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Anesth Analg 2008; 107:1110-1121 © 2008 International Anesthesia Research Society doi: 10.1213/ane.0b013e31818240db
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3 mo before randomization, intolerance to calcium channel blockers, hypersensitivity to sodium nitroprusside, nitroglycerin, or nicardipine, allergy to the lipid vehicle of clevidipine, permanent ventricular pacing, any condition or disease deemed by the investigator to place the patient at risk for participating, or participation in another investigation within 30 days of study start.
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Statistical Analysis
All statistical analyses were performed using the SAS® system (version 8.2, SAS Institute, Cary, NC) and presented using descriptive statistics. The randomized patient population was defined as all patients who qualified for the study based on prerandomization inclusion and exclusion criteria and were randomized to a treatment group. The modified intent-to-treat population was defined as all patients who were randomized into the trial and met postrandomization criteria for perioperative hypertension. The safety population was all randomized patients who received study drug. This report presents safety results based on analysis of the safety population, and efficacy results based on analysis of the modified intent-to-treat population. Data were pooled to provide an overall event rate for clevidipine and comparator arms. Prespecified analysis of each randomized comparison was also performed. P values for the primary end-point analysis were generated using the 
2 test.
AUCSBP-D was summarized descriptively by treatment group as total area of the SBP-time curve above or below the predefined SBP ranges (65–135 mm Hg intraoperatively, 75–145 mm Hg pre- and postoperatively). Due to asymmetric distribution of AUC, descriptive statistics are presented using range (minimum and maximum), inter-quartile range (first quartile [Q1] and third quartile [Q3]), median (second quartile), mean, and sd. P values for AUC analysis were generated using the Wilcoxon rank sum test, a nonparametric test applicable to asymmetric distributions. The significance level was designated at the two-sided 
level of 5%.
To increase our ability to discriminate among treatment groups in the assessment of BP control, we conducted a post hoc analysis in which AUC was calculated as the SBP range was narrowed by incrementally increasing the lower SBP limit by 10 mm Hg, 20 mm Hg, and 30 mm Hg. Additionally, multiple logistic regression analysis was performed to further explore the relationship between the incidence of death and treatment group while controlling for other potential risk factors.
RESULTS
Patients in the ECLIPSE trial were similar with respect to demographics and medical history across all treatment groups (579 received clevidipine or sodium nitroprusside; 546 clevidipine or nitroglycerin, and 381 clevidipine or nicardipine) (Tables 1 and 2). Preexisting chronic hypertension was common in all groups and nearly all patients were receiving antihypertensive medications before surgery. Patient characteristics, demographics, and cardiac surgical procedure groups are detailed in Tables 2 and 3. In all treatment groups, CABG was the most commonly performed procedure. Off-pump techniques were used in approximately 10%–20% of patients and the number of valve-related procedures was similar among all groups.
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The timing of drug administration among treatment groups is presented in Table 4. In the perioperative clevidipine: nitroglycerin and clevidipine: sodium nitroprusside studies, study drug was primarily initiated during the preoperative or intraoperative period. The majority of patients who initiated antihypertensive treatment pre- or intraoperatively also received therapy in the postoperative setting. Patients in the clevidipine: nicardipine study received the drug postoperatively per protocol as the half-life, volume of distribution, and slow offset of nicardipine was determined to make it less suitable for use in the pre- and intraoperative setting. The median overall infusion duration, total infusion volume, and average infusion rates were greater in the nitroglycerin group compared to patients receiving clevidipine. Overall infusion duration, infusion rates and infusion volumes were comparable between patients receiving clevidipine and sodium nitroprusside. The duration of infusion was similar between clevidipine and nicardipine with the total fluid volume infused and average infusion rate greater for nicardipine compared to clevidipine. The use of adjunctive, alternative antihypertensive drugs was similar among treatment groups. The use of these drugs for the control of hypertension tended to be higher in the sodium nitroprusside-treated group compared with the clevidipine group; with β blockers most commonly administered. There was also an increased tendency for the use of sodium nitroprusside as a second-line antihypertensive drug in patients treated with nitroglycerin compared to those treated with clevidipine (11% vs 2%, respectively).
