Beneficial Effects Of Carvedilol Research Articles

Beta-blockers in patients with liver cirrhosis: Pragmatism or perfection?

With increasing decompensation, hyperdynamic circulatory disturbance occurs in liver cirrhosis despite activation of vasoconstrictors. Here, the concept of a therapy with non-selective beta-blockers was established decades ago. They lower elevated portal pressure, protect against variceal hemorrhage, and may also have pleiotropic immunomodulatory effects. Recently, the beneficial effect of carvedilol, which blocks alpha and beta receptors, has been highlighted. Carvedilol leads to "biased-signaling" via recruitment of beta-arrestin. This effect and its consequences have not been sufficiently investigated in patients with liver cirrhosis. Also, a number of questions remain open regarding the expression of beta-receptors and its intracellular signaling and the respective consequences in the intra- and extrahepatic tissue compartments. Despite the undisputed role of non-selective beta-blockers in the treatment of liver cirrhosis, we still can improve the knowledge as to when and how beta-blockers should be used in which patients.

Beneficial effects of carvedilol with enzyme replacement therapy in Pompe disease

Beneficial effects of carvedilol with enzyme replacement therapy in Pompe disease

Carvedilol protects the kidneys of tumor-bearing mice without impairing the biodistribution or the genotoxicity of cisplatin

Cisplatin (Cisp) is an effective antitumor drug; however, it causes severe nephrotoxicity. Minimization of renal toxicity is essential, but the interference of nephroprotective agents, particularly antioxidants, with the antitumor activity of cisplatin is a general concern. We have recently demonstrated that the anti-hypertensive and antioxidant drug carvedilol (CV) protects against the renal damage and increases the survival of tumor–bearing mice without impairing the tumor reduction by cisplatin. So far, reports on the antioxidant mechanism of CV are controversial and there are no data on the impact of CV on the antitumor mechanisms of cisplatin. Therefore, this study addresses the effect of CV on mechanisms underlying the tumor control by cisplatin. CV did not interfere with the biodistribution or the genotoxicity of cisplatin. We also addressed the antioxidant mechanisms of CV and demonstrated that it does not neutralize free radicals, but is an efficient chelator of ferrous ions that are relevant catalyzers in cisplatin nephrotoxicity. The present data suggest that oxidative damage and genotoxicity play different roles in the toxicity of cisplatin on kidneys and tumors and therefore, some antioxidants might be safe as chemoprotectors. Altogether, our studies provide consistent evidence of the beneficial effect of CV on animals treated with cisplatin and might encourage clinical trials.

Dual targeting of TNF-α and free radical toxic stress as a promising strategy to manage experimental polycystic ovary

Context: It is now clear that oxidative stress (OS) and chronic low-grade inflammation are two main pathways involved in polycystic ovary syndrome (PCOS) pathogenesis. Therefore, simultaneous targeting of these pathways by means of carvedilol and Semelil (ANGIPARS™), as established medicines with dual anti-cytokine and anti-oxidant potential may be a therapeutic alternative approach to the current treatments.Objective: The objective of this study is to study the protective effects of carvedilol and ANGIPARS™ on inflammatory and oxidative response in hyperandrogenism-induced polycystic ovary (PCO).Materials and methods: The murine model of PCO was induced by letrozole (1 mg/kg/d; orally) and effective doses of carvedilol (10 mg/kg/d; orally) and ANGIPARS™ (2.1 mg/kg/d; orally) were administrated for 21 d in PCO and non-PCO healthy rats. Ovarian folliculogenesis, sex hormones concentrations, OS, inflammatory, and metabolic biomarkers were assessed in serum and ovaries.Results: PCO rats exhibited ovarian cystogenesis which was preserved by the application of carvedilol and ANGIPARS™. In comparison with controls, decreased level of the total antioxidant power (TAP) and higher levels of reactive oxygen species (ROS) and lipid peroxidation (LPO) in serum and ovaries (2.41 ± 0.67 versus 0.72 ± 0.11; and 0.17 ± 0.04 versus 0.05 ± 0.01; 5.48 ± 1.30 versus 10.56 ± 0.77; and 7.06 ± 1.94 versus 17.98 ± 0.98; p < 0.05, respectively) were detected in PCO rats. Moreover, the PCO rats exhibited hyperandrogenism due to a 3.7-fold increase in serum testosterone concentration (35.04 ± 3.17 versus 131.09 ± 13.24; p < 0.05) along with a 2.98-fold decrease in serum progesterone (6.19 ± 0.40 versus 18.50 ± 1.03; p < 0.05) and 5.2-fold decrease in serum estradiol (9.30 ± 0.61 versus 48.3 ± 2.10; p < 0.05) when compared with those of the control group. However, similar to the control group, normal levels of OS markers and sex hormones were detected in ANGIPARS™ and carvedilol co-treated PCO rats. Besides, when compared with controls, increased levels of TNF-α (770.75 ± 42.06 versus 477.14 ± 28.77; p < 0.05) and insulin (1.27 ± 0.10 versus 0.36 ± 0.05; p < 0.05) in PCO rats were significantly inhibited by carvedilol and ANGIPARS™ co-treatment.Discussion and conclusion: We evidenced the beneficial effects of carvedilol and ANGIPARS™ in PCO, which underpin the new alternative approach in using these kinds of medicines in female reproductive disorders.

