The Relationship between Acute Pressure Derangements & Comprehensive Vascular Protection in the Setting of CT Surgery Solomon Aronson, MD Program Co-Chairman FACC, FCCP, FAHA, FASE Professor and Executive Vice Chairman Dept of Anesthesiology Duke University Health System Solomon Aronson, MD Program Co-Chairman FACC, FCCP, FAHA, FASE Professor and Executive Vice Chairman Dept of Anesthesiology Duke University Health System Investigation Innovation Application

CME-accredited symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from The Medicines Company Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studies COI: Full faculty disclosures provided in syllabus and at the beginning of the program Welcome and Program Overview Welcome and Program Overview

Program Educational Objectives As a result of this educational activity, physicians will: Learn to manage the hemodynamic derangements and complications of serious and/or life-threatening elevations in systolic and/or diastolic blood pressure in the perioperative setting. Learn how to select among intravenous pharmacologic agents, including calcium channel blockers/dihydropyridines, that offer unique benefits for blood pressure control in the setting of cardiovascular disease. Learn how landmark trials and analyses focusing on BP reduction may have an impact on current and future strategies for management of BP elevations in the setting of cardiovascular surgery. Be able to assess the need for and implement optimal BP-lowering strategies for patients with serious and/or life-threatening elevations in systolic and/or diastolic BP in the setting of cardiothoracic surgery, with a special focus on neurologic end point optimization. As a result of this educational activity, physicians will: Learn to manage the hemodynamic derangements and complications of serious and/or life-threatening elevations in systolic and/or diastolic blood pressure in the perioperative setting. Learn how to select among intravenous pharmacologic agents, including calcium channel blockers/dihydropyridines, that offer unique benefits for blood pressure control in the setting of cardiovascular disease. Learn how landmark trials and analyses focusing on BP reduction may have an impact on current and future strategies for management of BP elevations in the setting of cardiovascular surgery. Be able to assess the need for and implement optimal BP-lowering strategies for patients with serious and/or life-threatening elevations in systolic and/or diastolic BP in the setting of cardiothoracic surgery, with a special focus on neurologic end point optimization.

Program Faculty Solomon Aronson, MD Program Co-Chairman Professor of Anesthesiology Duke University Medical Center Executive Vice Chair Department of Anesthesiology Durham, North Carolina Jerrold H. Levy, MD Program Co-Chairman Professor and Deputy Chair for Research Emory University School of Medicine Director of Cardiothoracic Anesthesiology Cardiothoracic Anesthesiology and Critical Care Emory Healthcare Atlanta, Georgia Solomon Aronson, MD Program Co-Chairman Professor of Anesthesiology Duke University Medical Center Executive Vice Chair Department of Anesthesiology Durham, North Carolina Jerrold H. Levy, MD Program Co-Chairman Professor and Deputy Chair for Research Emory University School of Medicine Director of Cardiothoracic Anesthesiology Cardiothoracic Anesthesiology and Critical Care Emory Healthcare Atlanta, Georgia Charles W. Hogue, Jr., MD Associate Professor of Anesthesiology Department of Anesthesiology and Critical Care Medicine Johns Hopkins University Medical School Baltimore, Maryland Charles W. Hogue, Jr., MD Associate Professor of Anesthesiology Department of Anesthesiology and Critical Care Medicine Johns Hopkins University Medical School Baltimore, Maryland

Faculty COI Disclosures Faculty COI Disclosures Solomon Aronson, MD Grant/Research Support: Abbott Consultant: The Medicines Company, Regado Bioscience Speakers Bureau: Baxter Major Shareholder: Medwave Jerrold H. Levy, MD Grant/Research Support: Alexion Consultant: Bayer HealthCare, Dyax, Novo Nordisk, and Organon Charles W. Hogue, Jr., MD Advisory Committee: The Medicines Company Speakers Bureau: The Medicines Company and Hospira Research Funding: NIH, American Heart Association Solomon Aronson, MD Grant/Research Support: Abbott Consultant: The Medicines Company, Regado Bioscience Speakers Bureau: Baxter Major Shareholder: Medwave Jerrold H. Levy, MD Grant/Research Support: Alexion Consultant: Bayer HealthCare, Dyax, Novo Nordisk, and Organon Charles W. Hogue, Jr., MD Advisory Committee: The Medicines Company Speakers Bureau: The Medicines Company and Hospira Research Funding: NIH, American Heart Association

The Relationship between Acute Pressure Derangements & Comprehensive Vascular Protection in the Setting of CT Surgery Solomon Aronson, MD Program Co-Chairman FACC,FCCP,FAHA,FASE Professor and Executive Vice Chairman Dept of Anesthesiology Duke University Health System Solomon Aronson, MD Program Co-Chairman FACC,FCCP,FAHA,FASE Professor and Executive Vice Chairman Dept of Anesthesiology Duke University Health System Investigation Innovation Application

A man is as old as his arteries Sir William Osler Investigation Innovation Application

Prevalence of HTN by Age NHANES: Source: NCHS and NHLBI. HTN Risk > 115/75

NHANES: Source: NCHS and NHLBI. Hypertension: Awareness and Control by Age

ChronicHypertension HypertensionEmergencies AcuteHypertensionSyndromes Acute and Chronic Hypertension: Clinical Context

Physiology Perioperative Hypertension Hyperadrenergic response to surgery Hyperadrenergic response to surgery Increase SVR, decrease preload Increase SVR, decrease preload Rapid intravascular volume shifts Rapid intravascular volume shifts Renin angiotensin activation Renin angiotensin activation Adrenergic stimulation (cardiac & neural) Adrenergic stimulation (cardiac & neural) Serotonergic overproduction Serotonergic overproduction Baroreceptor denervation Baroreceptor denervation Altered cardiac reflexes Altered cardiac reflexes Inadequate anesthesia Inadequate anesthesia Cross clamp Cross clamp Hyperadrenergic response to surgery Hyperadrenergic response to surgery Increase SVR, decrease preload Increase SVR, decrease preload Rapid intravascular volume shifts Rapid intravascular volume shifts Renin angiotensin activation Renin angiotensin activation Adrenergic stimulation (cardiac & neural) Adrenergic stimulation (cardiac & neural) Serotonergic overproduction Serotonergic overproduction Baroreceptor denervation Baroreceptor denervation Altered cardiac reflexes Altered cardiac reflexes Inadequate anesthesia Inadequate anesthesia Cross clamp Cross clamp SVR ; Humoral vasoconstrictors Mechanical stress Endothelial injury PermeabilityCoagulation Fibrinoid necrosis Marik P. Chest. 2007;131:

Perioperative Antihypertension Therapy During Cardiac Surgery Vuylsteke A et al. J Cardiothorac Vasc Anesth. 2000;14: N = 1660 patients, (N = 191 anesthesiologists) Mean MAP threshold for treatment PreoperativeIntraoperativePostoperativeICU Patients (%) Prior hypertension (n = 845) No prior hypertension (n = 815)

Blood Pressure Phenotypes Steady Component (MAP,SBP,DBP) Dynamic Component (Pulse Pres.) Steady Component (MAP,SBP,DBP) Dynamic Component (Pulse Pres.) Determinants MAP LV ejection PVR Determinants PP LV ejection Viscoelasticity Wave Reflection Determinants SBP Stroke Volume LV ejection Distensibility Wave Reflection

Remodeling Courtesy of Schiffrin EL. NormalNormal InwardEutrophicremodeling OutwardHypertrophicremodeling Small Arteries (eutrophic) in diastolic HTN Large Arteries (hypertrophic) in PPH Courtesy of Schiffrin EL.

Pathogenic Role of Mechanical Forces Oscillatory Shear Stress* Occurs sites prone to lesion formation Carotid bulb Carotid bulb Prox. Coronaries Prox. Coronaries Distal aorta Distal aorta High Shear Atheroprotective Low Shear Atherogenic Occurs sites prone to lesion formation Carotid bulb Carotid bulb Prox. Coronaries Prox. Coronaries Distal aorta Distal aorta High Shear Atheroprotective Low Shear Atherogenic * Wide PP Augments Oscillatory Shear Elevated Stretch with Hypertension Pro-Inflammatory / Atherogenic Elevated Stretch with Hypertension Pro-Inflammatory / Atherogenic Pressure/StretchPressure/Stretch

O NO PGI 2 Catecholamines AT-II ADH (vasopressin) Aldosterone TxA 2 Endothelium Endogenous vasoconstrictors The Endothelium Modulates Vascular Tone Courtesy of JJ Ferguson III, MD. Endogenous vasodilators O 2 - X

Proposed Vascular Pathophysiology of Hypertensive Urgency Vaughan CJ, Delanty N. Lancet. 2000;356: Courtesy of JJ Ferguson III, MD. Acute BP triggers cellular adhesion molecular expression NO PGI 2 Catecholamines AT-II ADH (vasopressin) Aldosterone TxA 2 ET 1 ( - )( + ) CAMs Endogenous vasodilators Endogenous vasoconstrictors O 2 -

