DRUG EVALUATION
Clevidipine and the management of acute hypertension
Clevidipine is a new ultra-short-acting calcium channel blocker of the dihydropiridine class. It is characterized by its vascular selectivity, extremely high clearance value and a small volume of distribution that together result in an extremely short half-life of approximately 1 min, thus allowing the rapid titration to the desired effect. In recent studies, the ESCAPE 1, ESCAPE 2, ECLIPSE and VELOCITY trials, clevidipine has shown a clear advantage in the management of acute hypertension when compared with placebo, as evidenced in ESCAPE 1 and 2. In the VELOCITY trial, clevidipine demonstrated a reduction in blood pressure of 6% at the 3-min mark, 15% within 9.5 min and 27% at the 18-h mark. The ECLIPSE trial compared clevidipine to sodium nitroprusside, nitroglycerin and nicarpidine. Clevidipine was demonstrated to be superior to the other agents in providing blood pressure control, and also provided a signifi cant reduction in mortality when compared with nitroprusside (1.7 vs 4.7%).
KEYWORDS: calcium channel blockers, clevidipine, hypertensive crisis, hypertensive Joseph Varon1† & emergency, hypertensive urgency Jorge E Angeles2 †Author for correspondence: One of the most common chronic medical con- in part, to its selectivity for arteriolar dilatation 1University of Texas ditions, affecting almost 30% of the population without affecting myocardial contractility, as Health Science Center, over the age of 20 years, and accounting for well as its null effect on venous capacitance [9]. 2219 Dorrington St, Houston, approximately 72 million people in the USA Its rapid onset of effect, high clearance and small TX 77030 3209, USA alone, is chronic hypertension [1] . While the volume of distribution make it a promising agent Tel.: +1 713 669 1670 chronic form of hypertension is more common for the management of acute severe hypertension Fax: +1 713 839 1467 than acute hypertension, the management of in situations when tight BP control is a critical [email protected] acute hypertension clinically represents a greater issue [10] . 2Universidad Autónoma de challenge. More frequent and severe compli- Baja California, México cations and poorer short-term prognosis are General aspects of acute common with acute hypertension as opposed hypertension to chronic hypertension. Acute elevations in There have been numerous terms used to defi ne blood pressure (BP) may result in severe clini- acute elevations in BP, and ‘hypertensive crises’ cal conditions such as hypertensive encephal- has been used to defi ne any acute elevation in opathy, acute aortic dissection, acute myocar- systolic BP (SBP) or diastolic BP (DBP) that dial infarction, acute renal failure, intracranial may, or may not, occur with end-organ dam- hemorrhage, acute heart failure and eclampsia, age. The Seventh Joint National Committee amongst others [2]. on Prevention, Detection, Evaluation, and Hypertensive crises are commonly encoun- Treatment of High Blood Pressure [11] further tered by emergency department (ED) personnel stated that a hypertensive emergency can be in a clinical setting, occurring in up to 27.5% of defi ned as an acute elevation associated with all nonsurgical emergencies presenting to the ED, end-organ damage; while an acute elevation of and up to 3% of all emergency room visits [3]. SBP and/or DBP without end-organ damage can Some of the most commonly used agents are be defi ned as a hypertensive urgency [11] . sodium nitroprusside and nitroglycerin. Both The differentiation between a hypertensive are intravenous, short-acting vasodilators, used emergency and hypertensive urgency is impor- in the management of acute hypertension due to tant, since either the presence or absence of high vascular resistance; however, both of these end-organ damage will dictate the urgency and agents present multiple adverse effects that limit aggressiveness of treatment. In a hypertensive their utility [4–7]. emergency, the rapid reduction and control Clevidipine is a relatively new ultra-short- of BP is essential to avoid further end-organ acting, dihydropyridine, calcium channel damage [11], while in a hypertensive urgency the blocker [8]. It is a potent arterial vasodilator due, BP control can be achieved with the use of oral