Effect of carvedilol on metabolic control in patients with type 2 diabetes mellitus and resistant hypertension

Vasodilating b blockers possess a better metabolic profile than traditional b blockers. However, limited data exists onwhether this beneficialmetabolic profile is maintained in diabetic patients with resistant hypertension who are already on diuretic therapy. We aimed, therefore, to evaluate the effect of carvedilol, a vasodilating b blocker, on metabolic control in patients with type 2 diabetes mellitus (T2DM) and resistant hypertension. Fifty-one consecutive patients (15 male and 36 female) of age 51 to 84 years old (mean 68) with T2DM (duration 14 years, range 15-31,7 years) and blood pressure (BP) > 130/80 mmHg were studied. All patients were already receiving combination therapy of at least 3 antihypertensive drugs, including a diuretic, when carvedilol was added. Patients were followed up for 6 months. Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), body mass index (BMI), HbA1c and lipids (TCHOL, Tg, HDL-C, LDL-C) were determined at baseline and after 6 months of therapy with carvedilol. A significant drop in TCHOL (194 + 58.8. vs 178.8 + 49.1 mg/dl, p<0.0001) and Tg (154.31 + 34.9 vs 133.96 + 42.1 mg/dl p<0.0001) was found, whereas there was a non significant change in HDL-C (50.8 + 10.2 mg/dl vs 50.3 + 9.5 mg/dl, p1⁄4NS), LDL-C (111.9 + 40.6 mg/dl vs 105.6 + 43.2 mg/dl, p1⁄4NS) and HbA1c (7.64 + 1.17 % vs 7,6 + 1,13%, p1⁄4NS). Additionally, a significant drop in SBP (158.4 + 13.5 vs 148.9 + 15.5 mmHg, p<0.001), DBP (86.6 + 12.2 vs 79.9 + 8.7 mmHg, p<0.001) and HR (86.7 + 12.2 vs 79.9 + 11.3 bpm, p<0.001) was noted. In patients with Type 2 Diabetes Mellitus and resistant hypertension carvedilol seems to maintain its positive effect on metabolic control even when added to diuretics. Further major long-term clinical trials are needed to prove the beneficial effect of carvedilol over non selective b-blockers on cardiovascular risk in these patients.

Efficacy of Carvedilol in Pediatric Heart Failure

Evaluation of: Huang M, Zhang X, Chen S et al. The effect of carvedilol treatment on chronic heart failure in pediatric patients with dilated cardiomyopathy: a prospective, randomized-controlled study. Pediatr. Cardiol. 34, 680-685 (2013). A role for β-blockers in children with heart failure has not been established. Huang et al. conducted a randomized trial of oral carvedilol in children with dilated cardiomyopathy treated with conventional therapy for a minimum of 1 month. The primary end points were Ross score, echocardiographic parameters, brain natriuretic peptide levels and a composite clinical end point. Of the subjects assessed at 6 months, 41 had received carvedilol (up to 0.8 mg/kg/day) and 37 had not (control group). Carvedilol had favorable effects on Ross score, left ventricular function and brain natriuretic peptide levels. However, improvement was also seen in the control group, although this was not as pronounced. Composite end points were similar in the carvedilol-treated and control groups. Only one serious adverse event was observed. The results suggest a possible beneficial effect of carvedilol when added to conventional therapy, but a number of limitations of study design restrict the conclusions that can be drawn.

