1. Blood Pressure Lability During Cardiac Surgery Is Associated With Adverse Outcomes Solomon Aronson, Edwin G. Avery, Cornelius Dyke, Joseph Varon, Jerrold H. Levy Presented at the American Society of Anesthesiologists (ASA) 2008 Annual Meeting. October 18–22, 2008, Orlando, FL.

2. Background Perioperative blood pressure (BP) variability during cardiac surgery and intraoperative hemodynamic abnormalities may be associated adverse outcome including death, stroke, renal dysfunction, perioperative myocardial infarction (MI), and increased mortality in this patient population Perioperative blood pressure (BP) variability during cardiac surgery and intraoperative hemodynamic abnormalities may be associated adverse outcome including death, stroke, renal dysfunction, perioperative myocardial infarction (MI), and increased mortality in this patient population Up to 86% of cardiac surgery patients require intravenous (IV) therapy to actively manage BP Up to 86% of cardiac surgery patients require intravenous (IV) therapy to actively manage BP Anesth Analg 2002:94;1079- 84. Anesth Analg 2002:95;273-7. Circulation 2007:115;733-42. Hypertension 2007;50:630-35. Anesth Analg 2008:107;1122-9, 2008

3. Background The Evaluation of Clevidipine in the Perioperative Treatment of Hypertension Assessing Safety Events (ECLIPSE) program was performed to compare the safety and efficacy of clevidipine butyrate intravenous emulsion (CLV) with nitroglycerin (NTG), sodium nitroprusside (SNP), and nicardipine (NIC) in the treatment of perioperative acute hypertension in patients undergoing cardiac surgery The Evaluation of Clevidipine in the Perioperative Treatment of Hypertension Assessing Safety Events (ECLIPSE) program was performed to compare the safety and efficacy of clevidipine butyrate intravenous emulsion (CLV) with nitroglycerin (NTG), sodium nitroprusside (SNP), and nicardipine (NIC) in the treatment of perioperative acute hypertension in patients undergoing cardiac surgery In ECLIPSE, poor perioperative BP control was a significant predictor of 30-day mortality In ECLIPSE, poor perioperative BP control was a significant predictor of 30-day mortality –Patients with poor blood pressure (BP) control are at higher risk of 30-day death, stroke, myocardial infarction (MI), and renal dysfunction compared with those with tight control (P<0.01, odds ratio 1.003, 95% confidence interval 1.001–1.004) –In other words, the worse the blood pressure control, the worse the outcome

4. Methods In the present study, data from the ECLIPSE program were examined further to determine whether the risk of 30-day adverse clinical outcomes (death, MI, stroke, and renal dysfunction) increased as systolic BP (SBP) became progressively more labile outside of a preselected BP target range In the present study, data from the ECLIPSE program were examined further to determine whether the risk of 30-day adverse clinical outcomes (death, MI, stroke, and renal dysfunction) increased as systolic BP (SBP) became progressively more labile outside of a preselected BP target range The ECLIPSE program comprised 3 prospective, randomized, open-label, parallel comparison studies of CLV to NTG or SNP perioperatively, or NIC postoperatively in patients undergoing cardiac surgery at 61 medical centers The ECLIPSE program comprised 3 prospective, randomized, open-label, parallel comparison studies of CLV to NTG or SNP perioperatively, or NIC postoperatively in patients undergoing cardiac surgery at 61 medical centers Of the 1964 patients enrolled, 1512 met post randomization inclusion criteria of requiring acute treatment of hypertension based on clinical determination (modified intent-to-treat population) Of the 1964 patients enrolled, 1512 met post randomization inclusion criteria of requiring acute treatment of hypertension based on clinical determination (modified intent-to-treat population) –Five were not included due to missing or incomplete area under the curve (AUC) data, for a total of 1507 patients

5. Methods The efficacy of CLV versus comparator drugs for the treatment of acute hypertension was assessed using AUC analysis of BP excursions beyond predetermined upper and lower limits, normalized per hour (AUCSBP-D) The efficacy of CLV versus comparator drugs for the treatment of acute hypertension was assessed using AUC analysis of BP excursions beyond predetermined upper and lower limits, normalized per hour (AUCSBP-D) –These ranges, chosen to reflect standard clinical practice and predefined for analysis purposes, were 65 to 135 mm Hg intraoperatively (from chest incision through chest closure) and 75 to 145 mm Hg pre- and postoperatively In a posthoc analysis, patients were grouped into quartiles (Qs 1–4) as defined by BP lability (Q4 was most labile and Q1 least labile) In a posthoc analysis, patients were grouped into quartiles (Qs 1–4) as defined by BP lability (Q4 was most labile and Q1 least labile)

