Anesth Analg 2008 Aronson 1110 21 HTN Reduction | Hypertension | Doctor Of Medicine

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Cardiovascular Anesthesiology Section Editor: Charles W. Houge, Jr. Cardiovascular and Thoracic Education Section Editor: Martin J. London Hemostasis and Transfusion Medicine Section Editor: Jerrold H. Levy The ECLIPSE Trials: Comparative Studies of Clevidipine to Nitroglycerin, Sodium Nitroprusside, and Nicardipine for Acute Hypertension Treatment in Cardiac Surgery Patients Solomon Aronson, MD, FACC, FCCP, FAHA, FASE* Cornelius M. Dyke, MD† Kevin A. Stierer, MD‡ Jerrold H. Levy, MD§ Albert
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  Cardiovascular Anesthesiology  Section Editor: Charles W. Houge, Jr. Cardiovascular and Thoracic Education Section Editor: Martin J. London Hemostasis and Transfusion Medicine Section Editor: Jerrold H. Levy  The ECLIPSE Trials: Comparative Studies of Clevidipine toNitroglycerin, Sodium Nitroprusside, and Nicardipine for  Acute Hypertension Treatment in Cardiac Surgery Patients Solomon Aronson, MD, FACC,FCCP, FAHA, FASE*Cornelius M. Dyke, MD†Kevin A. Stierer, MD‡ Jerrold H. Levy, MD§Albert T. Cheung, MD  Philip D. Lumb, MB, BS, FCCM¶Dean J. Kereiakes, MD#Mark F. Newman, MD* BACKGROUND: Acute hypertension during cardiac surgery can be difficult to manageand may adversely affect patient outcomes. Clevidipine is a novel, rapidly actingdihydropyridine L-type calcium channel blocker with an ultrashort half-life thatdecreases arterial blood pressure (BP). The Evaluation of CLevidipine In thePerioperative Treatment of Hypertension Assessing Safety Events trial (ECLIPSE)was performed to compare the safety and efficacy of clevidipine (CLV) withnitroglycerin (NTG), sodium nitroprusside (SNP), and nicardipine (NIC) in thetreatment of perioperative acute hypertension in patients undergoing cardiacsurgery. METHODS: We analyzed data from three prospective, randomized, open-label,parallel comparison studies of CLV to NTG or SNP perioperatively, or NICpostoperatively in patients undergoing cardiac surgery at 61 medical centers. Ofthe 1964 patients enrolled, 1512 met postrandomization inclusion criteria ofrequiring acute treatment of hypertension based on clinical criteria. The patientswere randomized 1:1 for each of the three parallel comparator treatment groups.The primary outcome was the incidence of death, myocardial infarction, stroke orrenal dysfunction at 30 days. Adequacy and precision of BP control was evaluatedand is reported as a secondary outcome. RESULTS: There was no difference in the incidence of myocardial infarction, stroke orrenal dysfunction for CLV-treated patients compared with the other treatmentgroups. There was no difference in mortality rates between the CLV, NTG or NICgroups. Mortality was significantly higher, though, for SNP-treated patientscompared with CLV-treated patients ( P  0.04). CLV was more effective comparedwith NTG ( P  0.0006) or SNP ( P  0.003) in maintaining BP within theprespecified BP range. CLV was equivalent to NIC in keeping patients within aprespecified BP range; however, when BP range was narrowed, CLV was associ-ated with fewer BP excursions beyond these BP limits compared with NIC. CONCLUSIONS: CLV is a safe and effective treatment for acute hypertension inpatients undergoing cardiac surgery. (Anesth Analg 2008;107:1110–21)  A cute perioperative hypertension and arterial bloodpressure (BP) lability affect up to 80% of patients under-going cardiac surgery 1,2 and up to 25% of patientsundergoingmajornoncardiacsurgery. 3 PerioperativeBPvariation increases the risk for myocardial ischemia,stroke, neurocognitive dysfunction, and bleeding. 2,4–8 Since nearly 30% of the United States population ishypertensive, it is not unusual for patients to present forsurgery with preexisting hypertension. 9 The presence ofpreexisting hypertension increases the likelihood ofacuteperioperativehypertensionandcanbeasignificantrisk factor for perioperative BP lability. 10,11 The etiology and treatment responsiveness of acuteperioperative hypertension differs from chronic hy-pertension. Acute perioperative hypertension may betransient and is characterized by excessive catechol-amine release, peripheral vasoconstriction, 12 and re-duced baroreceptor sensitivity. 