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CARDIOVASCULAR ANESTHESIOLOGY

Clevidipine Effectively and Rapidly Controls Blood Pressure Preoperatively in Cardiac Surgery Patients: The Results of the Randomized, Placebo-Controlled Efficacy Study of Clevidipine Assessing Its Preoperative Antihypertensive Effect in Cardiac Surgery-1

Jerrold H. Levy, MD^*, Miguel Y. Mancao, MD, Richard Gitter, MD, Dean J. Kereiakes, MD, FACC^||, Alina M. Grigore, MD^¶, Solomon Aronson, MD, FACC, FCCP, FAHA^#, and Mark F. Newman, MD^#

From the *Cardiothoracic Anesthesiology and Critical Care, Emory University Hospital, Atlanta, Georgia; Sacred Heart Health System, Pensacola, Florida; Birmingham Baptist Medical Center Montclair, Birmingham, Alabama; Lindner Research Center and ||Christ Hospital Heart and Vascular Center, The Linder Research Center, Cincinnati, Ohio; ¶Mayo Clinic Hospital, Department of Anesthesiology, Phoenix, Arizona; and #Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina.

Address correspondence and reprint requests to Jerrold H. Levy, MD, Cardiothoracic Anesthesiology and Critical Care, Emory University Hospital, 1364 Clifton Road, NE, Atlanta, GA 30322. Address e-mail to jerrold.levy{at}emoryhealthcare.org.

Abstract

BACKGROUND: Clevidipine is an ultrashort-acting, third-generation IV dihydropyridine calcium channel blocker that exerts rapid and titratable arterial blood pressure reduction, with fast termination of effect due to metabolism by blood and tissue esterases. As an arterial-selective vasodilator, clevidipine reduces peripheral vascular resistance directly, without dilating the venous capacitance bed. In this randomized, double-blind, placebo-controlled multicenter trial we evaluated the efficacy and tolerability of clevidipine in treating preoperative hypertension.

METHODS: One-hundred-fifty-two patients scheduled for cardiac surgery with current or recent hypertension were randomized to receive clevidipine or placebo preoperatively. One-hundred-five patients met postrandomization entrance criteria (systolic blood pressure [SBP] 160 mm Hg after inserting an arterial catheter) for reduction by 15% from baseline in SBP. The patients thus received infusions of clevidipine (0.4–8.0 µg · kg^–1 · min^–1) or 20% lipid emulsion (placebo) for at least 30 min. Treatment failure was defined as failure to reduce SBP by 15% from baseline or discontinuance of drug for any reason.

RESULTS: Patients treated with clevidipine demonstrated a 92.5% rate of treatment success and a significantly lower rate of treatment failure (7.5%, 4 of 53) than patients receiving placebo (82.7%, 43 of 52; P < 0.0001). Clevidipine achieved target blood pressures (SBP reduced by 15%) at a median of 6.0 min (95% confidence interval 6–8 min). A modest increase in heart rate from baseline occurred during clevidipine administration. Adverse events for each treatment group were similar.

CONCLUSIONS: Clevidipine was effective in rapidly decreasing blood pressure preoperatively to targeted blood pressure levels and was well tolerated in patients scheduled for cardiac surgery.

Acute hypertension in patients undergoing cardiac surgery contributes directly and indirectly to postoperative morbidity, including myocardial ischemia due to increased myocardial oxygen demand, bleeding due to possible disruption of arterial suture lines, and neurologic complications (1–6). It is generally accepted that the rapid, controlled treatment of increases in arterial blood pressure is important for minimizing the risk of postoperative morbidity and associated mortality (7). As many as half of cardiac surgery patients may need intervention with IV therapy for acute perioperative increases in arterial blood pressure (8).

Perioperative hypertension is primarily caused by increased sympathetic discharge with systemic vasoconstriction, and is often treated with IV therapy to induce vasodilation (3–5,8,9). However, IV antihypertensive drugs that do not act selectively on resistance vessels may induce precipitous hypotension in a patient population vulnerable to cardiovascular insult and potentially hypovolemia (4,9). Among currently available drugs, none provides the ideal combination of vascular selectivity, rapid onset and offset for precise titratability, and nontoxicity needed for tight arterial blood pressure control in patients at risk (4,8–10).