10.2217/14750708.5.6.751 © 2008 Future Medicine Ltd Therapy (2008) 5(6), 751–758 ISSN 1475-0708 751 DRUG EVALUATION Varon & Angeles
medications within the fi rst 24–48 h after its pain, dyspnea and changes in mental status [3]. presentation, with little or no change in fi nal It is important to keep in mind that there is no outcome [12,13] . specifi c BP that is associated with end-organ damage, and the elevation of BP is not the Epidemiology only factor contributing to organ damage. Hypertensive crises can account for 25% or more Moreover, the rate of increase should be taken of all medical emergencies presenting in the ED into account [2]. [3], and up to 3% of the total visits to the ED, Patients presenting with or as a hyperten- therefore making it one of the most commonly sive emergency need an immediate reduction encountered affl ictions in emergency settings. It in BP to reduce the risk of end-organ damage; is estimated that approximately 1% of chronically a general goal is to reduce mean arterial pres- hypertensive patients will experience a hyperten- sure (MAP) by 15–20% within the fi rst 2 h sive crisis in their lifetime [14] . Risk factors for of treatment. However, in hypertensive urgen- hypertensive crises include old age, African– cies there is no need to achieve a BP control American heritage, male gender, tobacco abuse, as urgently, and the target BP can be achieved obesity and diabetes mellitus [15,16] . The mor- over a period of 24–48 h [19] . In fact, rapid bidity and mortality of hyper tensive crises are reduction can result in a marked decrease in dependent on the degree of target organ damage, tissue perfusion, which can result in ischemia adequate BP control and adherence to treatment. or infarction [23–26]. In the untreated patients, the mortality rate at Most individuals presenting to the hospital 1 year can be as high as 79% [17], and among all with chronic hypertension and an elevated BP patients that present with hypertensive crises, exhibit a rightward shift of the pressure/fl ow there is a 5-year survival rate of 74% [18]. autoregulation curve with no acute end-organ damage [27]. Vascular injury leads to platelet and Pathophysiology fi brin deposition, breakdown of normal auto- As with chronic hypertension, the patho physiology regulation and, with ischemia, the release of of a hypertensive crisis is considered to be mul- vasoactive substances [27]. Altered autoregulation tifactorial. The factors that lead to a hyperten- also occurs in patients with acute severe hyper- sive crisis have not been entirely elucidated, but tension, and since end-organ damage is already include mechanical stress, injury, endothelial present, rapid and excessive correction of the damage, oxidative stress and renin–angiotensin BP can further reduce perfusion and propagate system activation [19] . further injury [1]. It is well known that endothelial damage will cause the rapid release of humoral agents, most Operative & postoperative noticeably vasoconstrictors that will increase hypertension systemic vascular resistance, although the ini- A hypertensive crisis may present during any sur- tiating factor is still not well understood [20,21]. gical setting, especially during cardiac surgery, The resulting increase in BP will, in turn, major vascular surgery (i.e., carotid endarter- increase the mechanical stress and endothelial ectomy and aortic surgery), neurosurgery, injury. The subsequent damage to the vascu- head and neck surgery, renal transplantation lar endothelium will result in the activation of and major trauma (e.g., burns or head injury). platelets and the coagulation cascade, with the Postoperative hypertension (BP ≥ 190 mmHg subsequent formation on thrombi resulting in and/or a diastolic BP of 100 mmHg on two con- ischemia, as well as the activation and release secutive readings following surgery) [28,29] could of proinfl ammatory cytokines such as IL-6, result in creating signifi cant adverse sequelae in vasoactive mediators and the renin–angiotensin both cardiac and noncardiac patients. Depending system. The result of these collective mecha- upon the population examined, the incidence of nisms can be further hypoperfusion, ischemia post operative hypertensive crises varies from 4 and end-organ damage [19,22] . to 35% of patients shortly after a surgical pro- cedure [30–32]. Greater attention should be given Clinical presentation to precise perioperative BP control, as excursions Patients with a hypertensive emergency usu- outside a targeted BP range have been shown to ally present to the ED with a complaint that be correlated with an increased risk of 30-day is directly related to the presence of end-organ mortality [33]. Individual consideration must be damage; some of the most common clini- given to this clinical syndrome due to the unique cal presentations include a patient with chest factors in the postoperative period and the