6. Methods The primary outcome was the incidence of death, MI, stroke, or renal dysfunction at 30 days as assessed by the Clinical Endpoints Committee The primary outcome was the incidence of death, MI, stroke, or renal dysfunction at 30 days as assessed by the Clinical Endpoints Committee Perioperative BP was controlled from preincision through the perioperative period with CLV (2–16 mg/h titrated to BP-lowering effect) versus a comparator (IV NTG, SNP, or NIC), dosed according to institutional practice Perioperative BP was controlled from preincision through the perioperative period with CLV (2–16 mg/h titrated to BP-lowering effect) versus a comparator (IV NTG, SNP, or NIC), dosed according to institutional practice –Patients were randomized 1:1 to study drugs

7. ECLIPSE Patient Characteristics AUC Study Population (N=1507) Quartile 1 AUC 0–<0.09 (n=376) Quartile 2 AUC 0.09–<4.77 (n=377) Quartile 3 AUC 4.77–<26.21 (n=377) Quartile 4 AUC ≥26.21 (n=377)P Value Median age, years (IQR) 63.0 (56.0, 72.0) 65.0 (57.0, 72.0) 66.0 (58.0, 73.0) 67.0 (60.0, 75.0) <0.0001 Male, n (%)279 (74.2) 289 (76.7) 277 (73.5) 260 (69.0) 0.114 White, n (%)323 (85.9) 331 (87.8) 312 (82.8) 277 (73.5) <0.0001 Median BMI, kg/m2 (IQR) 28.7 (25.6, 32.4) 28.7 (25.8, 32.2) 29.3 (25.7, 32.8) 28.0 (24.9, 31.5) 0.684 Screening SBP >160 or DBP >105, n (%) 29 (7.7) 55 (14.6) 81 (21.5) <0.0001 History of hypertension, n (%) 306 (81.4) 323 (85.7) 324 (85.9) 343 (91.0) 0.002 CHF, n (%)71 (18.9) 50 (13.3) 71 (18.8) 86 (22.8) 0.009 COPD, n46 (12.2) 65 (17.2) 55 (14.6) 52 (13.8) 0.261 Aronson S., et. al. American Society of Anesthesiologists (ASA) 2008 Annual Meeting. October 18–22, 2008, Orlando, FL.

8. ECLIPSE Patient Characteristics AUC Study Population (N=1507) Quartile 1 AUC 0–<0.09 (n=376) Quartile 2 AUC 0.09–<4.77 (n=377) Quartile 3 AUC 4.77–<26.21 (n=377) Quartile 4 AUC ≥26.21 (n=377)P Value Diabetes, n119 (31.6) 124 (32.9) 128 (34.0) 167 (44.3) 0.001 Recent MI (<6 months), n (%) 65 (17.3) 65 (17.2) 71 (18.8) 68 (18.0) 0.933 Previous CABG, n (%) 23 (6.1) 11 (2.9) 15 (4.0) 18 (4.8) 0.185 Previous TIA or stroke, n (%) 30 (8.0) 39 (10.3) 45 (11.9) 63 (16.7) 0.001 Median screening SBP, mm Hg (IQR) 131.0 (116.0, 144.0) 133.0 (120.0, 145.0) 138.0 (121.0, 151.0) 140.0 (125.5, 159.5) <0.0001 Median screening DBP, mm Hg (IQR) 70.0 (64.0, 79.0) 72.0 (64.0, 80.0) 71.0 (65.0, 80.0) 72.0 (62.5, 81.5) 0.196 Median preop serum creatinine, mg/dL (IQR) 1.00 (0.85, 1.18) 1.00 (0.87, 1.13) 1.00 (0.87, 1.15) 1.02 (0.85, 1.21) <0.0001 Median preop hemoglobin, g/dL (IQR) 14.02 (12.70, 15.20) 14.12 (12.91, 15.10) 14.00 (12.60, 15.24) 13.33 (11.80, 14.80) <0.0001 Aronson S., et. al. American Society of Anesthesiologists (ASA) 2008 Annual Meeting. October 18–22, 2008, Orlando, FL.

