyridine calcium Clevidipine is an IV dihydropyridine calcium channel blocker with an ultrashort half-life (~1 min)channel blocker with an ultrashort half-life (~1 min)
► Phase I & IIPhase I & II studies (300 pts) demonstrated: studies (300 pts) demonstrated: Dose: 2–16 mg/hr effectiveDose: 2–16 mg/hr effective11
► Phase IIIPhase III safety program required for FDA safety program required for FDA registration registration Evaluation: Death, MI, Stroke, Renal Evaluation: Death, MI, Stroke, Renal
DysfunctionDysfunction Comparators: Nitroglycerin (NTG), Sodium Comparators: Nitroglycerin (NTG), Sodium
nitroprusside (SNP), Nicardipine (NIC)nitroprusside (SNP), Nicardipine (NIC) Rapid onset: BP control in 5 minRapid onset: BP control in 5 min22
11Bailey J. Bailey J. AnesthesiologyAnesthesiology 2002;96:1086-94. 2002;96:1086-94. 22Levy J. Levy J. Anesth AnalgAnesth Analg 2006 (in press). 2006 (in press).
Blood Pressure Control with Clevidipine Compared with
Nitroglycerin, Sodium Nitroprusside, or Nicardipine in the Treatment of
Peri-operative Hypertension:
Eclipse - NTG
Eclipse - SNP
Eclipse - NIC
ECLIPSE 1, 2, and 3ECLIPSE 1, 2, and 3
Objectives of ECLIPSE TrialObjectives of ECLIPSE Trial
PrimaryPrimary ► Investigate the safety of clevidipine inInvestigate the safety of clevidipine in
perioperative HTN perioperative HTN
SecondarySecondary► Evaluate adverse eventsEvaluate adverse events► Examine blood pressure controlExamine blood pressure control
ECLIPSE: ProtocolsECLIPSE: Protocols
► Randomized (1:1), open-label, parallel group with Randomized (1:1), open-label, parallel group with active comparators: nitroglycerin (NTG), sodium active comparators: nitroglycerin (NTG), sodium nitroprusside (SNP), or nicardipine (NIC)nitroprusside (SNP), or nicardipine (NIC) NTG and SNP studies are perioperative and NIC NTG and SNP studies are perioperative and NIC
is postoperative is postoperative
► Patients undergoing cardiac surgery; CABG, Patients undergoing cardiac surgery; CABG, OPCAB, Valve, MIDCABOPCAB, Valve, MIDCAB
► Treatment with study drug allowed until discharge Treatment with study drug allowed until discharge from ICUfrom ICU
Data on file. The Medicines Company.Data on file. The Medicines Company.
ECLIPSE: Trial DesignECLIPSE: Trial Design
Clevidipinevs nitroglycerin
Clevidipine vs sodium
nitroprusside
Clevidipinevs nicardipine
Perioperative Perioperative Postoperative
ClevidipineN=268
NitroglycerinN=278
ClevidipineN=296
Sodiumnitroprusside
N=283
ClevidipineN=188
NicardipineN=193
1:1 1:1 1:1
Data on file. The Medicines Company.Data on file. The Medicines Company.
Inclusion CriteriaInclusion Criteria
Pre-randomizationPre-randomization
► ≥≥ 18 years of age18 years of age
► Written informed consentWritten informed consent
► Planned CABG, OPCAB, MIDCAB surgery and/or Planned CABG, OPCAB, MIDCAB surgery and/or valve repair/replacement surgeryvalve repair/replacement surgery
Post-randomizationPost-randomization
► Require treatment for perioperative HTNRequire treatment for perioperative HTN
Exclusion CriteriaExclusion Criteria
► Women of child bearing potentialWomen of child bearing potential
► CVA ≤ 3 months of randomizationCVA ≤ 3 months of randomization
► Intolerance to calcium channel blockersIntolerance to calcium channel blockers
► Hypersensitivity to NTG, SNP or NICHypersensitivity to NTG, SNP or NIC
► Allergy to the lipid vehicleAllergy to the lipid vehicle
► Permanent ventricular pacingPermanent ventricular pacing
► Any disease/condition that would put theAny disease/condition that would put thepatient at risk patient at risk
► Participation in another trial within 30 daysParticipation in another trial within 30 days
TreatmentTreatment
► ClevidipineClevidipine Initiated 2 mg/hr Initiated 2 mg/hr Titrated doubling increments Q 90s to 16 mg/hrTitrated doubling increments Q 90s to 16 mg/hr 40 mg/hr maximum 40 mg/hr maximum
► ComparatorsComparators (NTG, SNP, NIC) admin per (NTG, SNP, NIC) admin per institutional practiceinstitutional practice