13 Acute hypertensionhas been reported to worsen reperfusion injury, 14 humoral and cellular inflammatory response, 15,16 and From the *Department of Anesthesiology, Duke University Medi-cal Center, Durham, North Carolina; †Gaston Memorial Hospital,Gastonia, North Carolina; ‡The Heart Institute at St. Joseph MedicalCenter, Towson, Maryland; §Department of Anesthesiology, EmoryUniversity School of Medicine, Atlanta, Georgia;  Department ofAnesthesiology and Critical Care, University of Pennsylvania, Phila-delphia, Pennsylvania; ¶Department of Anesthesiology, Keck Schoolof Medicine, University of Southern California, Los Angeles, Califor-nia; and #The Christ Hospital Heart and Vascular Center/The LindnerResearch Center, Cincinnati, Ohio.Accepted for publication May 30, 2008.Supported by The Medicines Company, Parsippany, NJ. Jerrold H. Levy is editor of Hemostasis and Transfusion Medi-cine for the Journal. This manuscript was handled by Charles W.Hogue Jr, and Jerrold H. Levy was not involved in any way with theeditorial process or decision.Address correspondence and reprint requests to Solomon Aronson,MD, FACC, FCCP, FAHA, FASE, Department of Anesthesiology, DukeUniversityMedicalCenter,DukeSouth,Room102BakerHouse,Durham,NC 27710. Address e-mail to arons002@mc.duke.edu.Copyright © 2008 International Anesthesia Research Society DOI: 10.1213/ane.0b013e31818240db Vol. 107, No. 4, October 2008 1110  platelet activation 17 which may compromise micro-vascular blood flow. In addition, perioperative hyper-tension increases myocardial oxygen consumptionand left ventricular end-diastolic pressure, and con-tributes to subendocardial hypoperfusion and myocar-dial ischemia. 1,6,18 Despite its frequency and potentialmorbidity, there are no established guidelines fortreating acute hypertension in the perioperativepatient population and there is significant practicevariability. 19 The ideal drug for the management of hypertensionin cardiac surgical patients would be a short-actingparenteral drug that is easily and rapidly titratable.Commonly used drugs include sodium nitroprusside,nitroglycerin,  blockers, and calcium channel block-ers, as well as volatile anesthetics and sedatives. All ofthese drugs have limitations related to their potency,tolerance, toxicity, side effects, applicability, onset andoffset of action, and ease of use. Clevidipine is arapid-acting, dihydropyridine L-type calcium channelantagonist with an ultrashort half-life of approxi-mately one min 20–23 that decreases arterial pressure bydirect arterial vasodilation. It has selective action onarteriolar resistance vessels with no effect on venouscapacitance vessels. Reflex tachycardia and tachyphy-laxis have not been reported.The primary objective of this study was to comparethe safety of clevidipine to three commonly usedperioperative antihypertensive drugs (nitroglycerin,sodium nitroprusside, and nicardipine) in a cardiacsurgical population. The secondary end-point of BPcontrol was evaluated by measuring the magnitudeand duration of BP excursions above or below apredefined systolic blood pressure (SBP) range. METHODS Study Design The ECLIPSE (Evaluation of CLevidipine In thePerioperative Treatment of Hypertension AssessingSafety Events) trial was conducted in compliance withthe International Conference on Harmonization GoodClinical Practice guidelines and the Declaration ofHelsinki. The study was approved by the IRB at eachparticipating institution. The three studies making uptheECLIPSEtrialwereperformedunderIND65,114andwere registered at clinicaltrials.gov under the identifiersNCT00093886, NCT00093912, and NCT00093925. Writ-ten informed consent was obtained from all patients before enrollment. The ECLIPSE trial was randomized,open-label, prospective, and was conducted at 61 medi-cal centers in the United States between April 2004 andOctober 2006.Patients 18-yr-of-age or older and scheduled toundergo cardiac surgery (including on- or off-pumpcoronary artery bypass grafting [CABG], minimallyinvasive CABG and/or valve replacement or repairsurgery) at each participating institution were evalu-ated for study eligibility. Patients were excluded fromstudy for the following reasons: women of childbear-ing potential, cerebrovascular accident  3 mo beforerandomization, intolerance to calcium channel block-ers, hypersensitivity to sodium nitroprusside, nitro-glycerin, or nicardipine, allergy to the lipid vehicle ofclevidipine, permanent ventricular pacing, any condi-tion or disease deemed by the investigator to place thepatient at risk for