Overwhelmed control of vascular tone leads to coagulation cascade activation Overwhelmed control of vascular tone leads to coagulation cascade activation Loss of endothelial activity coupled with coagulation and platelets promotes DIC Loss of endothelial activity coupled with coagulation and platelets promotes DIC Proposed Vascular Pathophysiology of Hypertensive Emergency Vaughan CJ, Delanty N. Lancet. 2000;356: Courtesy of JJ Ferguson III, MD. TxA 2, PAI-1, TF

Hypertension,1999;34: Each 10 mmHg increase PP 11% increase stroke, 16% increase death & 12% increase in recurrent MI* Each 10 mmHg rise MAP 20% increase stroke Cardiac mass assoc with SBP Work to drive blood = SBP despite MAP & SVR Each 10 mmHg increase PP 11% increase stroke, 16% increase death & 12% increase in recurrent MI* Each 10 mmHg rise MAP 20% increase stroke Cardiac mass assoc with SBP Work to drive blood = SBP despite MAP & SVR *Increase PP assoc. decreased CBF MAP, SBP & PP Independently Predict Risk

SBP HTN and Adverse Events Anesth Analg 94; ,2002 Anesth Analg* 95;273-7,2002 *LOS > 10 days, or death, sBP > 160 mmHg Event rate % N = 2069 scheduled for CABG No ISH (n = 1457) ISH(n=612) Odds Ratio Renal failure/insufficiency ( ) Stroke ( ) LV dysfunction ( ) Renal failure/insufficiency, stroke, LV dysfunction, death ( )

Dependent on; Ventricular Ejection Viscoelastic properties Lg. arteries Wave Reflection Wave Reflection Pulse Pressure

Aronson et al; Circulation 115,733-42,2007 Renal RISK INDEX PP HTN and Adverse Events Preoperative Risk FactorsScoreIntraoperative Risk FactorsScore Age > 75 years7> Inotropes10 Pulse Pressure (mm HG)Intra-aortic Balloon Pump Cardiopulmonary Bypass >122 min >10016 History CHF9 MI6 Renal Disease13 Preoperative Risk FactorsScoreIntraoperative Risk FactorsScore Age > 75 years7> Inotropes10 Pulse Pressure (mm HG)Intra-aortic Balloon Pump Cardiopulmonary Bypass >122 min >10016 History CHF9 MI6 Renal Disease13

Aronson et al; Circulation 115,733-42,2007 Fontes, Aronson, Mathew, et al. Analg Anes 2007 Benjo, Thompson, Fine, et al Hypertension 2007 Cerebral (5.5 % vs. 2.8 %; P = 0.004) CHF (12.8 % vs. 7.8 %; P = 0.003), Cardiac death (4.7 % vs. 2.4 %; P = 0.001) CV surgery outcome ( PP > 80) Stroke (81.2 v 64.5 mmHg) each 10mmHg additive risk (OR 1.35; CI, ) (P = 0.001) Renal (8.6 % vs. 4.5 %; P = ), Renal death (3.7% vs. 1.1%) PP HTN and Adverse Events

Pathophysiology of Acute Hypertensive Syndromes Mechanical stress on the vessel wall BP BP Release of Local humoral vasoconstrictors Augments HTN Endothelial damage Activation of the clotting cascade Further release of humoral vasoconstrictors Fibrinoid necrosis of small blood vessels Pressure natriuresis Volume depletion RAAS activation Vasopressinendothelincatecholamines Major physiologic derangements Courtesy of JJ Ferguson III, MD.

"Zoned Out Blood Pressure Control in CT Surgery What Do RCT & Registries Tell Us About Acute Pressure Management and Outcomes Investigation Innovation Application Solomon Aronson, MD Program Co-Chairman FACC, FCCP, FAHA, FASE Professor and Executive Vice Chairman Dept of Anesthesiology Duke University Health System Solomon Aronson, MD Program Co-Chairman FACC, FCCP, FAHA, FASE Professor and Executive Vice Chairman Dept of Anesthesiology Duke University Health System

Acute Hypertension Hypertensive Urgency Severe HTN WITHOUT acute end-organ damage Requires BP control over several days-weeks Hypertensive Emergency Severe HTN (BP >180/120 mm Hg) WITH end-organ damage Requires immediate, aggressive BP control Perioperative Hypertension HTN* occurring prior to, during, or following surgical procedures Requires immediate BP control * Poorly defined

ECLIPSE: Trial Design 3 prospective, randomized, open-label, parallel comparisons of clevidipine to NTG or SNP periop, or NIC postop in pts undergoing cardiac surgery - 61 medical centers 3 prospective, randomized, open-label, parallel comparisons of clevidipine to NTG or SNP periop, or NIC postop in pts undergoing cardiac surgery - 61 medical centers Primary endpoint: Safety of clevidipine (death, myocardial infarction, stroke, renal) Primary endpoint: Safety of clevidipine (death, myocardial infarction, stroke, renal) Secondary endpoints: Other AEs, BP control Secondary endpoints: Other AEs, BP control 3 prospective, randomized, open-label, parallel comparisons of clevidipine to NTG or SNP periop, or NIC postop in pts undergoing cardiac surgery - 61 medical centers 3 prospective, randomized, open-label, parallel comparisons of clevidipine to NTG or SNP periop, or NIC postop in pts undergoing cardiac surgery - 61 medical centers Primary endpoint: Safety of clevidipine (death, myocardial infarction, stroke, renal) Primary endpoint: Safety of clevidipine (death, myocardial infarction, stroke, renal) Secondary endpoints: Other AEs, BP control Secondary endpoints: Other AEs, BP control Clevidipine vs Nitroglycerin Clevidipine vs Sodium Nitroprusside Clevidipine vs Nicardipine Clevidipine (n = 268) Nitroglycerin (n = 278) Clevidipine (n = 296) Sodium nitroprusside (n = 283) Clevidipine (n = 188) Nicardipine (n = 193) PerioperativePostoperative 1:1 Aronson et al. ACC 2007.

ECLIPSE Baseline Characteristics Clevidipine n=752 Comparators n=754 Age, median (range) 65 (24-87) 66 (19-89) Male72%74% Caucasian82%83% Hx HTN 88%85% CHF19%18% Insulin dependent diabetes 11%11% COPD14%15% Recent MI (< 6 mos) 17%18% Prior CABG 3%6% Data on file, The Medicines Company.

Incidence of Death, MI, Stroke, Renal Dysfunction Death 30-Day Events (%) (n = 729)(n = 700)(n = 707)(n = 700)(n = 705)(n = 712)(n = 710)(n = 719) MyocardialInfarctionStrokeRenalDysfunction Aronson et al. ACC 2007.

Aronson S et al. Presented at ACC BP Control Assessed via AUC Analysis Time (hours) Lower Upper SBP (mm Hg) Cumulative AUC calculated for excursions outside prespecified range. Lower AUC = tighter BP control. AUC = area under the curve

AUC Targeted BP Range by Treatment ECLIPSENTGECLIPSESNPECLIPSENIC mm Hg x min/h p = p = p = Clevidipine n=269 NTG n=278 Clevidipine n=295 SNP n=284 Clevidipine n=187 NIC n=194 Median AUC Range = Pre-/post-op SBP , Intra-op SBP Peri-operativePost-operative Only

SNP pts were outside the target BP range > compared to CLV pts [above and below (overshoot)] AUC above [CLV vs. SNP ] = 2.97 vs mmHg min/h, p=0.03. AUC below [CLV vs. SNP ] = 2.30 vs mmHg min/h, p= NTG pts did not meet target BP range as often compared with CLV AUC above [CLV vs. NTG ] = 2.76 vs mmHg min/h, p= AUC below the target range was similar between these groups. SNP pts were outside the target BP range > compared to CLV pts [above and below (overshoot)] AUC above [CLV vs. SNP ] = 2.97 vs mmHg min/h, p=0.03. AUC below [CLV vs. SNP ] = 2.30 vs mmHg min/h, p= NTG pts did not meet target BP range as often compared with CLV AUC above [CLV vs. NTG ] = 2.76 vs mmHg min/h, p= AUC below the target range was similar between these groups. ECLIPSE

AUC Predictive of Mortality at 30 Days P value Odds ratio 95% CI (Lower limit, Upper limit) Surgery duration (hour) < (1.240, 1.856) Age (year) (1.031, 1.110) Preop creatinine 1.2 mg/dL (1.392, 5.122) AUC (1 mm Hg*min) (1.001, 1.004) Additional surgical procedures (1.246, 4.655) Preop Hgb (g/dL) (0.707, 0.961) Preop SBP >160 or DBP > (1.147, 4.963) History of COPD (1.125, 4.812) History of recent MI (<6 months prior) (1.073, 4.497) Aronson et al. ACC 2007.