► Treatment duration up to discharge from the ICUTreatment duration up to discharge from the ICU
► Concomitant anti-hypertensives discouragedConcomitant anti-hypertensives discouraged
Outcome EndpointsOutcome Endpoints
Primary*Primary* (Cumulative rate of clinical outcomes at 30 days):(Cumulative rate of clinical outcomes at 30 days):
► DeathDeath► MI:MI: Symptomatic presentation, enzyme release, and/or new Symptomatic presentation, enzyme release, and/or new
ECG changesECG changes
► Stroke:Stroke: Hemorrhagic or ischemicHemorrhagic or ischemic
► Renal Dysfunction:Renal Dysfunction: Cr >2.0 with min absolute Cr >2.0 with min absolute changechange of of 0.70.7
SecondarySecondary► SAEs through day 7 SAEs through day 7 ► BP control during the first 24 h BP control during the first 24 h
* Blinded CEC adjudication of all primary measures* Blinded CEC adjudication of all primary measures
Statistical MethodsStatistical Methods
► AssumptionsAssumptions Sample size (1500 pts) recommended by FDA Sample size (1500 pts) recommended by FDA
for safety profile assessmentfor safety profile assessment
► Descriptive analytical methodsDescriptive analytical methods Pre-specified safety analysis population Pre-specified safety analysis population (pts (pts
according to actual treatment received) according to actual treatment received)
Data pooled to provide an overall event rate Data pooled to provide an overall event rate for Clevidipine & comparator armsfor Clevidipine & comparator arms
Pre-specified analysis of each randomized Pre-specified analysis of each randomized comparisoncomparison
Patient DispositionPatient Disposition
ClevidipineClevidipine ComparatorsComparators
Randomized patientsRandomized patients 971971 993993
Met post-randomization criteriaMet post-randomization criteria 755755 757757
Safety populationSafety population 752752 754754
Completed studyCompleted study 715715 719719
Did not complete studyDid not complete study Withdrew consentWithdrew consent Physician decisionPhysician decision Lost to follow upLost to follow up Adverse experienceAdverse experience Patient deathPatient death OtherOther
37370011
151500
202011
353511006600
282800
Baseline CharacteristicsBaseline Characteristics
ClevidipineClevidipinen=752n=752
Comparators Comparators n=754n=754
Age, median (range)Age, median (range) 65 (24-87)65 (24-87) 66 (19-89)66 (19-89)MaleMale 72%72% 74%74%CaucasianCaucasian 82%82% 83%83%Hx HTNHx HTN 88%88% 85%85%CHFCHF 19%19% 18%18%Insulin dependent diabetesInsulin dependent diabetes 11%11% 11%11%COPDCOPD 14%14% 15%15%Recent MI (< 6 mos)Recent MI (< 6 mos) 17%17% 18%18%Prior CABGPrior CABG 3%3% 6%6%
Procedural CharacteristicsProcedural Characteristics
ClevidipineClevidipinen=752n=752
Comparators Comparators n=754n=754
Surgery duration, median hrsSurgery duration, median hrs 3.323.32 3.233.23
ProcedureProcedure CABGCABG Valve replacement/repairValve replacement/repair CABG & Valve replacement/repairCABG & Valve replacement/repair OtherOther
77%77%14%14%9%9%
0.3%0.3%
77%77%12%12%11%11%0.1%0.1%
ECLIPSE NTG: Drug AdministrationECLIPSE NTG: Drug Administration
ClevidipineClevidipineN=268N=268
NitroglycerinNitroglycerinN=278N=278
Initiated Pre-OpInitiated Pre-Op 92 (34.3)92 (34.3) 119 (42.8)119 (42.8)
Initiated Intra-OpInitiated Intra-Op 145 (54.1)145 (54.1) 132 (47.5)132 (47.5)
Initiated Post-OpInitiated Post-Op 31 (11.6)31 (11.6) 27 (9.7)27 (9.7)
Overall Infusion Overall Infusion Duration Duration (median)(median)
3.35 hr3.35 hr 8.13 hr8.13 hr
Data on file. The Medicines Company. Data on file. The Medicines Company.
ECLIPSE SNP: Drug AdministrationECLIPSE SNP: Drug Administration
ClevidipineClevidipineN=296N=296
NitroprussideNitroprussideN=283N=283
Initiated Pre-OpInitiated Pre-Op 52 (17.6)52 (17.6) 34 (12.0)34 (12.0)
Initiated Intra-OpInitiated Intra-Op 161 (54.4)161 (54.4) 158 (55.8)158 (55.8)
Initiated Post-OpInitiated Post-Op 83 (28.0)83 (28.0) 90 (31.8)90 (31.8)
Overall Infusion Overall Infusion Duration Duration (median)(median)
4.03 hr4.03 hr 3.25 hr3.25 hr
Data on file. The Medicines Company. Data on file. The Medicines Company.