Clevidipine, the first third-generation IV dihydropyridine calcium channel blocker, exerts arterial-specific vasodilating effects and is characterized by an ultrafast onset and offset of effect in decreasing blood pressure (11,12). After IV administration, clevidipine is quickly cleared from the blood by nonspecific blood and tissue esterases, resulting in rapid elimination with a half-life of approximately 1 min (12–14). In healthy volunteers, arterial blood pressure and heart rate (HR) returned to baseline within 10–15 min after discontinuation of a short infusion (14). Rapid elimination of clevidipine is maintained after stopping either long (24 h) or short infusions (11,15).

Dose-finding and pharmacodynamic studies of clevidipine have demonstrated dose-dependent arterial blood pressure reduction without changes in cardiac filling pressures (11,12,16,17). To clearly demonstrate efficacy against placebo response before cardiac surgery, and to evaluate the time to achieve target arterial blood pressure in this high-risk patient population, the Phase III Efficacy Study of Clevidipine Assessing its Preoperative Antihypertensive Effect in Cardiac Surgery-1 (ESCAPE-1) trial was performed. The purpose of this randomized, double-blind, placebo-controlled trial was to determine the efficacy of IV clevidipine versus placebo as treatment for preoperative hypertension in cardiac surgery patients.

METHODS

The study was conducted at 12 study sites. At each site, the study was approved by an independent ethics committee or IRB. All patients provided written informed consent before initiation of any study-related procedures.

Patient Selection
For inclusion in the trial, patients 18 yr old and scheduled for cardiac surgery (including on-pump, off-pump or minimally invasive coronary artery bypass graft [CABG] surgery and/or cardiac valve repair or valve replacement surgery) were required to meet prerandomization inclusion criteria of hypertension within the past 6 mo needing treatment with antihypertensive medication, or active hypertension upon hospital admission. Patients were randomized to clevidipine or placebo groups based on a computer-generated randomization scheme (constructed using SAS software, version 8, SAS Institute, Cary, NC) and stratified by site in blocks of four in the order that the patients qualified. An interactive voice response system was used to randomize patients to treatment groups and to assign study medication. Patients were randomized on the day of surgery after meeting the prerandomization inclusion criteria; each successive patient per site was assigned a unique identification number. Patients were excluded from randomization if they had cerebrovascular accident within the past 3 mo; preexisting left bundle branch block or permanent ventricular pacing; known intolerance to calcium channel blockers; allergy to soybean oil or egg lecithin, or any other components of the lipid vehicle for clevidipine; or any other disease or condition exposing them to undue risk if they participated in the trial. Patients were also excluded if they had participated in another therapeutic drug or therapeutic device trial within 30 days of starting this study. Women of childbearing age were randomized only if they had a negative urine or serum pregnancy test.

After insertion of an arterial catheter, patients were treated with an IV infusion of clevidipine or placebo if they met prespecified postrandomization criteria: 1) systolic blood pressure (SBP) 160 mm Hg and 2) clinically assessed as needing a reduction in SBP by at least 15% from baseline. A threshold of 160 mm Hg was chosen to be high enough for a reduction by 15% to be clinically indicated in patients who were subsequently to receive induction of anesthesia. A reduction of 15% was thought to be a large enough change in SBP to exclude random, background fluctuations in arterial blood pressure, yet was low enough to be consistent with clinical practice and any safety concerns. Clinical assessment included the determination that the patient's SBP was stable at 160 mm Hg and that reduction by 15% was medically indicated and safe.

Study Medications and Patient Treatment
Clevidipine or placebo was administered via peripheral vein or central venous infusion, using either a syringe or volumetric pump. The use of sedation for the purpose of inserting a central venous catheter was permitted. The use of sedatives, ß blockers or vasodilators before and during study drug administration was recorded. During the first 30 min of study drug administration, the use of other medications and procedures specifically for the treatment of hypertension was prohibited for patients participating in the trial, unless treatment failure occurred. Drugs with antihypertensive properties were permitted during study drug administration only if used for another purpose besides treating hypertension (for example, nitroglycerin for managing ischemia or esmolol for managing tachycardia).

