American journal of cardiovascular drugs : drugs, devices, and other interventions
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Am J Cardiovasc Drugs · Jan 2009
ReviewClevidipine: a review of its use in the management of acute hypertension.
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=18 hours. ⋯ 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. -
Am J Cardiovasc Drugs · Jan 2008
The role of treprostinil in the management of pulmonary hypertension.
Pulmonary arterial hypertension (PAH) is a severely disabling disorder characterized by sustained elevations of pulmonary vascular resistance, ultimately leading to right-heart failure and death. Intravenous epoprostenol has been widely used in patients with PAH, leading to long-term clinical benefits and improved survival. Epoprostenol has to be delivered through a permanently implanted intravenous catheter, with the potential of life-threatening complications. ⋯ The dose of intravenous treprostinil has to be adjusted to approximately twice the dose of intravenous epoprostenol. Most patients have reported less severe adverse effects with intravenous treprostinil compared with intravenous epoprostenol. The assessment of the long-term efficacy and safety of continuous intravenous treprostinil requires further studies.
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Am J Cardiovasc Drugs · Jan 2007
Randomized Controlled Trial Multicenter StudyEffects of ACE inhibitors or beta-blockers in patients treated with the fixed-dose combination of isosorbide dinitrate/hydralazine in the African-American Heart Failure Trial.
In the A-HeFT (African-American Heart Failure Trial), treatment of African-American patients with New York Heart Association (NYHA) class III/IV heart failure (HF) with fixed-dose combination (FDC) of isosorbide dinitrate/hydralazine (I/H) reduced mortality and morbidity and improved patient reported functional status compared with standard therapy alone. ⋯ Based on the analysis of baseline medication use in the A-HeFT, FDC I/H was superior to placebo with or without beta-blockers or ACE inhibitor. However, beta-blockers but not ACE inhibitors and/or ARBs provided additional significant benefit in African-Americans with HF treated with FDC I/H. These analyses are hypotheses generating and their confirmation in clinical trials needs to be considered.
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Am J Cardiovasc Drugs · Jan 2007
Randomized Controlled Trial Clinical TrialDual therapy in hypertensive patients with coronary artery disease: the role of calcium channel blockers and beta-blockers.
The majority of hypertensive patients require combination therapy to achieve BP goals. Guidelines recommend dual therapy in newly diagnosed patients with BP > 160/100mm Hg. Calcium channel blocker (CCB)/ACE inhibitor and beta-blocker (beta-adrenoceptor antagonists)/diuretic combinations are among regimens considered effective for BP control. ACE inhibitors, beta-blockers, and CCBs are recommended for use in patients after myocardial infarction (MI). Statistical modeling from INVEST (INternational VErapamil-Trandolapril STudy), suggests an association between dual and triple therapy and decreased risk of primary outcome ([PO] first occurrence of death, nonfatal MI, or nonfatal stroke) in patients with hypertension and coronary artery disease (CAD). ⋯ This analysis shows that combination treatment with either Ve+ Tr or At +- HCTZ is effective in achieving BP control and produces similar outcomes in hypertensive patients with CAD.
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Am J Cardiovasc Drugs · Jan 2006
ReviewPharmacologic treatment of heart failure due to ventricular dysfunction by myocardial stunning: potential role of levosimendan.
The treatment of heart failure continues to pose a real challenge for clinicians. This condition is sometimes reversible and therapy should therefore pursue this outcome. In the context of coronary ischemic syndromes, myocardial stunning can cause heart failure and even cardiogenic shock, with important prognostic repercussions. ⋯ Clinical trials addressing the use and efficacy of intravenous levosimendan in acute heart failure in patients with systolic dysfunction or cardiogenic shock due to myocardial stunning are scarce. Beneficial effects on myocardial contractility in patients with myocardial stunning have only been shown in small clinical trials. A positive experience with levosimendan in a small series of patients with cardiogenic shock complicating ST-elevation myocardial infarction suggests that the use of this drug in cardiogenic shock should be further evaluated.