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The primary outcome, 30-day incidence of death, MI, stroke, or renal dysfunction, for all treatment groups is detailed in Table 5. There was no difference between the pooled clevidipine populations compared with the pooled comparator group for any of the 30-day safety outcome measures. There were no differences in death or adverse outcomes at the time of hospital discharge or Day 7 among groups. Within treatment groups, there were no differences in 30-day outcomes when clevidipine was compared with nitroglycerin and nicardipine. Results for clevidipine compared to sodium nitroprusside were similar as well except for the incidence of 30-day mortality, which was significantly higher in patients who had received sodium nitroprusside compared to clevidipine (4.7% vs 1.7%, P = 0.0445). However, multiple logistic regression analysis for treatment effect (clevidipine vs sodium nitroprusside) as an independent variable in a model that included other risk variables such as surgery duration, AUCSBP-D, age, and medical history, showed no statistically significant association between sodium nitroprusside use and 30-day mortality (odds ratio, 1.968, 95% confidence interval, 0.619–6.257, P = 0.25). Among 13 patients requiring treatment for hypertension who died in the sodium nitroprusside group, three had hypotension reported as an adverse event.
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Comparisons of the pooled data from the entire clevidipine population with the pooled data of the entire comparator group demonstrated that clevidipine was significantly more effective at keeping BP within the prespecified BP range (Table 6, Fig. 2).
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In an analysis of the individual treatment cohorts, clevidipine was significantly more effective at keeping BP within the prespecified range compared with nitroglycerin or sodium nitroprusside (Table 6, Fig. 3). The median total AUCSBP-D (representing SBP-time curve excursions outside the prespecified SBP ranges) was significantly lower for patients treated with clevidipine than for patients treated with nitroglycerin (4.14 mm Hg x min/h vs 8.87 mm Hg x min/h; P = 0.0006). In addition, patients treated with nitroglycerin did not meet the target BP range as often compared with clevidipine. The median AUC above the target BP range was significantly lower for clevidipine-treated patients compared to nitroglycerin-treated patients (2.76 mm Hg x min/h vs 7.94 mm Hg x min/h; P = 0.0002). The AUC below the target range was similar between these groups.
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For patients treated with clevidipine, the median total AUC was significantly lower compared with patients treated with sodium nitroprusside (4.4 mm Hg x min/h vs 10.5 mm Hg x min/h; P = 0.0027). In addition, patients treated with sodium nitroprusside had significantly greater SBP-time excursions outside the target BP range, both above and below (overshoot) compared to clevidipine. Above the target BP range, median AUC for clevidipine compared with sodium nitroprusside was 2.97 mm Hg x min/hr and 6.61 mm Hg x min/h, respectively (P = 0.031). Below the target BP range, mean AUC for clevidipine compared with sodium nitroprusside was 2.30 mm Hg x min/h and 8.38 mm Hg x min/h, respectively (P = 0.0006).
There were no differences in the median AUC at predetermined target BP ranges of 75–145 mm Hg postoperatively for patients treated with nicardipine compared to clevidipine (Table 6, Fig. 3).
When the target BP range was narrowed by raising the lower limit threshold by increments of 10 mm Hg, there was a direct and progressive increase in the difference of AUC for the pooled comparisons (Fig. 2) as well as each comparator drug when compared to clevidipine (Fig. 3). When the threshold for the lower BP range was 30 mm Hg higher (i.e., a narrower SBP range of 40 mm Hg), patients treated with clevidipine had significantly smaller SBP-time excursions outside of this range than patients treated with nicardipine (77.0 mm Hg x min/h vs 101.6 mm Hg x min/h, P = 0.0231) or sodium nitroprusside (100.2 mm Hg x min/h vs 127.9 mm Hg x min/h, P = 0.0068) (Fig. 3).
The incidence of the most commonly reported adverse events, including atrial fibrillation and sinus tachycardia, were similar for clevidipine and the comparator drugs. Atrial fibrillation was reported as an adverse event at an incidence of 33.6% vs 32.0% (clevidipine versus nitroglycerin); 36.1% vs 32.2% (clevidipine vs sodium nitroprusside); and 35.6% vs 35.2% (clevidipine vs nicardipine), all P = NS. The incidences of SAEs were similar among all groups and are listed in Table 7. Clinical laboratory data including change in triglyceride levels were similar between clevidipine and the comparator drugs. Clevidipine, which is administered in a lipid emulsion, did not cause an increase in triglyceride levels.