Patients received either IV clevidipine 0.5 mg/mL in a 20% lipid solution or placebo. Placebo was a 20% lipid emulsion identical to the clevidipine lipid vehicle. Both were supplied as sterile, white, opaque liquids in 100-mL single-use glass bottles. Blinded study drug infusion was started at 0.4 µg · kg^–1 · min^–1 (which is equivalent to approximately 2 mg/h in an 80 kg patient) and titrated to effect as tolerated by the patient in doubling increments approximately every 90 s up to a rate of 3.2 µg · kg^–1 · min^–1. More than 3.2 µg · kg^–1 · min^–1, study drug titration in serial increments of 1.5 µg · kg^–1 · min^–1 was permitted as tolerated up to a maximum rate of 8.0 µg · kg^–1 · min^–1 as defined for this study. The study drug could be temporarily stopped and restarted to achieve the desired arterial blood pressure effect. Study drug was administered for at least 30 min and allowed up to a maximum of 1 h or anesthesia induction, unless treatment failure (defined in the following section) occurred. No patients received study drug after anesthesia induction. Titration up to the maximum infusion rate of 8.0 µg · kg^–1 · min^–1 was required before treatment failure was identified, assuming that each dose was well tolerated by the patient and no safety issue arose. After treatment failure, alternative antihypertensive treatment could be instituted as per institutional practice.

Study Assessments
All patients were assessed for baseline SBP and diastolic blood pressure and other vital signs within 24 h before randomization. Baseline electrocardiogram, hematologic and biochemical laboratory screening, and medical history were obtained within 14 days before randomization. Antihypertensive efficacy was evaluated by comparing the incidence of treatment failure between the clevidipine and placebo treatment groups over the 30-min time period 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-min period from study drug initiation. The event causing each treatment failure was assessed and classified into one of three predefined categories: lack of efficacy (no change or an increase in SBP, or failure to achieve a nominal decrease in SBP by an acceptable time); insufficient efficacy (inability to achieve at least 15% reduction in SBP before the end of the 30-min treatment period); or safety reason. The study also evaluated time to target blood pressure (first reduction of SBP by 15% from baseline), change in mean arterial blood pressure (MAP) from baseline, and change in HR. SBP was measured via an indwelling arterial catheter. HR, SBP, and diastolic blood pressure were assessed every minute during the treatment period and for at least 30 min after termination of study drug infusion until these vital signs had stabilized at levels acceptable to the attending physician, up to the induction of anesthesia. The incidence of adverse events (AEs) occurring from study drug initiation until hospital discharge or 7 days, whichever came first, regardless of physician-assessed causal relationship with study drug, was recorded.

Statistical Analysis
Study sample size was determined based on the assumption that clevidipine would be more effective in decreasing SBP than placebo. Assuming a treatment success rate of 40% for patients treated with clevidipine and 12% for patients receiving placebo, it was calculated that 50 patients per treatment group would be required to demonstrate a difference between the two groups with 85% power at a two-sided significance level of 0.05. Efficacy results from this study were based on analysis of the modified intent-to-treat (MITT) population, defined as all patients who were randomized and met the prespecified postrandomization inclusion criteria immediately before treatment initiation. Comparisons were performed according to the randomized treatment assignment, regardless of the actual treatment received. Safety results were based on analysis of the safety population, defined as all randomized patients treated with study drug according to the actual treatment received. The incidence of treatment failure between treatment groups and other categorical parameters was analyzed using the ² test. Continuous parameters were calculated using an analysis of covariance (ANCOVA) model for absolute change from baseline with treatment as a factor and baseline as a covariate, and an analysis of variance (ANOVA) model for percentage change from baseline with treatment as a factor. Time to target arterial blood pressure was analyzed as a time-to-event parameter, using the log-rank test and Kaplan– Meier survival curves. All statistical comparisons were made using two-sided tests at the = 0.05 significance level.

RESULTS

One-hundred-fifty-two patients were enrolled into the study (76 in each treatment group) based on meeting prerandomization entrance criteria. Of this group, 105 patients met postrandomization treatment criteria of SBP 160 mm Hg, thus qualifying for treatment and inclusion into the MITT population. The MITT population consisted of 53 patients in the clevidipine group and 52 patients in the placebo group (Fig. 1). The number of MITT patients enrolled across the 12 study sites varied, with no single site contributing more than 11 patients. One patient in the MITT placebo group did not receive treatment because before administration, the assigned study medication was found to be frozen. Thus, the safety population consisted of 53 clevidipine patients and 51 placebo patients.

View larger version (22K): [in this window] [in a new window]   Figure 1. Patient populations analyzed: 53 clevidipine patients and 52 placebo patients met postrandomization criteria for treatment of preoperative hypertension (MITT population); 53 clevidipine and 51 placebo patients received study drug (safety population) and were evaluated according to actual treatment received. MITT = modified intent-to-treat population, consisting of randomized patients who qualified for study treatment according to prespecified study criteria for preoperative hypertension.