ECLIPSE NIC: Drug AdministrationECLIPSE NIC: Drug Administration
ClevidipineClevidipineN=188N=188
NicardipineNicardipineN=193N=193
Dosed During Dosed During Post-OpPost-Op 188 (100)188 (100) 193 (100)193 (100)
Overall Infusion Overall Infusion Duration Duration (median)(median)
5.55 hr5.55 hr 5.12 hr5.12 hr
Data on file. The Medicines Company. Data on file. The Medicines Company.
Primary EndpointPrimary 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
Primary Endpoint byPrimary Endpoint byTreatment ComparisonTreatment Comparison
ClevidipineClevidipine NTGNTG ClevidipineClevidipine SNPSNP ClevidipineClevidipine NICNIC
DeathDeath 2.8%2.8% 3.4%3.4% 1.7%1.7% 4.7%*4.7%* 4.4%4.4% 3.2%3.2%
MIMI 3.3%3.3% 3.5%3.5% 1.4%1.4% 2.3%2.3% 2.3%2.3% 1.1%1.1%
StrokeStroke 1.6%1.6% 2.3%2.3% 1.1%1.1% 1.5%1.5% 0.6%0.6% 1.1%1.1%
Renal Renal DysfunctionDysfunction 6.9%6.9% 8.1%8.1% 8.5%8.5% 9.1%9.1% 8.3%8.3% 5.9%5.9%
* p = 0.045
Serious Adverse EventsSerious Adverse Events
ClevidipineClevidipinen=752n=752
ComparatorsComparatorsn=754n=754
TotalTotal 17.7%17.7% 20.0%20.0%AFIBAFIB 2.4%2.4% 2.4%2.4%Respiratory failureRespiratory failure 1.1%1.1% 2.5%2.5%ARFARF 2.3%2.3% 1.7%1.7%Ventricular fibrillationVentricular fibrillation 0.9%0.9% 1.5%1.5%Cardiac arrestCardiac arrest 0.5%0.5% 1.1%1.1%CVACVA 0.5%0.5% 1.1%1.1%Post-procedural hemorrhagePost-procedural hemorrhage 0.5%0.5% 1.1%1.1%
ECLIPSE: Atrial FibrillationECLIPSE: Atrial Fibrillation
CLVCLV
n/N (%)n/N (%)
NTGNTG
n/N (%)n/N (%)
SNPSNP
n/N (%)n/N (%)
NICNIC
n/N (%)n/N (%)
Afib Afib (total)(total)275/752 275/752 (36.6)(36.6)
91/278 91/278 (32.7)(32.7)
95/283 95/283 (33.6)(33.6)
71/193 71/193 (36.8)(36.8)
Afib Afib (before March (before March 25, 2005)25, 2005)
108/296 108/296 (36.5)(36.5)
91/278 91/278 (32.7)(32.7)
25/111 25/111 (22.5)(22.5)
16/50 16/50 (32.0)(32.0)
Afib Afib (after March (after March 25, 2005)25, 2005)
67/188 67/188 (35.6)(35.6) N/AN/A 70/172 70/172
(40.7)(40.7)55/143 55/143 (38.5)(38.5)
► ECLIPSE was put on hold due to higher AF rates in clevidipine in March 2004 and restarted in December 2005
► No statistically significant differences in any of the arms or in overall comparison
Data on file. The Medicines Company. Data on file. The Medicines Company.
ECLIPSE Secondary Endpoint: ECLIPSE Secondary Endpoint: SBP Control Within Predefined Range Over 24 HoursSBP Control Within Predefined Range Over 24 Hours
SB
P
Time (24hrs)
Prespecified SBP ranges of 75 – 145 (pre and post-op), 65-135 (intra-op)
Lower
Upper
ECLIPSE: SummaryECLIPSE: Summary
► Largest safety program to ever be performed with Largest safety program to ever be performed with an intravenous antihypertensive (n=1,512)an intravenous antihypertensive (n=1,512)
► Balanced demographics and baseline Balanced demographics and baseline characteristicscharacteristics
► Met primary endpoints with adverse event rates Met primary endpoints with adverse event rates comparable across groupscomparable across groups
► Atrial fibrillation rates are equivalentAtrial fibrillation rates are equivalent
► AUC data suggests better overall BP control AUC data suggests better overall BP control compared with SNP and NTGcompared with SNP and NTG
Data on file. The Medicines Company. Data on file. The Medicines Company.
ConclusionsConclusions
► Clevidipine is a safe alternative to Clevidipine is a safe alternative to therapy with commonly used therapy with commonly used antihypertensive agentsantihypertensive agents
► Clevidipine demonstrated superior Clevidipine demonstrated superior blood pressure control as assessed by blood pressure control as assessed by integral analysis of excursions outside integral analysis of excursions outside specified ranges over timespecified ranges over time