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DISCUSSION
In the current study, clevidipine was shown to be as safe as its comparator drugs for the treatment of perioperative hypertension based on a similar frequency in the primary outcome of the 30-day incidence of death, MI, stroke, or renal dysfunction. When individual treatment comparisons were considered, there were no differences in the frequency of this primary outcome between patients receiving clevidipine compared with nitroglycerin, sodium nitroprusside, or nicardipine. We did observe a lower mortality rate, though, for patients treated with clevidipine compared with those receiving sodium nitroprusside, although this difference was only notable as a trend in a multiple logistic regression analysis. Our results further show that clevidipine was a more effective antihypertensive drug based on our analysis of the time and extent SBP was above or below the predefined BP ranges (AUC analysis for BP excursions) than nitroglycerin or sodium nitroprusside at any perioperative SBP range and better than nicardipine when the postoperative SBP range was reduced to 40 mm Hg from the predefined 70 mm Hg (Fig. 3). Clevidipine and nicardipine were similar in maintaining BP within the prespecified ranges, but this analysis was limited to the postoperative period based on the protocol design.
Acute perioperative hypertension, first identified as a risk factor for adverse cardiovascular outcome in 1929,25 is predominantly mediated by an increase in sympathetic activity, resulting in arteriolar vasoconstriction and increased systemic vascular resistance.26 Although intraoperative hemodynamic abnormalities have been reported to be associated with death, stroke, renal dysfunction, perioperative MI, and increased mortality, these studies often used a small sample size and lacked statistical power, were retrospective and included discontinuous data, included methods specific to certain patient populations and/or surgical procedures, and were not analyzed to determine specific target BP thresholds.27–30 Therefore, they provide limited information on the impact of perioperative hypertension management on patient outcomes. An association between hypertension and postoperative surgical bleeding has also been demonstrated.31 In part because of these strong associations, and because of other practical safety concerns related to the hydraulic pressure and aortovascular stress-strain modulation requirements during cardiac surgery with cardiopulmonary bypass (e.g., cannulation and decannulation), and the requirements of the postoperative period for weaning from mechanical ventilation and analgesia, manipulation and control of BP is commonly used during cardiac surgery.
Currently, nitroglycerin and sodium nitroprusside are commonly used during cardiac surgery to control BP; however, both have significant limitations. Nitroglycerin is a relatively weak arteriolar vasodilator with a primary effect on dilating venous capacitance vessels to reduce preload. Sodium nitroprusside also produces significant venodilation and causes reflex tachycardia, as well as inhibition of hypoxic pulmonary vasoconstriction, increase in intracranial pressure, and a redistribution of blood flow away from vital end-organs1,2 including the kidney32 and gastrointestinal tract. The use of sodium nitroprusside also is associated with systemic cyanide toxicity, a risk that may be accelerated during cardiac surgery requiring cardiopulmonary bypass.33 Sodium nitroprusside may be difficult to titrate and is recognized to cause unwanted ("overshoot") hypotension and hypertension. In a study comparing sodium nitroprusside with nicardipine, patients treated with sodium nitroprusside needed more time to reach target BP goals and required more dose adjustments. The venodilatory effects of sodium nitroprusside may produce unpredictable swings in BP in patients with diastolic dysfunction or hypovolemia.34 Nicardipine, a dihydropyridine calcium channel blocker, may be limited for use in the acute preoperative and intraoperative setting because of its long half-life, slower offset of action, and potential for increased serum levels in elderly patients or patients with altered hepatic function.24 Additionally, bolus doses of nicardipine, after IV infusion, appear to be needed to obtain the rapid onset of action seen with other vasodilator drugs like sodium nitroprusside.34
Clevidipine is a third-generation dihydropyridine calcium channel blocker, specifically designed for treatment of acute hypertension, with a rapid onset and offset of action. The characteristic of fast offset and onset is due to an easily hydrolyzable ester group in the clevidipine molecular structure22 which is rapidly metabolized by esterases in the blood and vascular tissues upon IV administration. The resulting ultrashort half-life of approximately 1 min20–22 makes clevidipine an attractive drug for patients who need rapid BP adjustments over time.
Implications for these data may become important as the selection of drugs to more narrowly control acute hypertension in the surgical and critical care setting is further investigated and guidelines are defined. This is also important because preexisting hypertension, especially among the elderly surgical population, is present in more than two-thirds of all patients 
60 yr,9 with upwards of 90% prevalence in cardiac surgery,35 and has been identified as an important risk factor for adverse outcome.4,35
Limitations of the study include the open-label design. However, adjudication of study end-points by an independent Clinical Events Committee was used to minimize any potential bias. Additionally, by protocol, clevidipine was dosed in a standard fashion at all study sites, whereas comparator drugs were administered according to institutional practice. This limitation enabled a real-world analysis that was more applicable to actual clinical practice.