Baseline Comparison of Treatment Groups
Baseline demographic variables and medical risk factors were similar between the clevidipine and placebo treatment groups (MITT population) except for age distribution, history of myocardial infarction (MI), and family history of coronary artery disease (Table 1). More clevidipine patients were 65-yr-old and had a medical history of MI compared with placebo patients, whereas more placebo patients reported a family history of coronary artery disease.

Procedural Characteristics and Previous/Concomitant Medications
Most patients in both the clevidipine and placebo treatment groups underwent primary CABG as the index procedure (Table 2). On the day of surgery, about a third of patients were premedicated for surgery before study drug administration, most often with midazolam (Table 3). Seven clevidipine-treated patients received a ß blocker on the day of surgery before study drug administration, compared with seven placebo-treated patients. During study drug administration, more placebo patients than clevidipine patients received nitroglycerin, probably because of the increased incidence of treatment failure in the placebo group.

Efficacy
Clevidipine was effective in reducing increased arterial blood pressure to target levels, with a statistically significantly lower rate of treatment failure among patients treated with clevidipine versus patients receiving placebo (7.5% vs 82.7%, P < 0.0001). Clevidipine-treated patients demonstrated a 92.5% rate of treatment success (Table 4). In most patients with treatment failure, the reason was identified as insufficient efficacy. No patients in the clevidipine group had treatment failure for lack of efficacy, and no patients in either group had treatment failure for safety reasons.

Clevidipine-treated patients reached target arterial blood pressures (first reduction of SBP by 15% from baseline) at a median time of 6 min (95% confidence interval 6–8 min). The median time for placebo was not estimable because too few patients in the placebo group reached the prespecified target of a 15% reduction in SBP relative to baseline. Clevidipine demonstrated a greater decrease in MAP from baseline compared with placebo that was statistically significant at the 5-min time point and for every 5 min thereafter to the end of the 30-min treatment period. For the lowest MAP assessed during the 30-min treatment period, the mean change from baseline was –34.8 mm Hg (–31.2%) in the clevidipine group, compared with –12.5 mm Hg (–11.2%) in the placebo group (P < 0.0001).

Study Drug Titration and Dose Response
More than half of patients in the clevidipine group (60%) demonstrated a reduction in SBP of 15% from baseline in response to study drug titration to infusion rates 3.2 µg · kg^–1 · min^–1, and 47.2% received 3.2 µg · kg^–1 · min^–1 as their highest titrated infusion rate (Table 5, safety population). Patients receiving placebo had more up-titrations of study drug than clevidipine-treated patients, as indicated by a higher mean total infusion amount (20.7 vs 16.6 mL, respectively) and lower mean infusion duration (25.5 vs 32.1 min). These results are consistent with the higher rate of treatment failure among placebo patients.

Safety
An increase in HR was observed during clevidipine administration (Fig. 2). The median HR at baseline was 71 bpm (minimum–maximum [min–max]: 48–120, n = 50) for clevidipine patients compared with 76 bpm (min–max: 53–126, n = 49) for placebo patients. The maximum HRs reported for the 30-min treatment period were median 84 bpm (min–max: 57–132) for clevidipine patients compared with 84 bpm (min–max: 57–133) for placebo patients. Among patients receiving clevidipine, HR changes were not observed after discontinuation of infusion. No clinically important differences between treatment groups with respect to other vital signs or laboratory results were observed at baseline or postbaseline during the study.

View larger version (9K): [in this window] [in a new window]   Figure 2. Mean percent change in heart rate and systolic blood pressure versus time during the efficacy evaluation period (clevidipine-treated patients only), demonstrating a modest increase in heart rate and rapid onset of arterial blood pressure-lowering effect. HR = heart rate; SBP = systolic blood pressure.

The types and rates of AEs were similar for each treatment group. The most often reported AEs for clevidipine versus placebo patients were pyrexia (fever), 18.9% (10 of 53) vs 13.7% (7 of 51); atrial fibrillation, 13.2% (7 of 53) vs 11.8% (6 of 51); acute renal insufficiency/failure, 9.4% (5 of 53) vs 2.0% (1 of 51); and nausea, 5.7% (3 of 53) vs 9.8% (5 of 51). None of these differences in AE rates was statistically significant. Other AEs occurred with a frequency of 5.7% in the clevidipine group. Overall, 5 (9.4%) clevidipine patients and 2 (3.9%) placebo patients were assessed by investigators as having possibly treatment-related AEs, each of which was unique.

