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 approximately 2 or approximately 10 minutes) in healthy volunteers receiving infusions of 0.91 or 3.2 mug/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 approximately 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 approximately 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 >or=15% from baseline in systolic BP (SBP) in <or=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 >or=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.