2. Landmark Advances and Complex Cases in Cardiovascular Anesthesiology Emerging Perspectives and Strategies for Optimizing Perioperative Blood Pressure Management 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 Investigations Advances Applications Solomon Aronson, MD Program Co-Chairman Professor of Anesthesiology Duke University Medical Center Executive Vice Chair Department of Anesthesiology Durham, North Carolina

3. 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

4. Program Educational Objectives As a result of this educational activity, participants 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 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 are indicated for blood pressure control in the setting of cardiovascular disease.Learn how to select among intravenous pharmacologic agents, including calcium channel blockers/dihydropyridines that are indicated 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.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. Understand the efficacy and safety profiles of specific pharmacologic agents used for anesthesiology-based control of systemic blood pressure.Understand the efficacy and safety profiles of specific pharmacologic agents used for anesthesiology-based control of systemic blood pressure. As a result of this educational activity, participants 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 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 are indicated for blood pressure control in the setting of cardiovascular disease.Learn how to select among intravenous pharmacologic agents, including calcium channel blockers/dihydropyridines that are indicated 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.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. Understand the efficacy and safety profiles of specific pharmacologic agents used for anesthesiology-based control of systemic blood pressure.Understand the efficacy and safety profiles of specific pharmacologic agents used for anesthesiology-based control of systemic blood pressure.

5. 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 Edwin G. Avery, MD, CPI Assistant Professor of Anesthesiology Department of Anesthesia and Critical Care Critical Care Massachusetts General Hospital Harvard Medical School Boston, Massachusetts Edwin G. Avery, MD, CPI Assistant Professor of Anesthesiology Department of Anesthesia and Critical Care Critical Care Massachusetts General Hospital Harvard Medical School Boston, Massachusetts

6. 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 Edwin G. Avery, MD Consultant: The Medicines Company, Covidien, Cubist Speakers Bureau: The Medicines Company Research Funding: The Medicines Company, Covidien, Cubist 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 Edwin G. Avery, MD Consultant: The Medicines Company, Covidien, Cubist Speakers Bureau: The Medicines Company Research Funding: The Medicines Company, Covidien, Cubist

7. The Case for BP Control During Cardiovascular Surgery Solomon Aronson, MD Program Co-Chairman FACC, FCCP, FAHA, FASE Professor and Executive Vice Chairman Dept of Anesthesiology Duke University Health System Investigations Advances Applications

8. Target glucose control Target temp control Target fluid control Target Hgb control Target HR control Target BP control Target Control

9. ECLIPSE: Trial Design 3 prospective, randomized, open-label, parallel comparisons 3 prospective, randomized, open-label, parallel comparisons Clevidipine to NTG or SNP periop, or NIC postop in pts undergoing cardiac surgery Clevidipine to NTG or SNP periop, or NIC postop in pts undergoing cardiac surgery 61 medical centers 61 medical centers Primary Safety Endpoint: (death, myocardial infarction, stroke, renal) Primary Safety Endpoint: (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. Anesth Analg. 2008 Oct;107(4):1110-21

10. Incidence 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. Anesth Analg. 2008 Oct;107(4):1110-21

11. BP Control Assessed via AUC Analysis Time (hours) Lower Upper 06122418 SBP (mm Hg) Cumulative AUC calculated for excursions outside prespecified range. Lower AUC = tighter BP control. AUC = area under the curve Aronson, et al. Anesth Analg. 2008 Oct;107(4):1110-21

12. AUC by Treatment Group ECLIPSENTGECLIPSESNPECLIPSENIC Clevidipine n=269 NTG n=278 Clevidipine n=295 SNP n=284 Clevidipine n=187 NIC n=194 Clevidipine n=751 All Comparators n=756 ECLIPSENTG/SNP/NIC Mean AUC (mmHg x min/h) Median value in Italics p = 0.0006p = 0.0027p = 0.0004 p = NS Anesth and Analg 2008, 107; 1111-22 CLV v SNP; Above (2.97 v 6.61, p=0.03) Below (2.30 v 8.38, p=0.0006) CLV v NTG; Above (2.76 v 7.94 p=0.0002) Below target range similar.

