Oral antiplatelet therapy in the secondary prevention of atherothrombotic events.

Am J Cardiovasc Drugs. 2009;9(3):197-209

Authors: Ling G, Ovbiagele B

Atherothrombosis is the leading cause of death worldwide and has a large economic impact. It is a pathologic process related to atherosclerosis, which leads to adverse clinical manifestations, including acute coronary syndrome, cerebrovascular disease, and peripheral arterial disease. Patients with atherothrombosis are at heightened risk for recurrent ischemic events or death, and therefore, secondary prevention is an important goal in the treatment of these patients. Antiplatelet therapies available for long-term secondary prevention include aspirin (acetylsalicylic acid), extended-release dipyridamole plus aspirin, and clopidogrel. A number of clinical trials have demonstrated the benefit of combined antiplatelet therapy in secondary prevention, supporting the recommendations made in current published guidelines. Although the efficacy and safety of antiplatelet agents is well established and supported by clinical trials, their utilization rate in patients with atherothrombosis remains suboptimal. Quality improvement initiatives have demonstrated effectiveness in promoting the awareness and implementation of treatment guidelines. This article reviews the benefits and risks of antiplatelet therapy in patients with cardiovascular disease with the aim of spurring greater adherence to treatment recommendations and, thereby, better patient outcomes.

PMID: 19463024 [PubMed - indexed for MEDLINE]

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Cocaine cardiotoxicity: a review of the pathophysiology, pathology, and treatment options.

Am J Cardiovasc Drugs. 2009;9(3):177-96

Authors: Phillips K, Luk A, Soor GS, Abraham JR, Leong S, Butany J

Cocaine is a powerful stimulant that gives users a temporary sense of euphoria, mental alertness, talkativeness, and a decreased need for food and sleep. Cocaine intoxication is the most frequent cause of drug-related death reported by medical examiners in the US, and these events are most often related to the cardiovascular manifestations of the drug. Once playing a vital role in medicine as a local anesthetic, decades of research have established that cocaine has the ability to cause irreversible structural damage to the heart, greatly accelerate cardiovascular disease, and initiate sudden cardiac death. Although pathologic findings are often reported in the literature, few images are available to support these findings, and reviews of cocaine cardiopathology are rare. We describe the major pathologic findings linked to cocaine abuse in earlier research, their underlying mechanisms, and the treatment approaches currently being used in this patient population. A MEDLINE search was conducted to identify all English language articles from January 2000 to June 2008 with the subject headings and key words ‘cocaine’, ‘heart’, ‘toxicity’, and ‘cardiotoxicity’. Epidemiologic, laboratory, and clinical studies on the pathology, pathophysiology, and pharmacology of the effects of cocaine on the heart were reviewed, along with relevant treatment options. Reference lists were used to identify earlier studies on these topics, and related articles from Google Scholar were also included. There is an established connection between cocaine use and myocardial infarction (MI), arrhythmia, heart failure, and sudden cardiac death. Numerous mechanisms have been postulated to explain how cocaine contributes to these conditions. Among these, cocaine may lead to MI by causing coronary artery vasoconstriction and accelerated atherosclerosis, and by initiating thrombus formation. Cocaine has also been shown to block K+ channels, increase L-type Ca2+ channel current, and inhibit Na+ influx during depolarization, all possible causes for arrhythmia. Additionally, cocaine use has been associated with left ventricular hypertrophy, myocarditis, and dilated cardiomyopathy, which can lead to heart failure if drug use is continued. Certain diagnostic tools, including ECG and serial cardiac markers, are not as accurate in identifying MI in cocaine users experiencing chest pain. As a result, clinicians should be suspicious of cocaine use in their differential diagnosis of chest pain, especially in the younger male population, and proceed more cautiously when use is suspected. Treatment for cocaine-related cardiovascular disease is in many ways similar to treatment for traditional cardiovascular disease. However use of beta-receptor antagonists and class Ia and III anti-arrhythmics is strongly discouraged if the patient is likely to continue cocaine use, because of documented adverse effects. The medical community is in urgent need of a pharmacologic adjunct to cocaine-dependence treatment that can deter relapse and reduce the risks associated with cardiovascular disease in these patients.

PMID: 19463023 [PubMed - indexed for MEDLINE]

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Clevidipine: a review of its use in the management of acute hypertension.

Am J Cardiovasc Drugs. 2009;9(2):117-34

Authors: Deeks ED, Keating GM, Keam SJ

ABSTRACT: 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.

PMID: 19331440 [PubMed - indexed for MEDLINE]

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