Dose Of Carvedilol Research Articles

Substituição do carvedilol pelo propranolol em pacientes com insuficiência cardíaca

Large clinical trials using the betablockers carvedilol, metoprolol, bisoprolol and nebivolol have demonstrated improvement of survival and symptoms in patients with heart failure. Despite the lack of scientific evidence, it is plausible that their beneficial effects are extensible to other betablockers.To evaluate the impact of the replacement of carvedilol for propranolol on left ventricular function, functional capacity, quality of life, pressure levels, and cardiac autonomic control in patients with heart failure.Twenty nine patients receiving optimized drug therapy including maximum tolerated doses of carvedilol were divided into two groups: replacement of carvedilol for propranolol (n = 15) and continued carvedilol (n = 14). At baseline and 6 months later, clinical and laboratorial assessments were carried out with radionuclide ventriculography, echocardiography, Minnesota questionnaire, walk test, APBM and Holter monitoring.The clinical and demographic characteristics were similar in the two groups at baseline. Individualized propranolol dose adjustment ensured a similar degree of beta-blockade, as assessed by resting heart rate and chronotropic reserve. The mean propranolol dose used was 109 +/- 43 mg/day. Only one patient presented with intolerance to propranolol, thus carvedilol was reintroduced. One death was recorded in group propranolol. Ejection fraction significantly increased in the propranolol group. No significant change was observed in the other cardiovascular variables after betablocker replacement.Our results indicate that replacement of carvedilol for propranolol in patients with heart failure is not associated with deterioration of the ejection fraction, functional capacity, quality of life, and other cardiovascular variables related to autonomic and blood pressure control., PP.0-0).

Effects of B-Blockers on outcome of patients with Chagas' cardiomyopathy with chronic heart failure

BackgroundA few studies have shown a beneficial effect of B-Blocker therapy on cardiac function and functional status in patients with chronic heart failure secondary to Chagas' cardiomyopathy. MethodsThe medical charts of patients routinely followed from January, 2000 to January, 2007 were reviewed to collect clinical, standard laboratory tests, 12-lead electrocardiogram, chest X-Ray, and Doppler echochardiogram variables. A Cox proportional hazards model was used to establish independent predictors of all-cause mortality for patients with Chagas' cardiomyopathy with chronic heart failure. ResultsA total of 231 consecutive patients were enrolled in the study. Median follow up was 19 (7, 46) months. Twenty (9%) patients underwent heart transplantation and 120 (52%) died during the investigation. Left ventricular systolic dimension (hazard ratio=1.04; 95% confidence interval=1.02 to 1.06; p<0.005) and need of inotropic support (hazard ratio=1.80; 95% confidence interval 1.2 to 2.60; p=0,03), were positively associated, whereas B-Blocker therapy (HR=0.34; 95% confidence interval 0.23 to 0.51; p<0.0005) was negatively associated with mortality. Mortality was significantly lower in patients taking in comparison to those not taking B-Blockers. Patients taking a mean daily dose of carvedilol>or=to 9.375mg had a marked decrease in mortality in comparison to those not on carvedilol therapy. ConclusionB-Blockers are effective, not detrimental, and may improve survival in Chagas' disease patients with chronic heart failure. A randomized trial is necessary to confirm these findings.

Inadequate control of heart rate in patients with stable angina: results from the European Heart Survey

AimsTo examine resting heart rate (HR) in a population presenting with stable angina in relation to prior and subsequent pharmacological treatment, comorbid conditions and clinical outcome.Methods and resultsThe European Heart...

Role of Beta-Adrenergic Receptor Gene Polymorphisms in the Long-Term Effects of Beta-Blockade with Carvedilol in Patients with Chronic Heart Failure

