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Acute Hypertension: The Need for IV Antihypertensive Therapy The First Third-Generation Intravenous Dihydropyridine Calcium Channel Blocker Cl Cl H CH3OOC H3C N H Nordlander M, et al. Cardiol Drug Reviews. 2004;22:227-250. COOCH2OOCC3H7 CH3 The Need for Intravenous (IV) Antihypertensive Therapy In acute hypertension, any scenario in which oral antihypertensive therapy is not feasible or desirable Hypertensive emergency – Acute elevations in BP associated with end-organ damage require immediate BP reduction Perioperative hypertension Less critical hypertensive scenarios when oral therapy is not feasible – Hypertensive urgency: acute elevation of BP without end-organ damage; requires reduction of BP within a few hours Calhoun DA. Hypertension: A Companion to Brenner and Recot’s the Kidney. Philadelphia, PA: WB Saunders Co.; 2000:715-718. Chobanian AV, et al. Hypertension. 2003;42:1206-1252. Varon J, Marik PE. CHEST. 2000;118:214-227. Varon J, Marik PE. Crit Care. 2003;7:374-384. Vaughan CJ, Delanty N. Lancet. 2000;356:411-417. Vidt DG. Hypertension Primer: The Essentials of High Blood Pressure. Dallas, TX: American Heart Association; 1999:437-440. 3 Acute Hypertension: Epidemiology Hypertensive emergencies – Occur in up to 500,000 patients annually – Affect >25% of patients presenting to the emergency department (ED) Perioperative hypertension – Common with cardiovascular surgery (30%–80%) – 80% incidence following carotid endarterectomy – Preoperative incidence: 50% of cardiac surgery patients and 25% of noncardiac surgery patients – Intraoperative incidence: 50% of patients undergoing cardiac surgery Biller J et al. Circulation. 1998;97:501-509. Cheung AT. J Card Surg. 2006;21:S8-S14. Erstad BL, Barletta JF. Ann Pharmacother. 2000;34:66-79. Goldman L, et al. N Engl J Med. 1977;297:845-850. Mansoor GA, Frishman WH. Heart Dis. 2002;4:358-371. National Center for Health Statistics: 1983-1990 Health Survey. Hyattesville, MD: US Dept of HHS. Towne JB, Bernhard VM. Surgery. 1980;88:575-580. Vuylsteke A, et al. J Cardiothorac Vasc Anesth. 2000;14:269-273. Zampaglione B, et al. Hypertension. 1996;27:144-147. 4 Treatment Goals for Hypertensive Emergency Prompt, but smooth reduction in BP – Reduce MAP by ≤25% during the first minute to 1 hour – If stable, reduce BP to 160/100–160/110 mm Hg in next 2–6 hours – Gradual reductions toward normal BP over next 24–48 hours – Exceptions requiring special care: ischemic stroke, stroke eligible for thrombolytic agents, aortic dissection Avoid excessive drops in BP – May cause renal, cerebral, or coronary ischemia – Need careful and close monitoring – Use an arterial catheter for monitoring BP Choice of pharmacologic agent should be tailored to patient – Based on risks, comorbidities, and type of end-organ damage US Department of Heath and Human Services. Bethesda, Md: National Institutes of Health. NIH Publication No. 04-5230. August 2004. 5 Current IV Antihypertensive Agents Agent Onset/ Duration Elimination Half-Life Adverse Events Cautions/Concerns Enalaprilat <15 min/ 12–24 h 11 h Precipitous fall in BP in high-renin states, headache, cough, renal failure, hyperkalemia, angioedema Avoid in acute MI, long duration of action Esmolol HCl 1–2 min/ 10–30 min 2–9 min Heart block, hypotension, nausea, bronchospasm, overt heart failure, cardiogenic shock Reduces cardiac output, which may impair organ perfusion Fenoldopam mesylate 5–15 min/ 30 min–4 h 5 min Tachycardia, headache, nausea, dizziness, flushing, hypotension, increased intraocular pressure Caution with glaucoma Hydralazine HCl 10–20 min/ 1–4 h 1h Marked hypotension, tachycardia, flushing Avoid in aortic dissection, MI, severe renal disease; prolonged and unpredictable effects; difficult to titrate Labetalol HCl <5 min/ 3–6 h 5.5 h Bradycardia (heart block), overt heart failure, cardiogenic shock, edema, nausea, vomiting Avoid in acute heart failure; severe bradycardia; heart block, asthma Nicardipine HCl 5–10 min/ 15 min–4 h 44.8 min Tachycardia, headache, nausea, flushing, thrombophlebitis, hypotension, vomiting Avoid in acute heart failure; caution with coronary ischemia; long duration of action Nitroglycerin 2–5 min/ 5–10 min 1–4 min Flushing, headache, vomiting, Reduction in preload and cardiac output hypotension, methemoglobinemia, undesirable in patients with compromised decreased arterial resistance, reflex renal and cerebral perfusion tachycardia Sodium nitroprusside Immediate/ 2–3 min 2–3 min Nausea, muscle twitching, sweating, thiocyanate and cyanide intoxication, hypotension Increases intracranial pressure; may reduce coronary perfusion pressure (coronary “steal”); cyanide toxicity 6 Goals of an Ideal Agent – Treat underlying pathophysiology – Rapid onset of action – Predictable dose response – Titratable to desired BP – Minimal dosage adjustments – Highly vascular selective – No increase in intracranial pressure – Rapidly reversible – Low risk of overshoot hypotension or adverse reaction – Easy conversion to oral agents – Acceptable cost–benefit ratio Levy JH. Anesthesiol Clin North Am. 1988;17:587-678. Oparil S et al. Am J Hypertens. 1999;12:653-664. 7 The Need for a New IV Antihypertensive Agent No one agent meets the goals of an ideal agent 8 Clevidipine: The First Third-Generation Calcium Channel Blocker Generic Name Brand Name Nifedipine Procardia®, Adalat® Nicardipine/Nicardipine I.V. Amlodipine Isradipine Felodipine Nimodipine/Nimodipine I.V. (Europe) Nisoldipine Cardene®/Cardene I.V. Norvasc® DynaCirc® Plendil® Nimotop®/Nimotop I.V. Clevidipine TBD First Generation Second Generation Third Generation Whiting RL, et al. Angiology. 1990;41:987-991. Sular® 9 The Clevidipine Molecule A rationally designed dihydropyridine calcium channel blocker Cl Cl H CH3OOC H3C N COOCH2OOCC3H7 CH3 H Nordlander M, et al. Cardiol Drug Reviews. 2004;22:227-250. 10 Clevidipine: Metabolized by Plasma and Tissue Esterases Clevidipine is rapidly metabolized by esterases in blood and extravascular tissue to an inactive carboxylic acid metabolite Cl Cl O O Cl O * O O Esterases O O Cl HO OH O O N H Clevidipine O + H H + O N 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. 11 Clevidipine Clinical Development Phase I Phase II Phase III N=89 N=300 N=1821 Healthy Volunteers Patients: Mild to Moderate Hypertension N=86 Patients: Perioperative N=214 Perioperative Hypertension N=1721 Severe Hypertension N=100 Tolerability, Safety, PK Dose Response Dose Response: Clevidipine vs Placebo ESCAPE: Efficacy Clevidipine vs Placebo VELOCITY: Severe Hypertension PK, Metabolism, Rates and Routes of Excretion PK/BP Hemodynamics: Clevidipine vs SNP ESCAPE: Efficacy Clevidipine vs Placebo PK PK/PD: Clevidipine vs Placebo BP, HR: Clevidipine vs SNP ECLIPSE: Safety vs NTG BP, Dose/PK ECLIPSE: Safety vs SNP BP: Clevidipine vs Placebo ECLIPSE: Safety vs NIC QTc Study Data on file. The Medicines Company. 12 Clevidipine Pharmacodynamics Clevidipine: Ultrashort Half-Life Approximate half-life: 1 min – T 1/2 (triphasic): alpha, 48 sec; beta, 2.3 min; terminal, 21.7 min – 85%–90% eliminated in first T 1/2 Triphasic Elimination Reproduced from Ericsson H, et al. Anesthesiology. 2000;92:993-1001. 14 Clevidipine: Linear Pharmacokinetics At steady state, there is a linear relationship between dosage and arterial blood concentrations Clevidipine Concentration at Css (nmol/L)* Linear relationship maintained for dosages as high as 21.9 mcg/kg/min 120 100 80 60 40 20 0 0 5 10 15 20 Dose Rate (nmol/kg/min) 25 30 35 *Css = concentration at steady state; median blood concentration of clevidipine obtained during the last 10 minutes of infusion. 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. 15 Clevidipine: Linear Dose Response Linear dose response in postoperative cardiac surgery patients Effective in 95% of patients at ≤3.2 mcg/kg/min n=19 100 Responders (%) 90 n=9 80 n=6 70 60 50 n=4 40 30 20 10 n=1 n=0 0 0 0.05 0.18 0.32 1.37 3.19 Infusion Rate (mcg/kg/min) Responders = treatment success: >10% decrease in MAP or >20% decrease in MAP at each measured concentration. Bailey JM, et al. Anesthesiology. 2002;96:1086-1094. 