I mm Hg x 60 min 2 mm Hg x 60 min 3 mm Hg x 60 min 4 mm Hg x 60 min 5 mm Hg x 60 min Odds Ratio 95% CI [Lower Limit, Upper Limit] 1.20 [1.06, 1.27] 1.43 [1.13, 1.61] 1.71 [1.20, 2.05] 2.05 [1.27, 2.61] 2.46 [1.35, 3.31] Excursions in Perioperative BP Control Related to Increased 30-day Mortality Data on file, The Medicines Company

Systolic BP Control Over 24 Hours Time (hours) SBP Lower Upper Lower

AUC Narrowed BP Range by Treatment ECLIPSE NTG ECLIPSE SNP ECLIPSE NIC mm Hg x min/h p = p = p = Clevidipine n=269 NTG n=278 Clevidipine n=295 SNP n=284 Clevidipine n=187 NIC n=194 Median AUC Range = Pre-/post-op SBP , Intra-op SBP Peri-operativePost-operative Only

Aronson S et al. SCCM Poster #557. Perioperative BP Lability Predicts Mortality in Patients Undergoing Cardiac Surgery Analysis of DUKE Heart Center database in pts undergoing CT surgery Analysis of DUKE Heart Center database in pts undergoing CT surgery N =5238 N = M BP evaluations 3.1M BP evaluations AUC ( mmHg) predictive of 30- day mortality AUC ( mmHg) predictive of 30- day mortality P= OR =1.02 per 100 mm Hg x min 95% CI [ ]

Mean Duration of Excursions Minutes SBP > 135 or 135 or < 95mmHg per incident P-Value < , O.R ( ) Samples (n=7187) DUKE patient population Development & validation datasets

P-Value Odds Ratio 95% CI Minutes SBP > 135 or 135 or < 95mmHg per incident< Surgery length (min) Parsonnet< Mean Duration of Incursions Minutes <95 mmHg (min) Minutes >135 mmHg (min)

Predictors of Postoperative Renal Dysfunction Odds ratio (95% CI) P value P value Preop serum Cr 1.2 mg/dL 4.71 ( ) < Race (African American) ( ) Primary CABG + valve ( ) BP (4 th quartile AUC*) ( ) Surgery duration (hours) ( ) Age (years) ( ) BMI 1.05 ( ) Aronson S et al. Presented at ASA Unadjusted *Excursions outside SBP mm Hg pre/postoperatively or mm Hg intraoperatively Unadjusted *Excursions outside SBP mm Hg pre/postoperatively or mm Hg intraoperatively N = 1512 undergoing cardiac surgery

Logistic Regression Results: Predictor of 30-Day Mortality P Value OR 95% C.I. Screening SBP (per 1 mm Hg increment) –1.061 AUC (per 1 mm Hg×min/hr increment) –1.007 AUC (per 1mmHg×min/hr increment), narrow range –1.004 BP Fluctuations Predict Short-Term Mortality in Patients Undergoing Cardiac Valve Surgery Minimizing SBP fluctuations within a narrow range improved 30-day mortality. Screening SBP was defined as the SBP within 24 hours prior to randomization. AUC calculated for excursions outside SBP range of 85–145 mmHg pre- and postoperatively, 75–135 mmHg intraoperatively. ACCP 2009

Cardiac Surgery Patients – Inadequate BP Control The worse the control, the poorer the outcomes. SCA 2008 Increased risk of 30-day death, CVA, MI and renal dysfunction vs patients with tight BP control

1500 pts, 21 hospitals, 79% therapy in ED 1500 pts, 21 hospitals, 79% therapy in ED Median age 58, Women 49%, AA 58% Median age 58, Women 49%, AA 58% Initial BP 201/110 Initial BP 201/110 90% HTN, 33% kidney history, 17% drug abuse 90% HTN, 33% kidney history, 17% drug abuse 1500 pts, 21 hospitals, 79% therapy in ED 1500 pts, 21 hospitals, 79% therapy in ED Median age 58, Women 49%, AA 58% Median age 58, Women 49%, AA 58% Initial BP 201/110 Initial BP 201/110 90% HTN, 33% kidney history, 17% drug abuse 90% HTN, 33% kidney history, 17% drug abuse Granger et al. SCCM February 2008 Reason for Admission Time to Initiation of IV Therapy

Systolic BP Control Over 24 Hours by First IV Antihypertensive n=982*Median Granger et al. SCCM February 2008 Regardless of 1st antihypertensive 50-75% of pts required > one agent

Systolic BP Control Over 24 Hours by First IV Antihypertensive n=982*Median Granger et al. SCCM February 2008

Baseline Characteristics of Study Population Brooks, et al. Am J Health Syst Pharm. Dec 15, 2007;64(24):

Primary and Secondary Endpoints a MAP = mean arterial pressure. b p < 0.05, nicardipine group versus all patients. a MAP = mean arterial pressure. b p < 0.05, nicardipine group versus all patients. Brooks, et al. Am J Health Syst Pharm. Dec 15, 2007;64(24): Outcome a All Patients (n=47) Nicardipine Group (n=21) Nitroprusside Group (n=18) Primary No (%) patients with appropriate MAP reduction at 2 hr 15 (32) 4 (19) 7 (39) No. (%) patients with excessive MAP reduction at 2 hr b 27 (57) 16 (76) 9 (50) No. (5) treatment failures at 2 hr 5 (11) 1 (5) 2 (11)

Primary and Secondary Endpoints a MAP = mean arterial pressure. b p < 0.05, nicardipine group versus all patients. c p < 0.05, nicardipine group versus nitroprusside group. d One patient was excluded from the analysis. a MAP = mean arterial pressure. b p < 0.05, nicardipine group versus all patients. c p < 0.05, nicardipine group versus nitroprusside group. d One patient was excluded from the analysis. Brooks, et al. Am J Health Syst Pharm. Dec 15, 2007;64(24): Outcome a All Patients (n=47) Nicardipine Group (n=21) Nitroprusside Group (n=18) Secondary No. (%) of patients with appropriate blood-pressure reduction at 6 hr 6 (13) 1 (5) 4 (22) Mean no. (range) of additional p.r.n. antihypertensive doses per patient c 4 (0-33) 6 (0-33) d 2 (0-5) Mean length of stay (range), days c 9 (2-41) 13 (2-41) d 7 (2-14) Mean duration (range) of i.v. therapy, hr 20 (1-74) 21 (3-74) d 16 (1-67) Mean time (range) until scheduled oral antihypertensives were started, hr 14 (0-72) 16 (0-48) 10 (0-72) No. (%) of patients meeting 2- or 6-hour goal b,c 26 (28) 5 (12) 11 (31)

Treatment-Related Adverse Events * p < 0.05, nicardipine group versus nitroprusside group; p < 0.05, nitroprusside group versus all patients. Brooks, et al. Am J Health Syst Pharm. Dec 15, 2007;64(24): No. (%) Adverse Event All Patients (n=47) Nicardipine (n=21) Nitroprusside (n=18) Hypotension* 42 (89) 21 (100) 14 (78) Tachycardia 15 (32) 9 (43) 5 (28) Bradycardia 9 (19) 2 (10) 4 (22) Acute Renal Failure 2 (4) 1 (5) 1 (6) Major Ischemia 2 (4) 1 (5) 1 (6)

SNP or NTG assoc with increased 30d mortality compared to Clevidipine SNP or NTG assoc with increased 30d mortality compared to Clevidipine SCA 2008 Pre-operative BP Control p-valueO.R 95% CI Treatment CLP v SNP/NTG , 38.4 Additional procedure , 21.2 Pre-op Scr > 1.2mg/dl , 17.8 Data on file, The Medicines Company.

"Under Pressure"Vascular Dysfunction and Acute Pressure Syndromes in the Setting of Cardiovascular Surgery Challenges, Innovations, and Landmark Trials (ECLIPSE)From Threat to Therapy Jerrold H Levy, MD, FAHA Professor of Anesthesiology Emory University School of Medicine Deputy Chairman for Research Director, Cardiothoracic Anesthesiology Cardiothoracic Anesthesiology and Critical Care Emory Healthcare Atlanta, Georgia Jerrold H Levy, MD, FAHA Professor of Anesthesiology Emory University School of Medicine Deputy Chairman for Research Director, Cardiothoracic Anesthesiology Cardiothoracic Anesthesiology and Critical Care Emory Healthcare Atlanta, Georgia Investigation Innovation Application

Evolution of Perioperative Care Changing demographics and increasing use of stenting and platelet inhibitors Changing demographics and increasing use of stenting and platelet inhibitors Older patients with comorbidities presenting for surgery and to ICUs with vascular and endothelial dysfunction due to multiple causes Older patients with comorbidities presenting for surgery and to ICUs with vascular and endothelial dysfunction due to multiple causes Endothelial and vascular dysfunction common across this cardiac, neurological, and critically ill patient populationsacute and chronic disease Endothelial and vascular dysfunction common across this cardiac, neurological, and critically ill patient populationsacute and chronic disease Changing demographics and increasing use of stenting and platelet inhibitors Changing demographics and increasing use of stenting and platelet inhibitors Older patients with comorbidities presenting for surgery and to ICUs with vascular and endothelial dysfunction due to multiple causes Older patients with comorbidities presenting for surgery and to ICUs with vascular and endothelial dysfunction due to multiple causes Endothelial and vascular dysfunction common across this cardiac, neurological, and critically ill patient populationsacute and chronic disease Endothelial and vascular dysfunction common across this cardiac, neurological, and critically ill patient populationsacute and chronic disease Estafanous FG, et al. Ann Thorac Surg. 1998;65: Fontana GP. Chest Surg Clin N Am. 1998;8: Verrier ED. J Am Coll Surg. 1999;188: Trends and Observations

Prevalence of high blood pressure in adults by age and sex Prevalence of Hypertension NHANES: Source: NCHS and NHLBI.