The Effect of Carvedilol on Blood Glucose Levels In Normal Albino Rats

Carvedilol is a commonly used drug in hypertension, congestive heart failure in diabetics. It has moderate calcium channel blocking property in addition to α1 and non selective β antagonistic activity. Though some studies bring forth the beneficial effects of Carvedilol in cardiovascular comorbidities in diabetes, there is no consensus on its effects on glycaemic levels. To evaluate the effect of oral Carvedilol administration for 5 days on blood glucose levels in normal albino rats through Oral Glucose Tolerance Test. Twelve adult albino rats of either sex weighing between 150 - 200 g were selected from central animal facility and randomly divided into 2 groups - Control [Distilled water (1ml/rat orally)] and Test (0.8mg/kg body weight orally) and the respective drugs were administered over 5 days. Following overnight fasting, on the fifth day 1 hour after the last dose of the respective drug, OGTT was performed. The CBG (Capillary Blood Glucose) levels were measured at 0 min, glucose (2g/kg body weight) dissolved in water was administered to all the rats orally. The blood sample from tail vein (obtained by tail snipping) at 60 and 150 minutes were analysed for CBG levels using a standardized glucometer. Data was presented as Mean ± SEM. One way ANOVA, independent samples t-test, non-parametric tests, percentages and cross tabs were used in the analysis of data within the same group and between different groups when required. Carvedilol group showed higher CBG levels at all time intervals of OGTT as compared to the Control group i.e., 0, 60 and 150 minutes, the highest being (103.8±5.029 )mg/dl at 60 minutes and was statistically significant. Carvedilol group however showed lesser inter-interval variation compared to the Control group at the same time intervals respectively but was statistically insignificant. Carvedilol has hyperglycaemic potential when given orally for 5 days in normal albino rats. Though it may be beneficial in diabetics for various comorbid conditions, the glycaemic control may worsen during its use in subjects with prediabetes, diabetes, high risk diabetes.

The Impact of Carvedilol and Metoprolol on Serum Lipid Concentrations and Symptoms in Patients with Hyperthyroidism

Background. Hyperthyroidism is associated with unpleasant symptoms and hypertension due to increased adrenergic tone. Therefore, beta-blockers are often used in hyperthyroid patients. While some beta-blockers (such as propronolol and metoprolol) may have unwanted effects on lipid profile, carvedilol, a new alpha- and beta-blocker, has been suggested to have some metabolic advantages with respect to lipid profiles in hypertensive patients. However, this has not been shown in hyperthyroid patients. Objective. We aimed to compare the effects of two beta-blockers (metoprolol and carvedilol) on the lipid profiles of hyperthyroid patients with hypertension. Methods. Thirty patients with hyperthyroidism and hypertension were randomly assigned to receive either carvedilol (n = 15) or metoprolol (n = 15). Thyroid-stimulating hormone (TSH), free T3, free T4, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride, and total cholesterol levels were measured before and following 3 months of treatment. Results. Systolic and diastolic blood pressure, heart rate, TSH, and free T4 improved significantly in both treatment groups. There were no statistically significant changes in the lipid parameters in either of the two treatment groups; however, triglyceride levels slightly decreased with carvedilol treatment. There were also no differences between the two groups in terms of the typical symptoms of hyperthyroidism. Conclusion. Carvedilol might be a preferred agent to treat hyperthyroid patients who have hypertension and dyslipidemia. This is likely due to the possible beneficial effect of carvedilol on lipid parameters, especially on triglyceride levels.

The Role of Carvedilol in the Treatment of Dilated and Anthracyclines-Induced Cardiomyopathy

Although chronic sympathetic activation provides inotropic and chronotropic support to the failing heart, such activation may also have deleterious effects, including the direct cardiotoxic effects of catecholamines, activation of the renin-angiotensin-aldosterone system and an increase in myocardial oxygen demand. These observations indicate that β-blockade might be beneficial in the treatment of heart failure resulting from dilated cardiomyopathy or ischaemic heart disease. Carvedilol is a non-selective β-blocker acting on β1-, β2-, and α1-adrenoceptors. It possesses potent anti-oxidant and anti-apoptotic properties, along with neuroprotective, vasculoprotective, cardioprotective effects, and it has reduced overall mortality in patients with heart failure in controlled clinical trials. Its role in treating cardiomyopathy requires focus. The fact that anthracyclines are cardiotoxic seriously narrows their therapeutic index in cancer therapy. The cardiotoxic risk increases with the cumulative dose and may lead to congestive heart failure and dilated cardiomyopathy in adults and in children. This review focuses on recent research regarding the beneficial effects of carvedilol in the treatment of dilated cardiomyopathy and to revisit the available evidence on the cardioprotection of carvedilol when associated with anthracycline and to explain the mechanisms underlying the benefits of their co-administration.