The use of adjunctive, alternative antihypertensive drugs was similar between groups. Patients who received nitroglycerin received more second-line sodium nitroprusside administration for the control of hypertension, suggesting that nitroglycerin, in addition to the increased AUC above the target SBP limit, is an ineffective antihypertensive drug in cardiac surgical patients. An important and consistent finding from all three studies with clevidipine was that the BP results after treatment with clevidipine were remarkably similar, indicating that predictable BP control can be achieved with clevidipine throughout the operative setting.
The primary purpose of this study was to evaluate the safety of clevidipine compared with other commonly used antihypertensive drugs in patients undergoing cardiac surgery. Although the composite safety end-point of 30-day death, MI, stroke, or renal dysfunction was similar among the treatment groups, we did find that patients treated with clevidipine had a lower mortality rate than those treated with sodium nitroprusside. It is possible that these observations were due to confounding factors among the treatment groups not considered in our analysis. Indeed, the number of patients undergoing higher-risk combined CABG and cardiac valve surgery was higher in the sodium nitroprusside group compared with the clevidipine group, although this difference was not statistically significant (primary and repeat combination CABG and valve surgery for clevidipine versus sodium nitroprusside: P = 0.18). In addition, the small number of observed events in this analysis may have led to a type I error. Regardless, whether the drug choice for treating perioperative hypertension can modify risk for mortality after cardiac surgery requires further prospective study.
ACKNOWLEDGMENTS
The authors acknowledge the work of the GPRO study group/ECLIPSE investigators in the conduct of this trial. A large number of individuals contributed to the completion of this research, including:
Randleman CD Jr, MD, Byrne N, Cardio-Thoracic Surgeons, PC, Birmingham, AL; Mancao MY Jr, MD, Huckaby D, Discovery Alliance International, Inc., Pensacola, FL; McCoy CP, MD, Marden J, RN, Research Support Personnel LLC, Wichita, KS; Stone ME, MD, Mitchell-Bligen M, RN, Mount Sinai School of Medicine, New York, NY; Warltier DC, MD, PhD, Hudetz J, PhD, Zablocki V.A. Medical Center, Milwaukee, WI; Cheung AT, MD, University of Pennsylvania Medical Center, Philadelphia, PA; Augoustides YG, MD, University of Pennsylvania Medical Center, Philadelphia, PA; DeBoer DA, MD, Brown P, PA, Saint Francis Hospital, Evanston, IL; Casterline JB, MD, Sauers L, RN, BSN, Cardio-Thoracic Surgeons, PC, Birmingham, AL; Moustoukas N, MD, Ruth Anna Wanstrath, BSN, Touro Infirmary, New Orleans, LA; Sharma R, MD, Gunn G, Criterion Research, Inc., St. Petersburg, FL; Eaton M, MD, Bailey L, RN, University of Rochester, Rochester, NY; Daon E, MD, Legler S, Saint Lukes Hospital, Kansas City, MO; Higgs W, MD, Trice A, RN, Discovery Alliance-Mobile Infirmary Medical Center, Mobile, AL; Levy JH., MD, Egan K, Emory Hospital, Atlanta, GA; Sladen RN, MD, Park H, Columbia University College of Physicians and Surgeons, New York, NY; Bonvino S, MD, Koppisetti S, Montefiore Medical Center, New York, NY; Savransky Y, MD, Moltz KS, PA, Montefiore Medical Center, New York, NY; Kereiakes DJ, MD, Garza D, RN, Lindner Clinical Trial Center, Cincinnati, OH; Mora-Mangano C, MD, Plonowska M, MD, Stanford University Medical Center, Stanford, CA; Chen JC, MD, Gervacio A, Kaiser Permanente Medical Center, Honolulu, HI; Miller DL, MD, Chien G, MD, Marshall