13. Systolic BP Control Over 24 Hours Time (hours) SBP Lower Upper 06122418 Lower

14. AUC Narrowed BP Range by Treatment ECLIPSENTGECLIPSESNPECLIPSENIC mm Hg x min/h p = 0.0556 p = 0.0068 p = 0.0231 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 105-145, Intra-op SBP 95-135 Peri-operativePost-operative Only

15. mm Hg x min/h specified +10 +20 +30 P=0.0027 P=0.0009 P=0.0003 P=0.0068 n=295 n=284 n=187 n=194 P=0.8508 P=0.8949 P=0.3086 P=0.0231 n=278 n=269 P=0.0006 P=0.0002 P=0.0016 P=0.0556 Intra-op SBP (mmHg) Pre/post SBP (mmHg) 65 75 95 105 75 85 95

16. AUC Predictive of Mortality at 30 Days P value Odds ratio 95% CI (Lower limit, Upper limit) Surgery duration (hour) <0.00011.517 (1.240, 1.856) Age (year) 0.00031.070 (1.031, 1.110) Preop creatinine 1.2 mg/dL 0.00312.670 (1.392, 5.122) AUC (1 mm Hg*min) 0.00691.003 (1.001, 1.004) Additional surgical procedures 0.00892.409 (1.246, 4.655) Preop Hgb (g/dL) 0.01350.824 (0.707, 0.961) Preop SBP >160 or DBP >105 0.02282.386 (1.147, 4.963) History of COPD 0.02282.326 (1.125, 4.812) History of recent MI (<6 months prior) 0.03122.197 (1.073, 4.497) Aronson S et al. ACC Annual Meeting. 2007.

17. 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. 01234

18. Predicted Probability of 30-day Mortality Increase from 0.006 to 0.013 Low-risk Patients Increase from 0.186 to 0.325 High-risk Patients

19. Mean Duration of Excursions Minutes SBP > 130 or 130 or < 105 mmHg per incident P-Value < 0.0001, O.R.-1.07 (1.04-1.102) N=7808 pts 3.1M BP measured Duke population Above 5 min +/- 4 Below 11 min +/- 9 Combined 8 min Aronson S et al. Critical Care Medicine. 2008; 36 (Suppl); 557 Min<95 mmHg (min)0.0041.025 1.008-1.042 Min>135 mmHg (min)0.0131.033 1.007-1.059 P-Value OR 95% CI 8 min predicted mortality 1.9%; 10 min = 2.1%; 15 min = 2.8%; 20 min = 3.5%

20. Predictors of 30-day Renal Dysfunction Total AUC of SBP excursions outside the range of 85-145 mmHg pre- and postoperatively, and 75-135 mmHg intraoperatively; AUC 75th percentile analyzed. Aronson S, et al. Anesthesiology. 2007; 107: A1253 Multiple logistic regression analysis Candidate variables; Candidate variables;Demographics Baseline characteristics Medical history Treatment group Proc characteristics AUC p<0.05 required.

21. xxxxx Avery EG, et al. Anesthesia and Analgesia. 2008; 106 (SCA Supp); 69

22. BP excursions > 60 min O.R. 95% C I 1 mmHg/min 1.171.02-1.34 2 mmHg/min 1.381.05-1.81 3 mmHg/min 1.611.07-2.43 4 mmHg/min 1.891.10-3.27 5 mmHg/min 2.221.12-4.39 AUC calc for excursions outside sBP range of 85-145 mmHg pre, post-op, & 75-135 mmHg intra-op AUC Predicts 30-Day MI risk Avery EG, et al. Anesthesia and Analgesia. 2008; 106 (SCA Supp); 69 Multiple Logistic Regression Analysis ECLIPSE trial: Myocardialinfarction Quartile 1 Quartile 2 Quartile 3 Quartile 4