Endothelial and Vascular Dysfunction are the Hallmarks of our Patients Angina Fibrosis And Muscle Loss Heart Failure Death Sudden Death Myocardial Ischemia Ischemia P GC P GC Glomerular Sclerosis Hypertension Diabetes Insulin Resistance Dyslipidemia Endothelial Dysfunction ROSInflammation Cell Injury Angiotensin II Aldosterone Endothelin-1 Glycosylated Proteins Release of ET-1 Release of ET-1 Production of TGF Production of TGF NO NO Unstable Angina Myocardial Infarction Coronary Artery Disease Plaque Rupture Altered Extracellular Matrix (mesangium) Atherosclerosis Tubulointerstitial Damage Albumin Shunting Through Membrane Pores Oxidative Stress Inflammation Schiffrin EL. Am J Hypertens 2004;17(12): Calcification Renal Failure Endothelial Dysfunction

Perioperative Hypertension The Cardiothoracic Surgery Setting Patients with preoperative hypertension are at increased risk for perioperative complications 1 Patients with preoperative hypertension are at increased risk for perioperative complications 1 Approximately 30% to 56% of patients undergoing routine cardiac surgery experience acute rises in blood pressure that require administration of a parenteral antihypertensive agent 2 Approximately 30% to 56% of patients undergoing routine cardiac surgery experience acute rises in blood pressure that require administration of a parenteral antihypertensive agent 2 Antihypertensive therapy is often needed to manage life- threatening arterial bleeding, myocardial ischemia, or cardiac failure 3 Antihypertensive therapy is often needed to manage life- threatening arterial bleeding, myocardial ischemia, or cardiac failure 3 Patients with preoperative hypertension are at increased risk for perioperative complications 1 Patients with preoperative hypertension are at increased risk for perioperative complications 1 Approximately 30% to 56% of patients undergoing routine cardiac surgery experience acute rises in blood pressure that require administration of a parenteral antihypertensive agent 2 Approximately 30% to 56% of patients undergoing routine cardiac surgery experience acute rises in blood pressure that require administration of a parenteral antihypertensive agent 2 Antihypertensive therapy is often needed to manage life- threatening arterial bleeding, myocardial ischemia, or cardiac failure 3 Antihypertensive therapy is often needed to manage life- threatening arterial bleeding, myocardial ischemia, or cardiac failure 3 1. Sladen, IARS Rev Course Lectures, 2002, p100; DeQuattro, J Cardiovasc Pharmacol Ther, Cheung, J Card Surg, 2006, S8; Estafanous, Am J Cardiol, 1980, p685; Landymore, Can J Surg, Cheung, J Card Surg, 2006, S8. The Problems

Considerations for Perioperative BP Control During Cardiac Surgery Acute, Severe Elevations in Blood Pressure are Triggered by Multiple Perioperative Events Acute, Severe Elevations in Blood Pressure are Triggered by Multiple Perioperative Events Intraoperative Events Intraoperative Events Induction Induction Cannulation Cannulation Protamine and hemostasis (aortotomy/suture lines) Protamine and hemostasis (aortotomy/suture lines) Chest closure Chest closure Transport Transport Postoperative Events Postoperative Events Temperature management (warming and shivering) Temperature management (warming and shivering) Emergence Emergence Weaning and extubation Weaning and extubation Volume status Volume status Acute, Severe Elevations in Blood Pressure are Triggered by Multiple Perioperative Events Acute, Severe Elevations in Blood Pressure are Triggered by Multiple Perioperative Events Intraoperative Events Intraoperative Events Induction Induction Cannulation Cannulation Protamine and hemostasis (aortotomy/suture lines) Protamine and hemostasis (aortotomy/suture lines) Chest closure Chest closure Transport Transport Postoperative Events Postoperative Events Temperature management (warming and shivering) Temperature management (warming and shivering) Emergence Emergence Weaning and extubation Weaning and extubation Volume status Volume status

Goals for an Ideal Antihypertensive Agent in Setting of Cardiac Surgery Rapid onset of action Rapid onset of action Predictable dose response Predictable dose response Titratable to desired BP Titratable to desired BP Highly vascular selective Highly vascular selective Maintain stroke volume and cardiac output Maintain stroke volume and cardiac output Rapidly reversible Rapidly reversible Low risk of overshoot hypotension Low risk of overshoot hypotension Low risk of adverse reactions Low risk of adverse reactions Rapid onset of action Rapid onset of action Predictable dose response Predictable dose response Titratable to desired BP Titratable to desired BP Highly vascular selective Highly vascular selective Maintain stroke volume and cardiac output Maintain stroke volume and cardiac output Rapidly reversible Rapidly reversible Low risk of overshoot hypotension Low risk of overshoot hypotension Low risk of adverse reactions Low risk of adverse reactions Levy JH. Anesthesiol Clin North Am. 1988;17: Oparil S et al. Am J Hypertens. 1999;12: Desirable Properties for Intravenous Agent

Therapeutic Approaches to Arterial Vasodilation: Armamentarium ACE inhibition ACE inhibition Alpha-1 adrenergic blockade Alpha-1 adrenergic blockade Calcium channel blockade Calcium channel blockade Dopamine-1 stimulation Dopamine-1 stimulation Ganglionic blockade Ganglionic blockade Cyclic nucleotide stimulation Cyclic nucleotide stimulation PDE inhibition PDE inhibition Potassium channel modulation Potassium channel modulation ACE inhibition ACE inhibition Alpha-1 adrenergic blockade Alpha-1 adrenergic blockade Calcium channel blockade Calcium channel blockade Dopamine-1 stimulation Dopamine-1 stimulation Ganglionic blockade Ganglionic blockade Cyclic nucleotide stimulation Cyclic nucleotide stimulation PDE inhibition PDE inhibition Potassium channel modulation Potassium channel modulation Levy JH: The ideal agent for perioperative hypertension. Acta Anaesth Scand 1993; 37(S): Treatment Options Treatment Options

Hypertension in Surgical Patients (1) Patients who are normotensive may become hypertensive Patients who are normotensive may become hypertensive Most blood pressure changes develop acutely and require rapid intervention with IV agents Most blood pressure changes develop acutely and require rapid intervention with IV agents Characterized by systemic vasoconstriction with intravascular hypovolemia Characterized by systemic vasoconstriction with intravascular hypovolemia Patients may have preoperative biventricular dysfunction Patients may have preoperative biventricular dysfunction Patients who are normotensive may become hypertensive Patients who are normotensive may become hypertensive Most blood pressure changes develop acutely and require rapid intervention with IV agents Most blood pressure changes develop acutely and require rapid intervention with IV agents Characterized by systemic vasoconstriction with intravascular hypovolemia Characterized by systemic vasoconstriction with intravascular hypovolemia Patients may have preoperative biventricular dysfunction Patients may have preoperative biventricular dysfunction Levy JH: Management of systemic and pulmonary hypertension. Tex Heart Inst J 2005;32: Principles and Practice Considerations

BP may be maintained at lower levels to avoid graft/suture line disruption BP may be maintained at lower levels to avoid graft/suture line disruption Patients are being Fast Tracked Patients are being Fast Tracked Mechanical manipulation, suturing with potential risk for vascular spasm Mechanical manipulation, suturing with potential risk for vascular spasm Ventricular dysfunction is common in patients with normal preop function due to stunning/ reperfusion injury Ventricular dysfunction is common in patients with normal preop function due to stunning/ reperfusion injury BP may be maintained at lower levels to avoid graft/suture line disruption BP may be maintained at lower levels to avoid graft/suture line disruption Patients are being Fast Tracked Patients are being Fast Tracked Mechanical manipulation, suturing with potential risk for vascular spasm Mechanical manipulation, suturing with potential risk for vascular spasm Ventricular dysfunction is common in patients with normal preop function due to stunning/ reperfusion injury Ventricular dysfunction is common in patients with normal preop function due to stunning/ reperfusion injury Hypertension in Cardiac Surgical Patients (2) Levy JH: Management of systemic and pulmonary hypertension. Tex Heart Inst J 2005;32: Principles and Practice Considerations

Nitropusside: Issues and Concerns Nitropusside: Issues and Concerns Metabolized to CN, then thiocyanate Metabolized to CN, then thiocyanate Problematic Aspects Pregnancy Pregnancy Coronary steal Coronary steal Dose dependent in CBF Dose dependent in CBF –Caution with high ICP Hypoxemia ( V/Q mismatch) Hypoxemia ( V/Q mismatch) Requires special delivery system Requires special delivery system Usually requires direct arterial pressure monitoring Usually requires direct arterial pressure monitoring Metabolized to CN, then thiocyanate Metabolized to CN, then thiocyanate Problematic Aspects Pregnancy Pregnancy Coronary steal Coronary steal Dose dependent in CBF Dose dependent in CBF –Caution with high ICP Hypoxemia ( V/Q mismatch) Hypoxemia ( V/Q mismatch) Requires special delivery system Requires special delivery system Usually requires direct arterial pressure monitoring Usually requires direct arterial pressure monitoring