16 Clevidipine: Rapid Offset After discontinuation of clevidipine infusion, there was a rapid clearance BP returned to baseline in <10 minutes in healthy volunteers 100 Clevidipine Infusion MAP MAP (mm Hg) and HR (beats/min) 90 80 70 60 50 40 –5 0 5 10 15 20 25 30 35 Time (min) Reproduced from Ericsson H, et al. Anesthesiology. 2000;92:993-1001. 17 Clevidipine: Rapid Onset BP-lowering effects seen within 1–2 minutes of clevidipine infusion SBP Changes % Change From Baseline 10 5 0 –5 –10 –15 –20 SBP –25 –30 0 5 10 15 20 Time (min) SBP changes for patients receiving clevidipine during a 30-minute treatment period. Levy JH, et al. Anesthesiology. 2005;103:A354. 25 30 18 Clevidipine Selectivity/Hemodynamics Selectivity of Calcium Channel Antagonists Cl O O O H3C O Cl O H N CH3 O CH3 O * O Nicardipine Clevidipine Clevidipine Nicardipine Diltiazem Verapamil NO2 NO2 N H IV Agent CH3 COCH3 CH3OC COCH2CH2NCH2 H3COC O H3C O H N Nifedipine Vasodilation Myocardial Depression SA Node Suppression AV Node Suppression 5 5 3 4 0 0 2 4 0 0 5 5 0 0 4 5 *The chiral center of clevidipine. SA = sinoatrial; AV = atrioventricular. Kerins DM, et al. In: Goodman and Gilman’s Pharmacological Basis of Therapeutics. 2001:843-870. Massie BM. Am J CardioI. 1997;80:23I-32I. 20 Clevidipine: Vascular Selectivity Clevidipine is selective for vascular as opposed to myocardial smooth muscle therefore has no negative inotopic or chonotropic effects as opposed to other calcium channel blockers (e.g.diltiazem and verapamil) Nordlander M, et al. Cardiol Drug Reviews. 2004;22:227-250. Data on file. The Medicines Company. 21 Clevidipine: Additional Findings Animal and Ex Vivo Data Clevidipine: Evaluation of Cardioprotection Study hypothesis: clevidipine may provide a cardioprotective effect during myocardial ischemia and reperfusion – Rationale: probable mechanism related to blocking action of calcium channel Study design: pig ischemia model – Local administration of clevidipine into left anterior descending coronary artery (LAD) during late ischemia and early perfusion – Pigs subjected to 45-minute ligation of LAD followed by 4 hours of reperfusion – Five groups received either vehicle, synthase inhibitor, clevidipine, clevidipine in combination with an NO synthase inhibitor, or clevidipine in combination with an NO synthase inhibitor and an NO precursor Gourine AV, et al. Cardiovasc Res. 2001;51:100-107. Gourine AV, et al. J Cardiovasc Pharmacol. 2002;40:564-570. Nordlander M, et al. Cardiol Drug Reviews. 2004;22:227-250. 23 Clevidipine: Evaluation of Cardioprotection Study results: clevidipine reduced infarct size and preserved coronary endothelial function – Endothelium-dependent coronary vasodilation induced by substance P was significantly larger in the clevidipine group – Coronary endothelial function was preserved Infarct Size Clevidipine Reduced Infarct Size Compared With Vehicle (P<0.001) 100 90 80 70 60 50 40 30 20 10 0 86 +2% 59 +3% Vehicle Group Gourine A, et al. Cardiovasc Res. 2001;51:100-107. Clevidipine Group 24 Clevidipine: Evaluation of Renal Protection Study hypothesis: clevidipine may provide protection of renal function in ischemia/reperfusion – Rationale: calcium channel blockers have proven efficacy in providing organ protection in experimental models Study design: a rat model was used to evaluate the efficacy of clevidipine vs fenoldopam in protecting renal function – Experimental model of ischemia/reperfusion-induced acute renal failure – Renal failure induced by occlusion of the left renal artery for 40 minutes followed by release – Four groups received either saline, clevidipine, fenoldopam, or high-dose fenoldopam – Agent infused for 60 minutes, beginning 10 minutes before release of occlusion Stephens CT, Jandhyala BS. Exp Hypertens. 2002;24:301-313. 25 Clevidipine: Evaluation of Renal Protection Study results: renal protection observed with clevidipine therapy in a rat model of ischemic renal failure – Both agents were potent diuretics and natriuretics – Clevidipine infusion caused: – No change in renal blood blow – Fenoldopam infusion caused: – Increased renal blood flow – Following ischemia reperfusion injury: – Clevidipine markedly improved tubular function, while fenoldopam did not Conclusion: protection may be related to reduced calcium-mediated cellular injury and reduced oxygen free radical–mediated injury Stephens CT, Jandhyala BS. Exp Hypertens. 2002;24:301-313. 26 Clevidipine: Evaluation of Splanchnic Protection Hypothesis: clevidipine may provide splanchnic protection through increased vascular resistance Study design: in a rat model, clevidipine was infused into occluded, ischemic mesenteric arteries prior to reperfusion Study results: clevidipine prevented intense increases in mesenteric vascular resistance resulting from induced ischemia – Facilitated significant recovery of mesenteric blood flow – Prevented deterioration of mesenteric circulation during reperfusion Conclusion: behavior consistent with the action of calcium channel blockers, believed to be linked to their mechanism of action Goyal M, Jandhyala B. FASEB J. 1997;11:A285. Abstract 1654. 27 Clevidipine: Evaluation of Vasospasm Prevention Study hypothesis: clevidipine may offer an alternative to nitroglycerin for the prevention of vasospasm during CABG surgery – Spasm of of arterial grafts is common and may compromise myocardial perfusion – Resistance to nitroglycerin may limit its effectiveness in patients with long-term exposure to this agent Study design: ex vivo model – Human internal mammary artery (IMA) segments obtained during CABG surgery were precontracted with a thromboxane A2 analog – Clevidipine and nitroglycerin were added to segments to assess their effect on vasoconstriction – Clevidipine was tested in segments with and without intact endothelium Huraux C, et al. Anesth Analg. 1997;85:1000-1004. 28 Clevidipine: Evaluation of Vasospasm Prevention Study result: both clevidipine and nitroglycerin reversed vasospasm Clevidipine Response – Vasoconstricted IMAs relaxed with clevidipine in the presence or absence of endothelium 25 % Relaxation Conclusion: clevidipine may be a good alternative to nitroglycerin 0 50 75 Endothelium + Endothelium – 100 9 8 7 6 5 – log (mol/L) 4 Mean Clevidipine Concentration Reproduced from Huraux C, et al. Anesth Analg. 1997;85:1000-1004. 29 Clevidipine: Effect on Systemic and Coronary Arterial Resistance Study objective: to compare the acute systemic and coronary hemodynamic effects of clevidipine with those of sodium nitroprusside (SNP) and nitroglycerin (NTG) Study design: normal anesthetized pig model – Crossover design with a total of 8 pigs – SNP > washout > clevidipine – Clevidipine > washout > SNP – NTG > washout > clevidipine – Clevidipine > washout > NTG – Hemodynamic and perfusion measurements taken in multiple stages – Standard hemodynamics with flow probes, pressure monitors – Microsphere technique for pre-capillary perfusion Data on file. The Medicines Company. 30 Data on file. The Medicines Company. Stop Infusion MAOP – 30% MAOP – 15% Washout Colored Microsphere Colored Microsphere MAOP –30% MAOP –15% Microsphere Analysis Euthanasia Surgical Instrumentation Drug I Infusion Re-stable Hemodynamics Stop Infusion Colored Microsphere Colored Microsphere Baseline Hemodynamics Effect on Systemic and Coronary Arterial Resistance: Experimental Design Drug II Infusion 31 Effect on Systemic and Coronary Arterial Resistance: Mean Aortic Pressure % Change From Baseline Mean Aortic Pressure 0 –10 NTG SNP Clevidipine –20 –30 0 Dose 1 Dose 2 Mean ± SE; n = 8 in clevidipine group; n = 4 in SNP group; n = 4 in NTG group. Data on file. The Medicines Company. Dose 3 Dose 4 32 Effect on Systemic and Coronary Arterial Resistance: Total Peripheral Resistance % Change From Baseline Total Peripheral Resistance 0 –10 NTG SNP Clevidipine –20 –30 0 Dose 1 Dose 2 Mean ± SE; n = 8 in clevidipine group; n = 4 in SNP group; n = 4 in NTG group. Data on file. The Medicines Company. Dose 3 Dose 4 33 % Change in MAOP, CBF, CAR Clevidipine 50 25 MAOP CBF 0 –25 –50 Dose 0 0.35 0.7 1.4 2.8 % Change in MAOP, CBF, CAR % Change in MAOP, CBF, and CAR Effect on Systemic and Coronary Arterial Resistance: Epicardial Coronary Hemodynamics NTG 50 25 MAOP CBF 0 –25 –50 Dose 0 0.625 1.25 2.5 5 50 SNP 1 25 MAOP CBF 0 –25 –50 Dose 0 0.35 0.7 1.4 Data on file. The Medicines Company. 