23. Logistic Regression Results: Predictor of 30-Day Mortality P Value OR 95% C.I. Screening SBP (per 1 mm Hg increment) 0.00131.0381.014–1.061 AUC (per 1 mm Hg×min/hr increment) 0.01461.0041.001–1.007 AUC (per 1mmHg×min/hr increment), narrow range 0.00781.0021.001–1.004 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

24. Summary and Conclusions 1.Tight control of perioperative hypertension is an important objective 2.Tightening blood pressure control zone during perioperative CV surgery may improve clinical outcomes 3.Clevidipine possesses pharmacokinetic and pharmacodynamic properties that are consistent with optimizing blood pressure control during cardiovascular surgery. 4.Landmark trials support new approaches to blood pressure therapy

25. "Under PressureOut of Control" Vascular Dysfunction and Acute Pressure Syndromes in the Setting of Cardiovascular Surgery Challenges, Innovations, and Landmark Trials for the CV Anesthesiologist 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 Investigations Advances Applications

26. Evolution of Perioperative Care 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, vascular, and circulatory dysfunction common across this cardiac, neurological, and critically ill patient populationsacute and chronic disease Endothelial, vascular, and circulatory dysfunction common across this cardiac, neurological, and critically ill patient populationsacute and chronic disease Estafanous FG, et al. Ann Thorac Surg. 1998;65:383-389. Fontana GP. Chest Surg Clin N Am. 1998;8:871-890. Verrier ED. J Am Coll Surg. 1999;188:104-110. Trends and Observations

27. 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):1192-1200 Calcification Renal Failure Endothelial Dysfunction

28. 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 Levy JH: Management of systemic and pulmonary hypertension. Tex Heart Inst J 2005;32:467-471. Principles and Practice Considerations

29. 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;32:467-471. Principles and Practice Considerations

30. Nitroprusside: Issues and Concerns Nitroprusside: 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

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

32. 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 Levy JH: Management of systemic and pulmonary hypertension. Tex Heart Inst J 2005;32:467-471. Principles and Practice Considerations

33. 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. 2001:843-870. 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

34. 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 1.Clarke B, et al. Br J Pharmacol. 1983;79:333P. 2.Lambert CR, et al. Am J Cardiol. 1987;60:471-476. 3.Silke B, et al. Br J Clin Pharmacol. 1985;20:169S-176S. 4.Lambert CR, et al Am J Cardiol. 1985;55:652-656. 5.Visser CA, et al. Postgrad Med J. 1984;60:17-20. 6.Silke B, et al. Br J Clin Pharmacol. 1985;20:169S-176S. 7.Nishiyama MT, et al. Can J Anaesth. 2000;47:1196-1201.

35. 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

36. Vasospasm/Vascular Dysfunction Studies Salmenperra MT: Effects of PDE inhibitors on the human IMA. Anesth Analg 1996; 82: 954-957. Salmenperra MT: Effects of PDE inhibitors on the human IMA. Anesth Analg 1996; 82: 954-957. Huraux C: Vasodilator effects of clevidipine on human IMA. Anesth Analg 1997; 85: 1000-1004. Huraux C: Vasodilator effects of clevidipine on human IMA. Anesth Analg 1997; 85: 1000-1004. Huraux C: A comparative eval of multiple vasodilators on human IMA. Anesthesiology 1998;88:1654-1659. Huraux C: A comparative eval of multiple vasodilators on human IMA. Anesthesiology 1998;88:1654-1659. Huraux C: Superoxide production, risk factors, and EDRF relaxations in human IMAs. Circulation 1999;99:53-59. Huraux C: Superoxide production, risk factors, and EDRF relaxations in human IMAs. Circulation 1999;99:53-59. Tsuda A: Reversal of histamine-induced vasodilation in the human IMA. Anesth Analg 2001;93:1453-1459. Tsuda A: Reversal of histamine-induced vasodilation in the human IMA. Anesth Analg 2001;93:1453-1459. Sato N: Vasodilatory effects of hydralazine, nicardipine, nitroglycerin and fenoldopam in the human umbilical artery. Anesth Analg 2003;96:539-544. Sato N: Vasodilatory effects of hydralazine, nicardipine, nitroglycerin and fenoldopam in the human umbilical artery. Anesth Analg 2003;96:539-544. Tanaka KA: In vitro effects of antihypertensive drugs on TxA2 (U46619)- induced vasoconstriction in human IMA. Br J Anaesth 2004;93:257-262. Tanaka KA: In vitro effects of antihypertensive drugs on TxA2 (U46619)- induced vasoconstriction in human IMA. Br J Anaesth 2004;93:257-262.