9. ECLIPSE Procedural Characteristics AUC Study Population (N=1507) Quartile 1 AUC 0– <0.09 (n=376) Quartile 2 AUC 0.09– <4.77 (n=377) Quartile 3 AUC 4.77– <26.21 (n=377) Quartile 4 AUC ≥26.21 (n=377) Median duration of surgery, h (IQR) 3.32 (2.60, 4.27) 3.30 (2.65, 4.00) 3.13 (2.53, 4.00) 3.33 (2.65, 4.25) Duration on pump, h (IQR) 1.48 (1.08, 2.00) 1.38 (1.08, 1.83) 1.35 (0.98, 1.73) 1.49 (1.12, 1.98) Type of primary surgical procedure, n (%) CABG263 (69.9) 287 (76.1) 288 (76.4) 276 (73.2) Valve repair or replacement 46 (12.2) 45 (11.9) 43 (11.4) 42 (11.1) CABG and valve repair42 (11.2) 26 (6.9) 24 (6.4) 35 (9.3) Other0 (0.0) 1 (0.3) Aronson S., et. al. American Society of Anesthesiologists (ASA) 2008 Annual Meeting. October 18–22, 2008, Orlando, FL.

10. ECLIPSE Procedural Characteristics AUC Study Population (N=1507) Quartile 1 AUC 0– <0.09 (n=376) Quartile 2 AUC 0.09– <4.77 (n=377) Quartile 3 AUC 4.77– <26.21 (n=377) Quartile 4 AUC ≥26.21 (n=377) Type of repeat surgical procedure, n (%) CABG13 (3.5) 10 (2.7) 12 (3.2) Valve repair or replacement 8 (2.1) 3 (0.8) 5 (1.3) CABG and valve repair4 (1.1) 5 (1.3) 4 (1.1) 6 (1.6) Other0 (0.0) Aronson S., et. al. American Society of Anesthesiologists (ASA) 2008 Annual Meeting. October 18–22, 2008, Orlando, FL.

11. Results Patients in Q4 (ie, the highest SBP excursions outside a specified range) were found to be at highest risk for 30-day adverse clinical outcomes Patients in Q4 (ie, the highest SBP excursions outside a specified range) were found to be at highest risk for 30-day adverse clinical outcomes The incidence of adverse outcomes increased as the AUC increased from Q1 to Q4 The incidence of adverse outcomes increased as the AUC increased from Q1 to Q4 –By Kaplan-Meier analysis, the 30-day risk of having an adverse clinical outcome was 8.8% Q1, 10.1% Q2, 10.1% Q3, and 14.4% Q4 –The risk of having an event was significantly greater in the Q4 group when compared with both the Q1 group (P=0.016) and the Q1 through Q3 groups combined (P=0.012) –Significantly fewer patients in Q4 were treated with CLV versus the comparators (P=0.0002) Q4 (CLV 157: comparators [CMP] 220) versus Qs 1 to 3 (CLV 594: CMP 536)Q4 (CLV 157: comparators [CMP] 220) versus Qs 1 to 3 (CLV 594: CMP 536)

12. Summary of 30-day Composite Outcome in Patients with Perioperative Hypertension Aronson S., et. al. American Society of Anesthesiologists (ASA) 2008 Annual Meeting. October 18–22, 2008, Orlando, FL.

13. Summary of 30-day Composite Outcome in Patients with Perioperative Hypertension Aronson S., et. al. American Society of Anesthesiologists (ASA) 2008 Annual Meeting. October 18–22, 2008, Orlando, FL.

14. Conclusions Cardiac surgery patients with inadequate BP control are at increased risk of 30-day death, stroke, MI, and renal dysfunction compared with patients with tight BP control Cardiac surgery patients with inadequate BP control are at increased risk of 30-day death, stroke, MI, and renal dysfunction compared with patients with tight BP control CLV appears to offer superior BP control in surgical patients in this clinical setting CLV appears to offer superior BP control in surgical patients in this clinical setting CLV appears to offer superior perioperative BP control in cardiac surgery patients compared with the combined comparators SNP, NTG, and NIC as shown by the decreased number of patients in Q4 who were receiving CLV CLV appears to offer superior perioperative BP control in cardiac surgery patients compared with the combined comparators SNP, NTG, and NIC as shown by the decreased number of patients in Q4 who were receiving CLV –This observation requires further investigation in prospective, randomized clinical trials