2.8 34 Clevidipine Washout SNP Whole Layer Myocardial Perfusion (Epi + Endo) 3 Flow (mL/min•g) 2.5 2 1.5 Baseline Clevidipine Re-stable SNP 1 0.5 0 0 8 Data on file. The Medicines Company. 16 24 32 40 35 NTG Washout Clevidipine Whole Layer Myocardial Perfusion (Epi + Endo) 3 Baseline NTG Flow (mL/min•g) 2.5 Re-stable Clevidipine 2 1.5 1 0.5 0 0 8 Data on file. The Medicines Company. 16 24 32 40 36 Clevidipine: Summary – The first third-generation IV dihydropyridine calcium channel blocker – Rapid onset: BP-lowering effects seen within 1–2 minutes of infusion – Ultrashort half-life with rapid offset: BP returned to baseline in <10 minutes – Specific for vascular smooth muscle: no chronotropic or inotropic effects – Lowered BP in >90% of patients with perioperative hypertension – Well tolerated in extensive safety trials – In animal model, demonstrated a cardioprotective effect during myocardial ischemia and reperfusion 37 Clevidipine Phase III Studies: Perioperative Hypertension ESCAPE-1: Preoperative ESCAPE-2: Postoperative ESCAPE: Perioperative Efficacy Trials ESCAPE-1 ESCAPE-2 Preoperative Hypertension (SBP >160 mm Hg) Postoperative Hypertension (SBP >140 mm Hg) Placebo n=52 Placebo n=49 Clevidipine n=53 Clevidipine n=61 Levy JH et al. Anesth Analg. 2007;105:918-925. Data on file. The Medicines Company. 39 ESCAPE Protocol Design: two double-blind, randomized, placebo-controlled trials – ESCAPE-1: 100 preoperative patients with SBP ≥160 mm Hg – ESCAPE-2: 100 postoperative patients with SBP ≥140 mm Hg Primary endpoint: need for alternative hypertensive agent due to lack of efficacy (either no BP reduction or reduction by a minimum of 15% from the baseline) or a safety issue Data on file. The Medicines Company. 40 ESCAPE Results: Onset and Time-to-Target Effect Onset of BP-lowering effect: within 1–2 minutes of infusion Time to target BP (15% reduction): ESCAPE-1 = 6.0 min*; ESCAPE-2 = 5.3 min† ESCAPE-2 % Change From Baseline % Change From Baseline ESCAPE-1 10 5 0 –5 –10 –15 –20 SBP –25 –30 0 5 10 15 20 Time (min) 25 30 SBP Changes 5 0 –5 –10 –15 SBP –20 –25 –30 0 5 10 15 20 Time (min) 25 30 SBP Changes Levy JH et al. Anesth Analg. 2007;105:918-925. Data on file, The Medicines Company. *Reproduced from Levy JH, et al. Anesthesiology. 2005;103:A354. †Reproduced from Singla N, et al. Anesthesiology. 2005;103:A292. 41 ESCAPE Results: Success Rate Clevidipine was successful in lowering BP to target in >90% of patients with preoperative or postoperative hypertension*† % Success 100 92.5 n=53 91.8 n=61 80 Clevidipine 60 40 20 17.3 n=52 20.4 n=49 Placebo 0 ESCAPE-1 ESCAPE-2 *Dose of 0.4–8.0 mcg/kg/min in preoperative and postoperative coronary and/or valve surgery patients. †Treatment success defined by the absence of bailout (discontinuation of clevidipine or failure to reduce SBP by ≥15%). Levy JH et al. Anesth Analg. 2007;105:918-925. Singla N, et al. Anesthesiology. 2005;103:A292. 42 ESCAPE Results: Safety In ESCAPE-1 and ESCAPE-2 trials* – Clevidipine was well tolerated – AEs were similar between clevidipine- and placebo-treated patients – AEs were as expected for a cardiac surgery population – Three AEs considered related to clevidipine treatment: atrial fibrillation, thrombophlebitis, and insomnia (1 patient each) – No clinically relevant reflex tachycardia *Modified intent-to-treat population; total of 215 randomized pre- and post-surgery patients. Data on file. The Medicines Company. Levy JH et al. Anesth Analg. 2007;105:918-925. Singla N, et al. Anesthesiology. 2005;103:A292. 43 Blood Pressure Control with Clevidipine Compared with Nitroglycerin, Sodium Nitroprusside, or Nicardipine in the Treatment of Perioperative Hypertension: Results of the Three Randomized ECLIPSE Trials Solomon Aronson, MD,FACC,FCCP,FAHA,FASE Professor and Executive Vice Chairman, Dept of Anesthesiology Duke University Health System Background Perioperative hypertension may be associated with life-threatening complications1-2 Over 50% of cardiac surgery patients experience acute perioperative hypertension requiring an IV agent1,3-4 Current intravenous antihypertensive therapies have limitations 1Cheung, 2Aronson, A. J Card Surg, 2006, S8 S. Anesth Analg 2002; 94:1079-84 3Estafanous, F. Am J Cardiol, 1980, p685; 4Landymore, R. Can J Surg, 1980 45 Rationale Clevidipine is a rationally designed IV dihydropyridine calcium channel blocker with an ultrashort half-life (~1 min) Phase I & II studies (300 patients) demonstrated: – Dose: 2–16 mg/h effective in controlling BP1 – Rapid onset: BP control within 5 min2 Phase III safety program – Endpoints: death, MI, stroke, renal dysfunction – Comparative agents: nitroglycerin (NTG), sodium nitroprusside (SNP), nicardipine (NIC) 1Bailey 2Levy J. Anesthesiology 2002;96:1086-94 JH et al. Anesth Analg. 2007;105:918-925. 46 Objectives Primary – Safety of Clevidipine in perioperative hypertension in cardiac surgery patients (Death, MI, Stroke, Renal Dysfunction) Secondary – Other adverse events – Blood pressure control Aronson S et al. Abstract 1020-169. American College of Cardiology Annual Meeting; March 24-27 2007; New Orleans, LA. Data of file, The Medicines Company. 47 Inclusion Criteria Pre-randomization – ≥ 18 years of age – Written informed consent – Planned CABG and/or valve repair/replacement surgery Post-randomization – Require treatment for perioperative hypertension per investigator decision Data of file, The Medicines Company. 48 Exclusion Criteria Women of child bearing potential CVA ≤ 3 months of randomization Intolerance to calcium channel blockers Hypersensitivity to NTG, SNP or NIC Allergy to the lipid vehicle Permanent ventricular pacing Any disease/condition that would put the patient at risk Participation in another trial within 30 days Data of file, The Medicines Company. 49 Treatment Clevidipine – Initiated at 2 mg/h either pre-op, intra-op, post-op – Titrated every 90 seconds in doubling increments until lowering of BP achieved or maximum dose of 16 mg/h – 40 mg/h maximum Comparators (NTG, SNP, NIC) as per institutional practice Treatment duration until ICU discharge Concomitant antihypertensive administered per investigator choice, but discouraged Data of file, The Medicines Company. 50 ECLIPSE: Trial Design Perioperative Perioperative Postoperative Clevidipine vs nitroglycerin Clevidipine vs sodium nitroprusside Clevidipine vs nicardipine 1:1 1:1 1:1 Clevidipine N=268 Nitroglycerin N=278 Data on file. The Medicines Company. Clevidipine N=296 Sodium nitroprusside N=283 Clevidipine N=188 Nicardipine N=193 51 Endpoints Primary* (Cumulative rate of clinical outcomes at 30 days): – Death – MI: symptomatic presentation, enzyme release, &/or new ECG changes – Stroke: Hemorrhagic or ischemic – Renal Dysfunction: Cr >2.0 mg/dL with increase ≥ 0.7 mg/dL Secondary – SAEs through day 7 – BP control during the first 24 h * Blinded CEC adjudication of all primary measures Aronson S et al. Abstract 1020-169. American College of Cardiology Annual Meeting; March 24-27 2007; New Orleans, LA. Data of file, The Medicines Company. 52 Statistical Methods Assumptions – Sample size 1500 patients recommended by FDA for safety profile assessment Descriptive analytical methods – Prespecified safety analysis by treatment received – Pooled data for clevidipine and all comparator arms – Prespecified analyses of clevidipine versus each comparator Data of file, The Medicines Company. 53 Study Completion Clevidipine Comparators Randomized patients 971 993 Met post-randomization criteria 755 757 Safety population 752 754 Completed study 715 719 Did not complete study Withdrew consent Physician decision Lost to follow up Adverse experience Patient death Other 37 0 1 15 0 20 1 35 1 0 6 0 28 0 Data on file, The Medicines Company. 54 Baseline Characteristics Clevidipine n=752 Comparators n=754 65 (24-87) 66 (19-89) Male 72% 74% Caucasian 82% 83% Hx HTN 88% 85% CHF 19% 18% Insulin dependent diabetes 11% 11% COPD 14% 15% Recent MI (< 6 mos) 17% 18% Prior CABG 3% 6% Age, median (range) Data on file, The Medicines Company. 