Beta-blockers are mainstay of current treatment of heart failure (HF). Beta-adrenergic receptors (AR) single nucleotide gene polymorphisms (SNPs) may influence the sensitivity and density of beta-AR. We assessed the relation between three common beta-AR SNPs and the response to carvedilol administration. We studied 183 consecutive patients with chronic HF due to ischemic or nonischemic cardiomyopathy, a LV ejection fraction (LVEF) < or = 0.35, not previously treated with beta-blockers. Each patient underwent gated-SPECT radionuclide ventriculography, cardiopulmonary exercise testing and invasive hemodynamic monitoring at baseline and after 12 months of carvedilol administration at maintenance dosages. The beta1-AR gene Arg389Gly and the beta2-AR gene Arg16Gly SNPs were not related to the response to carvedilol administration. Homozygotes for the Glu27Glu allele showed a greater increase in the LVEF, compared to the other patients (+13.0 +/- 12.2% versus +7.1 +/- 8.1% in the Gln27Gln homozygotes, and 8.3 +/- 11.4% units in the Gln27Glu heterozygotes; p = 0.022 by ANOVA). Glu27Glu homozygotes also showed a greater decline in the pulmonary wedge pressure both at rest and at peak exercise. Gln27Glu SNP was selected amongst the determinants of the LVEF response to carvedilol at multivariable analysis, in addition to the cause of cardiomyopathy, baseline systolic blood pressure and the dose of carvedilol administered. Beta1-AR Arg389Gly and beta2-AR Arg16Gly SNPs are not related to the response to carvedilol therapy. In contrast, the Gln27Glu SNP is a determinant of the LVEF response to this agent in patients with chronic HF.

Clinical trials update from the American Heart Association meeting 2009: HEAAL, FAIR‐HF, J‐CHF, HeartMate II, PACE and a meta‐analysis of dose‐ranging studies of beta‐blockers in heart failure

This article provides information and a commentary on trials relevant to the pathophysiology, prevention, and treatment of heart failure presented at the annual meeting of the American Heart Association held in Orlando, Florida in 2009. Unpublished reports should be considered as preliminary, as analyses may change in the final publication. Patients with heart failure randomized to high-dose losartan treatment (150 mg) in the HEAAL study had a reduced risk of death or heart failure hospitalization compared with patients in the low-dose (50 mg) group. In FAIR-HF, patients with heart failure and concomitant iron deficiency but without severe anaemia who received iron supplementation therapy demonstrated an improvement in symptoms at 24 weeks compared with placebo. The J-CHF study was too small and was stopped too early to provide definitive evidence about the optimal dose of carvedilol for Japanese patients with heart failure. Results from the HeartMate II study suggest that continuous-flow left ventricular assist devices may offer benefits over pulsatile-flow devices for long-term support in patients with advanced heart failure. In the PACE study, atrial synchronized right ventricular pacing induced adverse effects on left ventricular function compared with atrial synchronized biventricular pacing in patients with standard pacing indications and a normal ejection fraction.

Carvedilol can Prevent Cardiac Events in Duchenne Muscular Dystrophy

Heart failure is one of the most serious complications in Duchenne muscular dystrophy (DMD). Beta-blocker medication is known to improve the prognosis of chronic heart failure of adults, but its efficacy and safety for DMD patients has not been fully assessed. Thus we conducted a multicenter open trial. Fifty-four DMD patients participated; 41 received carvedilol (BB group) and 13 did not (non BB group). All patients with an ejection fraction of less than 50% received angiotensin-converting enzyme inhibitor. Then, patients in BB group were started on carvedilol. The mean maintenance dose of carvedilol in BB group was 7.85+/-2.80 mg/day. Clinical signs and cardiac function were monitored regularly and statistical analysis was done. The survival rate free from primary endpoints (death, deterioration of heart failure and severe arrhythmia) was higher in the BB group. The survival rate free from all-cause death was also higher in the BB group, although not significantly higher. Patients with primary endpoints received lower maintenance doses of carvedilol and presented higher mean heart rates (HR) during the observation period. In the BB group, mean HR at enrollment and the reduction of mean HR were correlated with the change of ejection fraction. Although serious adverse events were rare during the introduction of carvedilol, patients with advanced cardiac dysfunction required a longer period for up-titration and frequently presented with minor complaints. The present study suggests that carvedilol is relatively safe and can prevent cardiac events even in patients with DMD.