Carvedilol reduces myocardial no-reflow by decreasing endothelin-1 via activation of the ATP-sensitive K+ channel

It has been verified that carvedilol can attenuate myocardial no-reflow. However, the effects of carvedilol on adenosine triphosphate-sensitive K(+) (K(ATP)) channel and endothelin-1 (ET-1) are unknown. Forty mini-swines were randomized into 5 study groups: 8 control, 8 carvedilol pretreatment, 8 glibenclamide (K(ATP) channel blocker)-treated, 8 carvedilol and glibenclamide-pre-treated and 8 sham-operated. An acute myocardial infarction(AMI) and reperfusion model was created with a three-hour occlusion of the left anterior descending coronary artery followed by one-hour reperfusion. Compared with the control group, carvedilol significantly decreased the area of no-reflow (myocardial contrast echocardiography: from 78.5+/-4.5% to 24.9+/-4.1%, pathological means: from 82.3+/-1.9% to 25.8+/-4.3% of ligation area, respectively; all p < 0.01) and reduced necrosis size from 98.5+/-1.3% to 74.4+/-4.7% of ligation area, p < 0.05). It also decreased plasma ET-1 and myocardial tissue ET-1. However, glibenclamide abrogated the protective effect of carvedilol. The beneficial effect of carvedilol on myocardial no-reflow could be due to its effect on ET-1 via the activation of the K(ATP) channel.

Should beta‐blocker therapy be reduced or withdrawn after an episode of decompensated heart failure? Results from COMET

It is unclear whether beta-blocker therapy should be reduced or withdrawn in patients who develop acute decompensated heart failure (HF). We studied the relationship between changes in beta-blocker dose and outcome in patients surviving a HF hospitalisation in COMET. Patients hospitalised for HF were subdivided on the basis of the beta-blocker dose administered at the visit following hospitalisation, compared to that administered before. In COMET, 752/3029 patients (25%, 361 carvedilol and 391 metoprolol) had a non-fatal HF hospitalisation while on study treatment. Of these, 61 patients (8%) had beta-blocker treatment withdrawn, 162 (22%) had a dose reduction and 529 (70%) were maintained on the same dose. One-and two-year cumulative mortality rates were 28.7% and 44.6% for patients withdrawn from study medication, 37.4% and 51.4% for those with a reduced dosage (n.s.) and 19.1% and 32.5% for those maintained on the same dose (HR,1.59; 95%CI, 1.28-1.98; p<0.001, compared to the others). The result remained significant in a multivariable model: (HR, 1.30; 95%CI, 1.02-1.66; p=0.0318). No interaction with the beneficial effects of carvedilol, compared to metoprolol, on outcome was observed (p=0.8436). HF hospitalisations are associated with a high subsequent mortality. The risk of death is higher in patients who discontinue beta-blocker therapy or have their dose reduced. The increase in mortality is only partially explained by the worse prognostic profile of these patients.

Differential effect of β‐blocker therapy on insulin resistance as a function of insulin sensitizer use: results from GEMINI

To determine whether the beneficial effects of carvedilol on insulin resistance (IR) are affected by the concomitant use of insulin sensitizers [thiazolidinediones (TZDs) and metformin]. Changes in HbA1c and homeostasis model assessment-insulin resistance (HOMA-IR) were assessed over 5 months, comparing carvedilol with metoprolol tartrate according to insulin sensitizer (TZDs and metformin) use. In TZD/metformin users, carvedilol patients showed a 5.4% decrease [95% confidence interval (CI) -11.9, 1.6; P = 0.13] and metoprolol tartrate patients showed a 2.8% decrease (95% CI -8.5, 3.2; P = 0.35) in HOMA-IR. The -2.6% difference between treatments was not significant (95% CI -10.7, 6.2; P = 0.55). In contrast, those not taking TZD/metformin experienced a 13.2% increase in HOMA-IR on metoprolol tartrate (95% CI 3.2, 24.1; P < 0.01) and a 4.8% decrease in HOMA-IR on carvedilol (95% CI -14.6, 6.0; P = 0.37), with a significant treatment difference of -15.9% favouring carvedilol (95% CI -26.6, -3.6; P = 0.01). There was no significant treatment interaction for the use of TZD/metformin and HbA1c. A statistically significant treatment difference was observed for HbA1c after 5 months favouring carvedilol after adjusting for insulin sensitizer use (-0.11%, 95% CI -0.214, -0.009; P = 0.03). In patients with diabetes and hypertension not taking insulin sensitizers, the use of metoprolol tartrate resulted in a worsening of insulin resistance, an effect not seen with carvedilol. However, in TZD/metformin users the difference between the beta-blockers was not statistically significant.