752 Therapy (2008) 5(6) future science group Clevidipine & acute hypertension DRUG EVALUATION
transient nature itself of postoperative hyperten- 1 min (TABLE 1) [10,37] . This short half-life allows a sion. Patients with perioperative hyper tension, as more rapid titration to the desired effect, as the with other forms of severe hypertension, usually drug rapidly achieves steady blood concentra- have a history of hypertension. tions after the infusion is initiated [38,39], and has a negligible effect on BP after the infusion Initial management has ended [8]. Clevidipine does not inhibit or There are numerous drugs that are commonly induce any cytochrome P450 (CYP) enzyme, utilized for the management of acute hyper- and exhibits no clinically relevant drug interac- tension, but among currently available drugs, tions [101] . Therefore, clevidipine is well toler- none have the ideal combination of vascular ated when used concomitantly with β-blockers selectivity, rapid onset and fast termination and other antihypertensive agents. of action, with a low incidence of side effects. Nitroprusside and nitroglycerin are both short- Pharmacodynamics acting intravenous vaso dilators; nitroprusside Clevidipine has a rapid onset of effect in has long been the most commonly used drug 2–3 min [37] and exerts its effect by inhibition of for hypertensive crises due to its rapid onset of transmembrane infl ux of calcium ions through effects and well-demonstrated effi cacy, but its the voltage-dependent l-type calcium channels use has been decreasing due to severe disadvan- [40]. Like other drugs of the dihydropyridine tages such as low arteriolar selectiveness, toxicity family, such as nicardipine and nifedipine, a key and severe side effects such as tachyphylaxis, characteristic of clevidipine is its arterial dila- refl ex tachycardia and rebound hypertension tion selectivity. This allows for the rapid reduc- [34]. Nitroglycerin has never been considered tion of BP by reducing vascular resistance, but a fi rst-line treatment for the management of without venous dilation, thereby not affecting acute hypertension due to lower effi cacy than preload; thus, having minimal effect on cardiac nitroprusside and other medications, and its function, it will not affect stroke volume, car- known role in causing hypotension and refl ex diac output or heart rate [41], making it safe to tachycardia [1,17,19] . use in patients with renal or hepatic dys function Another group of medications currently avail- without dose adjustment. Clevidipine is formu- able for acute BP control is the calcium chan- lated and administered in a lipid emulsion, but nel blockers, particularly those of the dihydro- has shown no negative net effects on serum pyridine class. These agents have a demonstrated triglyceride levels. effi cacy and vascular selectivity; however, many Blood pressure reduction with clevidipine is of the currently available medications such as rapidly reversed after discontinuation or reduc- nicardipine have a long half-life and prolonged tion of the infusion. In most patients, full recov- effect that typically last from 4 to 6 h, which is ery of blood pressure is achieved in 5–15 min not advantageous [17] . after the infusion is stopped [101] . In a recent study that compared clevidipine with sodium Role of clevidipine nitroprusside, there was a signifi cantly greater Clevidipine is the latest generation calcium (p < 0.001) increase in heart rate in patients channel blocker of the dihydropyrimidine treated with nitroprusside, resulting in a greater family, with characteristics of arterial selectiv- demand for oxygen and a greater risk for myo- ity, extremely rapid onset of action and high cardial ischemia [34]. Clevidipine is not associated clearance [9,35–37]. with coronary steal or ischemia.