37. 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: 1000-1004.

38. Cl Cl H CH 3 OOC H3CH3CH3CH3C COOCH 2 OOCC 3 H 7 CH 3 N H The Clevidipine Molecule Clevidipine is the first ultrashort acting dihydropyridine intravenous calcium channel blocker

39. 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;55:61-67. Bailey JM, et al. Anesthesiology. 2002;96:1086-1094. Ericsson H, et al. Drug Metab Dispos. 1999;27:558-564. Ericsson H et al. Eur J Clin Pharmacol. 1999;55:61-67. Ericsson H, et al. Eur J Pharm Sci. 1999;8:29-37.

40. Perioperative BP Control: ESCAPE Trials Design: 2 double-blind, randomized, placebo-controlled trials Design: 2 double-blind, randomized, placebo-controlled trials Primary end point: comparison of the incidence of treatment failure* between the clevidipine butyrate and placebo treatment groups over 30 minutes from initiation of study drug Primary end point: comparison of the incidence of treatment failure* between the clevidipine butyrate and placebo treatment groups over 30 minutes from initiation of study drug *Treatment failure was defined as the premature and permanent discontinuation of study drug infusion for any reason, or the failure to decrease SBP by 15% from baseline at any time within the 30-minute period from study drug initiation. BP=blood pressure; HTN=hypertension; SBP=systolic blood pressure. Levy JH, et al. Anesth Analg. 2007;105:918-925; Singla N, et al. Anesth Analg. 2008;107:59-67. Preoperative HTN (SBP 160 mmHg) Postoperative HTN (SBP 140 mmHg) Placebo (n=52) Clevidipine (n=53) Placebo (n=49) Clevidipine (n=61) ESCAPE-1ESCAPE-2 Please see Important Safety Information and accompanying full Prescribing Information.

41. Clevidipine butyrate Rapidly Controlled BP Levy JH, et al. Anesth Analg. 2007;105:918-925; Singla N, et al. Anesth Analg. 2008;107:59-67; Data on file. The Medicines Company. Please see Important Safety Information and accompanying full Prescribing Information. *In ESCAPE-2, the decrease in placebo group SBP reflects the number of placebo patients (n=49 at baseline) who bailed out during the 30-minute infusion period (n=10 remaining at 30 minutes). BP=blood pressure; SBP=systolic blood pressure. ESCAPE-1 (N=105) ESCAPE-2 (N=110) 51015202530 Mean change in SBP from baseline (%) Time (minutes) 0 -5 -15 -20 -25 -30 0 -10 0 -5 -15 -20 -25 -30 051015202530 Mean change in SBP from baseline (%) Time (minutes) -10 Clevidipine Placebo * Target BP reached in ~6 minutes Target BP reached in ~5 minutes Clevidipine Placebo

42. *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 120 100 80 60 40 20 0 0510152035 Clevidipine Concentration at Css (nmol/L)* at Css (nmol/L)* Dose Rate (nmol/kg/min) 2530 Reproduced from Ericsson H, et al. Anesthesiology. 2000;92:993-1001. Ericsson H, et al. Anesthesiology. 2000;92:993-1001. Ericsson H, et al. Br J Clin Pharmacol. 1999;47:531-538.