Treatment failure for safety reasons did not occur in either treatment group during the 30-min treatment period. Two patients were withdrawn from the study because of an AE: one from the placebo group because of exacerbation of hypertension, and one from the clevidipine group because of decreased hemoglobin, which was evaluated as unrelated to the study drug. Two patients in the placebo group were reported as having had an MI, compared with no patients in the clevidipine group. One patient death was reported during the study period. The patient was in the clevidipine group and died on postoperative day 1 as a result of a mediastinal hemorrhage, which was not considered to be related to the study drug.

DISCUSSION

In this randomized, double-blind, placebo-controlled trial, IV clevidipine was shown to be effective for treating preoperative hypertension with a 92.5% success rate in decreasing SBP at least 15% from baseline when titrated to effect in a high-risk patient population scheduled for cardiac surgery. This efficacy for clevidipine compared with placebo occurred against a background of other preoperative interventions that could affect hemodynamic response, with a median time of 6 min for achieving target arterial blood pressure in the acute preoperative setting. These findings extend what is known of clevidipine's therapeutic value from smaller dose-finding and pharmacodynamic studies, and support its use in a broader perioperative setting.

There is an unmet need for a rapid-acting, fast-offset IV antihypertensive drugs providing rapid, tight arterial blood pressure control in the perioperative setting without the disadvantages of unpredictable or prolonged arterial blood pressure reduction, myocardial depression, adverse drug effects, or drug– drug interactions (4,8–10). Clevidipine is a third-generation dihydropyridine calcium channel blocker that incorporates an easily hydrolyzable ester group in its chemical structure as part of rational drug design (11). As a result, clevidipine is rapidly metabolized by blood and tissue esterases independent of kidney and liver function (11,13–15). In addition to fast onset and offset, esterase-based metabolism may partially account for the lack of drug toxicity, little to no risk of cytochrome P450-associated drug interactions (11,18), and tolerance of clevidipine by a high-risk patient population with previous cardiovascular disease.

The present study evaluated the efficacy of clevidipine in decreasing SBP to a predetermined target immediately before anesthesia induction for cardiac surgery. Preoperative cardiac surgery patients were chosen as the study population based on their likelihood of developing hypertension and on the high-risk nature of cardiac surgery (1–3), and because a preoperative study design allowed for the safe and ethical use of placebo. The use of placebo control made it possible to evaluate clevidipine's efficacy against fluctuations in arterial blood pressure in the acute care setting. Placebo was administered during a controlled treatment period before surgery under a study design allowing for the use of an alternative parenteral antihypertensive drug for any reason, at any time after initiation of study drug.

One limitation of the present placebo-controlled investigation is that it could not be designed to evaluate clevidipine during surgery for ethical reasons (i.e., not treating hypertension), and therefore involved a somewhat artificial preoperative treatment strategy. Adequate premedication and the effects of anesthesia induction on arterial blood pressure are important considerations before administering antihypertensive treatment during the preoperative period. Our study, which evaluated the short-term response to treatment of acutely hypertensive patients with either a known history of hypertension or active untreated hypertension, some of whom may have responded to higher doses of premedication or anesthesia induction, does not suggest otherwise. However, the results of the present study as designed provide clear evidence of rapid, controlled clevidipine efficacy in a highly relevant clinical setting. Cardiac surgery patients in the immediate preoperative period could be considered representative of other high-risk patient populations needing urgent IV management of hypertension in complex acute-care settings.

Another potential study limitation was the influence of premedication on arterial blood pressure. Because the present study was designed as an acute assessment of antihypertensive treatment over 30 min, and included comparison of active treatment to placebo, it is unlikely that any effects of premedication on study results would have gone unnoticed. In any case, the administration of preoperative sedatives and ß blockers/vasodilators (permitted in the present study if given for another purpose besides hypertension) was balanced between the clevidipine and the placebo groups (Table 3), suggesting little to no effect on study outcome.

In a previous double-blind study of 30 patients after cardiac surgery (19), clevidipine was compared with sodium nitroprusside with respect to efficacy and hemodynamic effects. Patients were randomized to clevidipine or sodium nitroprusside after elective CABG and were treated postoperatively if they became hypertensive (MAP >90 mm Hg for at least 10 min). No statistically significant difference in efficacy (inversely measured as area under the MAP-time curve when MAP exceeded or decreased below the target arterial blood pressure window) was found between clevidipine and sodium nitroprusside. A significantly larger increase in HR (assessed as area under the HR-time curve, P < 0.001) was observed for sodium nitroprusside compared with clevidipine. Clevidipine-treated patients showed less change in central venous pressure and less need for fluid replacement than patients treated with sodium nitroprusside.