Beta-Blocker Treatment of Stable Heart Failure in Primary Care

Beta-blocker treatment of stable heart failure in primary care. The objective was to evaluate the feasibility and tolerability of uptitrating beta-blockers in patients with stable systolic heart failure seen in primary care. Before and after intervention study. The study was conducted in two primary care centers in Barcelona, Spain. Consecutive samples of patients with systolic heart failure who had not received previous beta-blocker treatment were recruited between April 2004 and April 2006. Treatment was started with the lowest dose of bisoprolol or carvedilol and the dose was doubled every two weeks in the absence of contraindications. Patients were followed up for 6 months. The study included 88 patients (76.1% male, 23,9% female, mean age 64.88 years). Of these, 57.1% were treated with bisoprolol and 42.9% with carvedilol. Overall, 75.0% reached the target dose, 21.7% tolerated a dose lower than the target dose, and 3.3% had the beta-blocker withdrawn (due to bradycardia in 1.1%, syncope in 1.1%, and stroke in 1.1%). Adverse events were experienced by 70.4%, the majority of which (57.95%) were resolved without changing treatment. The most common were nausea (42.04%), asthenia (35.22%), and increased dyspnea (17.04%). There were significant improvements in functional class and ejection fraction. The majority of adverse events were mild. Treatment was withdrawn in only a few patients and most reached the recommended target dose. Appropriately trained primary care physicians can uptitrate beta-blockers in heart failure patients without undue concern.

Carvedilol may alleviate late cardiac remodelling following surgical ventricular restoration

Surgical ventricular restoration (SVR) can be effective to treat ischaemic cardiomyopathy or left ventricular (LV) aneurysm. However, the initial improvement in LV function does not always last long because of LV remodelling. Beta-blockers prevent LV remodelling of failing hearts; however, their effects following SVR have not been elucidated. Thus, we sought to investigate the effects of a potent beta-blocker, carvedilol, on LV remodelling and function following SVR in rats with myocardial infarction. Rats, which developed LV aneurysm 4 weeks after coronary artery ligation, underwent SVR. They were orally administered a vehicle (vehicle group), and low or high dose of carvedilol (20 or 50 mg kg(-1)day(-1) for C20 or C50 group) for 4 weeks following SVR (n=7 in each group). Four weeks following SVR, late cardiac remodelling was alleviated only in the C50 group (LV end-diastolic area: 65+/-4 mm(2) vs 74+/-11 mm(2) and 76+/-11 mm(2) for C50, C20 and vehicle groups; p=0.039 and p=0.013, respectively). There was no difference in LV systolic function (end-systolic elastance) among the three groups; however, LV diastolic functions (LV end-diastolic pressure and the time constant of isovolumic relaxation) were significantly better in the C20 and C50 groups. Histologically, the percentage of myocardial fibrosis in the C50 group (4.1+/-0.2%) was lower than those in the C20 (6.7+/-0.4%, p<0.0001) and vehicle (7.5+/-0.6%, p<0.0001) groups. The mRNA expression of transforming growth factor-beta1 and brain natriuretic peptide in the C50 group were lower than those in the C20 and the vehicle groups. High-dose carvedilol alleviated LV remodelling and diastolic dysfunction following SVR accompanying with reduction in myocardial fibrosis. Blockade of beta-adrenergic receptor may be a promising adjuvant therapy in patients following SVR.

β‐Receptor Selectivity of Carvedilol and Metoprolol Succinate in Patients with Heart Failure (SELECT Trial): A Randomized Dose‐Ranging Trial

To determine whether metoprolol succinate (a beta(1)-selective beta-blocker) remains beta(1)-selective compared with carvedilol (a nonselective beta-blocker) during upward titration of doses in patients with American College of Cardiology (ACC) stage C heart failure. Prospective, randomized, parallel-arm study. Setting. General clinical research center. Twenty-five beta-blocker-naïve adults with New York Heart Association functional classes II or III heart failure (i.e., ACC stage C). Intervention. Patients received either immediate-release carvedilol 3.125 mg twice/day or controlled-release metoprolol succinate 25 mg once/day; doses were titrated upward by doubling the dose every 2 weeks until reaching a maximum tolerated dose or a goal dose of carvedilol 25 mg twice/day and metoprolol 200 mg/day. Before each dose titration, terbutaline (a beta-receptor agonist) was infused at 6 mg/kg over 1 hour for determination of beta(2)-blockade. Patients were studied at baseline and after each dose titration of metoprolol succinate (at 25, 50, 100, and 200 mg once/day) and immediate-release carvedilol (at 3.125, 6.25, 12.5, and 25 mg twice/day). Glucose and potassium concentrations were measured twice serially at baseline, every 10 minutes during infusion, every 15 minutes for the first hour after infusion, and every 30 minutes for the second hour after infusion. The median area under the concentration-time curve (AUC) was calculated for changes in glucose and potassium concentrations. As assessed by glucose AUC, there was no significant difference in the degree of beta(2)-blockade between metoprolol 200 mg and carvedilol 25 mg. In contrast to these data, the degree of beta(2)-blockade as assessed by potassium AUC was greater for carvedilol compared with metoprolol across all doses. In this ACC stage C heart failure population, carvedilol was nonselective at all clinically relevant doses, whereas metoprolol succinate was beta(1)-selective at low doses and became progressively nonselective at higher doses.