43. Reproduced from Ericsson H, et al. Anesthesiology. 2000;92:993-1001. Clevidipine Ultrashort Half-Life Clinically relevant half-life: Approximately 1 minute Clinically relevant half-life: Approximately 1 minute Arterial and venous clevidipine blood samples

44. 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 Reproduced from Ericsson H, et al. Anesthesiology. 2000;92:993-1001. 100 90 80 70 60 50 40 –50510152035 MAP (mm Hg) and HR (beats/min) Time (min) 2530 Clevidipine Infusion MAP

45. *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 8 4 4 0 0 0 0 0.375 0.75 1.5 3 3 0 0 10 6 6 2 2 mcg/kg/min Central Venous Pressure Clevidipine and Arterial Selectivity 1400 Units 1200 1000 0 0 C1 0.375 0.75 1.5 3 3 C2 Systemic Vascular Resistance mcg/kg/min C2 Mean Arterial Pressure 90 80 70 * * C1 0.375 0.75 1.5 3 3 mcg/kg/min mm Hg Kieler-Jensen N, et al. Acta Anaesthesiol Scand. 2000;44:186-193.

46. Preoperative HR Changes in Non-Anesthetized Patients Postoperative HR Changes in Anesthetized Patients Clevidipine: Minimal Effect on Heart Rate 10 5 0 –5 051015202530 % Change From Baseline Time (min) HR HR changes for patients during the 30-minute treatment period 5 0 –5 051015202530 % 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.

47. 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 Aronson, et al. Anesth Analg. 2008 Oct;107(4):1110-21

48. 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 Aronson, et al. Anesth Analg. 2008 Oct;107(4):1110-21

49. Procedural Characteristics Clevidipine n=752 Comparators n=754 Surgery Duration: Median Hours 3.323.23 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% Aronson, et al. Anesth Analg. 2008 Oct;107(4):1110-21

50. 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 Aronson, et al. Anesth Analg. 2008 Oct;107(4):1110-21

51. 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 Aronson, et al. Anesth Analg. 2008 Oct;107(4):1110-21

52. 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 Aronson, et al. Anesth Analg. 2008 Oct;107(4):1110-21

53. RESULTS Primary Endpoint Death 30-Day Events (%) n=729n=700n=707n=700n=705n=712n=710n=719 MI Stroke Renal Dysfunction Renal Dysfunction Aronson, et al. Anesth Analg. 2008 Oct;107(4):1110-21

54. Primary End Points by Treatment Comparison End Points End PointsClevidipineNTGClevidipineSNPClevidipineNICDeath2.8%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 Aronson, et al. Anesth Analg. 2008 Oct;107(4):1110-21

55. Serious Adverse Events Serious Adverse Events Serious Adverse EventsClevidipinen=752Comparatorsn=754Total17.7%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% Aronson, et al. Anesth Analg. 2008 Oct;107(4):1110-21

56. Double the dose every 90 sec initially, then as BP approaches goal, increase dose by less than double and lengthen time between dose adjustments to every 5-10 min ~1- to 2-mg/h increase will generally produce an additional 2- to 4-mmHg decrease in SBP Non–Weight-Based Dosing Regimen Please see Important Safety Information and accompanying full Prescribing Information. Initiate clevidipine butyrate IV infusion at 1-2 mg/h Monitor BP and heart rate continuously during infusion, and then until vital signs are stable Prescribing Information; August 1, 2008. BP=blood pressure; IV=intravenous; SBP=systolic blood pressure.