participating, or participation inanother investigation within 30 days of study start.The ECLIPSE study consisted of three parallel trialswhere patients were randomly assigned on a 1:1 basisto receive clevidipine or a comparator drug (sodiumnitroprusside, nitroglycerin, or nicardipine). After en-rollment and treatment randomization, the need forantihypertensive treatment was determined by thestudy physician in accordance with department clini-cal practice and relevant institutional guidelines (e.g.,postoperative intensive care unit guidelines). Drug Administration Study drug was administered IV, either peripher-ally or centrally, with an infusion pump. Treatmentwas titrated to achieve a BP level deemed appropriate by the study physician and continued until dischargefrom the intensive care unit. Use of nonstudy drugmedications to treat hypertension during study drugadministration was discouraged. If the desired BPeffect was not attained or maintained with eitherclevidipine or a comparator drug, or if there was asafety concern, an alternative IV antihypertensivecould be used per institutional practice to decrease BP.All antihypertensive medications were recorded.Clevidipine was initiated at an infusion rate of 0.4  g  kg  1  min  1 and was titrated as tolerated in dou- bling increments every 90 s up to 3.2  g  kg  1  min  1 .Infusion rates above 3.2  g  kg  1  min  1 were guided by the patient’s response and permitted in serialincrements of 1.5  g  kg  1  min  1 . Infusion rates be-tween 4.4 and 8.0  g  kg  1  min  1 were administeredfor no longer than 2 h. Titration to higher infusionrates, up to the maximum infusion rate of 8.0  g  kg  1  min  1 , was required before switching to oradding alternative antihypertensive drugs, assumingthat each dose was well tolerated by the patient andthere were no safety concerns. Due to protocol-specified lipid load restrictions, no more than 500 mLof clevidipine infusion (formulated in 20% lipid emul-sion) was administered in the first 24-h period, and themaximum amount of lipid permitted as part of drugadministration was 2.5 g/kg/24 h.There were no protocol-specified limitations foradministering sodium nitroprusside, nitroglycerin ornicardipine and investigators were given freedom touse these drugs as they normally would in clinicalpractice for treatment of perioperative hypertension.The dose and duration of therapy were recorded.Clevidipine was compared to sodium nitroprussideand nitroglycerin in the preoperative, intraoperative, Vol. 107, No. 4, October 2008 © 2008 International Anesthesia Research Society 1111  and postoperative periods. The comparison of clevi-dipine with nicardipine was restricted to the postop-erative period, since nicardipine is not generally used before or during surgery due to its long half-life andpotential for higher serum levels in elderly patients orpatients with decreased hepatic metabolism. 24 Study End-Points The primary end-point of the ECLIPSE trials wassafety as assessed by the incidence of death, stroke,myocardial infarction (MI), and renal dysfunctionfrom the initiation of study drug infusion throughpostoperative day 30. Death was defined as all-causemortality. Stroke (hemorrhagic or ischemic) was diag-nosed by a neurologist based on physical examinationand/or brain imaging results. The diagnosis of MI was based on the presence of new 12-lead electrocardio-gram changes consistent with myocardial injuryand/or cardiac iso-enzyme increases. Renal dysfunc-tion was defined as a postoperative serum creatininelevel of  2.0 mg/dL (177  mol/L) and an increase inserum creatinine of  0.7 mg/dL (62  mol/L) frompreoperative baseline, and/or the need for hemodialy-sis, venovenous filtration, arterial venous filtration, orperitoneal dialysis after surgery. An independentClinical Events Committee, blinded to treatment,made the final determination as to whether each safetyevent qualified as a primary end-point based onpreestablished criteria uniformly applied to each de-termination. In addition, CK-MB and serum creatininelaboratory definitions were used as database triggersto identify MI and renal safety end-point events forconsideration by the Clinical Events Committee.The efficacy of clevidipine versus comparator drugfor the treatment of acute hypertension was assessedusing area under the curve (AUC) analysis of BPexcursions beyond predetermined upper and lowerlimits, normalized per hour (AUC SBP-D ). AUC SBP-D