Forced Expiratory Volume in 1 Second (FEV 1) as a Predictor of Carvedilol Dose Optimization in Chronic Heart Failure with Chronic Airway Disease

Forced Expiratory Volume in 1 Second (FEV 1) as a Predictor of Carvedilol Dose Optimization in Chronic Heart Failure with Chronic Airway Disease

Effect of carvedilol on β-adrenoceptor density on peripheral lymphocytes from patients with chronic heart failure

Objective To explore the effect of carvedilol on a-adrenoceptor density on peripheral lymphocytes from patients with chronic heart failure(CHF).Methods 112 CHF patients[New York Heart Association(NYHA) class Ⅱ ~Ⅳ) were randomly received either low dose carvedilol(12.5mg/d,n=56) or high dose carvedilol(50mg/d,n=56) for three months. Echocardiographic examinations were performed before and after drug administration. The maximum density of a-adrenoceptor( β max) on peripheral lymphocytes was measured by radioligand binding assay using 3H-dihydroalprenolol.Results The total study population consisted of 105 patients. The left ventricular end-diastolic dimension(LVEDD) and left ventricular end-systolic dimension(LVESD) were significantly decreased, the left ventricular ejection fraction(LVEF) was significantly increased after drug treatment. Compared with the low dose carvedilol group, the high dose carvedilol groun showed that LVEDD and LVESD were significantly decreased(P< 0.05), whereas LVEF significantly increased(P<0.01). The level of β max was much lower in those patients with more severe symptoms(NYHA class Ⅱ ~ Ⅴ). The level of β max was not significantly changed before and after drug treatment in the low dose carvedilol group, but was significantly decreased after drug treatment in the high dose carvedilol group(P < 0.05).Conclusion High dose carvedilol is more effective than low dose in attenuating left ventricular remodeling and in improving systolic function after heart failure. The beneficial effect of earvedilol is not depending on the change of β -adrenoceptor density. Key words: Heart failure ; β3-adrenoceptor ; Lymphocyte ; Carvedilol

Heart rate dynamic during an exercise test in heart failure patients with different sensibilities of the carvedilol therapy: Heart rate dynamic during exercise test

Background Some trials suggest that the titration of Carvedilol is based on rest heart rate from 50 to 60 bpm and a target daily dose of 50 mg/day. Aim To evaluate the heart rate dynamic in heart failure patients with different sensibilities of the Carvedilol therapy during an exercise test. Methods Patients were divided into four groups and submitted a treadmill cardiopulmonary exercise test: heart rate > 60 bpm and Carvedilol < than 50 mg/day (30 patients) (non-optimized group); heart rate > 60 bpm and Carvedilol > = 50 mg/day (19 patients) (non-optimized low-sensibility); heart rate between 50 and 60 bpm and Carvedilol > = 50 mg/day (16 patients) (optimized); heart rate between 50 and 60 bpm and Carvedilol < 50 mg/day (10 patients) (optimized high-sensible group). Results The heart rate peak and the percentage of the peak heart rate in relation with the maximum heart rate predicted for age during the cardiopulmonary exercise test were the same between the non-optimized (128 ± 13, bpm; 74 ± 7%) and non-optimized low-sensibility (136 ± 20, bpm; 78 ± 8%) groups, and between the optimized (105 ± 25, bpm; 60 ± 13%) and optimized high-sensible (108 ± 16, bpm; 62 ± 8%) groups. The heart rate reserve was the same. Conclusion The heart rate dynamic was almost the same between groups with rest heart rate > 60 bpm and between groups < 60 bpm, independently of the Carvedilol dose. Based on these findings, we propose a new method to titrate carvedilol therapy by the cardiopulmonary exercise test.