Beneficial effects of carvedilol as a concomitant therapy to angiotensin-converting enzyme inhibitor in patients with ischemic left ventricular systolic dysfunction

Studies are scant on the effects of short-term carvedilol treatment as an adjuvant to angiotensin-converting enzyme (ACE) inhibitor in patients with left ventricular (LV) systolic dysfunction. The objective of this study was to find the effects of short-term treatment of carvedilol on patients with ischemic LV systolic dysfunction (defined as LV ejection fraction (LVEF) <or=30% on 2D echocardiography) undergoing coronary artery bypass surgery (CABG). There were 74 patients that received ACE inhibitor without any beta-blocker (control) and 67 patients that received carvedilol in addition to ACE inhibitor following CABG (carvedilol group). After 1 month of drug administration following CABG, the control group was found to have significantly greater percent improvement in LVEF (29.1% +/- 5.39%) as compared with the carvedilol group (15.3% +/- 4.89%). However, after 3 and 6 months, LVEF levels were found to be significantly greater in the carvedilol group as compared with the control group. Further, at 6 months of drug administration, LV end systolic diameter was significantly less in the carvedilol group (39.11 +/- 1.10 mm) as compared with the control group (43.49 +/- 1.39 mm). Thus, carvedilol produces beneficial effect on short-term administration in terms of LV contractility when given along with ACE inhibitor as compared with ACE inhibitor therapy alone.

Carvedilol preserves endothelial junctions and reduces myocardial no-reflow after acute myocardial infarction and reperfusion

Introduction Myocardial no-reflow, has been associated with alterations in endothelial junctions, which is regulated in part by endothelial dysfunction. Carvedilol is an alpha1 and nonselective beta-adrenergic receptor antagonist with antioxidative properties known to protect endothelial function. Therefore, we hypothesized that carvedilol might also have protective effects on myocardial no-reflow and endothelial junctions. Methods Thirty-two mini-swines were randomized into 4 study groups: 8 in control, 8 pretreated with carvedilol (1 mg/kg/d) for 3 days, 8 in propranolol (nonselective beta-adrenergic receptor antagonist)-pretreated for 3 days and 8 in sham-operated. Acute myocardial infarction and reperfusion model was created with 3 h occlusion of the left anterior descending coronary artery followed by 1 h reperfusion. Coronary ligation area (LA) and area of no-reflow were determined with both myocardial contrast echocardiography (MCE) in vivo and pathological means (Path). Myocardial vascular endothelial (VE)-cadherin, beta-catenin and gamma-catenin were assessed by immunoblot. Results Compared with the control group, carvedilol significantly improved ventricular function, increased coronary blood flow from 50.6 ± 3.1% to 72.1 ± 3.8% of the baseline at 1 h of reperfusion ( P < 0.01), decreased area of no-reflow (MCE: from 78.5 ± 4.5% to 24.9 ± 4.1%, Path: from 82.3 ± 1.9% to 25.8 ± 4.3% of LA respectively, all P < 0.01), reduced necrosis area from 98.5 ± 1.3% to 74.4 ± 4.7% of LA ( P < 0.05). The levels of VE-cadherin, β-catenin, and γ-catenin in the reflow myocardium were significantly greater in the carvedilol group (all P < 0.05). However, propranolol failed to significantly modify area of no-reflow, VE-cadherin, β-catenin and γ-catenin levels (all P > 0.05). Conclusion Pretreatment with carvedilol preserves endothelial junctions and reduces myocardial no-reflow after acute myocardial infarction and reperfusion. The beneficial effect of carvedilol was not due to its β-blocking action.