was analyzed as the summation of the integratedSBP-time curve excursions, capturing the product ofmagnitude (mm Hg) and duration (min) of BP outsidethe predefined SBP ranges. These ranges, chosen toreflect standard clinical practice and prespecified foranalysis purposes, were 65–135 mm Hg intraopera-tively (from chest incision through chest closure) and75–145 mm Hg pre- and postoperatively.AUC SBP-D was calculated from the BP recordedfrom the initiation of study drug infusion througheither the removal of the arterial line or 24 h afterstudy drug initiation, whichever occurred first. Preop-eratively, BP was recorded every 15 min; intraopera-tively, every 5 min; and postoperatively every 15 minfor 4 h, then once every hour through 24 h (compari-son with nitroglycerin or sodium nitroprusside). Forthe comparison with nicardipine, BP was recordedevery 15 min for the first 6 h, then once every hourthrough 24 h. Hemodynamic data were measured byarterial line and entered into an electronic database.The total area of the SBP-time curve outside (eitherabove or below) the predefined SBP ranges was cal-culated (Fig. 1) and normalized per hour (AUC SBP-D ).AUC SBP-D was expressed in units of mm Hg  min/h.In addition, vital signs, clinical laboratory data, fluidadministration, the incidence of reflex tachycardia,and serious adverse events (SAEs) including the inci-dence of atrial fibrillation during study drug admin-istration were also captured. SAEs were recorded upto 30 days postoperatively. Statistical Analysis All statistical analyses were performed using theSAS ® system (version 8.2, SAS Institute, Cary, NC)and presented using descriptive statistics. The ran-domized patient population was defined as allpatients who qualified for the study based on preran-domization inclusion and exclusion criteria and wererandomized to a treatment group. The modified intent-to-treat population was defined as all patients whowere randomized into the trial and met postrandom-ization criteria for perioperative hypertension. Thesafety population was all randomized patients whoreceived study drug. This report presents safety re-sults based on analysis of the safety population, andefficacy results based on analysis of the modifiedintent-to-treat population. Data were pooled toprovide an overall event rate for clevidipine andcomparator arms. Prespecified analysis of each ran-domized comparison was also performed. P values forthe primary end-point analysis were generated usingthe   2 test.AUC SBP-D was summarized descriptively by treat-ment group as total area of the SBP-time curve aboveor below the predefined SBP ranges (65–135 mm Hgintraoperatively, 75–145 mm Hg pre- and postopera-tively). Due to asymmetric distribution of AUC,descriptive statistics are presented using range (mini-mum and maximum), inter-quartile range (first quar-tile [Q1] and third quartile [Q3]), median (secondquartile), mean, and sd . P values for AUC analysiswere generated using the Wilcoxon rank sum test, a Figure 1. Schematic illustration of the AUC calculation for anindividual patient from the ECLIPSE trial. AUC SBP-D cap-tures the magnitude and duration of arterial blood pressure(BP) excursions outside the predefined systolic BP (SBP)ranges (65–135 mm Hg intraoperatively, 75–145 mm Hg pre-and postoperatively). 1112 The ECLIPSE Trial ANESTHESIA & ANALGESIA  nonparametric test applicable to asymmetric distribu-tions. The significance level was designated at thetwo-sided  level of 5%.To increase our ability to discriminate among treat-ment groups in the assessment of BP control, weconducted a post hoc analysis in which AUC wascalculated as the SBP range was narrowed by incre-mentally increasing the lower SBP limit by 10 mm Hg,20 mm Hg, and 30 mm Hg. Additionally, multiplelogistic regression analysis was performed to furtherexplore the relationship between the incidence ofdeath and treatment group while controlling for otherpotential risk factors. RESULTS Patients in the ECLIPSE trial were similar withrespect to demographics and medical history across alltreatment groups (579 received clevidipine or sodiumnitroprusside; 546 clevidipine or nitroglycerin, and381 clevidipine or nicardipine) (Tables 1 and 2). Pre-existing chronic hypertension was common in allgroups and nearly all patients were receiving antihy-pertensive medications before surgery. Patient charac-teristics, demographics, and cardiac surgical proceduregroups are