Nitrovasodilators Na + CN NO + CN Fe ++ CN Na + Sodium Nitroprusside

Nitroprusside Therapy Potent venodilator/arterial vasodilator Potent venodilator/arterial vasodilator Cardiac output is often affected due to venodilation Cardiac output is often affected due to venodilation Volume replacement is often required for venodilation Volume replacement is often required for venodilation Potent venodilator/arterial vasodilator Potent venodilator/arterial vasodilator Cardiac output is often affected due to venodilation Cardiac output is often affected due to venodilation Volume replacement is often required for venodilation Volume replacement is often required for venodilation Levy JH: Management of systemic and pulmonary hypertension. Tex Heart Inst J 2005;32: Principles and Practice Considerations

IV DHP Calcium Channel Blockers 1st Generation: Nifedipine 1st Generation: Nifedipine 2nd Generation: Nicardipine, isradipine 2nd Generation: Nicardipine, isradipine 3rd Generation: Clevidipine 3rd Generation: Clevidipine 1st Generation: Nifedipine 1st Generation: Nifedipine 2nd Generation: Nicardipine, isradipine 2nd Generation: Nicardipine, isradipine 3rd Generation: Clevidipine 3rd Generation: Clevidipine Evolution of Therapeutic Options

Selectivity of Calcium Channel Antagonists MyocardialSA NodeAV Node MyocardialSA NodeAV Node IV AgentVasodilationDepressionSuppressionSuppression IV AgentVasodilationDepressionSuppressionSuppression Clevidipine5000 Clevidipine5000 Nicardipine5000 Nicardipine5000 Diltiazem3254 Diltiazem3254 Verapamil4455 Verapamil4455 MyocardialSA NodeAV Node MyocardialSA NodeAV Node IV AgentVasodilationDepressionSuppressionSuppression IV AgentVasodilationDepressionSuppressionSuppression Clevidipine5000 Clevidipine5000 Nicardipine5000 Nicardipine5000 Diltiazem3254 Diltiazem3254 Verapamil4455 Verapamil4455 *The chiral center of clevidipine; SA = sinoatrial; AV = atrioventricular. Kerins DM, et al. In: Goodman and Gilmans Pharmacological Basis of Therapeutics. 2001: Massie BM. Am J CardioI. 1997;80:23I-32I. Clevidipine Cl O O O O O O O O N N H H O O O O * * COCH 2 CH 2 NCH 2 NO 2 CH 3 O N H O H3CH3C H 3 COC Nifedipine NO 2 COCH 3 CH 3 O O N N H H O O H3CH3C H3CH3C CH 3 OC NicardipineNicardipine

Properties of Dihydropyridines Arterial vasodilator 1 Arterial vasodilator 1 Decreases SVR 2-6 Decreases SVR 2-6 More selective for vascular smooth muscle than cardiac muscle 1 More selective for vascular smooth muscle than cardiac muscle 1 No significant increase in ICP 7 No significant increase in ICP 7 No direct inotropic or dromotropic effects 2-6 No direct inotropic or dromotropic effects 2-6 Arterial vasodilator 1 Arterial vasodilator 1 Decreases SVR 2-6 Decreases SVR 2-6 More selective for vascular smooth muscle than cardiac muscle 1 More selective for vascular smooth muscle than cardiac muscle 1 No significant increase in ICP 7 No significant increase in ICP 7 No direct inotropic or dromotropic effects 2-6 No direct inotropic or dromotropic effects Clarke B, et al. Br J Pharmacol. 1983;79:333P. 2.Lambert CR, et al. Am J Cardiol. 1987;60: Silke B, et al. Br J Clin Pharmacol. 1985;20:169S-176S. 4.Lambert CR, et al Am J Cardiol. 1985;55: Visser CA, et al. Postgrad Med J. 1984;60: Silke B, et al. Br J Clin Pharmacol. 1985;20:169S-176S. 7.Nishiyama MT, et al. Can J Anaesth. 2000;47:

Hemodynamic Effects of Nicardipine Lambert CR: Am J Cardiol 1993;71:420. ControlNicardipine HR 71 ± ± 14 MAP 107 ± ± 9 PAOP 9 ± 4 8 ± 3 MPAP 15 ± 3 16 ± 4 RAP 8 ± 3 8 ± 2 CI 2.2 ± ± 0.4 LVdP/dT 1509 ± ± 485 LVEF % 57 ± 9 68 ± 7

Arterial Spasm Loss of endothelial function via vascular injury and platelet activation is potential mechanism Loss of endothelial function via vascular injury and platelet activation is potential mechanism Other mechanisms include NO scavenging by hemoglobin Other mechanisms include NO scavenging by hemoglobin Thromboxane, a potent constrictor, has been implicated Thromboxane, a potent constrictor, has been implicated Only certain drugs will completely reverse arterial spasm Only certain drugs will completely reverse arterial spasm Loss of endothelial function via vascular injury and platelet activation is potential mechanism Loss of endothelial function via vascular injury and platelet activation is potential mechanism Other mechanisms include NO scavenging by hemoglobin Other mechanisms include NO scavenging by hemoglobin Thromboxane, a potent constrictor, has been implicated Thromboxane, a potent constrictor, has been implicated Only certain drugs will completely reverse arterial spasm Only certain drugs will completely reverse arterial spasm Mechanism Mechanism

Vasospasm/Vascular Dysfunction Studies Salmenperra MT: Effects of PDE inhibitors on the human IMA. Anesth Analg 1996; 82: Salmenperra MT: Effects of PDE inhibitors on the human IMA. Anesth Analg 1996; 82: Huraux C: Vasodilator effects of clevidipine on human IMA. Anesth Analg 1997; 85: Huraux C: Vasodilator effects of clevidipine on human IMA. Anesth Analg 1997; 85: Huraux C: A comparative eval of multiple vasodilators on human IMA. Anesthesiology 1998;88: Huraux C: A comparative eval of multiple vasodilators on human IMA. Anesthesiology 1998;88: Huraux C: Superoxide production, risk factors, and EDRF relaxations in human IMAs. Circulation 1999;99: Huraux C: Superoxide production, risk factors, and EDRF relaxations in human IMAs. Circulation 1999;99: Tsuda A: Reversal of histamine-induced vasodilation in the human IMA. Anesth Analg 2001;93: Tsuda A: Reversal of histamine-induced vasodilation in the human IMA. Anesth Analg 2001;93: Sato N: Vasodilatory effects of hydralazine, nicardipine, nitroglycerin and fenoldopam in the human umbilical artery. Anesth Analg 2003;96: Sato N: Vasodilatory effects of hydralazine, nicardipine, nitroglycerin and fenoldopam in the human umbilical artery. Anesth Analg 2003;96: Tanaka KA: In vitro effects of antihypertensive drugs on TxA2 (U46619)- induced vasoconstriction in human IMA. Br J Anaesth 2004;93: Tanaka KA: In vitro effects of antihypertensive drugs on TxA2 (U46619)- induced vasoconstriction in human IMA. Br J Anaesth 2004;93: Salmenperra MT: Effects of PDE inhibitors on the human IMA. Anesth Analg 1996; 82: Salmenperra MT: Effects of PDE inhibitors on the human IMA. Anesth Analg 1996; 82: Huraux C: Vasodilator effects of clevidipine on human IMA. Anesth Analg 1997; 85: Huraux C: Vasodilator effects of clevidipine on human IMA. Anesth Analg 1997; 85: Huraux C: A comparative eval of multiple vasodilators on human IMA. Anesthesiology 1998;88: Huraux C: A comparative eval of multiple vasodilators on human IMA. Anesthesiology 1998;88: Huraux C: Superoxide production, risk factors, and EDRF relaxations in human IMAs. Circulation 1999;99: Huraux C: Superoxide production, risk factors, and EDRF relaxations in human IMAs. Circulation 1999;99: Tsuda A: Reversal of histamine-induced vasodilation in the human IMA. Anesth Analg 2001;93: Tsuda A: Reversal of histamine-induced vasodilation in the human IMA. Anesth Analg 2001;93: Sato N: Vasodilatory effects of hydralazine, nicardipine, nitroglycerin and fenoldopam in the human umbilical artery. Anesth Analg 2003;96: Sato N: Vasodilatory effects of hydralazine, nicardipine, nitroglycerin and fenoldopam in the human umbilical artery. Anesth Analg 2003;96: Tanaka KA: In vitro effects of antihypertensive drugs on TxA2 (U46619)- induced vasoconstriction in human IMA. Br J Anaesth 2004;93: Tanaka KA: In vitro effects of antihypertensive drugs on TxA2 (U46619)- induced vasoconstriction in human IMA. Br J Anaesth 2004;93:

