Brand Name: CleviprexTM
Generic Name: Clevidipine 1
Manufacturer: Hospira, Inc. 3
Drug Class: Dihydropyridine calcium channel blocker, Antihypertensive 1
Uses:
Used for the treatment of hypertension when oral therapy is not a feasible route of administration. 1,2,3
Mechanism of Action:
Clevidipine is a dihydropyridine L-type calcium channel blocker, which is vasoselective and short-acting. 1 The selectivity of clevidipine is associated with greater inotropic effects compared to chronotropic. 2 Vascular resistance is decreased by causing systemic, coronary, and pulmonary vasodilation. 2 Clevidipine has not been shown to have effects on venous capacitance vessels. 2 Mean arterial pressure is decreased without an increase in stroke volume, a change in venous return, or cardiac filling pressure. 2
Pharmacokinetics:1,3
Tmax |
N/A |
Vd |
0.17L/kg in arterial blood at SS |
t1/2 |
Initial t1/2 of 1 minute accounts for 85-90% elimination, terminal t1/2 is 15 minutes |
Clearance |
0.03L/h/kg of metabolite, 0.05L/min/kg of clevidipine |
Protein binding |
>99.5% protein bound |
Bioavailability |
100% |
Metabolism: Esterases in arterial blood rapidly hydrolyzes clevidipine to inactive metabolites. Clevidipine is cleaved to a hemiacetal ester and butyric acid. The hemiacetal ester further metabolizes by glucuronidation, oxidation, and decarboxylation before it is excreted.
Elimination: 63-74% of clevidipine is renally excreted and 7- 22% is excreted in the feces.
Efficacy:
Aronson S, Dyke CM, Stierer KA, Levy JH, Cheung AT, Lumb PD, Kereiakes DJ, Newman MF. The ECLIPSE trials: comparative studies of clevidipine to nitroglycerin, sodium nitroprusside, and nicardipine for acute hypertension treatment in cardiac surgery patients. Anesth Analg. 2008 Oct;107(4):1110-21.
Study design: 3 prospective, randomized, open-label, parallel comparison studies of clevidipine to nitroglycerin or sodium nitroprusside perioperatively, or nicardipine postoperatively in patients undergoing cardiac surgery at 61 medical centers in the United States.
Description of study: The primary end point was safety; assessed by the incidence of death, stroke, myocardial infarction, and renal dysfunction from the initiation of clevidipine infusion to postoperative day 30. The efficacy was assessed using AUC analysis of blood pressure excursions beyond predetermined upper and lower limits, normalized per hour (AUCSBP-D). Vital signs, clinical laboratory data, fluid administration, the incidence of reflex tachycardia, and serious adverse events including the incidence of atrial fibrillation during study drug administration were reported up to 30 days postoperatively. The data was pooled from all the clevidipine and comparative arms for an overall event rate.
Results: There was no statistical difference in the primary outcome, 30-day incidence of death, MI, stroke, or renal dysfunction, among all the treatment groups. The only exception was the 30-day mortality rate was higher in patients who received sodium nitroprusside compared to clevidipine (4.7% vs. 1.7% P=0.0445). However, once regression analysis was preformed it was determined that this did not hold statistical significant, because of the differences in independent variables. Based on pooled analysis and analysis of individual treatment cohorts clevidipine was shown to be more effective in maintaining the targeted prespecified BP range compared to nitroglycerin and sodium nitroprusside with reported P values being statistically significant. Patients treated with sodium nitroprusside had an increased number of measurements outside the targeted blood pressure range (both above and below). There was not a significant difference in the incidence of atrial fibrillation in all the groups.
Limitations: The design of the study was open label, making potential biases an issue. The Medicines Company supported the trial, which may be considered a conflict of interest. The results were gathered from three previous trials, and variability among the studies was not accounted for in the post hoc analysis.
Conclusion: This study established both safety and efficacy with the use of clevidipine in the treatment of cardiac patients both pre and postoperatively. In addition to safety and efficacy, clevidipine was compared to current treatment modalities. The results of the comparison established that clevidipine is more easily titrated to reach targeted blood pressure ranges than the other drug treatments. Despite the limitations of the study, this study holds clinical value in the role clevidipine has in the treatment of pre and postoperative hypertension.
Singla N, Warltier DC, Gandhi SD, Lumb PD, Sladen RN, Aronson S, Newman MF, Corwin HL. Treatment of acute postoperative hypertension in cardiac surgery patients: an efficacy study of clevidipine assessing its postoperative antihypertensive effect in cardiac surgery-2 (ESCAPE-2), a randomized, double-blind, placebo-controlled trial. Anesth Analg. 2008 Jul;107(1):59-67.