Dose-Dependent Prognostic Effect of Carvedilol in Patients With Chronic Heart Failure Special Reference to Ranscardiac Gradient of Norepinephrine

The effect of the dose of carvedilol on cardiac sympathetic nerve activity (CSA) and mortality remain uncertain in patients with chronic heart failure (CHF). To compare the dose of carvedilol and the transcardiac gradient of norepinephrine (NE), a biomarker of CSA, and prognosis in patients with CHF, hemodynamic parameters and plasma levels of NE, N-terminal brain natriuretic peptide (NT-proBNP) in the aortic root and coronary sinus were measured in 107 patients with systolic CHF who received carvedilol. Patients were divided into 2 groups [group I: low dose (<10 mg/day, n=41) and group II: high dose (>or=10 mg/day, n=66)]. There was no difference between the 2 groups for the hemodynamic parameters. The dose of carvedilol did not correlate with plasma NE, but was significantly correlated with the transcardiac increase in NE. During a median follow-up of 4.3 years, 13 patients died of cardiac disease. In the Cox stepwise multivariate analyses, a high level of transcardiac increase in NE (P<0.001), high level of plasma log NT-proBNP (P=0.004) and low dose of carvedilol (P=0.012) were significant independent predictors. The carvedilol dose is important for the management of CSA and prognosis in patients with systolic CHF.

ORGANOPROTECTIVE EFFECTS OF THE FIXED COMBINATION OF ANGIOTENSIN-CONVERTING ENZYME INHIBITOR LISINOPRIL AND DIURETIC HYDROCHLOROTHIAZIDE

Aim. To compare the antihypertensive and metabolic effects of combined therapy (carvedilol reception and «School of the hypertensive patient») with these of the carvedilol monotherapy in young patients with arterial hypertension (HT) of 1-2 degrees with overweight and obesity. Material and methods. 63 out-patients with HT of 1-2 degrees (aged 18-27 y.o.) with overweight and obesity were included in the open parallel randomized clinical preventive trail. Patients wеre randomized into 2 groups. All hypertensive patients received the carvedilol (Vedicardol, Sintez, Russia) 25 mg daily. Carvedilol dose was enlarged twice in case of insufficient antihypertensive effect. Patients of the main group (n=32) also passed through the special educational program «School for hypertensive patients». Changes in blood pressure (BP) level, body mass index, biochemical markers and risk factors were evaluated initially and in 24 weeks of therapy. Results. Patients of the main group had more significant risk factor manifestations decrease than in group of comparison. More significant body mass index decrease was also observed in the main group in comparison with group of comparison: from 32,5±0,4 to 26,4±0,7 kg/m2 (p&lt;0,01) and from 31,8±0,8 to 28,9±1,18 kg/m2 (p&lt;0,05), respectively. In patients of the main group systolic and diastolic BP decreased by 20,1% and 25,6%, respectively, wile in patients of the group of comparison – by 18,9% and 26%, respectively. Conclusion. It is reasonable to combine carvedilol therapy with special training in the young hypertensive patients with overweight and obesity.

RESULTS OF THE CAMELLIA TRAIL: IMPLEMENTATION IN A PRIMARY HEALTH CARE

Aim. To compare the antihypertensive and metabolic effects of combined therapy (carvedilol reception and «School of the hypertensive patient») with these of the carvedilol monotherapy in young patients with arterial hypertension (HT) of 1-2 degrees with overweight and obesity. Material and methods. 63 out-patients with HT of 1-2 degrees (aged 18-27 y.o.) with overweight and obesity were included in the open parallel randomized clinical preventive trail. Patients wеre randomized into 2 groups. All hypertensive patients received the carvedilol (Vedicardol, Sintez, Russia) 25 mg daily. Carvedilol dose was enlarged twice in case of insufficient antihypertensive effect. Patients of the main group (n=32) also passed through the special educational program «School for hypertensive patients». Changes in blood pressure (BP) level, body mass index, biochemical markers and risk factors were evaluated initially and in 24 weeks of therapy. Results. Patients of the main group had more significant risk factor manifestations decrease than in group of comparison. More significant body mass index decrease was also observed in the main group in comparison with group of comparison: from 32,5±0,4 to 26,4±0,7 kg/m2 (p&lt;0,01) and from 31,8±0,8 to 28,9±1,18 kg/m2 (p&lt;0,05), respectively. In patients of the main group systolic and diastolic BP decreased by 20,1% and 25,6%, respectively, wile in patients of the group of comparison – by 18,9% and 26%, respectively. Conclusion. It is reasonable to combine carvedilol therapy with special training in the young hypertensive patients with overweight and obesity.