Studies on Arteriolar Vasodilators Nitroglycerin is the most potent; but nitrate tolerance occur Nitroglycerin is the most potent; but nitrate tolerance occur Milrinone, dihydropyridines, PGE1, were also effective at therapeutically used doses Milrinone, dihydropyridines, PGE1, were also effective at therapeutically used doses Nitroglycerin is the most potent; but nitrate tolerance occur Nitroglycerin is the most potent; but nitrate tolerance occur Milrinone, dihydropyridines, PGE1, were also effective at therapeutically used doses Milrinone, dihydropyridines, PGE1, were also effective at therapeutically used doses Huraux: Anesthesiology 1998;88:1654. A Comparative Evaluation of the Effects of Multiple Vasodilators on Human IMA

Vasodilator Effects of Clevidipine on Human IMA Clevidipine was effective anti-vasospasm agent at therapeutically used doses Clevidipine was effective anti-vasospasm agent at therapeutically used doses Huraux C, Makita T, Szlam F, Nordlander M, Levy JH: Anesth Analg 1997; 85:

Simulated Drug Level Curves =Full loading dose = [Cp] x Vdss = Smaller loading dose =[Cp] x Vc = No loading dose Time (Half-life) Therapeutic Concentration Range Therapeutic Concentration Range Plasma Drug Level

Cl H CH 3 OOC H3CH3C COOCH 2 OOCC 3 H 7 CH 3 N H The Clevidipine Molecule Clevidipine is the first ultrashort acting dihydropyridine intravenous calcium channel blocker

Clevidipine Metabolized by Plasma and Tissue Esterases Clevidipine is rapidly metabolized by esterases in blood and extravascular tissue to an inactive carboxylic acid metabolite Clevidipine is rapidly metabolized by esterases in blood and extravascular tissue to an inactive carboxylic acid metabolite + OH O H H O Clevidipine Cl O O O O N H O O * Esterases + O O N H O O H Primary metabolite *The chiral center of clevidipine. Reproduced from Ericsson H, et al. Eur J Clin Pharmacol. 1999;55: Bailey JM, et al. Anesthesiology. 2002;96: Ericsson H, et al. Drug Metab Dispos. 1999;27: Ericsson H et al. Eur J Clin Pharmacol. 1999;55: Ericsson H, et al. Eur J Pharm Sci. 1999;8:29-37.

SBP changes for patients receiving clevidipine during a 30-minute treatment period –5 –10 –15 –20 –25 – % Change From Baseline Time (min) SBP SBP Changes SBP Changes Clevidipine Rapid Onset of Action BP-lowering effects are seen within 2–3 minutes of clevidipine infusion BP-lowering effects are seen within 2–3 minutes of clevidipine infusion Levy JH, et al. Anesth Analg. 2007;105(4):918.

*Css = concentration at steady state; median blood concentration of clevidipine obtained during the last 10 minutes of infusion. Clevidipine Linear Pharmacokinetics At steady state, there is a linear relationship between dosage and arterial blood concentrations At steady state, there is a linear relationship between dosage and arterial blood concentrations Linear relationship maintained for dosages as high as 21.9 mcg/kg/min Linear relationship maintained for dosages as high as 21.9 mcg/kg/min At steady state, there is a linear relationship between dosage and arterial blood concentrations At steady state, there is a linear relationship between dosage and arterial blood concentrations Linear relationship maintained for dosages as high as 21.9 mcg/kg/min Linear relationship maintained for dosages as high as 21.9 mcg/kg/min Clevidipine Concentration at Css (nmol/L)* at Css (nmol/L)* Dose Rate (nmol/kg/min) 2530 Reproduced from Ericsson H, et al. Anesthesiology. 2000;92: Ericsson H, et al. Anesthesiology. 2000;92: Ericsson H, et al. Br J Clin Pharmacol. 1999;47:

Clevidipine Rapid Offset After discontinuation of clevidipine infusion, there was rapid clearance After discontinuation of clevidipine infusion, there was rapid clearance BP returned to baseline in <10 minutes in healthy volunteers BP returned to baseline in <10 minutes in healthy volunteers After discontinuation of clevidipine infusion, there was rapid clearance After discontinuation of clevidipine infusion, there was rapid clearance BP returned to baseline in <10 minutes in healthy volunteers BP returned to baseline in <10 minutes in healthy volunteers Reproduced from Ericsson H, et al. Anesthesiology. 2000;92: – MAP (mm Hg) and HR (beats/min) Time (min) 2530 Clevidipine Infusion MAP

Reproduced from Ericsson H, et al. Anesthesiology. 2000;92: Clevidipine Ultrashort Half-Life Clinically relevant half-life: Approximately 1 minute Clinically relevant half-life: Approximately 1 minute Arterial and venous clevidipine blood samples

*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 mcg/kg/min Central Venous Pressure Clevidipine and Arterial Selectivity 1400 Units C C2 Systemic Vascular Resistance mcg/kg/min C2 Mean Arterial Pressure * * C mcg/kg/min mm Hg Kieler-Jensen N, et al. Acta Anaesthesiol Scand. 2000;44:

Preoperative HR Changes in Non-Anesthetized Patients Postoperative HR Changes in Anesthetized Patients Clevidipine: Minimal Effect on Heart Rate – % Change From Baseline Time (min) HR HR changes for patients during the 30-minute treatment period 5 0 – % Change From Baseline Time (min) HR HR changes for patients during the 30-minute treatment period Levy JH, et al. Anesth Analg. 2007;105(4):918. Singla N, et al. Anesthesiology. 2005;103:A292.

Clevidipine Clinical Development Tolerability, Safety, PK Dose Response ESCAPE: Efficacy Clevidipine vs Placebo VELOCITY Severe Hypertension PK, Metabolism, Rates and Routes of Excretion PK/BP ESCAPE: Efficacy Clevidipine vs Placebo PKPK/PD: Clevidipine vs Placebo Clevidipine vs Placebo ECLIPSE: Safety vs NTG QTc Study ECLIPSE: Safety vs SNP ECLIPSE: Safety vs NIC Dose Response: Clevidipine vs Placebo Hemodynamics: Clevidipine vs SNP BP, HR: Clevidipine vs SNP BP, HR: Clevidipine vs SNP BP, Dose/PK BP: Clevidipine vs Placebo Phase I N=89 Phase II N=300 Healthy Volunteers Patients: Mild to Moderate Hypertension N=86 Phase III N=1821 Perioperative Hypertension N=1721 Severe Hypertension N=100 Patients: Perioperative N=214 Data on file. The Medicines Company.

Acknowledgements ECLIPSE Trial Cornelius Dyke, MD Dean Kereiakes, MD Jerrold H. Levy, MD Philip Lumb, MD Albert Cheung, MD Howard Corwin, MD Solomon Aronson, MD* Mark Newman, MD *Acknowledgement and thanks to Dr. Solomon Aronson, who first 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 *Acknowledgement and thanks to Dr. Solomon Aronson, who first 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

ECLIPSE Rationale Clevidipine is an IV dihydropyridine calcium channel blocker with an ultrashort half-life (~1 min) Clevidipine is an IV dihydropyridine calcium channel blocker with an ultrashort half-life (~1 min) Phase I and II studies (300 pts) demonstrated: Phase I and II studies (300 pts) demonstrated: Dose: 2–16 mg/hr effective 1Dose: 2–16 mg/hr effective 1 Phase III safety program required for FDA registration Phase III safety program required for FDA registration Evaluation: Death, MI, Stroke, Renal DysfunctionEvaluation: Death, MI, Stroke, Renal Dysfunction Comparators: Nitroglycerin (NTG), Sodium nitroprusside (SNP), Nicardipine (NIC)Comparators: Nitroglycerin (NTG), Sodium nitroprusside (SNP), Nicardipine (NIC) Rapid onset: BP control in 5 min 2Rapid onset: BP control in 5 min 2 Clevidipine is an IV dihydropyridine calcium channel blocker with an ultrashort half-life (~1 min) Clevidipine is an IV dihydropyridine calcium channel blocker with an ultrashort half-life (~1 min) Phase I and II studies (300 pts) demonstrated: Phase I and II studies (300 pts) demonstrated: Dose: 2–16 mg/hr effective 1Dose: 2–16 mg/hr effective 1 Phase III safety program required for FDA registration Phase III safety program required for FDA registration Evaluation: Death, MI, Stroke, Renal DysfunctionEvaluation: Death, MI, Stroke, Renal Dysfunction Comparators: Nitroglycerin (NTG), Sodium nitroprusside (SNP), Nicardipine (NIC)Comparators: Nitroglycerin (NTG), Sodium nitroprusside (SNP), Nicardipine (NIC) Rapid onset: BP control in 5 min 2Rapid onset: BP control in 5 min 2 1 Bailey J. Anesthesiology 2002;96: Levy J. Anesth Analg. 2007;105(4):918.