Study design: A prospective, double-blind, randomized, placebo controlled trial that was performed at 15 medical centers.
Description of study: This is an efficacy study to assess clevidipine in the management of postoperative hypertension after cardiac surgery. The primary end point studied was the incidence of treatment failure. Treatment failure was defined as the inability to decrease SBP by at least 15% or the premature/permanent discontinuation of clevidipine for any reason within 30 minutes of initiation. Non-study drugs or other procedures used for the treatment of hypertension were prohibited for the first 30 minutes of infusion of the study drug. The categories of treatment failure included lack of efficacy, insufficient efficacy, and safety reasons. Secondary endpoints recorder were time to the first reduction of SBP by at least 15% from baseline, change in mean arterial blood pressure from baseline, and change in heart rate. Results: Clevidipine had greater treatment success than placebo (91.8% vs. 20.4%; P<0.001). A total of 5 patients failed treatment with clevidipine, 2 for insufficient efficacy and 3 for safety reasons. Clevidipine had a median time to target systolic blood pressure of 5.3 minutes (95% CI, 4-7 minutes). Reflex tachycardia was not observed in patients who received clevidipine for the 30-minute infusion period. Adverse effect rates were comparable among both groups. The incidence of serious adverse effects was 16.4% for clevidipine and 12.2% for placebo.
Limitations: The Medicine’s Company supported this trial which may be a potential bias in the study. Limitations of the study were not listed in the article. The study had some differences in baseline characteristics among patient groups. The use of beta-blockers and other vasodilators before surgery and during the administration of study drug may have impacted the true efficacy results.
Conclusions: Clevidipine showed an increased efficacy in the treatment of postoperative hypertension when compared to placebo in patients undergoing cardiac surgery. This study provided promising data in determining the clinical efficacy and safety with clevidipine use in cardiac surgery patients. However, future studies need to be done comparing clinical standards of treatment to define clevidipine’s actual therapeutic role.
Levy JH, Mancao MY, Gitter R, Kereiakes DJ, Grigore AM, Aronson S, Newman MF. 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. Anesth Analg. 2007 Oct;105(4):918-25.
Study design: The ESCAPE-1 trial was a randomized, double-blind, placebo controlled trial designed to determine the efficacy of clevidipine for treatment of preoperative hypertension in cardiac surgery patients.
Description of study: This study evaluates the efficacy and tolerability of clevidipine in the treatment of preoperative hypertension. Efficacy was evaluated by comparing the incidence of treatment failure. Each event causing treatment failure was classified into one of three categories; lack of efficacy, insufficient efficacy, or safety reason. Change in mean arterial blood pressure from baseline and time to target blood pressure was also measured in the study (time to at least a 15% reduction from baseline). Adverse events were recorded from the initiation of the drug for 7 days or until the patient was discharged (whichever came first).
Results: Clevidipine had a lower rate of treatment failure than placebo (7.5% vs. 82.7%; P<0.0001). The 4 patients that were considered failures to treatment had an insufficient response. None of the patients in either group had treatment failure due to safety reasons, and all the patients in the clevidipine group had some response to the medication. The median time to reach targeted arterial blood pressures was 6 minutes (95% CI 6-8 min) for the clevidipine group. There was a greater decrease in mean MAP from baseline in the clevidipine group compared to the placebo. Patients who received clevidipine treatment had an increase in heart rate compared to placebo, but then normalized after discontinuation of infusion. All other adverse effects reported did not show a statistically significant difference.
Limitations: The Medicine’s Company supported this study and may have posed a conflict of interest. One limitation listed in the study was the lack of use of clevidipine during surgery, due to ethical reasons. In addition to clevidipine other medications were also given preoperatively such as; beta-blockers, benzodiazepams, and opioid analgesics which may have affected the clinical markers measured in this trial.
Conclusion: This study displayed the increased efficacy of clevidipine in the treatment of preoperative hypertension compared to placebo. However, there were a small number of patients enrolled in the study. Although clevidipine was determined to have a limited number of adverse effects and a low incidence of treatment failure, more studies need to be done to further determine clevidipine’s clinical use. Future studies should compare clevidipine to a more standard care of practice other than placebo with a larger number of patients enrolled.