55 Procedural Characteristics Clevidipine n=752 Comparators n=754 3.32 3.23 – CABG 77% 77% – Valve replacement/repair 14% 12% – CABG & Valve replacement/repair 9% 11% 0.3% 0.1% Surgery duration, median hrs Procedure – Other Data on file, The Medicines Company. 56 Primary Endpoint 30-Day Events (%) 10% Clevidipine Comparators 8% 7.9% 7.9% 6% 3.8% 4% 2.8% 2.3% 2.4% 1.7% 2% 1.1% 0% n=719 n=729 n=700 n=707 n=700 n=705 n=712 n=710 Death MI Stroke Renal Dysfunction Data on file, The Medicines Company. 57 Primary Endpoint by Treatment Comparison Clevidipine NTG Clevidipine SNP Clevidipine NIC Death 2.8% 3.4% 1.7% 4.7%* 4.4% 3.2% MI 3.3% 3.5% 1.4% 2.3% 2.3% 1.1% Stroke 1.6% 2.3% 1.1% 1.5% 0.6% 1.1% Renal Dysfunction 6.9% 8.1% 8.5% 9.1% 8.3% 5.9% Perioperative * p=0.045 Perioperative Postoperative Only Aronson S et al. Abstract 1020-169. American College of Cardiology Annual Meeting; March 24-27 2007; New Orleans, LA. Data of file, The Medicines Company. 58 ECLIPSE NTG: Primary Endpoint Clevidipine n/N (%) N=270 Nitroglycerin n/N (%) N=278 P Value Death 7/254 (2.8) 9/266 (3.4) 0.67 MI 8/248 (3.2) 8/260 (3.1) 0.92 Stroke 4/247 (1.6) 6/260 (2.3) 0.57 Renal Dysfunction 17/250 (6.8) 21/260 (8.1) 0.58 • MI defined as symptomatic presentation, cardiac enzyme determinations, and/or new ECG changes • Stroke: hemorrhagic or ischemic • Renal dysfunction defined as creatinine of >2 mg/dL with minimum of absolute increase ≥ 0.7 mg/dL Aronson S et al. Abstract 1020-169. American College of Cardiology Annual Meeting; March 24-27 2007; New Orleans, LA. Data of file, The Medicines Company. 59 ECLIPSE SNP: Primary Endpoint Clevidipine n/N (%) N=293 Nitroprusside n/N (%) N=283 P Value Death 5/286 (1.7) 13/274 (4.7) 0.045 MI 4/281 (1.4) 6/264 (2.3) 0.460 Stroke 3/281 (1.1) 4/262 (1.5) 0.632 Renal Dysfunction 24/284 (8.5) 24/265 (9.1) 0.802 • MI defined as symptomatic presentation, cardiac enzyme determinations, and/or new ECG changes • Stroke: hemorrhagic or ischemic • Renal dysfunction defined as creatinine of >2 mg/dL with minimum of absolute increase ≥ 0.7 mg/dL Data on file. The Medicines Company. 60 ECLIPSE NIC: Primary Endpoint Clevidipine n/N (%) N=188 Nicardipine n/N (%) N=193 P Value Death 8/181 (4.4) 6/189 (3.2) 0.530 MI 3/173 (2.3) 2/183 (1.1) 0.372 Stroke 1/173 (0.6) 2/183 (1.1) 0.595 Renal Dysfunction 15/180 (8.3) 11/185 (5.9) 0.375 • MI defined as symptomatic presentation, cardiac enzyme determinations, and/or new ECG changes • Stroke: hemorrhagic or ischemic • Renal dysfunction defined as creatinine of >2 mg/dL with minimum of absolute increase ≥ 0.7 mg/dL Data on file. The Medicines Company. 61 ECLIPSE: Blood Pressure Control Clevidipine AUC (mm Hg X min/h) Comparators AUC (mm Hg X min/h) P Value ECLIPSE–NTG 4.14 8.87 <0.001 ECLIPSE–SNP 4.37 10.50 0.003 ECLIPSE–NIC 1.76 1.69 0.851 Data on file. The Medicines Company. 62 ECLIPSE Secondary Endpoint: SBP Control Within Predefined Range Over 24 Hours SBP 145 75 Time (24 hrs) • Prespecified SBP ranges of 75–145 (pre and post-op); 65–135 (intra-op) Data on file. The Medicines Company. 63 ECLIPSE Secondary Endpoint AUC: Systolic Blood Pressure Control Over 24 Hours SBP Upper Lower Lower 0 6 12 18 24 Time (hours) Data on file, The Medicines Company. 64 Blood Pressure AUC by Treatment Group 50 p = 0.0006 p = NS p = 0.0004 44.48 45 Mean AUC (mmHg x min/h) Median value in Italics p = 0.0027 40.40 39.51 40 35.84 35 28.02 30 24.33 25 20 22.37 16.30 15 5 0 10.50 8.87 10 7.79 4.37 4.14 3.79 1.76 Clevidipine n=269 NTG n=278 ECLIPSE NTG Data on file, The Medicines Company. Clevidipine n=295 SNP n=284 ECLIPSE SNP Clevidipine n=187 1.69 NIC n=194 ECLIPSE NIC Clevidipine All Comparators n=751 n=756 ECLIPSE NTG/SNP/NIC 65 Total AUC Outside Targeted BP Range p=0.0002 111.5 mm Hg x min/h 120 Clevidipine Comparators 100 n=751 87.7 n=756 80 60 p<0.0001 40 33.1 p<0.0001 p=0.0004 20 3.8 7.8 23.1 6.6 12.5 0 SBP Ranges: 75-145 pre-/post-op 65-135 intra-op 85-145 pre-/post-op 75-135 intra-op 95-145 pre-/post-op 85-135 intra-op 105-145 pre-/post-op 95-135 intra-op Median AUC Data on file, The Medicines Company. 66 Total AUC Outside Targeted BP Range by Treatment Perioperative Postoperative Only p = 0.0027 12 10.50 p = 0.0006 mm Hg x min/h 10 8.87 8 6 4.14 4.37 4 p = 0.8508 1.76 2 1.69 0 Clevidipine NTG n=269 n=278 ECLIPSE NTG Clevidipine SNP n=295 n=284 ECLIPSE SNP Clevidipine NIC n=187 n=194 ECLIPSE NIC Median AUC Range = Pre-/post-op SBP 75-145, Intra-op SBP 65-135 Data of file, The Medicines Company. 67 Total AUC Outside Narrowed BP Range by Treatment Perioperative 140 p = 0.0556 mm Hg x min/h 120 Postoperative Only p = 0.0068 127.87 p = 0.0231 108.57 101.59 100.17 100 83.74 76.95 80 60 40 20 0 Clevidipine NTG n=269 n=278 ECLIPSE NTG Clevidipine SNP n=295 n=284 ECLIPSE SNP Clevidipine NIC n=187 n=194 ECLIPSE NIC Median AUC Range = Pre-/post-op SBP 105-145, Intra-op SBP 95-135 Data of file, The Medicines Company. 68 Perioperative BP Control : Clevidipine vs SNP P=0.0068 140 127.9 Clevidipine n=295 Sodium Nitroprusside mm Hg x min/h 120 100 100.2 n=284 80 P=0.0003 60 40 P=0.0027 20 4.4 10.5 41.5 P=0.0009 17.3 23.6 8.9 0 SBP Ranges: 75-145 pre-/post-op 65-135 intra-op Median AUC 85-145 pre-/post-op 75-135 intra-op 95-145 pre-/post-op 85-135 intra-op 105-145 pre-/post-op 95-135 intra-op Data on file. The Medicines Company. 69 Perioperative BP Control : Clevidipine vs NTG P=0.0556 mm Hg x min/h 120 108.6 Clevidipine n=269 Nitroglycerin n=278 100 83.7 80 60 P=0.0016 40 34.2 P=0.0002 P=0.0006 20 4.1 8.9 23.4 14.9 6.0 0 SBP Ranges: Median AUC 75-145 pre-/post-op 65-135 intra-op 85-145 pre-/post-op 75-135 intra-op 95-145 pre-/post-op 85-135 intra-op 105-145 pre-/post-op 95-135 intra-op Data on file. The Medicines Company. 70 Postoperative BP Control : Clevidipine vs NIC 120 P=0.0231 Clevidipine Nicardipine mm Hg x min/h 100 101.6 n=187 n=194 77.0 80 60 P=0.3086 40 P=0.8949 P=0.8508 21.6 22.8 20 1.8 1.7 5.3 5.7 0 SBP Ranges: Median AUC 75-145 post-op 85-145 post-op 95-145 post-op 105-145 post-op Data on file. The Medicines Company. 71 Serious Adverse Events Clevidipine n=752 Comparators n=754 Total 17.7% 20.0% AFIB 2.4% 2.4% Respiratory failure 1.1% 2.5% ARF 2.3% 1.7% Ventricular fibrillation 0.9% 1.5% Cardiac arrest 0.5% 1.1% CVA 0.5% 1.1% Post-procedural hemorrhage 0.5% 1.1% Data on file. The Medicines Company. 72 Use of Concomitant Antihypertensive Agents Clevidipine vs. NTG Clevidipine vs. SNP 156 (57.8) 158 (56.8) Clevidipine vs. NIC 127 (42.8) 150 (52.8) 76 (40.4) 77 (39.5) Clevidipine vs Comparators (Pooled Data) 359 (47.5) 385 (50.9) Data on file. The Medicines Company. 73 ECLIPSE NTG: Drug Administration 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) Dosed During Pre-op 92 (34.3) 119 (42.8) Dosed During Intra-op 229 (85.4) 245 (88.1) Dosed During Post-op 187 (69.8) 226 (81.3) 3.35 h 8.13 h 21.8 mL 74.8 mL Overall Infusion Duration (Median) Total Infusion Volume (Median) Data on file. The Medicines Company. 74 ECLIPSE SNP: Drug Administration 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) Dosed During Pre-op 52 (17.6) 34 (12.0) Dosed During Intra-op 209 (70.6) 185 (65.4) Dosed During Post-op 219 (74.0) 204 (72.1) 4.03 h 3.25 h 26.5 mL 25.6 mL Overall Infusion Duration (Median) Total Infusion Volume (Median) Data on file. The Medicines Company. 75 ECLIPSE NIC: Drug Administration Dosed During Post-op Overall Infusion Duration (Median) Total Infusion Volume (Median) Data on file. The Medicines Company. Clevidipine N=188 Nicardipine N=193 188(100) 193(100) 5.55 h 5.12 h 56.4 mL 163.8 mL 76 ECLIPSE: Demographics, Baseline Characteristics Clevidipine Nitroglycerin Age (median) 65.0 64.0 Male Sex (%) 79.9 74.5 Hx HTN (%) 83.6 86.3 Age (median) 64.0 65.0 Male Sex (%) 70.2 76.1 Hx HTN (%) 85.5 80.6 Age (median) 66.5 67.0 Male Sex (%) 67.0 71.5 Hx HTN (%) 96.3 87.6 Data on file. The Medicines Company. Nitroprusside Nicardipine 77 ECLIPSE: Adverse Events and BP Control AUC Quartile Death MI Stroke Renal Data on file. The Medicines Company. 