Clevidipine for hypertensive emergencies

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Clevidipine is rapid acting, easily titratable, low risk of hypotensive overshoot

Introduction

As emergency physicians, we frequently face the clinical scenario of hypertensive emergency: a patient’s blood pressure rises to a critical tipping point, which can lead to the development of life-threatening end-organ damage such as hypertensive encephalopathy, hemorrhagic stroke, acute pulmonary edema, aortic dissection or acute renal failure. We must choose a drug that can rapidly decrease the patient’s blood pressure, but need to avoid dropping the blood pressure too low, which is associated with equally undesirable outcomes of ischemic stroke and myocardial infarction. Which drug do you reach for? Nicardipine? Labetalol? Nitroglycerin? We review a newer drug on the block, clevidipine.

Clevidipine is a potent, short-acting and easily titratable arterial vasodilator which can be a valuable tool in the emergency physician’s armamentarium to treat hypertensive emergencies.

How it works

Clevidipine, marketed under the drug name Cleviprex, is an intravenous dihydropyridine calcium channel blocker. Clevidipine acts by inhibiting calcium ion influx through the L-type calcium channels in arterial smooth muscle cells. This vasodilates the arterial bed, reducing systemic vascular resistance and decreasing mean arterial pressure. Because it is highly selective for vascular, and not myocardial, smooth muscle, it has little to no effect on cardiac contractility or cardiac conduction.

Onset of action is rapid, within two to four minutes of infusion. It is short acting, with duration of action around five to 15 minutes, which allows close titration. Because clevidipine is metabolized primarily by plasma esterases rather than the kidney or liver, dosing adjustments are not required in renal or hepatic failure, increasing its margin of safety.1 Although reflex tachycardia is a risk of many antihypertensives, studies on clevidipine show no or very little associated increase in heart rate, and a very low risk of hypotensive overshoot.(2)

In the news

Clevidipine was approved by the FDA in 2008 for the treatment of hypertension when oral therapy is not preferred or is not feasible. It is commonly used for hypertensive emergency and for blood pressure control during cardiac surgery.

While this latter category is not relevant for the emergency physician, studies in patients with acute neurologic injury, including intracerebral hemorrhage, subarachnoid hemorrhage, and acute ischemic stroke, demonstrate the clevidipine provided rapid blood pressure control without causing hypotensive overshoot in the majority of patients.(2) Clevidipine also performed well in comparative studies with other antihypertensives. The ECLIPSE trial, which was a randomized, multicenter phase III study, showed that clevidipine was more effective in maintaining blood pressure within the target range in cardiac surgery patients than nitroglycerin and sodium nitroprusside, and had similar efficacy to nicardipine, with no increase in major adverse events.(3)

Use of clevidipine in acute heart failure is somewhat controversial. Emerging data suggests that clevidipine is safe and effective for blood pressure control in acute heart failure.4 However current guidelines still warn against use of dihydropyridine calcium channel blockers in acute heart failure due to lack of benefit and potential harms, though not clevidipine specifically.(5)

Comparison to nicardipine

It also compares favorably to its cousin, nicardipine, another dihydropyridine calcium channel blocker used widely in the management of hypertensive emergency. While the two drugs have similar rapid onset of action, clevidipine has a much brief duration of action, lasting minutes compared to three hours with nicardipine. Therefore clevidipine can be more easily titrated.(1)

While initial studies reported that clevidipine had a quite high incidence of atrial fibrillation, up to 36%, these numbers have not been duplicated in subsequent studies. A retrospective review comparing clevidipine and nicardipine in the treatment of acute hemorrhagic and ischemic stroke found the two agents had essentially equivalent times to achieve target blood pressure and time spent at goal blood pressure, with no differences in efficacy outcomes or incidence of adverse effects such as acute kidney injury. Although it had higher rates of atrial fibrillation, this did not reach statistical significance.(6)

Another advantage of clevidipine is that it has a smaller infusion volume than nicardipine, which could be beneficial in fluid-restricted patients. Disadvantages include higher cost and concerns about worsening of hypertriglyceridemia, since it is formulated in a lipid emulsion.