57. Non–Weight-Based Dosing Regimen (contd) The desired therapeutic response for most patients occurs at doses of 4-6 mg/h The desired therapeutic response for most patients occurs at doses of 4-6 mg/h Most patients were treated with maximum doses of 16 mg/h or less Most patients were treated with maximum doses of 16 mg/h or less There is limited short-term experience with doses up to 32 mg/h There is limited short-term experience with doses up to 32 mg/h Because of lipid load restrictions, no more than 1,000 mL or an average of 21 mg/h of clevidipine infusion is recommended per 24-hour period Because of lipid load restrictions, no more than 1,000 mL or an average of 21 mg/h of clevidipine infusion is recommended per 24-hour period In clinical trials, 55 hypertensive patients were treated with >500 mL of clevidipine infusion per 24-hour period In clinical trials, 55 hypertensive patients were treated with >500 mL of clevidipine infusion per 24-hour period There is little experience with infusion durations beyond 72 hours at any dose There is little experience with infusion durations beyond 72 hours at any dose Prescribing Information; August 1, 2008. Please see Important Safety Information and accompanying full Prescribing Information.

58. Simulated Drug Level Curves =Full loading dose = [Cp] x Vdss = Smaller loading dose =[Cp] x Vc = No loading dose Time (Half-life) 0 10 20 30 40 50 60 0123456 Therapeutic Concentration Range Therapeutic Concentration Range Plasma Drug Level

59. 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.

60. 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

61. Blood Pressure Control Courtesy of J. Ferguson, MD BP Time Extent Extent Duration Bleeding Vascular damage Ischemia Hypoperfusion Threshold is higher with pre-existing bleeding or vascular injury (ICH, Aortic dissection, etc) Threshold is higher with pre-existing end-organ damage (kidney, heart, brain) Efficacy Threshold Safety Threshold

62. Case Studies in Acute Hypertension Edwin G. Avery, MD, CPI Assistant Professor of Anesthesiology Massachusetts General Hospital Heart Center Harvard Medical School Investigations Advances Applications

63. Case Studies of Acute Hypertension Case Study #1 Type A Aortic Dissection www.radpod.org

64. Case Studies of Acute Hypertension Case Study #1 Acknowledgement Thank you to Dr. Michael England for sharing this interesting case

65. Case Study 1: Type A Aortic Dissection HPI: presented to ED complaining of sudden onset of severe chest pain and shortness of breath.HPI: presented to ED complaining of sudden onset of severe chest pain and shortness of breath. PHM/PSH: obesityPHM/PSH: obesity Allergies: NKDAAllergies: NKDA Medications: noneMedications: none Fam Hx: noncontributoryFam Hx: noncontributory ROS: unremarkableROS: unremarkable www.edpma.com 44-year-old female presents for surgical correction of a Type A dissection

66. General: anxious, grossly obese.General: anxious, grossly obese. Ht: 62 inches Wt: 102 kgHt: 62 inches Wt: 102 kg VS: 141/45 (R=L) ; HR 80s reg ; Resp 18; SpO2 96% RAVS: 141/45 (R=L) ; HR 80s reg ; Resp 18; SpO2 96% RA Neuro: alert & oriented x3; no gross deficitsNeuro: alert & oriented x3; no gross deficits Pulmonary: B/L ralesPulmonary: B/L rales Cardiac: S 1 S 2 reg, grade IV syst. murmurCardiac: S 1 S 2 reg, grade IV syst. murmur Extrem: 2+ palpable B/L UE & LE; no edemaExtrem: 2+ palpable B/L UE & LE; no edema turbosquid.com Case Study 1: Type A Aortic Dissection

67. Chem: Heme: ECG: no ischemic changes CT: TEE: 141 112 20 4.0 24 1.2 < 110 10 250 < > 39 12.3 LFTs Coags WNL WNL Case Study 1: Type A Aortic Dissection