ECLIPSE Randomized (1:1), open-label, parallel group with active comparators: nitroglycerin (NTG), sodium nitroprusside (SNP), or nicardipine (NIC) Randomized (1:1), open-label, parallel group with active comparators: nitroglycerin (NTG), sodium nitroprusside (SNP), or nicardipine (NIC) NTG and SNP studies are perioperative and NIC is postoperative NTG and SNP studies are perioperative and NIC is postoperative Treatment with study drug allowed until discharge from ICU Treatment with study drug allowed until discharge from ICU Patients undergoing cardiac surgery; CABG, OPCAB, Valve, MIDCAB Patients undergoing cardiac surgery; CABG, OPCAB, Valve, MIDCAB Randomized (1:1), open-label, parallel group with active comparators: nitroglycerin (NTG), sodium nitroprusside (SNP), or nicardipine (NIC) Randomized (1:1), open-label, parallel group with active comparators: nitroglycerin (NTG), sodium nitroprusside (SNP), or nicardipine (NIC) NTG and SNP studies are perioperative and NIC is postoperative NTG and SNP studies are perioperative and NIC is postoperative Treatment with study drug allowed until discharge from ICU Treatment with study drug allowed until discharge from ICU Patients undergoing cardiac surgery; CABG, OPCAB, Valve, MIDCAB Patients undergoing cardiac surgery; CABG, OPCAB, Valve, MIDCAB Data on file. The Medicines Company. Protocols Protocols

ECLIPSE: Trial Design Clevidipine vs nitroglycerin Clevidipine vs sodium nitroprusside Clevidipine vs nicardipine Perioperative Postoperative Clevidipine N=268 Nitroglycerin N=278 Clevidipine N=296 Sodium nitroprusside N=283 Clevidipine N=188 Nicardipine N=193 1:1 Data on file. The Medicines Company.

Treatment Protocol Clevidipine Clevidipine Initiated 2 mg/hrInitiated 2 mg/hr Titrated doubling increments Q 90s to 16 mg/hrTitrated doubling increments Q 90s to 16 mg/hr 40 mg/hr maximum40 mg/hr maximum Comparators (NTG, SNP, NIC) administered per institutional practice Comparators (NTG, SNP, NIC) administered per institutional practice Treatment duration up to discharge from the ICU Treatment duration up to discharge from the ICU Concomitant antihypertensives discouraged Concomitant antihypertensives discouraged Clevidipine Clevidipine Initiated 2 mg/hrInitiated 2 mg/hr Titrated doubling increments Q 90s to 16 mg/hrTitrated doubling increments Q 90s to 16 mg/hr 40 mg/hr maximum40 mg/hr maximum Comparators (NTG, SNP, NIC) administered per institutional practice Comparators (NTG, SNP, NIC) administered per institutional practice Treatment duration up to discharge from the ICU Treatment duration up to discharge from the ICU Concomitant antihypertensives discouraged Concomitant antihypertensives discouraged

Outcome Endpoints Primary End Points* (Cumulative rate of clinical outcomes at 30 days): DeathDeath MI: Symptomatic presentation, enzyme release, and/or new ECG changesMI: Symptomatic presentation, enzyme release, and/or new ECG changes Stroke: Hemorrhagic or ischemicStroke: Hemorrhagic or ischemic Renal Dysfunction: Cr >2.0 with min absolute change of 0.7Renal Dysfunction: Cr >2.0 with min absolute change of 0.7 Secondary End Points SAEs through day 7SAEs through day 7 BP control during the first 24 hBP control during the first 24 h Primary End Points* (Cumulative rate of clinical outcomes at 30 days): DeathDeath MI: Symptomatic presentation, enzyme release, and/or new ECG changesMI: Symptomatic presentation, enzyme release, and/or new ECG changes Stroke: Hemorrhagic or ischemicStroke: Hemorrhagic or ischemic Renal Dysfunction: Cr >2.0 with min absolute change of 0.7Renal Dysfunction: Cr >2.0 with min absolute change of 0.7 Secondary End Points SAEs through day 7SAEs through day 7 BP control during the first 24 hBP control during the first 24 h * Blinded CEC adjudication of all primary measures

Patient Disposition PopulationsClevidipineComparators Randomized patients Met post-randomization criteria Safety population Completed study Did not complete study Withdrew consent Withdrew consent Physician decision Physician decision Lost to follow up Lost to follow up Adverse experience Adverse experience Patient death Patient death Other Other

Baseline Characteristics Historical Features Clevidipine n=752 Comparators n=754 Age, median (range) 65 (24-87) 66 (19-89) Male72%74% Caucasian82%83% History of Hypertension 88%85% CHF19%18% Insulin dependent diabetes 11%11% COPD14%15% Recent MI (< 6 mos) 17%18% Prior CABG 3%6%

Procedural Characteristics Clevidipine n=752 Comparators n=754 Surgery Duration: Median Hours Procedure CABG CABG Valve replacement/repair Valve replacement/repair CABG & Valve replacement/repair CABG & Valve replacement/repair Other Other77%14%9%0.3%77%12%11%0.1%

ECLIPSE NTG Drug Administration Timing and Duration Clevidipine N=268 Nitroglycerin N=278 Initiated Pre-Op 92 (34.3) 119 (42.8) Initiated Intra-Op 145 (54.1) 132 (47.5) Initiated Post-Op 31 (11.6) 27 (9.7) Overall Infusion Duration (median) 3.35 hr 8.13 hr Data on file. The Medicines Company.

ECLIPSE SNP: Drug Administration Timing and Duration Clevidipine N=296 Nitroprusside N=283 Initiated Pre-Op 52 (17.6) 34 (12.0) Initiated Intra-Op 161 (54.4) 158 (55.8) Initiated Post-Op 83 (28.0) 90 (31.8) Overall Infusion Duration (median) 4.03 hr 3.25 hr Data on file. The Medicines Company.

ECLIPSE NIC: Drug Administration Timing and Duration Clevidipine N=188 Nicardipine N=193 Dosed During Post-Op 188 (100) 193 (100) Overall Infusion Duration (median) 5.55 hr 5.12 hr Data on file. The Medicines Company.

RESULTS Primary Endpoint Death 30-Day Events (%) n=729n=700n=707n=700n=705n=712n=710n=719 MI Stroke Renal Dysfunction Renal Dysfunction

Primary End Points by Treatment Comparison End Points End PointsClevidipineNTGClevidipineSNPClevidipineNIC Death2.8%3.4%1.7%4.7%*4.4%3.2% MI3.3%3.5%1.4%2.3%2.3%1.1% Stroke1.6%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

Serious Adverse Events Serious Adverse Events Serious Adverse EventsClevidipinen=752Comparatorsn=754 Total17.7%20.0% Atrial fibrillation (AF) 2.4%2.4% Respiratory failure 1.1%2.5% Acute renal failure (ARF) 2.3%1.7% Ventricular fibrillation 0.9%1.5% Cardiac arrest 0.5%1.1% CVA0.5%1.1% Post-procedural hemorrhage 0.5%1.1%

ECLIPSE: Atrial Fibrillation ArrhythmiaCLV n/N (%) NTG SNP NIC Atrial fibrillation (Total) 275/752 (36.6) 91/278 (32.7) 95/283 (33.6) 71/193 (36.8) Atrial fibrillation (before March 25, 2005) 108/296 (36.5) 91/278 (32.7) 25/111 (22.5) 16/50 (32.0) Atrial fibrillation (after March 25, 2005) 67/188 (35.6) N/A 70/172 (40.7) 55/143 (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.

ECLIPSE Secondary Endpoint Systolic Blood Pressure Control Over 24 Hours Time (hours) SBP Lower Upper Lower ECLIPSE Trial; Presented at ACC, March 27, 2007.

Logistic Regression Results Predictors of Mortality Mortality Predictors P-Value Odds Ratio 95% CI [Lower Limit, Upper Limit] Surgery Duration (hour) < [1.240, 1.856] Age (year) [1.031, 1.110] Pre-op Creatinine 1.2 mg/dL [1.392, 5.122] AUC (area outside the range) [1.001, 1.004] Additional surgical procedures [1.246, 4.655] Pre-op Hgb (g/dL) [0.707, 0.961] Pre-op SBP >160 or DBP > [1.147, 4.963] History of COPD [1.125, 4.812] History of recent MI (<6 months prior) [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 by Magnitude of AUC Odds Ratio 95% CI [Lower Limit, Upper Limit] 1.20 [1.06, 1.27] 1.43 [1.13, 1.61] 1.71 [1.20, 2.05] 2.05 [1.27, 2.61] 2.46 [1.35, 3.31]

SUMMARY (1) Multiple pharmacologic agents produce vasodilation via different mechanisms. Multiple pharmacologic agents produce vasodilation via different mechanisms. Arterial vasoconstriction is characteristic of perioperative hypertension with intravascular hypovolemia. Arterial vasoconstriction is characteristic of perioperative hypertension with intravascular hypovolemia. Nitrovasodilators decrease both preload and resistance vessels Nitrovasodilators decrease both preload and resistance vessels DHP CCBs produce arterial selective vasodilation that controls BP without producing venodilation or negative inotropic and conduction effects, and reverses vasospasm in the IMA and other vascular beds. DHP CCBs produce arterial selective vasodilation that controls BP without producing venodilation or negative inotropic and conduction effects, and reverses vasospasm in the IMA and other vascular beds. Multiple pharmacologic agents produce vasodilation via different mechanisms. Multiple pharmacologic agents produce vasodilation via different mechanisms. Arterial vasoconstriction is characteristic of perioperative hypertension with intravascular hypovolemia. Arterial vasoconstriction is characteristic of perioperative hypertension with intravascular hypovolemia. Nitrovasodilators decrease both preload and resistance vessels Nitrovasodilators decrease both preload and resistance vessels DHP CCBs produce arterial selective vasodilation that controls BP without producing venodilation or negative inotropic and conduction effects, and reverses vasospasm in the IMA and other vascular beds. DHP CCBs produce arterial selective vasodilation that controls BP without producing venodilation or negative inotropic and conduction effects, and reverses vasospasm in the IMA and other vascular beds.