1st 2nd 3rd 4th 1st 2nd 3rd 4th 1st 2nd 3rd 4th 1st 2nd 3rd 4th All Agents Combined (N=1512) n/N (%) 7/380 (1.8) 14/375 (3.7) 11/374 (2.9) 16/378 (4.2) 6/380 (1.6) 9/375 (2.4) 7/374 (1.9) 11/378 (2.9) 4/380 (1.1) 4/375 (1.1) 6/374 (1.6) 6/378 (1.6) 24/380 (6.3) 24/375 (6.4) 25/374 (6.7) 39/378 (10.3) 78 ECLIPSE: Summary of Adverse Events Clevidipine n/N (%) Nitroglycerin n/N (%) Pts with at least one AE 267/268 278/278 (99.6) (100) Pts with at least one SAE 43/268 51/283 (16.0) (18.3) Pts with at least one AE 296/296 283/283 (100) (100) Pts with at least one SAE 57/296 66/283 (19.3) (23.3) Pts with at least one AE 187/188 193/193 (100) (100) Pts with at least one SAE 33/188 34/193 (17.6) (17.6) Data on file. The Medicines Company. Nitroprusside n/N (%) Nicardipine n/N (%) 79 ECLIPSE: Atrial Fibrillation Afib (total) CLV n/N (%) NTG n/N (%) SNP n/N (%) NIC n/N (%) 275/752 (36.6) 91/278 (32.7) 95/283 (33.6) 71/193 (36.8) • No statistically significant differences in any of the arms or in overall comparison Data on file. The Medicines Company. 80 Conclusions Clevidipine is a safe alternative to currently available intravenous antihypertensive agents Clevidipine demonstrated superior efficacy in blood pressure control as compared to currently available intravenous antihypertensive agents over the first 24 hours of therapy Aronson S et al. Abstract 1020-169. American College of Cardiology Annual Meeting; March 24-27 2007; New Orleans, LA. Data of file, The Medicines Company. 81 Blood Pressure Control is an Independent Predictor of Short-term Mortality in Cardiac Surgery Patients: Analysis from the Three Randomized ECLIPSE Trials Solomon Aronson, MD,FACC,FCCP,FAHA,FASE Professor and Executive Vice Chairman, Dept of Anesthesiology Duke University Health System Statistical Analysis Data pooled for 1512 patients A multiple logistic regression analysis was performed to determine the association of BP control with 30-day mortality BP control was expressed as the cumulative area under the curve (AUC) outside specified SBP ranges AUC was analyzed as a continuous variable Data on file, The Medicines Company. 83 SBP Control Within Predefined Range Over 24 Hours SBP 145 75 Time (24 hrs) • Prespecified SBP ranges of 75–145 (pre and post-op); 65–135 (intra-op) Data on file. The Medicines Company. 84 Logistic Regression Model Selection Candidate variables included: – Demographics – Baseline characteristics – Medical history – Treatment group – AUC – Procedural characteristics p<0.05 required for inclusion in final output Data on file, The Medicines Company. 85 Logistic Regression Results: Predictors of Mortality P-Value Odds Ratio 95% CI [Lower Limit, Upper Limit] Surgery Duration (hour) <0.0001 1.517 [1.240, 1.856] Age (year) 0.0003 1.070 [1.031, 1.110] Pre-op Creatinine ≥ 1.2 mg/dL 0.0031 2.670 [1.392, 5.122] AUC (1mmHg*min) 0.0069 1.003 [1.001, 1.004] Additional surgical procedures 0.0089 2.409 [1.246, 4.655] Pre-op Hgb (g/dL) 0.0135 0.824 [0.707, 0.961] Pre-op SBP >160 or DBP > 105 0.0228 2.386 [1.147, 4.963] History of COPD 0.0228 2.326 [1.125, 4.812] History of recent MI (<6 months prior) 0.0312 2.197 [1.073, 4.497] Data on file, The Medicines Company. 86 30-Day Mortality by Magnitude of AUC Odds Ratio 95% CI [Lower Limit, Upper Limit] I mmHg x 60 min 1.20 [1.06, 1.27] 2 mmHg x 60 min 1.43 [1.13, 1.61] 3 mmHg x 60 min 1.71 [1.20, 2.05] 4 mmHg x 60 min 2.05 [1.27, 2.61] 5 mmHg x 60 min 2.46 [1.35, 3.31] 0 Data on file, The Medicines Company. 1 2 3 4 87 Conclusions Excursions outside a targeted BP range are correlated with 30-day mortality This relationship is direct and proportionate to the magnitude of excursions outside the BP range These data suggest that great attention should be given to precise peri-operative BP control Future analysis of this finding is warranted Data on file, The Medicines Company. 88 Clevidipine: Arterial Selectivity Systemic Vascular Resistance Mean Arterial Pressure † † † 70 Units mm Hg * 1200 1000 0 C1 0.375 0.75 1.5 3 C2 mcg/kg/min ‡ † † † mm Hg 1400 90 80 Central Venous Pressure C1 0.375 0.75 1.5 3 C2 mcg/kg/min *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. Kieler-Jensen N, et al. Acta Anaesthesiol Scand. 2000;44:186-193. 12 10 8 6 4 2 0 0 0.375 0.75 1.5 3 0 mcg/kg/min 89 Clevidipine: Coronary Effects In postoperative patients – Increased stroke volume, cardiac output – No reflex increase in HR or changes in cardiac preload – Lower SVR, higher cardiac filling pressures and RVEDV vs SNP 6 5 4 3 2 1 0 Stroke Volume * 75 mL/beat L • min–1 Cardiac Output C1 0.375 0.75 1.5 3 C2 † 70 65 0 C1 Infusion Rate (µg • kg–1 • min–1) *P<0.05. †P<0.001. SVR = systemic vascular resistance; RVEDV = right ventricular end-diastolic volume. Data from Kieler-Jensen N, et al. Acta Anaesthesiol Scand. 2000;44:186-193. 0.375 0.75 1.5 3 Infusion Rate (µg • kg–1 • min–1) C2 90 Clevidipine: Minimal Effect on Heart Rate 10 5 HR 0 –5 0 5 10 15 20 Time (min) Postoperative HR Changes in Anesthetized Patients % Change From Baseline % Change From Baseline Preoperative HR Changes in Non-Anesthetized Patients 25 30 HR changes for patients during the 30-minute treatment period 5 0 HR –5 0 5 10 15 20 Time (min) 25 30 HR changes for patients during the 30-minute treatment period Levy JH et al. Anesth Analg. 2007;105:918-925. Levy JH et al. Anesthesiology. 2005;103:A354. Singla N et al. Anesthesiology. 2005;103:A292. 91 92 What is VELOCITY? Multi-center, Phase III, open-label, single-arm, study to confirm the safety of IV clevidipine for patients who present to the ED (or ICU) with severe hypertension requiring parenteral treatment for at least 18 h Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American College of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA. 93 VELOCITY: Rationale Clevidipine is a rationally designed IV dihydropyridine calcium channel blocker with an ultrashort half-life (~1 min) Phase I & II studies (300 patients) demonstrated: – Dose: 2–16 mg/h effective1 – Rapid onset: BP control in 5 min2 Clevidipine’s quick onset/offset, good safety profile, predictable dose-response effect, good hemodynamic properties, and easy titration make it a good candidate for treatment of severe hypertension in acute care settings 1Bailey 2Levy J. Anesthesiology. 2002;96:1086-1094. JH et al. Anesth Analg. 2007;105:918-925. 94 VELOCITY: Rationale (cont.) Phase III safety and efficacy study – Evaluation: to confirm the safety and efficacy of clevidipine in patients with severe HTN using a predefined, non-weight based dosing algorithm – Population: patients presenting in the Emergency Department with severe HTN (SBP >180 mmHg or DBP >115 mmHg) assessed at 2 successive occasions 15 min apart at baseline Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American College of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA. 95 VELOCITY: Objectives Primary Confirm the safety of a titration dosing regimen of an IV infusion of clevidipine for the treatment of severe HTN – Efficacy: percentage of patients in whom SBP fell within the initial SBP target range within 30 min of initiating infusion – Safety: percentage of patients in whom SBP fell below the lower limit of the initial SBP target range within 3 min of initiating infusion Data on file. The Medicines Company. 96 VELOCITY: Objectives (cont.) Secondary Efficacy: – Time to attainment of 30-min SBP target range Safety: – Change in heart rate during the 30-min period from initiation of infusion – Dose of clevidipine during the treatment period – Of the patients converted to oral antihypertensive therapy, the proportion of those with successful transition, defined as SBP within the last specified target range at 6 hr after cessation of clevidipine infusion – Safety of prolonged infusion of clevidipine (≥18 hr) Data on file. The Medicines Company. 97 VELOCITY: Enrollment Criteria Inclusion Criteria – Age 18 years and older – Systolic BP >180 mmHg and/or diastolic BP >115 mmHg assessed on 2 successive occasions, 15 min apart – Provide written informed consent before initiation of any study-related procedures Exclusion Criteria – SBP ≤180 mmHg and DBP ≤115 mmHg – Expectation that the patient will not tolerate IV antihypertensive therapy for a minimum of 18 hr – Known or suspected aortic dissection Data on file. The Medicines Company. 98 VELOCITY: Treatment Clevidipine – Selection of Initial Target Range (ITR) was determined prior to the initiation of clevidipine – ITR was determined for each individual patient – The difference between the upper and lower ITR was between 20 mmHg and 40 mmHg Data on file. The Medicines Company. 