68. Diagnosis Type A Aortic Dissection w/severe aortic insufficiency Management Immediate β-blockadeImmediate β-blockade Control SBP with IV antihypertensive to prevent aortic rupture & further extension of dissectionControl SBP with IV antihypertensive to prevent aortic rupture & further extension of dissection Proceed to the OR for immediate surgical correction (ascending aortic replacement, +/- AVR)Proceed to the OR for immediate surgical correction (ascending aortic replacement, +/- AVR) www.radiologyassistant.nl Case Study 1: Type A Aortic Dissection

69. ManagementManagement β-blockade: reduces dP/dtβ-blockade: reduces dP/dt IV antihypertensive: reduces shear forces on the weakened aortic wallIV antihypertensive: reduces shear forces on the weakened aortic wall Surgical correction: reduces observed Type A dissection mortality (~2% per hour). Uncorrected in-hospital mortality (58%) vs. surgically corrected (27.4 %)1.Surgical correction: reduces observed Type A dissection mortality (~2% per hour). Uncorrected in-hospital mortality (58%) vs. surgically corrected (27.4 %)1. www.radiologyassistant.nl Hagan et al. Jama 2000;283:897 Case Study 1: Type A Aortic Dissection

70. In the OR Case Study 1: Type A Aortic Dissection

71. In the OR

72. CPB Induction Incision Case Study 1: Type A Aortic Dissection In the OR

73. In the OR – The Zone CPB Induction Incision 120 95 Case Study 1: Type A Aortic Dissection

74. In the OR – the drugs CPB SNP CLV SNP sodium nitroprusside CLV clevidipine NTG nitroglycerin Induction Incision NTG Case Study 1: Type A Aortic Dissection

75. In the OR – the drugs CPB SNP CLV NTG SNP sodium nitroprusside CLV clevidipine NTG nitroglycerin Clevidipine dose adjustment (mg/hr) Induction Incision 10 0 24 6 8 Case Study 1: Type A Aortic Dissection

76. Summary The ultra-short acting dihydropyridine calcium channel blocker, clevidipine, can be used to safely and effectively manage the acute hypertension that accompanies one of the most morbid and potentially mortal disorders of the cardiovascular system. Case Study 1: Type A Aortic Dissection

77. Case Studies of Acute Hypertension Case Study #2 Acute Coronary Syndrome http://library.med.utah.edu

78. Case Study #2 Acknowledgement Thank you to Dr. Charles Pollack at the University of Pennsylvania for sharing this interesting case Case Studies of Acute Hypertension

79. Case Study #2: Acute Coronary Syndrome 58 y/o male presents to ED with chest pain of acute onset radiating to left jaw and shoulder, accompanied by SOB58 y/o male presents to ED with chest pain of acute onset radiating to left jaw and shoulder, accompanied by SOB Triage vital signs were pulse 92/min, resp 24/min, and BP 212/126 mm HgTriage vital signs were pulse 92/min, resp 24/min, and BP 212/126 mm Hg PMH included known CAD, CHF, and hyperlipidemiaPMH included known CAD, CHF, and hyperlipidemia ECG performed in TriageECG performed in Triage http://mykentuckyheart.com

80. Acute Anterior STE Myocardial Infarction Case Study #2: Acute Coronary Syndrome

81. Physical examination: symmetrical bounding pulses, diaphoresis, and rales in both lung basesPhysical examination: symmetrical bounding pulses, diaphoresis, and rales in both lung bases Management:Management: ASA 325 mg ASA 325 mg Clopidogrel 600 mg Clopidogrel 600 mg Unfractionated heparin by IV infusion Unfractionated heparin by IV infusion Nitroglycerin by IV infusion Nitroglycerin by IV infusion Beta-blockers are held because of concern over heart failure Beta-blockers are held because of concern over heart failure Prior to cath lab transfer: recheck BP is 196/118; and patient is diagnosed withPrior to cath lab transfer: recheck BP is 196/118; and patient is diagnosed with www.etopiamedia.net STEMI + Hypertensive Emergency Case Study #2: Acute Coronary Syndrome