Pharmacokinetics Table 1. Pharmacology of clevidipine. Clevidipine is structurally similar to other dihy- Characteristic Value dropyridines, but has an extra ester link that Class Dihydropyridine allows its rapid hydrolyzation to its inactive Pharmacokinetics carboxylic acid metabolite in the blood (<10% total elimination) and extravascular tissues. Metabolism Ester hydrolysis in blood Clevidipine is excreted principally through urine Metabolite Inactive carboxylic metabolite H152/81 Plasma protein binding >99.5% and fecal pathways (FIGURE 1) [36]. This results in a -1 high clearance value (median blood clearance is Volume of distribution 0.51–0.58 l/kg 0.125 l/min-1/kg-1 [37]), coupled with the small Half-life Phase 1 = 1.6 volume of distribution of 0.51–0.58 l/kg-1, result- Phase 2 = 15.5 -1 -1 ing in an ultra-short half-life of approximately Blood clearance 0.105 l/min /kg
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Clinical trials failure, than the placebo group, which had a suc- ESCAPE-1 cess rate of just 20.4%. The clevidipine-treated Recent trials include the Efficacy Study group also showed a considerably greater reduc- of Clevidipine Assessing Its Preoperative tion in MAP than the placebo group 2 min after Antihypertensive Effect in Cardiac Surgery the respective infusion was started (p = 0.0004 ): (ESCAPE-1), a trial in which 105 patients sched- -5.9%, which equates to -5.7 mmHg, in the cle- uled for cardiac surgery that either had or recently vidipine group, versus -0.1%, which corresponds had hypertension were randomized into two to a decrease in 0.1 mmHg, in the placebo group. groups in which one received a 0.4–0.8 µg/kg/min The increased effi cacy of clevidipine is more evi- infusion of clevidipine, while the other group dent when comparing the greatest mean change: received an infusion of 20% lipid emulsion. The in the clevidipine group there was a reduction clevidipine group had a signifi cantly lower rate of of 28.1 mmHg, compared with a reduction of treatment failure (failure to reduce SBP by more -8.9 mmHg in the placebo group (p < 0.0001) than 15% from the baseline BP or the termina- [43]. In ESCAPE-2, it was demonstrated that tion of infusion) than the placebo group (7.5 vs clevidipine was effective and safe in the rapid 82.7%; p < 0.0001). Clevidipine patients reached treatment of acute postoperative hypertension the targeted BP at a median time of 6 min, while after cardiac surgery. the median time for placebo patients could not be determined due to the small number of patients VELOCITY who actually reached the target BP [35]. In this The Prolonged Infusion of Clevidipine Results and other studies, clevidipine reduced BP to target in Safe and Predictable Blood Pressure Control in more than 90% of patients with perioperative in Patients with Acute Severe Hypertension hypertension [35,42]. The authors concluded that (VELOCITY) trial consisted of an open-label, clevidipine was effective in rapidly decreasing single-arm, multicenter study of 126 patients blood pressure preoperatively to targeted blood who presented to the ED or intensive care unit pressure levels, and was well-tolerated in patients with acute hypertension. The goal of the study scheduled for cardiac surgery. was to determine the percentage of patients whose SBP dropped below a preset intended tar- ESCAPE-2 get with an initial dose of 2 mg/h within 3 min The Effi cacy Study of Clevidipine Assessing Its (safety end point, i.e., overshoot), as well as the Postoperative Antihypertensive Effect in Cardiac percentage that reach an individualized target Surgery-2 (ESCAPE-2) is a double-blind, pla- range within 30 min (effi cacy end point). In cebo-controlled trial that examined and com- this trial, clevidipine showed a rapid and effec- pared the effi cacy and safety of clevidipine in the tive reduction in BP, with a decrease of 6% setting of hypertension in post-cardiac surgery (i.e., 12 mmHg) within the 3-min mark, and patients. The trial consisted of 110 patients that a reduction of 15% within 9.5 min. The trial met criteria for post-operative hypertension who also demonstrated the effi cacy of clevidipine were randomized to receive either 0.4–0.8 µg/ in a relatively long-term infusion, with a 27% kg/min or a 20% lipid emulsion for 30 min (i.e., 55 mmHg) reduction in BP at 18 h after the to a maximum of 1 h. The clevidipine group initiation of the infusion [44]. The 18 h was pre- had a signifi cantly better success rate (91.8%; specifi ed by study design. Likewise, VELOCITY p < 0.0001), defi ned as the absence of treatment demonstrated that clevidipine is safe and effec- tive in subsets of patients with severe hyperten- sion and heart failure or renal dysfunction. This Cl data is consistent with data obtained from the ESCAPE trials, which showed a fi rst reduction of 15% from the baseline at a median time of Cl O O O 6 min in the ESCAPE-1 trial, and 5.3 min in H ESCAPE-2. The authors concluded that cle- O O O vidipine, dosed in a non-weight-based manner, was safe and effective in a cohort of patients H C N CH 3 H 3 with severe hypertension at a starting dose of 2 mg/h, followed by simple titration during 18 h
C21H23Cl2NO6 or more of continuous infusion. Patients were effectively managed via simple blood pressure Figure 1. Clevidipine. cuff monitoring throughout.
754 Therapy (2008) 5(6) future science group Clevidipine & acute hypertension DRUG EVALUATION