Use and Risk Management of Carvedilol for the Treatment of Heart Failure in the Community in England

In the UK, the licence for carvedilol was extended in 1998 to include symptomatic heart failure (New York Heart Association [NYHA] class II and III heart failure) with the recommendation that initiation and up-titration should be under the supervision of a hospital physician. A post-marketing surveillance study was conducted to address the UK regulatory authority's request for monitoring the use and safety of carvedilol prescribed for heart failure in clinical practice. To investigate adherence to risk management recommendations for the use of carvedilol for heart failure, monitor how patients' subsequent care was managed and collect event data to evaluate the safety profile of carvedilol used for the treatment of heart failure. An observational cohort study using a modified prescription-event monitoring technique identified patients from dispensed primary care prescriptions in England (August 1999 to June 2001). An eligibility questionnaire was used to identify patients who had been prescribed carvedilol for heart failure for the first time after 31 July 1999. Up to three follow-up questionnaires were sent to the prescribers of eligible patients, requesting demographic information, dosage, supervision of treatment, status of cardiac failure and event information. 2311 patients met the eligibility criteria. For 1666 patients, one or more valid follow-up questionnaires were returned: 68.5% were male; male median age 66 years; female median age 72 years; the observation period was up to 3 years. Hospital physicians supervised initiation of treatment and first up-titration in 85.6% and 61.4% of patients, respectively. 49.2% of patients were prescribed the recommended starting dosage of carvedilol (6.25 mg/day). Approximately 25% of patients started on a lower dose than recommended, and the same proportion were prescribed a higher dose. NYHA status of cardiac failure between starting treatment and the third questionnaire improved for 39.5% of patients, deteriorated for 10.9%, and 11.7% of those for whom NYHA status was given died. Adverse drug reactions (ADRs) were reported for 2.4% of patients; the most commonly reported ADR was malaise/lassitude. Overall, 27.1% of patients stopped taking carvedilol. None of the 163 deaths were attributed to carvedilol. Regulatory guidelines for the use and risk management of carvedilol in heart failure were mostly followed, and most patients appeared to benefit from treatment with carvedilol for heart failure. Malaise/lassitude was the main reason for discontinuing treatment. Further investigations may be warranted to examine the prescribing of carvedilol at lower than recommended doses.

Comparison of the pharmacokinetic properties of bisoprolol and carvedilol in healthy dogs

To compare the pharmacokinetic properties and bioavailability following oral and IV administration of bisoprolol, a second-generation beta1-adrenoceptor-selective blocking agent, with those of carvedilol, a third-generation beta1/beta2 and alpha1-adrenoceptor blocking agent, in dogs. 12 healthy adult Beagles. A prospective, parallel group study was performed. The dogs were allocated to 1 of 2 groups (6 dogs/group) and were administered orally a 1 mg/kg dose of either bisoprolol or carvedilol. Following a 1-week washout period, each cohort received a 1 mg/kg dose of the same drug IV. Blood samples were collected before and after drug administration, and serum concentrations, pharmacokinetic variables, and bioavailability for each agent were assessed. After oral administration of bisoprolol, the geometric mean value of the area under the concentration-time curve extrapolated to infinity (AUCinf) was 2,195 microg/L (coefficient of variation [CV], 15%). After IV administration of bisoprolol, the dose-normalized geometric mean AUCinf was 2,402 microg/L (CV, 19%). Oral bioavailability of bisoprolol was 91.4%. After oral administration of carvedilol, the geometric mean AUCinf was 70 microg/L (CV, 81%). After IV administration of carvedilol, the geometric mean AUCinf was 491 microg/L (CV, 23%). Oral bioavailability of carvedilol was 14.3%. Total body clearance was low (0.42 L/h/kg) for bisoprolol and high (2.0 L/h/kg) for carvedilol. After oral administration, carvedilol underwent extensive first-pass metabolism and had limited bioavailability; bisoprolol had less first-pass effect and higher bioavailability. Collectively, these differences suggested that, in dogs, bisoprolol has less interindividual pharmacokinetic variability, compared with carvedilol.