82. Hemodynamic Control 170 160 Case Study #2: Acute Coronary Syndrome

83. Clevidipine (mg/hr) 0 12 6 4 2 8 10 196 192 188 176 168 166 162 Case Study #2: Acute Coronary Syndrome Hemodynamic Control

84. Summary Clevidipine can be used safely and effectively to care for a patient with an acute coronary syndrome using a peripheral IV and a blood pressure cuff. There was no evidence of coronary steal or worsening of this patients chest pain. Target BP control was obtained in less than 10 minutes. Case Study #2: Acute Coronary Syndrome

85. Case Study #3 Aortic Valve Replacement Case Studies of Acute Hypertension

86. Case Study 3: Aortic Valve Replacement HPI: presented with symptoms of shortness of breath and DOE.HPI: presented with symptoms of shortness of breath and DOE. PHM/PSH: AS, MI, CAD (stents x2), HTN (brittle), Chol, TIAs secondary to spontaneous cholesterol emboliPHM/PSH: AS, MI, CAD (stents x2), HTN (brittle), Chol, TIAs secondary to spontaneous cholesterol emboli Allergies: NKDAAllergies: NKDA Medications: metoprololMedications: metoprolol Fam Hx: noncontributoryFam Hx: noncontributory ROS: as per HPI o/w unremarkableROS: as per HPI o/w unremarkable 78-year-old male presents for aortic valve replacement

87. General: fatigued appearingGeneral: fatigued appearing Ht: 72 inches Wt: 90 kgHt: 72 inches Wt: 90 kg VS: 128/62 (R=L) ; HR 60s reg ; Resp 18; SpO2 98% RAVS: 128/62 (R=L) ; HR 60s reg ; Resp 18; SpO2 98% RA Neuro: alert & oriented x3; no gross deficitsNeuro: alert & oriented x3; no gross deficits Pulmonary: CTA bilaterallyPulmonary: CTA bilaterally Cardiac: S 1 S 2 reg, grade IV syst. murmurCardiac: S 1 S 2 reg, grade IV syst. murmur Extrem: 2+ palpable B/L UE & LE; no edemaExtrem: 2+ palpable B/L UE & LE; no edema Case Study 3: Aortic Valve Replacement

88. Chem: Heme: ECG: no ischemic changes TEE: Aortic stenosis (AVA 0.7 cm 2 ), gradient (P 51/M 32 mmHg w/CI 2.9 L/min/m 2 ) 139 103 25 4.5 24 1.3 < 91 6.8 172 < > 41.2 14.1 LFTs Coags WNL WNL Case Study 3: Aortic Valve Replacement

89. Diagnosis Severe Aortic Stenosis with left ventricular hypertrophy Management Surgical aortic valve replacement with a bioprosthesisSurgical aortic valve replacement with a bioprosthesis Control heart rate, maintain NSR, manage SBP with an IV antihypertensive to prevent LV wall stress and MVO 2, avoid hypotensive overshootsControl heart rate, maintain NSR, manage SBP with an IV antihypertensive to prevent LV wall stress and MVO 2, avoid hypotensive overshoots Case Study 3: Aortic Valve Replacement

90. In the OR Case Study 3: Aortic Valve Replacement

91. In the OR Case Study 3: Aortic Valve Replacement

92. In the OR - The Zone Induction CPB 2 4 8 16 2 0 2 4 0 F F Clevidipine (mg/hr) F - Fentanyl bolus Case Study 3: Aortic Valve Replacement

93. Summary Clevidipine can be used safely and effectively to provide hemodynamic support for patients with complex cardiovascular disease profiles (i.e. need to strictly ovoid overshoot hypotension [AS] & reflex tachycardia [AS, LVH, CAD]). Target BP control was expeditiously obtained and maintained in this patient. Case Study 3: Aortic Valve Replacement

94. Case Study #2: Acute Coronary Syndrome Thank You