Beneficial effects of carvedilol on cardiomyocyte apoptosis and bcl-2/bax expression after acute myocardial infarction an experiment with rats

To investigate the beneficial effects of carvedilol on cardiomyocyte apoptosis and related gene expression after acute myocardial infarction (AMI). Eighty-three female SD rats underwent ligation of left anterior descending coronary artery, and were randomly assigned to 2 groups 24 hours later: carvedilol (n = 40, 10 mg.kg(-1).d(-1)was administered via direct gastric gavage 24 hs after the ligation, Group C) and AMI control group (n = 43, normal saline of the same volume was given by gastric gavage, Group MI). Another 27 rats were used as sham operation group (Group S, administered with normal saline too). The rats of each group were killed and their hearts were taken out 48 hours and 4 weeks after observation respectively (MI-48 h, MI-4 week, C-48 h, C-4 week, S-48 h, and S-4 week subgroups). TUNEL and DNA gel electrophoresis were used to detect the cardiomyocyte apoptosis. Immunohistochemistry and Western blotting were used to detect the expression of bcl-2 and bax. The apoptotic indices of the infracted/scar, border and non-infarcted areas at any time-point of Group MI were all significantly higher than those of Group S (all P < 0.05). Only the apoptotic indices of the infracted/scar and border areas of the C-4 week subgroup were significantly lower than those of the MI-4 week subgroup (both P < 0.05), and were close to those of the non-infarcted area. DNA gel electrophoresis showed that the positive rate of Group S at any time-point were both 0, the positive rate of MI-48 h subgroup and C-48 h subgroup were both significantly higher than that of Group S (both P < 0.05) without significant difference between these 2 groups, and the positive rates of the MI-4 week subgroup and C-4 week subgroup were both 0. Immunohistochemistry showed that the bax gene expression was slightly to significantly increased in the infarcted/scar, border, and non-infarcted areas of the MI-48 h and MI-4 week subgroups. The bcl-2 expression was significantly increased only in the infracted area of the MI-48 h subgroup. The bcl-2 expression was slightly increased in the infracted and border areas of the C-48 h subgroup and the bax expression was significantly decreased in the infracted/scar area of the C-4 week subgroup. Western blotting showed that (1) the bcl-2 expression of the S-4 week subgroup was significantly higher than that of the S-48 h subgroup (P < 0.05), (2) the bcl-2 expression and bax expression of the MI-48 h subgroup were significantly higher than that of the S-48 h subgroup (P < 0.05 - 0.01), the bcl-2/bax ratio of the MI-48 h subgroup was significantly lower that that of the S-48 h subgroup, however, there were no significant differences in the bcl-2 and bax expression and bcl-2/bax ratio between the MI-4 week subgroup and S-48 h subgroup (all P > 0.05), and (3) There were no significant difference in the bcl-2 and bax expression between Group A and Group S (all P > 0.05), however, the bcl-2/bax ratios at the 2 time-points of Group C were both significantly higher than those of Group MI. Cardiomyocyte apoptosis occurs in the infarction/scar, border and non-infarcted areas after AMI. Prolonged treatment with carvedilol reduces cardiomyocyte apoptosis in the scar and border areas and increases the expression ratio of bcl-2/bax.

Are β-blockers needed in patients receiving spironolactone for severe chronic heart failure? An analysis of the COPERNICUS study

The beneficial effects of beta-blockers and aldosterone receptor antagonists are now well established in patients with severe systolic chronic heart failure (CHF). However, it is unclear whether beta-blockers are able to provide additional benefit in patients already receiving aldosterone antagonists. We therefore examined this question in the COPERNICUS study of 2289 patients with severe CHF receiving the beta1-beta2/alpha1 blocker carvedilol compared with placebo. Patients were divided post hoc into subgroups according to whether they were receiving spironolactone (n = 445) or not (n = 1844) at baseline. Consistency of the effect of carvedilol versus placebo was examined for these subgroups with respect to the predefined end points of all-cause mortality, death or CHF-related hospitalizations, death or cardiovascular hospitalizations, and death or all-cause hospitalizations. The beneficial effect of carvedilol was similar among patients who were or were not receiving spironolactone for each of the 4 efficacy measures. For all-cause mortality, the Cox model hazard ratio for carvedilol compared with placebo was 0.65 (95% CI 0.36-1.15) in patients receiving spironolactone and 0.65 (0.51-0.83) in patients not receiving spironolactone. Hazard ratios for death or all-cause hospitalization were 0.76 (0.55-1.05) versus 0.76 (0.66-0.88); for death or cardiovascular hospitalization, 0.61 (0.42-0.89) versus 0.75 (0.64-0.88); and for death or CHF hospitalization, 0.63 (0.43-0.94) versus 0.70 (0.59-0.84), in patients receiving and not receiving spironolactone, respectively. The safety and tolerability of treatment with carvedilol were also similar, regardless of background spironolactone. Carvedilol remained clinically efficacious in the COPERNICUS study of patients with severe CHF when added to background spironolactone in patients who were practically all receiving angiotensin-converting enzyme inhibitor (or angiotensin II antagonist) therapy. Therefore, the use of spironolactone in patients with severe CHF does not obviate the necessity of additional treatment that interferes with the adverse effects of sympathetic activation, specifically beta-blockade.