99 VELOCITY: Treatment (cont.) Clevidipine initiated at 2 mg/hr via peripheral vein Titrated in doubling increments Q3 min, not to exceed 32 mg/hr, to achieve pre-specified ITR Infusion rate could have been decreased at the investigators discretion in order to achieve the target SBP Infusion was maintained or further titrated after the first 30 min to achieve the desired long-term reduction in SBP Treatment duration for at least 18 hr and not exceeding 96 hr BP monitoring was done with a BP cuff Data on file. The Medicines Company. 100 VELOCITY: Treatment – Transition to Oral Therapy If transition to an oral antihypertensive agent was required, the agent could be given 1 hr prior to the anticipated cessation of clevidipine infusion but not before the 18 hr time point At any time following the administration of the oral agent, the clevidipine infusion could have been down-titrated or terminated in order to achieve the desired BP level If the BP rose to an undesirable level upon cessation of the infusion, additional oral therapy may have been added or clevidipine infusion may have been restarted Data on file. The Medicines Company. 101 VELOCITY: Sites Data on file. The Medicines Company. 102 VELOCITY Study ‘Statistics’ No of sites: No of enrolling sites: Enrollment period (FPI to LPI): Highest enrollers: 14 12 4th Sept 06 to 28th Jan 07 (146 days) ~5 mths Dr Garrison/Mary Jones: 40 patients Dr Varon/Michelle Bunch/Carliss Ramos: 39 patients Database lock: (LPO to DB Lock): 11 days Data on file. The Medicines Company. 103 VELOCITY: Patient Demographics Parameter Value Age (yrs) 53.5 ± 15 Gender (%) Male 48 Female 52 BMI (kg/m2) 30 ± 7.6 Race (%) African American 77 White 16 Hispanic 6 Asian 1 SBP (mmHg) 202 ± 22 DBP (mmHg) 111 ± 21 ITR (high, low) 175, 143 Safety Population, N=126. Mean ± SD Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American College of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA. 104 VELOCITY: Results – Medical History, Comorbidity, and EndOrgan Dysfunction Medical History Percent (%) End organ injury 81 Myocardial infarction 5 Renal disease 25 Dialysis dependent 11 Coronary artery disease 28 Hypertension 97 Previous hospitalization for hypertension 31 Congestive heart failure 18 Dyslipidemia 37 Smoker Current / Former 39 / 21 Diabetes 31 Stroke 11 Safety Population, N=126. Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American College of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA. 105 VELOCITY: Patient Disposition ITT (patients enrolled) N=131 SBP ≤UL of target range n=14 mITT (patients with SBP >UL of target range) N=117 No clevidipine n=5 Safety (patients who received at least 1 dose) N=126 <18 hr treatment n=9 DNC n=12 Completed Patients n=105 ≥18 hr continuous infusion n=117 DNC n=7 Completed Patients n=114 DNC=did not complete. Data on file, The Medicines Company. Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American College of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA. Completed Patients n=110 106 In VELOCITY… “End-organ damage” is inclusive of acute and chronic findings readily apparent in the ED: – Hypertensive changes on funduscopy – LVH on ECG – Renal dysfunction – Serum creatinine (above the normal lab limits) – Calculated creatinine clearance < 90 mL/min – > Trace proteinuria – > Trace hematuria – Acute heart failure – Acute focal neurologic abnormalities – Objective evidence of ACS – Ischemic ST-segment changes – Positive biomarkers of myocardial necrosis Data on file. The Medicines Company. 107 VELOCITY: Results Initial infusion rate 2 mg/hr (4 mL/hr) Time to first achievement to Initial Target Range (ITR) – 10.9 min (95% CI 9.0, 15.0) – Median dose 4 mg/hr (max 11 mg/hr) mITT population Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American College of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA. 108 VELOCITY: Results 89% of patients achieved pre-specified ITR within 30 min – An additional 7% of patients achieved ITR after 30 min – Of the 96% of patients who did not have protocol violations with selection of ITR, 90% achieved the ITR within 30 min From drug initiation to 30 min – Median infusion rate 6 mg/h (max 15 mg/h) Time to a 15% drop in blood pressure 9.5 min Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American College of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA. 109 VELOCITY: Results Only 2 patients (1.6%) fell below the lower ITR limit within first 3 min – One patient had narrower than specified ITR (205-195 mmHg), SBP was 15 mmHg below the lower limit – One patient lower limit was 160 mmHg and SBP fell 4 mmHg below this – Both patients continued clevidipine infusion beyond 18 hr without AEs – No hypotensive events were reported mITT population Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American College of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA. Data on file. The Medicines Company. 110 Percent of Patients VELOCITY: Probability of Having Attained Initial SBP Range 100 90 80 70 60 50 40 30 20 10 0 91% 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Minutes K-M Analysis Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American College of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA. 111 % Reduction from Baseline SBP (Mean ± SE) VELOCITY: Results – Change in BP (30 min) 0 -5 -6% -10 -15 -21% -16.5% -20 -25 3 6 9 12 15 18 21 24 27 30 Time after start of infusion (min.) mITT population Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American College of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA. 112 % Reduction from Baseline SBP (Mean ± SE) VELOCITY: Results – Change in BP (18 hour) 0 -5 -10 -15 -20 -25 -30 0 3 6 9 12 15 18 Time after start of infusion (hours) Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American College of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA. 113 VELOCITY: Results – Safety TEAEs by Organ System Class, >5% End Organ Injury Yes (N=102) No (N=24) All Patient s (N=126) n (%) n (%) n (%) Number of patients with at least one TEAE 41 (40.2) 9 (37.5) 50 (39.7) Nervous system disorders 12 (11.8) 5 (20.8) 17 (13.5) General disorders and administration site conditions 9 (8.8) 3 (12.5) 12 (9.5) Gastrointestinal disorders 7 (6.9) 2 (8.3) 9 (7.1) Investigations 9 (8.8) 0 (0.0) 9 (7.1) Cardiac disorders 7 (6.9) 1 (4.2) 8 (6.3) Respiratory, thoracic, and mediastinal disorders 6 (5.9) 1 (4.2) 7 (5.6) System Organ Class TEAE=treatment-emergent adverse events. Data on file. The Medicines Company. 114 VELOCITY: Results – Transition to Oral Antihypertensives Transition to oral antihypertensive therapy was successful in 91.3% of patients Of the 11 not transitioning to oral therapy within 6 h of IV termination: – 2.4% could not be converted from clevidipine – 3.2% did not reach the 18-h end point for transition eligibility – 3.2% had contraindications to oral transition – Contraindications included 3 patients having severe medical events preventing the initiation of oral therapy and 1 patient receiving another IV therapy Of the 118 patients eligible for transition, 97.5% did so within 6 h Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American College of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA. Data on file. The Medicines Company. 115 What We Learned From VELOCITY Reliably lowered BP to pre-specified target range in 90% of patients within 30 min Predictably reached target BP without overshoot in a median 10.9 min Clevidipine was easy to administer and well tolerated – Peripheral venous administration and BP monitoring via a cuff was safe and feasible in the ED Peacock FW et al. IV clevidipine for hypertension: safety, efficacy and transition to oral therapy. Poster presented at the American College of Emergency Physicians Annual Meeting; October 8-11, 2007; Seattle, WA. Data on file. The Medicines Company. 