Contraindications:
Clevidipine is contraindicated in patients with a known hypersensitivity to egg or soy, have severe aortic stenosis, or defective lipid metabolism. 1,2,3
Precautions: 3
Clevidipine can cause hypotension and reflex tachycardia. Dose should be decreased if either occurs. Approximately 0.2g of lipids are contained in 1 ml of clevidipine. Therefore, lipid restrictions may be required for patients that have been diagnosed with lipid metabolism disorders. Due to the negative inotropic effects of calcium channel blockers, patients with a history of heart failure should be carefully monitored. Clevidipine should not be used to reverse the effects of b-blocker withdrawal. Prolonged infusions with clevidipine in patients who are not transitioned to other antihypertensive therapy are at risk for rebound hypertension. These patients should be monitored for at least 8 hours after the infusion is stopped. No information is available in treating patients with hypertension associated with pheochromocytoma.
Adverse Effects:1
Cardiovascular Effects |
||
Occurred in 21% of patients with postoperative hypertension |
||
<1% of patients in clinical studies had cardiac arrest |
||
Systemic hypotension may result with therapy of clevidipine |
||
<1% of patients were reported to have an MI in clinical studies |
||
Rebound hypertension may occur patients should be monitored |
||
Reflex tachycardia can occur, dose should then be decreased |
||
<1% of patients were reported to have syncope |
||
Gastrointestinal Effects |
||
Nausea |
4.8,21% of patients reported nausea in separate trials |
|
Vomiting |
3.2% of patients |
|
Neurologic Effects |
||
Headache |
6.3% of patients |
|
Respiratory Effects |
||
Dyspenia |
<1% of patients |
|
Renal Effects |
|
|
Acute Renal Failure |
9% (5/53) of patients had renal failure with preoperative treatment |
|
Drug Interactions:
Clevidipine has low potential to interact with other drugs.3 Additive hypotensive effects can occur with concomitant use of beta-blockers, alpha-blockers, diuretics, monoamine oxidase inhibitors, and ethanol. 2 Addition of calcium channel blockers to general anesthetics can potentiate depression of cardiac contractility, conductivity, and automaticity.2 NSAIDs can block vasodilatory prostaglandins decreasing the effects of antihypertensives. 2 Estrogen containing oral contraceptives can cause fluid retention resulting in an increased blood pressure. 2 Calcium salts are used to reverse the effects of calcium channel blockers, patients receiving both calcium and clevidipine should be monitored for therapeutic response. Clevidipine should be used with caution in patients on ritonavir due to the prolongation of PR interval. 2 Clevidipine and ritonavir both prolong the PR interval; caution should be used with combined therapy. 2 Ephedra (Ma Huang) and Yohimbine can increase blood pressure antagonizing the antihypertensive effects of clevidipine. 2 Hawthorn (Crataegus laevigata) decrease peripheral vascular resistance causing an increased reduction in blood pressure.2
Dosing/Administration1:
Clevidipine is for IV use only, and further dilution is not recommended.
Usual Adult Dosage: Initially 1-2 mg/hr IV infusion and titrated to reach target blood pressure. Dose titration should be doubled initially at 90 second intervals, and then intervals should be lengthened to 5-10 minutes. 1-2mg/hr decreases systolic blood pressure 2 to 4 mmHg. Maximum recommended dosage is 16mg/hr. Doses up to 32mg/hr have been administered for severe hypertension, but data is limited. Maintenance dose is 4-6mg/hr IV infusion. Clevidipine should be titrated downward when transitioning to oral therapy to allow for onset of action of oral therapy. Duration of therapy is usually less than 24 hours, however it may be extended to 72 hours.
Renal Impairment Dosing: May be initiated at 1-2mg/hr
Hepatic Impairment Dosing: May be initiated at 1-2mg/hr
Geriatric Dosing: Should be initiated at low dose and titrated with caution
Pediatric Dosing: Not indicated for pediatrics
Uses in special circumstances:
Effects in Pregnancy: Category C, data is not available. Animal studies have shown increased mortality in maternal and fetal rats. Clevidipine should only be used if the benefits of treatment outweigh the risk.
Conclusion:
Clevidipine is a short-acting dyhydropyridine calcium channel blocker indicated for the use of hypertension when oral therapy is not an available. Clevidipine may be particularly useful in the critical care setting to allow for a fast and accurate decrease in blood pressure in order to reach goal. The ease of titration is enabled by the rapid metabolism of clevidipine by esterases. Clevidipine has been shown to be both effective and have a low potential of serious adverse effects as reported in the study trials mentioned above. Clevidipine showed both safety and efficacy when compared to placebo, nitroglycerin, sodium nitroprusside, and nicardipine for the treatment of hypertension pre and postoperatively in patients undergoing cardiac surgery.
Recommended References:
Prepared by: Marci L. Pursglove, Doctor of Pharmacy Candidate.