SUMMARY (2) ECLIPSE is the largest safety program ever performed with an intravenous antihypertensive (n=1,512) agents that examine management of acute, severe hypertension in the perioperative setting ECLIPSE is the largest safety program ever performed with an intravenous antihypertensive (n=1,512) agents that examine management of acute, severe hypertension in the perioperative setting AUC data suggests better overall BP control with clevidipine compared with SNP and NTG AUC data suggests better overall BP control with clevidipine compared with SNP and NTG Clevidipine represents a safe alternative to commonly used antihypertensive agents in the cardiovascular surgery setting, and demonstrated superior blood pressure control as assessed by integral analysis of excursions outside specified ranges over time Clevidipine represents a safe alternative to commonly used antihypertensive agents in the cardiovascular surgery setting, and demonstrated superior blood pressure control as assessed by integral analysis of excursions outside specified ranges over time Data supports importance of precise blood pressure control in a critically ill patient population Data supports importance of precise blood pressure control in a critically ill patient population Clevidipine represents the first potential nitroprusside replacement for clinicians Clevidipine represents the first potential nitroprusside replacement for clinicians ECLIPSE is the largest safety program ever performed with an intravenous antihypertensive (n=1,512) agents that examine management of acute, severe hypertension in the perioperative setting ECLIPSE is the largest safety program ever performed with an intravenous antihypertensive (n=1,512) agents that examine management of acute, severe hypertension in the perioperative setting AUC data suggests better overall BP control with clevidipine compared with SNP and NTG AUC data suggests better overall BP control with clevidipine compared with SNP and NTG Clevidipine represents a safe alternative to commonly used antihypertensive agents in the cardiovascular surgery setting, and demonstrated superior blood pressure control as assessed by integral analysis of excursions outside specified ranges over time Clevidipine represents a safe alternative to commonly used antihypertensive agents in the cardiovascular surgery setting, and demonstrated superior blood pressure control as assessed by integral analysis of excursions outside specified ranges over time Data supports importance of precise blood pressure control in a critically ill patient population Data supports importance of precise blood pressure control in a critically ill patient population Clevidipine represents the first potential nitroprusside replacement for clinicians Clevidipine represents the first potential nitroprusside replacement for clinicians

Comprehensive Neurovascular Protection in Patients Undergoing Cardiac Surgery Investigation Innovation Application Charles W. Hogue, Jr., MD Associate Professor of Anesthesiology Department of Anesthesiology and Critical Care Medicine Johns Hopkins University Medical School Baltimore, Maryland Charles W. Hogue, Jr., MD Associate Professor of Anesthesiology Department of Anesthesiology and Critical Care Medicine Johns Hopkins University Medical School Baltimore, Maryland

Neurovascular Protection

Vascular Stiffness and Cardiovascular Outcomes Reflected pulse wave returns early in systole Reflected pulse wave returns early in systole Rising systolic blood but declining diastolic B/P (rising pulse pressure) Rising systolic blood but declining diastolic B/P (rising pulse pressure) Increases strain on myocardium Increases strain on myocardium Exposes micro-circulation of brain and kidney to chronically high pressures and resultant pathophysiologic changes Exposes micro-circulation of brain and kidney to chronically high pressures and resultant pathophysiologic changes

Pulsatile Pressure Changes in the Vascular Tree ORourke. J Am Coll Cardiol 2006;50:1-13

Pulse Pressure Predicts Stroke Development After Cardiac Surgery Benjo et al. Hyperten 2007;50: Pulse Pressure Predicted Probability of Stroke

DWI and PWI in Acute Stroke DWI identifies densely ischemic tissue/infarctDWI identifies densely ischemic tissue/infarct PWI identifies area surrounding the core infarct getting enough blood to survive, not enough to functionPWI identifies area surrounding the core infarct getting enough blood to survive, not enough to function PWI-DWI (diffusion-perfusion mismatch) ~ ischemic penumbraPWI-DWI (diffusion-perfusion mismatch) ~ ischemic penumbra DWI identifies densely ischemic tissue/infarctDWI identifies densely ischemic tissue/infarct PWI identifies area surrounding the core infarct getting enough blood to survive, not enough to functionPWI identifies area surrounding the core infarct getting enough blood to survive, not enough to function PWI-DWI (diffusion-perfusion mismatch) ~ ischemic penumbraPWI-DWI (diffusion-perfusion mismatch) ~ ischemic penumbra Densely Ischemic Tissue Marginally Perfused Brain DWI PWI Acute aphasic deficits are due to both areas of structural damage and areas of hypoperfusion

Before BP Elevation After BP Elevation BA 22 BA 37 Neurovascular Protection

SPECT Imaging Before CABG Moraca et al. J Thorac Cardiovasc Surg 2006;131:540-6

Watershed Strokes Detected with DWI After Cardiac Surgery Watershed infarcts present in 68% of 98 strokes Watershed infarcts present in 68% of 98 strokes MAP 10 mm Hg during CPB risk 4 fold for bilateral watershed infarct c/w other infarct patterns MAP 10 mm Hg during CPB risk 4 fold for bilateral watershed infarct c/w other infarct patterns Watershed infarcts present in 68% of 98 strokes Watershed infarcts present in 68% of 98 strokes MAP 10 mm Hg during CPB risk 4 fold for bilateral watershed infarct c/w other infarct patterns MAP 10 mm Hg during CPB risk 4 fold for bilateral watershed infarct c/w other infarct patterns Gottesman et al. Stroke 2006;37:2306

Blood Pressure Management During CPB CBF-BP autoregulation believed intact ( -stat) CBF-BP autoregulation believed intact ( -stat) Lower limit MAP of 50 mmHg? Lower limit MAP of 50 mmHg? Higher CBF might be deleterious Higher CBF might be deleterious Increase cerebral embolic load Increase cerebral embolic load Wash-out cardioplegia via non-coronary collaterals Wash-out cardioplegia via non-coronary collaterals CBF-BP autoregulation believed intact ( -stat) CBF-BP autoregulation believed intact ( -stat) Lower limit MAP of 50 mmHg? Lower limit MAP of 50 mmHg? Higher CBF might be deleterious Higher CBF might be deleterious Increase cerebral embolic load Increase cerebral embolic load Wash-out cardioplegia via non-coronary collaterals Wash-out cardioplegia via non-coronary collaterals

TCD Arterial B/P NIRS A/D Conversion PC Continuous moving Pearson correlation coefficient*: CBFv and MAP Mx NIRs and MAP COx * Non-overlapping 10 sec values sampled at 0.1 Hz to eliminate high frequency noise from respiration and pulse according to Nyquist theorem. Correlations are 10 sec averaged data over 300 sec Neurovascular Protection

Autoregulation Monitoring using ICM+ CBF: MAP r < 0 CBF: MAP r > MAP LMCA CBF V

Cerebral Autoregulation Chronic hypertensive Prior Stroke Cerebral Blood Flow MAP (mm Hg) 0 CBF: MAP r < 0 CBF: MAP r > 0

Autoregulatory Threshold: COx vs Doppler Brady et al. Stroke. 2007;38: Brady et al. Stroke. 2007;38:

Neurovascular Protection

Approach to High Risk Patient We dont know where to keep MAP We dont know where to keep MAP MAP > 70 mmHg (???) MAP > 70 mmHg (???) NIRS monitoring NIRS monitoring We dont know where to keep MAP We dont know where to keep MAP MAP > 70 mmHg (???) MAP > 70 mmHg (???) NIRS monitoring NIRS monitoring

Preload Sensitive Pulse Pressure V P Neurovascular Protection

Conclusions Cerebral vascular disease is prevalent in contemporary cardiac surgery practice Cerebral vascular disease is prevalent in contemporary cardiac surgery practice Blood pressures during CPB deemed safe in the past may expose patients to cerebral hypoperfusion and brain injury Blood pressures during CPB deemed safe in the past may expose patients to cerebral hypoperfusion and brain injury Blood pressure within a tight range may be preferable Blood pressure within a tight range may be preferable Individualized blood pressure management based on NIRS? Individualized blood pressure management based on NIRS? Cerebral vascular disease is prevalent in contemporary cardiac surgery practice Cerebral vascular disease is prevalent in contemporary cardiac surgery practice Blood pressures during CPB deemed safe in the past may expose patients to cerebral hypoperfusion and brain injury Blood pressures during CPB deemed safe in the past may expose patients to cerebral hypoperfusion and brain injury Blood pressure within a tight range may be preferable Blood pressure within a tight range may be preferable Individualized blood pressure management based on NIRS? Individualized blood pressure management based on NIRS?