116 Perioperative Blood Pressure Control Predicts Renal Dysfunction in Cardiac Surgery Patients Solomon Aronson, MD,1 Albert Cheung, MD,2 Kevin Stierer, MD,3 Jerrold H. Levy, MD,4 Philip Lumb, MD5 for the DCRI-GPRO Investigators 1Dept of Anesthesiology, Duke University Medical Center, Durham, NC; 2Dept of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA; 3Heart Institute at St. Joseph Medical Center, Towson, MD; 4Dept of Anesthesiology, Emory University School of Medicine, Atlanta, GA; 5Dept of Anesthesiology, Keck School of Medicine, University of Southern California, Los Angeles, CA Aronson S et al. Perioperative blood pressure control predicts renal dysfunction in cardiac surgery patients. Presented at the American Society of Anesthesiologists Annual Meeting. Oct. 15, 2007; San Francisco, CA. 117 Background As many as 56% of cardiac surgery patients develop perioperative hypertension requiring IV therapy.1 Perioperative hypertension in cardiac surgery patients is associated with life-threatening complications,1-2 but evidence that active BP control improves outcomes is lacking. The recently completed ECLIPSE trials showed that perioperative BP control (assessed as integral analysis of SBP excursions outside specified ranges over time) is associated with treatment protocol.3 In addition, logistic regression analysis of pooled ECLIPSE data showed that perioperative BP control is a significant predictor of 30-day mortality4 (p<0.01, OR 1.003 [95% CI 1.001-1.004]). Further analysis of the ECLIPSE database was performed to evaluate perioperative BP control as a predictor of renal dysfunction at 30 days. 1. Cheung AT. J Card Surg. 2006;21:S8-S14. 2. Aronson S et al. Circulation. 2007;115:733-742. 3. Aronson S et al. Blood pressure control with clevidipine compared with nitroglycerin, sodium nitroprusside, or nicardipine in the treatment of perioperative hypertension: results of the three randomized ECLIPSE trials. Am Col Cardiol. March 27, 2007; New Orleans, LA. 4. Aronson S et al. Blood pressure control is an independent predictor of short-term mortality in cardiac surgery patients: Analysis from the three randomized ECLIPSE trials. Late-breaking clinical trials. Am Coll Cardiol. March 26, 2007; New Orleans, LA. 118 Methods (slide 1 of 2) The 3 open-label ECLIPSE trials compared clevidipine with NTG, SNP or NIC for perioperative BP management in cardiac surgery patients. Clevidipine is an IV dihydropyridine calcium channel blocker with an ultrashort half-life (~1 min). Pre-randomization inclusion criteria: ≥18 years old; planned CABG, OPCAB, or valve surgery. Post-randomization inclusion criterion: needing treatment for perioperative hypertension. Exclusion criteria: CVA ≤3 months of randomization; permanent ventricular pacing; hypersensitivity, intolerance or allergy to study drugs; any disease/condition that would put patient at risk. Clevidipine was initiated at 2 mg/h and titrated in doubling increments Q 90s up to 16 mg/h (40 mg/h maximum); comparators administered per institutional practice. Aronson S et al. Perioperative blood pressure control predicts renal dysfunction in cardiac surgery patients. Presented at the American Society of Anesthesiologists Annual Meeting. Oct. 15, 2007; San Francisco, CA. 119 Methods (slide 2 of 2) Patients were treated up to ICU discharge. Hemodynamics were monitored for 24 h post-study drug initiation. Multiple logistic regression analysis was performed on pooled data from all 3 ECLIPSE trials to assess the relationship between BP control and 30-day renal dysfunction (Cr >2.0 with minimum increase of 0.7 mg/dL). Blood pressure control was assessed as the cumulative AUC outside specified SBP ranges; AUC was analyzed as a binary variable. Aronson S et al. Perioperative blood pressure control predicts renal dysfunction in cardiac surgery patients. Presented at the American Society of Anesthesiologists Annual Meeting. Oct. 15, 2007; San Francisco, CA. 120 Safety Population Baseline Characteristics Patients N=1506 Age, median (range) 65 (19-89) Male 73% Caucasian 83% History of HTN 86% CHF 19% COPD 14% Recent MI (<6 mos) 18% Prior CABG 4% Aronson S et al. Perioperative blood pressure control predicts renal dysfunction in cardiac surgery patients. Presented at the American Society of Anesthesiologists Annual Meeting. Oct. 15, 2007; San Francisco, CA. 121 Safety Population Procedural Characteristics Patients N=1506 Treatment Clevidipine 49.9% NTG 18.5% SNP 18.8% NIC 12.8% Surgery duration, median hrs 3.48 Procedure CABG 73.9% Valve repair or replacement 11.7% CABG & valve surgery 8.4% Other 0.2% Aronson S et al. Perioperative blood pressure control predicts renal dysfunction in cardiac surgery patients. Presented at the American Society of Anesthesiologists Annual Meeting. Oct. 15, 2007; San Francisco, CA. 122 Logistic Regression Model Multiple logistic regression analysis with model-building processes was performed to identify variables predicting an increased risk of 30-day renal dysfunction. Candidate variables included: – Demographics – Baseline characteristics – Medical history – Treatment group – Procedural characteristics – AUC For inclusion in final output, p<0.05 was required. Aronson S et al. Perioperative blood pressure control predicts renal dysfunction in cardiac surgery patients. Presented at the American Society of Anesthesiologists Annual Meeting. Oct. 15, 2007; San Francisco, CA. 123 Results of Logistic Regression Predictors of 30-day Renal Dysfunction 95% Odds Confidence P value Ratio Interval Pre-op serum Cr ≥1.2 mg/dl <0.0001 5.466 3.506, 8.521 Pre-op hemoglobin (g/dL) <0.0001 0.785 0.699, 0.881 Body mass index 0.0074 1.049 1.013, 1.087 Surgery duration (hour) 0.0077 1.292 1.070, 1.559 Age (year) 0.0086 1.033 1.008, 1.059 BP (4th quartile of AUC*) 0.0126 1.785 1.132, 2.815 Race (African American) 0.0151 2.164 1.161, 4.035 Primary CABG + valve 0.0165 1.944 1.129, 3.348 *Total AUC of the magnitude and duration of SBP excursions outside the range of 85-145 mmHg pre- and postoperatively, and 75-135 mmHg intraoperatively; patients with AUC ≥75th percentile analyzed. Aronson S et al. Perioperative blood pressure control predicts renal dysfunction in cardiac surgery patients. Presented at the American Society of Anesthesiologists Annual Meeting. Oct. 15, 2007; San Francisco, CA. 124 Results of AUC Comparison by Treatment Median Total AUC (4th Quartile) of BP Excursions outside Targeted SBP range p=0.008 400 354.6 mm Hg x min/h 350 300 n=187 Clevidipine Comparators n=189 250 p<0.0001 200 150 327.2 p<0.0001 p<0.0001 82.4 100 50.4 161.2 121.9 93.4 64.4 50 0 75-145 pre-/postop 85-145 pre-/postop 95-145 pre-/postop 105-145 pre-/postop 75-135 intraop 95-135 intraop 85-135 intraop 65-135 intraop Comparison between CLV and all comparators combined (pooled data) of total AUC (median) for BP excursions outside specified SBP ranges in mmHg Patients with AUC in ≥75th percentile (those with greatest magnitude and duration of BP excursions outside target SBP range) analyzed For the targeted SBP range and increasingly narrow ranges (lower limit increased by increments of 10 mmHg), patients treated with CLV had lower AUC than patients in all other treatment groups combined Aronson S et al. Perioperative blood pressure control predicts renal dysfunction in cardiac surgery patients. Presented at the American Society of Anesthesiologists Annual Meeting. Oct. 15, 2007; San Francisco, CA. 125 Conclusions Perioperative BP excursions outside a targeted SBP range are correlated with renal dysfunction at 30 days. Cardiac surgery patients with the greatest magnitude and/or duration of BP excursions outside the SBP range (4th quartile AUC) were at risk of renal dysfunction at 30 days. This result is consistent with the previously reported relationship between BP control and 30-day mortality. Patients with the greatest magnitude and/or duration of BP excursions outside target SBP range (4th quartile AUC) showed improved BP control with clevidipine. These findings suggest that treatment to attain more precise perioperative BP control is important and may be especially significant in patients who are most at risk for labile perioperative BP. Further study of the relationship between perioperative BP control and patient outcomes is warranted. Aronson S et al. Perioperative blood pressure control predicts renal dysfunction in cardiac surgery patients. Presented at the American Society