Adverse Events

The most commonly reported adverse reactions with clevidipine include atrial fibrillation, acute kidney injury, and nausea. As with any antihypertensive medication, clevidipine may cause systemic hypotension, and blood pressure should be lowered at an appropriate rate and goal for the specific clinical condition. It should not be used in patients with severe aortic stenosis because of the risk of precipitating severe hypotension.

Although rare, reflex tachycardia may occur with it, which can lead to myocardial ischemia or infarction in patients with underlying coronary artery disease. If reflex tachycardia occurs, the dose of clevidipine should be lowered. Patients should be monitored for at least eight hours after the clevidipine infusion is stopped because they can develop rebound hypertension, especially if patients are not transitioned to oral antihypertensives.

Contraindications

It is contraindicated in patients with soy or egg allergies because these products are used to produce the emulsion. It should also not be used in patients with severe hypertriglyceridemia or other defective lipid metabolism, since it is formulated with a 20% fat emulsion and hypertriglyceridemia is an expected side effect with high-dose or prolonged therapy.(7)

Dosing and adjustments

The initial dose is 1 to 2 mg/hour. The dose may be doubled at 90 second intervals. As goal blood pressure is approached, the dose can be increased at a small fraction, every five to 10 minutes, for a max dose of 21 mg/hour. For every 1 to 2 mg/hour increase in dose, you can expect a reduction of systolic blood pressure of approximately 2 to 4 mm Hg.(8) Dosing adjustments are not needed for renal failure. For geriatric patients, dosing should be initiated at the lower end of the dosing range.

Special Considerations

Clevidipine is pregnancy category C. Adverse events have been observed in animal studies, and alternative antihypertensives should be selected in pregnant women who require treatment for hypertension. It is not known if it is excreted in breast milk.(7)

Cost

A 25 mg (50 mL) vial of Cleviprex costs $83.

References
  1. Rosenfeldt Z, Conklen K, Jones B, Ferrill D, Deshpande M, Siddiqui FM. Comparison of Nicardipine with Clevidipine in the Management of Hypertension in Acute Cerebrovascular Diseases. J Stroke Cerebrovasc Dis. April 2018. doi:10.1016/j.jstrokecerebrovasdis.2018.03.001.
  2. Keating GM. Clevidipine: A Review of Its Use for Managing Blood Pressure in Perioperative and Intensive Care Settings. Drugs. 2014;74(16):1947-1960. doi:10.1007/s40265-014-0313-6.
  3. Aronson S, Dyke CM, Stierer KA, et al. The ECLIPSE Trials: Comparative Studies of Clevidipine to Nitroglycerin, Sodium Nitroprusside, and Nicardipine for Acute Hypertension Treatment in Cardiac Surgery Patients. Anesth Analg. 2008;107(4):1110-1121. doi:10.1213/ane.0b013e31818240db.
  4. Watson K, Broscious R, Devabhakthuni S, Noel ZR. Focused Update on Pharmacologic Management of Hypertensive Emergencies. Curr Hypertens Rep. 2017;20(7):56. doi:10.1007/s11906-018-0854-2.
  5. Leixcomp: Clevidipine: Drug information. www.uptodate.com. Published 2018. Accessed April 27, 2018.
  6. Elliott W et al. Drugs used for the treatment of hypertensive emergencies – UpToDate. https://www-uptodate-com.libproxy.lib.unc.edu/contents/drugs-used-for-the-treatment-of-hypertensive-emergencies?search=clevidipine&source=search_result&selectedTitle=2~15&usage_type=default&display_rank=4. Accessed April 27, 2018.
  7. Lexicomp: Clevidipine. UptoDate. www.uptodate.com. Accessed June 11, 2018.
  8. Barrett TW, Schriger DL. Pollack CV, Varon J, Garrison NA, et al. Clevidipine, an Intravenous Dihydropyridine Calcium Channel Blocker, Is Safe and Effective for Treatment of Patients With Acute Severe Hypertension. Ann Emerg Med. 2009;53(3):339-340. doi:10.1016/j.annemergmed.2009.01.003.

ABOUT THE AUTHORS

Karen Serrano, MD is an assistant professor in the department of emergency medicine at the University of North Carolina.

Dr. Shenvi is an assistant professor in the department of emergency medicine at the University of North Carolina. She authors RX Pad each month in EPM.

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