Carvedilol in Chronic Heart Failure: past, Present and Future

Large randomized clinical trials of bisoprolol, carvedilol and metoprolol have conclusively demonstrated the efficacy and confirmed safety of beta-blockers in patients with chronic heart failure. Recently, the beneficial effects of carvedilol in patients with heart failure soon after an acute myocardial infarction have also been shown. Despite this, beta-blockers remain under-prescribed in this condition. This is of particular importance as heart failure is common and increasing in prevalence. In this article, when to start beta-blockade and which beta-blocker to use is considered. Since carvedilol is the most studied beta-blocker in heart failure and has a broad range of activities that extend beyond beta-blockade, whether it has possible advantages over other beta-blockers is discussed. Also, how the use of beta-blockade might evolve with the introduction of device-related therapy in heart failure is considered.

Importance of antioxidant and antiapoptotic effects of beta-receptor blockers in heart failure therapy.

The present study was carried out to determine whether beneficial effects of carvedilol in congestive heart failure (CHF) are mediated via its beta-adrenergic blocking, antioxidant, and/or alpha-adrenergic blocking action. Rabbits with heart failure induced by rapid cardiac pacing were randomized to receive subcutaneous carvedilol, metoprolol, propranolol plus doxazosin, or placebo pellets for 8 wk and compared with sham-operated rabbits without pacing. We found rapid cardiac pacing produced clinical heart failure, left ventricular dilation, and decline of left ventricular fractional shortening. This was associated with an increase in left ventricular end-diastolic pressure, decrease in left ventricular first derivative of left ventricular pressure, and myocyte hypertrophy. Tissue oxidative stress measured by GSH/GSSG was increased in the heart with increased oxidation product of mitochondrial DNA, 8-oxo-7,8-dihydro-2'-deoxyguanosine, increase of Bax, decrease of Bcl-2, and increase of apoptotic myocytes as measured by anti-single-stranded DNA monoclonal antibody. Administration of carvedilol and metoprolol, which had no effect in sham animals, attenuated cardiac ventricular remodeling, cardiac hypertrophy, oxidative stress, and myocyte apoptosis in CHF. In contrast, propranolol plus doxazosin, which has less antioxidant effects, produced smaller effects on left ventricular function and myocyte apoptosis. In all animals, GSH/GSSG correlated significantly with changes of left ventricular end-diastolic dimension (r = -0.678, P < 0.0001), fractional shortening (r = 0.706, P < 0.0001), and apoptotic myocytes (r = -0.473, P = 0.0001). Thus our findings suggest antioxidant and antiapoptotic actions of carvedilol and metoprolol are important determinants of clinical beneficial effects of beta-receptors in the treatment of CHF.

835-3 Beta-blocker dose does not influence the beneficial effects of carvedilol compared to metroprolol in the patients with heart failure: Results from the carvedilol or Metoprolol European Trial (COMET)

835-3 Beta-blocker dose does not influence the beneficial effects of carvedilol compared to metroprolol in the patients with heart failure: Results from the carvedilol or Metoprolol European Trial (COMET)

1012-103 Blood pressure changes do not influence the beneficial effects of carvedilol compared to metoprolol in the patients with heart failure: Results from COMET (carvedilol or metoprolol European trial)

1012-103 Blood pressure changes do not influence the beneficial effects of carvedilol compared to metoprolol in the patients with heart failure: Results from COMET (carvedilol or metoprolol European trial)