In the present study, clevidipine was shown to be well tolerated with an AE profile similar to that of placebo and consistent with outcomes expected in cardiac surgery (20,21). A modest increase in HR was observed during clevidipine administration, as has been reported with other IV dihydropyridines (22,23) and in studies of clevidipine in essential hypertension and postcardiac surgery (16,19). This finding represents a positive attribute of clevidipine in patients susceptible to myocardial ischemia (24).

The results of the present study support the conclusion that clevidipine is an effective treatment for preoperative hypertension with a good safety profile when titrated to effect in cardiac surgery patients. Target arterial blood pressures were achieved with clevidipine within minutes of initiating IV administration and drug titration. Current large-scale studies of clevidipine's safety compared with nitroglycerin, sodium nitroprusside, and nicardipine in cardiac surgery patients, and of the effects of prolonged clevidipine infusion in severely hypertensive patients, should further add to our understanding of the clinical utility of clevidipine.

APPENDIX

The following institutions, clinical investigators, and research coordinators participated in the conduct of this trial: Atlanta VA Medical Center, Atlanta, GA—J.H. Levy, MD, K. Tanaka, MD, K. Egan, RN, S. Chan, S. Bigsby, P. Patel; Baptist Health Systems Montclair, Birmingham, AL—R. Gitter, MD, H.W. Knott, MD, C.D. Randleman Jr, MD, J.B. Casterline, MD, K. Spray, RN; The Christ Hospital, Cincinnati, OH—D.J. Kereiakes, MD, T.D. Ivey, MD, D.L. Mitts, MD, G.A. Answini, MD, D.K. Garza, RN, M.P. Connor, RN; Houston Northwest Medical Center, Houston, TX—T.C. Osborn, MD, C.M. Kitten, MD, D.G. Stroud, MD, D.S. Bhatia, MD, M. Bittman; MacNeal Hospital, Berwyn, IL—S. Aronson, MD, P. Porcelli; Memorial Hermann Memorial City Hospital, Houston, TX—H. Minkowitz, MD, J.G. Baerenstecher, MD, P. Lindley; Regional Medical Center Bayonet Point, Hudson, FL—R.S. Waters, MD, M. DeSantis, MD, G. Gunn; Sacred Heart Hospital, Pensacola, FL—M.Y. Mancao, MD, C. Yount-Malone; St. Luke's Episcopal Hospital, Houston, TX—A.M. Grigore, MD, D. Hirsch, MD, J.M. Anton, MD, J.R. Cooper, MD, L.Q. Chen, MD, N.A. Nussmeier, MD, E. Dragon, J. Dean; St. Vincent Medical Center, Los Angeles, CA—A. Gheissari, MD, R. Gottner, MD, E. Capouya, MD, S.A. Hillman, MD, J. Barra; Swedish Medical Center, Seattle, WA—L. Heller, MD, I. Wright, MD, D. Stout, MD, S. Knapp, MD, B. Lee, MD, J. Lew, MD, B. Tupper, MD, M. Uppal, MD, R. Woodland, MD, I. Rasmussen; Wake Forest University School of Medicine, Winston-Salem, NC—R.C. Prielipp, MD, J.F. Butterworth IV, MD, R.L. Royster, MD, D.A. Zvara, MD, L. Groban, MD, N. Pailes, MD, J. Bennett.

Footnotes

Accepted for publication June 18, 2007.

Dr. Jerrold Levy, Section Editor for Hemostasis and Transfusion Medicine, was recused from all editorial decisions related to this manuscript.

Sponsored by The Medicines Company.

Drs. Mancao, Gitter, and Grigore have no financial disclosures. Dr. Newman has received financial support from Duke University for work contracted by The Medicines Company. Drs. Aronson and Levy have received consultant fees from The Medicines Company. Dr. Kereiakes has received honoraria related to advisory activities and the development of educational materials from Conor Medsystems, Cordis, Core Valve, Eli Lilly and CO, Guidant Corporation, Boston Scientific, and Medtronic, and has received grant support related to research activities from Pfizer, Conor Medsystems, Cordis, Boston Scientific and Medtronic.

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