detailed in Tables 2 and 3. In all treatmentgroups, CABG was the most commonly performedprocedure. Off-pump techniques were used in ap-proximately 10%–20% of patients and the number ofvalve-related procedures was similar among allgroups.The timing of drug administration among treatmentgroups is presented in Table 4. In the perioperative clevi-dipine: nitroglycerin and clevidipine: sodium nitro-prusside studies, study drug was primarily initiatedduring the preoperative or intraoperative period. Themajority of patients who initiated antihypertensivetreatment pre- or intraoperatively also receivedtherapy in the postoperative setting. Patients in theclevidipine: nicardipine study received the drug post-operatively per protocol as the half-life, volume ofdistribution, and slow offset of nicardipine was deter-mined to make it less suitable for use in the pre- andintraoperative setting. The median overall infusionduration, total infusion volume, and average infusionrates were greater in the nitroglycerin group com-pared to patients receiving clevidipine. Overall infu-sion duration, infusion rates and infusion volumeswere comparable between patients receiving clevidip-ine and sodium nitroprusside. The duration of infu-sion was similar between clevidipine and nicardipinewith the total fluid volume infused and averageinfusion rate greater for nicardipine compared toclevidipine. The use of adjunctive, alternative antihy-pertensive drugs was similar among treatmentgroups. The use of these drugs for the control ofhypertension tended to be higher in the sodiumnitroprusside-treated group compared with the clevi-dipine group; with  blockers most commonly admin-istered. There was also an increased tendency for theuse of sodium nitroprusside as a second-line antihy-pertensive drug in patients treated with nitroglycerincompared to those treated with clevidipine (11% vs2%, respectively).The primary outcome, 30-day incidence of death,MI, stroke, or renal dysfunction, for all treatmentgroups is detailed in Table 5. There was no difference between the pooled clevidipine populations comparedwith the pooled comparator group for any of the30-day safety outcome measures. There were no dif-ferences in death or adverse outcomes at the time ofhospital discharge or Day 7 among groups. Withintreatment groups, there were no differences in 30-dayoutcomes when clevidipine was compared with nitro-glycerin and nicardipine. Results for clevidipine com-pared to sodium nitroprusside were similar as wellexcept for the incidence of 30-day mortality, whichwas significantly higher in patients who had receivedsodium nitroprusside compared to clevidipine (4.7%vs 1.7%, P  0.0445). However, multiple logisticregression analysis for treatment effect (clevidipine vssodium nitroprusside) as an independent variable in amodel that included other risk variables such assurgery duration, AUC SBP-D , age, and medical history,showed no statistically significant association betweensodium nitroprusside use and 30-day mortality (oddsratio, 1.968, 95% confidence interval, 0.619–6.257, P  0.25). Among 13 patients requiring treatment for hyper-tension who died in the sodium nitroprusside group,three had hypotension reported as an adverse event.Comparisons of the pooled data from the entireclevidipine population with the pooled data of theentire comparator group demonstrated that clevidip-ine was significantly more effective at keeping BPwithin the prespecified BP range (Table 6, Fig. 2).  Table 1. Patient Disposition from the ECLIPSE Program CLV NTG CLV SNP CLV NIC Patients randomized 312 316 363 376 296 301Patients who met postrandomization criteria(mITT population)270 278 297 284 188 195Patients who did not receive study medication a 2 0 1 1 1 1Patients who received study medication(safety population)268 278 296 283 188 193Total safety population 546 579 381 CLV  clevidipine; NTG  nitroglycerin; SNP  sodium nitroprusside; NIC  nicardipine; mITT   modified intent-to-treat. a  Two patients in the CLV:NIC treatment group did not receive study medication and were excluded from the safety population. In addition, one patient in the same treatment group was randomizedto NIC but received CLV instead. This patient was excluded from the NIC safety population and included in the CLV safety population. Vol. 107, No. 4, October 2008 © 2008 International Anesthesia Research Society 1113
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