of Anesthesiologists Annual Meeting. Oct. 15, 2007; San Francisco, CA. 126 The Pharmacokinetics and Pharmacodynamics of Clevidipine after Prolonged Continuous Infusion in Patients with Essential Hypertension William B. Smith, MD,1 Thomas C. Marbury, MD,2 Steven F. Komjathy, MD,3 Mark Sumeray, MD4 1New Orleans Center for Clinical Research, Knoxville, TN; 2Orlando Clinical Research Center, Orlando, FL; 3PRA International Clinical Pharmacology Center, Lenexa, KS; 4The Medicines Company, Parsippany, NJ Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO. 127 Background Clevidipine is a novel 3rd-generation dihydropyridine calcium channel blocker under study as IV treatment for acute and severe hypertension.1 As an arterioselective vasodilator, clevidipine directly reverses arterial vasoconstriction, which predominantly underlies hypertension.2,3 Clevidipine is rapidly eliminated through esterase metabolism and demonstrates an ultrashort half-life of approx 1 min and a fast-on, fast-off pharmacologic profile4,5 Prior to this study, clinical experience with prolonged clevidipine infusion was limited This study evaluated the pharmacology and safety of continuous prolonged (72 h) clevidipine infusion in patients with mild to moderate essential hypertension. 1. Nordlander M et al. Cardiovascr Drug Rev. 2004;22(3):227-250. 2. Kieler-Jensen N et al. Acta Anaesthesiol Scand. 2000;44:186-193. 3. Marik PE et al. CHEST 2007;131:1949-1962. 4. Ericsson H et al. Anesthesiol. 2000;92:993-1001. 5. Ericsson H et al. Br J Clin Pharmacol 1999;47:531-538. 128 Methods (slide 1 of 3) Study Design: randomized, placebo-controlled, single-blind study in patients with mild to moderate essential hypertension. Treatment: – Clevidipine (0.5 mg/mL in 20% lipid emulsion) in dose cohorts of 2.0 mg/h, 4.0 mg/h, 8.0 mg/h, or 16.0 mg/h; or – Placebo (Intralipid 20% lipid emulsion) Clevidipine administered IV at initial infusion rate of 2.0 mg/h and force-titrated by doubling increments every 3 min to target dose. Placebo administered similarly. Target dose maintained continuously for 72 hours. Patients were followed for 7 days from study drug initiation. Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO. 129 Methods (slide 2 of 3) Patient Selection: Patients aged 18-80 years old with mild to moderate essential hypertension (treated or untreated) Treated patients withdrew from oral anti-HTN medications for 8-14 days prior to study drug administration While untreated, patients were assessed for systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) at least twice, at least 30 min apart, on 3 separate days to confirm study eligibility To be eligible, patients had to have: – SBP ≥140 and <200 mmHg, and/or DBP ≥95 and <115 mmHg; and – HR <120 bpm Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO. 130 Methods (slide 3 of 3) Other inclusion criteria: – Clinical laboratory results (screening chemistry, hematology, fasting lipid panel) within normal limits and/or considered clinically insignificant – Negative drug / alcohol screening tests – Negative urine pregnancy test (women of childbearing potential) Exclusion criteria included: – Taking 5 or more oral anti-hypertension meds – Secondary hypertension – Severe cardiovascular disease such as severe arrhythmia, CHF, aortic dissection or ischemia requiring nitrates – MI or CVA within last 6 months – History of cerebral hemorrhage or intracranial tumor – Liver failure or cirrhosis – Unwilling to stop smoking or stop caffeine or alcohol intake during study Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO. 131 Results Patient Population: 61 patients were enrolled; 1 patient in Cohort 3 withdrew prior to PK evaluation; 60 patients completed the study Intent-to-treat (ITT) and safety populations (N=61): – Cohort 1 (clevidipine 2.0 mg/h): 10 patients – Cohort 2 (clevidipine 4.0 mg/h): 10 patients – Cohort 3 (clevidipine 8.0 mg/h): 18 patients – Cohort 4 (clevidipine 16.0 mg/h): 10 patients – Cohort 5 (placebo): 13 patients Per-protocol population (N=53): – Cohorts 1-4: 10 patients in each cohort – Cohort 5: 13 patients – Defined as all patients who received 72 h treatment at target dose and had blood samples for PK analysis drawn correctly – (excludes the 1 patient who withdrew and 7 patients in Cohort 3 whose blood samples were drawn from the clevidipine IV cannula) Dose cohorts were balanced with respect to baseline characteristics Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO. 132 Screening Demographics and Medical History Clevidipine Placebo N=13 2.0 mg/h N=10 4.0 mg/h N=10 8.0 mg/h N=18 16.0 mg/h N=10 55 56 47 52 56 Mean weight (kg) 88.1 87.4 105.3 93.6 99.9 2 32.1 30.2 34.3 30.6 34.4 Mean age (yr) Mean BMI (kg/m ) Male 7 (53.8%) 5 (50.0%) 7 (70.0%) 14 (77.8%) 7 (70.0%) Smoker 3 (23.1%) 2 (20.0%) 2 (20.0%) 2 (11.1%) 0 (0.0%) Dyslipidemia 2 (15.4%) 5 (50.0%) 1 (10.0%) 3 (16.7%) 2 (20.0%) Diabetes (non-insulin-dep) 2 (15.4%) 3 (30.0%) 3 (30.0%) 3 (16.7%) 3 (30.0%) Diabetes (insulindep) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Angina pectoris 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) COPD 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (10.0%) Renal disease 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Stroke 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) ITT / Safety Population Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO. 133 Pharmacodynamics All clevidipine dose cohorts showed a rapid onset of drug effect (decrease in SBP from baseline) Clevidipine drug effect was consistent throughout the 72-h treatment period, with no evidence of diminishing effect (tolerance) Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO. 134 Mean % Change in SBP from Baseline vs Time Over the Entire Study Drug Infusion Period (All Cohorts) PP Population SBP returned to baseline after drug treatment was stopped, with no evidence of rebound Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO. 135 Mean % Change in SBP from Baseline vs Time after the End of Study Drug Infusion (Cohort 1 vs Placebo) (Cohort 2 vs Placebo) (Cohort 3 vs Placebo) (Cohort 4 vs Placebo) Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO. 136 Pharmacokinetics Clevidipine was rapidly metabolized throughout the 72-h infusion period Clevidipine blood concentrations decreased bi-exponentially following infusion The concentration-time profile for clevidipine was similar across all dose cohorts Calculated clevidipine mean clearance = ~30 L/min, and was similar across dose cohorts Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO. 137 Mean Clevidipine Blood Concentrations vs Time over the 72-h Infusion Time through 60 min PostInfusion (All Cohorts) Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO. 138 Mean Blood Clevidipine Concentrations vs Time from End of Infusion to 1 h Post-Infusion (All Cohorts) Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO. 139 Safety No deaths or serious adverse events (AEs) occurred during the study One patient had AEs (facial pressure, headache and nausea) leading to clevidipine discontinuation and study withdrawal; all AEs resolved the same day they occurred The most commonly reported AEs across treatments and dose levels were headache and infusion site reaction, swelling, and erythema No dose- or treatment-related differences in AE incidence, description, severity or duration were apparent between the clevidipine dose cohorts Other clinical safety assessments (ECG, laboratory results) were unremarkable overall Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO. 140 Conclusions After prolonged (72 h) continuous clevidipine infusion: – No drug tolerance developed – The decrease from baseline in SBP was maintained at relatively constant levels – No evidence of rebound HTN was observed upon discontinuation – A rapid return to baseline SBP was observed after stopping clevidipine infusion across all dose levels – Clevidipine PK and PD are consistent with previously reported findings1 Prolonged (72 h) continuous clevidipine infusion was well tolerated by patients with essential hypertension. Smith WB et al. Abstract 221. American College of Clinical Pharmacy Annual Meeting. October 14-17 2007; Denver, CO. 141