P, MS, Portland V.A. Medical Center, Portland, OR; Gheissari A, MD, Parker S, RN, Providence Saint Joseph Medical Center, Burbank, CA; Falcucci O, MD, Ponton T, RN, Virginia Commonwealth University Medical Center, Richmond, VA; Lumb PD, MB BS FCCM, McIntee D, Los Angeles County and University of Southern California Medical Center, Los Angeles, CA; Stella JF, DO, Enger EL, PhD, Heart Care Research Foundation, Blue Island, IL; Reardon MJ, MD, Davydov D, MD, The Methodist Hospital, CTSU, Houston, TX; Tahta S, MD, Hanneman A, RN BSN, The International Heart Institute, Missoula, MT; Singla N, MD, Villalobos L, MHA CRC, Huntington Memorial Hospital, Pasadena, CA; Doty J., MD, Flores J, RN, Salt Intermountain Health Care, Salt Lake City, UT; Rongione AJ, MD, Kelly SL, RN, Rx Trials at Inova Fairfax Hospital, Falls Church, VA; Harlan JL, MD, Burks J, RN BSN, Cardiothoracic Surgeons, PC, Birmingham, AL; Boylan M, MD, Allen K, Whiteside Research, Duluth, MN; Johnston G, MD, Crews L, RN, Saint Joseph Research Center, Tacoma, WA; Van Meter C Jr, MD, Kersker L, RN, Ochsner Clinic Foundation, New Orleans, LA; Kanchuger MS, MD, Ahmed R, New York University Medical Center, New York, NY; Katz D, MD, Degelia A, MemorialCare Medical Centers, Laguna Hills, CA; Richardson J Jr, MD, Phillips K, RN, Cardio-Thoracic Surgeons, PC, Birmingham, AL; Klodell CT, MD, Staples NL, RN, University of Florida Health Science Center, Gainesville, FL; Lichtenthal PR, MD, A.V. Patula, University of Arizona Medical Center, Tucson, AZ; Shenaq SA, MD, M. Bolos, Michael E DeBakey V.A. Medical Center, Houston, TX; Russell I, MD PhD, Tarnow JL, RCP RR, University of California San Francisco, San Francisco, CA; Minkowitz H., MD, Lindley P, Memorial Hermann Healthcare System, Houston, TX; Stierer K, MD, Dudek A, RN, Midatlantic Cardiovascular Associates, Towson, MD; Malias MA, MD, Parker NJ, RN CCRC, Health First Clinical Research Institute, Melbourne, FL; Roth EM, MD, Crone DS, RN BSN, Sterling Research Group, Ltd., Cincinnati, OH; Silverman NA, MD, P. Lowes, Henry Ford Hospital, Detroit, MI; Cammack PL, MD, Wallace-Jones M, LPN, Drug Research and Analysis Corporation, Montgomery, AL; Osborn TC, MD, Bittman M, Tomball Regional Hospital, Houston, TX; Avery E, MD, Donnelly A, RN, Massachusetts General Hospital, Boston, MA; Kwan SK, MD, Wallace-Jones M, LPN, Drug Research and Analysis Corporation, Montgomery, AL; Arthur Grimball, MD, Fosythe M, Cardiothoracic Surgery Center, PLC, Jackson, TN; Gitter R, MD, Khitin H, Thoracic and Cardiovascular Surgeons, PC, Birmingham, AL; Ronson RS, MD, Armstrong K, RN, Lamberth and Ronson, PC, Birmingham, AL; Magovern CJ, MD, Guarino T, RN, Morristown Memorial Hospital, Morristown, NJ; Reynolds RR, MD, Robertson MA, RN, Cardiac and Thoracic Surgical Associates, Ltd., Richmond, VA; Richardson J Jr, MD, Phillips K, RN, Cardio-Thoracic Surgeons, PC, Birmingham, AL; Wolfgang T, MD, Wittenbraker M, ACNP, Cardiac and Thoracic Surgical Associates, Mechanicsville, VA; Hahn C, MD, Bartle K, NP, Cardiac and Thoracic Surgical Associates, Richmond, VA; Bladergroen MR, MD, Wittenbraker M, ACNP, Cardiac and Thoracic Surgical Associates, Richmond, VA; Dyke C, MD, Deal N, RN, Carolina Cardiovascular and Thoracic Surgery Associates, Gastonia, NC.
Footnotes
Accepted for publication May 30, 2008.
Supported by The Medicines Company, Parsippany, NJ.
Jerrold H. Levy is editor of Hemostasis and Transfusion Medicine for the Journal. This manuscript was handled by Charles W. Hogue Jr, and Jerrold H. Levy was not involved in any way with the editorial process or decision.
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