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Clevidipine

A Review of its Use in the Management of Acute Hypertension

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Summary

Abstract

Clevidipine (Cleviprex™), a late-generation dihydropyridine calcium channel antagonist available as a lipid emulsion for intravenous infusion, is approved in the US for the reduction of blood pressure (BP) when oral therapy is not feasible or desirable. Intravenous clevidipine is effective in the treatment of both acute preoperative and postoperative hypertension in adult cardiac surgery patients, and with a rapid onset and short duration of action the drug can be easily titrated for predictable BP control. Moreover, in terms of controlling acutely elevated BP in this patient population, clevidipine is more effective than sodium nitroprusside or nitroglycerin in the perioperative setting, and has an efficacy no different from that of nicardipine in the postoperative setting. Data from a noncomparative study also indicate that intravenous clevidipine is effective in the treatment of adults with acute severe hypertension. Clevidipine is generally well tolerated in these patient populations, and has a safety profile generally similar to that of sodium nitroprusside, nitroglycerin, or nicardipine in cardiac surgery patients. Additional comparative data are required to definitively position clevidipine with respect to other agents, particularly in patients with acute severe hypertension, and there is potential for its use to be investigated in other appropriate clinical settings requiring acute BP control. In the meantime, the clinical data currently available indicate that intravenous clevidipine has potential as an option for the treatment of acute perioperative hypertension during cardiac surgery and hypertensive emergencies in adults.

Pharmacologic Properties

Clevidipine inhibits L-type calcium channels in a voltage-dependent manner and exhibits a high degree of vascular selectivity in vitro. The BP-lowering effects of the drug are rapid and dose dependent, and are achieved by decreasing systemic vascular resistance without affecting venous capacitance vessels or cardiac filling pressures, with offset of effect within 5–15 minutes. Clevidipine had greater effects on arterial vasodilation and lesser effects on venodilation compared with sodium nitroprusside in hypertensive post-coronary artery bypass graft (post-CABG) patients. Clevidipine was not associated with reflex increases in heart rate in normotensive post-CABG patients or post-cardiac surgery patients, although elevations in heart rate were seen in healthy volunteers, cardiac surgery patients who received the drug preoperatively, and patients with acute severe hypertension. Data from animal studies suggest that clevidipine may protect against myocardial and renal injury caused by ischemia and/or reperfusion.

Steady-state concentrations of clevidipine in arterial and venous blood were rapidly attained (within ≈2 or ≈10 minutes) in healthy volunteers receiving infusions of 0.91 or 3.2 μg/kg/min. The relationship between intravenous clevidipine infusion dose and steady-state blood concentration was linear over wide dose ranges in patients with mild to moderate hypertension and in healthy volunteers. Clevidipine is highly plasma protein bound and rapidly distributed, and has a low volume of distribution at steady state. It is rapidly metabolized via hydrolysis by esterases in the blood and extravascular tissues to a major metabolite that is inactive as an antihypertensive. Concentrations of clevidipine in the blood fall rapidly in a multiphasic fashion after termination of infusion. The initial phase is rapid (half-life of ≈1 minute) and accounts for the majority of clevidipine exposure after an intravenous bolus dose and for 85–90% of its elimination; the terminal elimination half-life is ≈15 minutes. Clevidipine metabolites are excreted mainly via the urine and feces and the drug has a high mean total blood clearance. The clearance of clevidipine was significantly lower during hypothermic cardiopulmonary bypass than before the procedure.

Therapeutic Efficacy

Intravenous clevidipine, administered by infusion, was effective in the treatment of both acute preoperative and postoperative hypertension in adult cardiac surgery patients in two large, well designed, phase III trials. Few clevidipine recipients had evidence of treatment failure, whereas most placebo recipients failed treatment (primary endpoint) and the between-group difference was significant. Clevidipine produced rapid reductions of ≥15% from baseline in systolic BP (SBP) in ≤6 minutes, and rapidly improved mean arterial BP relative to placebo, with such benefits sustained for all or half of the 30-minute treatment period.

