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Controlled-release carvedilol in the management of systemic hypertension and myocardial dysfunction.

ABSTRACT: Cardiovascular disease is the leading cause of death worldwide. Within the treatment armamentarium, beta-blockers have demonstrated efficacy across the spectrum of cardiovascular disease--from modification of a risk factor (ie, hypertension) to treatment after an acute event (ie, myocardial infarction). Recently, the use of beta-blockers as a first-line therapy in hypertension has been called into question. Moreover, beta-blockers as a class are saddled with a misperception of having poor tolerability. However, vasodilatory beta-blockers such as carvedilol have a different hemodynamic action that provides the benefits of beta-blockade with the addition of vasodilation resulting from alpha 1-adrenergic receptor blockade. Vasodilation reduces total peripheral resistance, which may produce an overall positive effect on tolerability. Recently, a new, controlled-release carvedilol formulation has been developed that provides the clinical efficacy of carvedilol but is indicated for once-daily dosing. This review presents an overview of the clinical and pharmacologic carvedilol controlled-release data.

SUBMITTER: Frishman WH

PROVIDER: S-EPMC2663448 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Controlled-release carvedilol in the management of systemic hypertension and myocardial dysfunction.

Frishman William H WH Henderson Linda S LS Lukas Mary Ann MA

Vascular health and risk management 20080101 6

Cardiovascular disease is the leading cause of death worldwide. Within the treatment armamentarium, beta-blockers have demonstrated efficacy across the spectrum of cardiovascular disease--from modification of a risk factor (ie, hypertension) to treatment after an acute event (ie, myocardial infarction). Recently, the use of beta-blockers as a first-line therapy in hypertension has been called into question. Moreover, beta-blockers as a class are saddled with a misperception of having poor tolera ...[more]

PMID: 19337551

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Project description:Hypertension treatment commonly requires multiple agents to achieve target blood pressure (BP). β-blockers and angiotensin-converting enzyme inhibitors (ACEIs) are commonly co-prescribed in clinical practice although few data are available that test their additivity on BP lowering. The efficacy and safety of once-daily extended-release carvedilol (carvedilol CR) combined with the ACEI lisinopril in a double-blind, randomized, factorial design study were studied. Patients (N=656) with stage 1 or 2 hypertension were randomized evenly to 1 of 15 groups for 6 weeks: carvedilol CR monotherapy 20 mg, 40 mg, or 80 mg/d; lisinopril monotherapy 10 mg, 20 mg, or 40 mg/d; or 1 of 9 combinations of carvedilol CR plus lisinopril initiated simultaneously. Primary efficacy measures (assessed by ambulatory BP monitoring [ABPM]) were change from baseline in 24-hour mean diastolic BP (DBP) and in trough (20-24 hours) DBP. Continuous efficacy variables were assessed using analysis of covariance. Whether any combination dose was superior to its monotherapy components was assessed using the Hung AVE procedure. Despite the presence of additional BP lowering observed with most of the combinations compared with their monotherapy components, the Hung AVE test was not significant for either primary efficacy measures. Post hoc analyses of the high-dose combination groups (carvedilol CR/lisinopril regimens of 80/10 mg, 80/20 mg, 80/40 mg, 20/40 mg, and 40/40 mg) showed a significant treatment difference compared with both carvedilol CR 80 mg and lisinopril 40 mg for 24-hour mean DBP but not for trough DBP. With the exception of dizziness, individual adverse events did not increase with ascending doses or combinations. The superiority of initiating combination treatment with carvedilol CR and lisinopril compared with the monotherapy components was not demonstrated with the ABPM measurements. Nonetheless, the post hoc assessment combining all high-dose groups did produce significant 24-hour mean BP reduction when compared with the high-dose monotherapy groups. The tolerability profile of initiating combination therapy was generally comparable to the initiation of treatment with monotherapy.

Project description:Background and aimsThe triggering factors of sepsis-induced myocardial dysfunction (SIMD) are poorly understood and are not addressed by current treatments. S100A8/A9 is a pro-inflammatory alarmin abundantly secreted by activated neutrophils during infection and inflammation. We investigated the efficacy of S100A8/A9 blockade as a potential new treatment in SIMD.MethodsThe relationship between plasma S100A8/A9 and cardiac dysfunction was assessed in a cohort of 62 patients with severe sepsis admitted to the intensive care unit of Linköping University Hospital, Sweden. We used S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 and S100A9-/- mice for therapeutic and mechanistic studies on endotoxemia-induced cardiac dysfunction in mice.ResultsIn sepsis patients, elevated plasma S100A8/A9 was associated with left-ventricular (LV) systolic dysfunction and increased SOFA score. In wild-type mice, 5 mg/kg of bacterial lipopolysaccharide (LPS) induced rapid plasma S100A8/A9 increase and acute LV dysfunction. Two ABR-238901 doses (30 mg/kg) administered intraperitoneally with a 6 h interval, starting directly after LPS or at a later time-point when LV dysfunction is fully established, efficiently prevented and reversed the phenotype, respectively. In contrast, dexamethasone did not improve cardiac function compared to PBS-treated endotoxemic controls. S100A8/A9 inhibition potently reduced systemic levels of inflammatory mediators, prevented upregulation of inflammatory genes and restored mitochondrial function in the myocardium. The S100A9-/- mice were protected against LPS-induced LV dysfunction to an extent comparable with pharmacologic S100A8/A9 blockade. The ABR-238901 treatment did not induce an additional improvement of LV function in the S100A9-/- mice, confirming target specificity.ConclusionElevated S100A8/A9 is associated with the development of LV dysfunction in severe sepsis patients and in a mouse model of endotoxemia. Pharmacological blockade of S100A8/A9 with ABR-238901 has potent anti-inflammatory effects, mitigates myocardial dysfunction and might represent a novel therapeutic strategy for patients with severe sepsis.

Dataset Information

Controlled-release carvedilol in the management of systemic hypertension and myocardial dysfunction.

Publications

Controlled-release carvedilol in the management of systemic hypertension and myocardial dysfunction.

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