Dosing of Beta-Blocker Therapy Before, During, and After Hospitalization for Heart Failure (from Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure)

Heart failure (HF) guidelines recommend that beta blockers be titrated to achieve the target doses shown to be effective in major clinical trials, if tolerated. Little is known, however, regarding the doses of beta blockers used in patients with HF in routine clinical practice before, during, and after hospitalization for HF. The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) enrolled 5,791 patients admitted with HF in a registry with prespecified 60- to 90-day follow-up at 91 academic and community hospitals throughout the United States. Among 2,373 patients with systolic HF eligible for beta blockers at discharge, 1,350 (56.9%) were receiving beta-blocker therapy before admission and continued on therapy, and 632 (26.6%) were newly started. The mean total daily dose for beta blockers before hospital admission was <1/2 the recommended target dose (carvedilol 21.5 +/- 17.8 mg and metoprolol succinate 69.2 +/- 51.9 mg), with infrequent up- or down-titration during the HF hospitalization. More than 2/3 of patients had no change in their beta-blocker doses in the first 60 to 90 days after hospital discharge. At 60- to 90-day postdischarge follow-up, only 17.5% and 7.9% of patients were being treated with recommended target doses of carvedilol and metoprolol succinate, respectively. In conclusion, these data reveal that the doses of beta blockers applied in clinical practice are substantially less that the doses achieved in randomized clinical trials in HF and recommended in national guidelines. In the first 60 to 90 days after hospital discharge, little up-titration in beta-blocker dosing occurs. Further efforts are needed to help understand and overcome this beta-blocker titration gap.

Carvedilol increases blood pressure response to phenylephrine infusion in heart failure subjects with systolic dysfunction: Evidence of improved vascular α 1-adrenoreceptor signal transduction

Alpha(1)-adrenergic receptor (alpha(1)-AR) stimulation produces smooth muscle contraction, vasoconstriction, and myocyte hypertrophy, suggesting a potential therapeutic role for alpha(1)-AR antagonists to reduce cardiac workload and myocardial hypertrophy. Preliminary reports suggest that vascular alpha(1)-ARs are desensitized in heart failure (HF) in a manner similar to myocardial beta(1)-ARs. We examined alpha(1)-AR signal transduction by repeat phenylephrine (PE) infusions in patients with HF receiving chronic carvedilol therapy. Twelve subjects with HF not currently receiving beta-blockers were up-titrated to maximum tolerable doses of carvedilol. Subjects underwent alpha(1)-AR stimulation testing at study baseline, 2 weeks after each dose titration, and 6 months after maintenance of maximum carvedilol dose. Phenylephrine infusions began at 0.5 microg kg(-1) min(-1), with dose titrations every 10 minutes, to a maximum of 5 microg kg(-1) min(-1). Phenylephrine dose response was evaluated by the PE rate required to elicit a 20 mm Hg increase in systolic blood pressure (BP), designated PS(20). All doses of carvedilol significantly reduced preinfusion measures of heart rate, systolic BP, diastolic BP, and mean arterial pressure. However, carvedilol also produced a paradoxical trend toward PS(20) reduction (indicating increased PE response) that reached significance at the completion of carvedilol dose titration (PS(20) ratio vs baseline = 0.78; P < .001). All effects were maintained over a 6-month treatment period with no evidence of tolerance. Increasing BP response to PE infusion suggests improvement in vascular alpha(1)-AR signal transduction with chronic carvedilol therapy. This effect is evident despite no detectable tolerance to preinfusion BP reductions. The varying affinities of alpha(1)-AR subtypes for carvedilol and PE may have contributed to this finding.

Pharmacokinetic/pharmacodynamic modeling of the cardiovascular effects of beta blockers in humans

Pharmacokinetic-pharmacodynamic (PK/PD) analysis is useful study in clinical pharmacology, also PK/PD modeling is major tools for PK/PD analysis. In this study, we sought to characterize the relationship between the cardiovascular effects and plasma concentrations of the beta blocker drugs carvedilol and atenolol using PK/PD modeling in healthy humans. One group received oral doses of atenolol (50 mg) and the other group received oral doses of carvedilol (25 mg). Subsequently, blood samples were taken, and the effects of the drugs on blood pressure were determined. Plasma concentrations of drugs were measured by HPLC, and PK/PD modeling performed by applied biophase model, plasma drug concentrations were linked to the observed systolic blood pressure (SBP) and diastolic blood pressure (DBP) via an effect compartment. The model parameters were estimated using the ADAPT II program. In PK/PD analysis, it was observed the time delay between plasma concentration and effect and the time delay between SBP and DBP. The two time delays were properly explained by PD parameter "Keo" in applied biophase model. As conclusion, the biophase PK/PD model described the relationship between the plasma concentrations of the drugs and the cardiovascular effects, including the time delay between systolic blood pressure and diastolic blood pressure.