Furthermore, in three large, randomized, open-label, multicenter, phase III trials in adult cardiac surgery patients with acute hypertension, intravenous clevidipine maintained SBP within prespecified target limits more effectively than intravenous nitroglycerin or sodium nitroprusside in the perioperative setting, and with an efficacy not significantly different from that of intravenous nicardipine in the postoperative setting.

Intravenous clevidipine was also effective in lowering BP in adults with acute severe hypertension in a large, noncomparative, open-label, multicenter, phase III study. The target SBP range was achieved by most patients (88.9%) within 30 minutes of initiating clevidipine treatment (primary efficacy endpoint) [median time 10.9 minutes] and few patients (1.6%) had SBP fall below the lower limit of their target range within the first 3 minutes of the infusion (primary safety endpoint). The majority (91%) of patients made successful transitions to oral antihypertensive agent therapy after receiving intravenous clevidipine for ≥18 hours.

Tolerability

Intravenous clevidipine was safe and generally well tolerated in cardiac surgery patients with acute hypertension in large, randomized, clinical trials. Clevidipine was as safe as nitroglycerin, sodium nitroprusside, or nicardipine with regard to the incidence of myocardial infarction, stroke, or renal dysfunction (primary safety endpoints) in patients with perioperative or postoperative hypertension. Moreover, clevidipine recipients had an incidence of death (primary safety endpoint) not significantly different to that in nitroglycerin or nicardipine recipients and significantly lower than in sodium nitroprusside recipients, although this significant between-group difference was not confirmed by the findings of multiple logistic regression analysis after accounting for other factors. Clevidipine demonstrated a tolerability profile similar to that of placebo in patients with preoperative or postoperative hypertension, with the nature and incidence of treatment-emergent adverse events generally being similar between treatment groups. The most common treatment-emergent adverse events associated with clevidipine in the active comparator-controlled trials included atrial fibrillation and sinus tachycardia, although the incidence of such events did not differ from that seen with nitroglycerin, sodium nitroprusside, or nicardipine. Intravenous clevidipine was also generally well tolerated in patients with acute severe hypertension, regardless of infusion duration, in a large, noncomparative study. Most adverse events associated with clevidipine were mild or moderate in severity and considered unrelated to study drug, with the most commonly reported being headache, nausea, chest discomfort, and vomiting.

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Authors and Affiliations

  1. Wolters Kluwer Health | Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand

    Emma D. Deeks, Gillian M. Keating & Susan J. Keam

  2. an editorial office of Wolters Kluwer Health, Philadelphia, Pennsylvania, USA

    Gillian M. Keating

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Correspondence to Emma D. Deeks.

Additional information

Various sections of the manuscript reviewed by: S. Aronson, Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA; J.M. Bailey, Critical Care Medicine, Northeast Georgia Medical Center, Gainesville, Georgia, USA; A.T. Cheung, Department of Emergence Medicine, Pennsylvania Hospital, University of Pennsylvania, Philadelphia, Pennsylvania, USA; J.H. Levy, Department of Cardiothoracic Anesthesiology and Critical Care, Emory University Hospital, Atlanta, Georgia, USA; C.V. Pollack, Department of Emergence Medicine, Pennsylvania Hospital, University of Pennsylvania, Philadelphia, Pennsylvania, USA; J. Varon, University of Texas Medical Branch at Galveston, St Luke’s Episcopal Hospital/Texas Heart Institute, and University of Texas Health Science Center at Houston, Houston, Texas, USA; A. Vuylsteke, Department of Anaesthesia and Intensive Care, Papworth Hospital NHS Foundation Trust, Cambridge, England.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘clevidipine’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database ofWolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE, and AdisBase search term was ‘clevidipine’. Searches were last updated 25 February 2009.

Selection: Studies in patients with acute hypertension who received clevidipine. Inclusion of studies was based mainly on the methods section of the trials.When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Clevidipine, calcium channel antagonist, acute hypertension, pharmacodynamics, pharmacokinetics, therapeutic use, safety, tolerability.

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Deeks, E.D., Keating, G.M. & Keam, S.J. Clevidipine. Am J Cardiovasc Drugs 9, 117–134 (2009). https://doi.org/10.1007/BF03256583

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