Controlled-Release Carvedilol

? A new once-daily controlled-release (CR) capsule formulation of the nonselective β- and α1-adrenoceptor antagonist carvedilol is now available for use in the treatment of essential hypertension, heart failure (HF), and left ventricular dysfunction following myocardial infarction (MI). ? Carvedilol CR had equivalent β1-adrenoceptor antagonist activity to carvedilol immediate release (IR) in patients with hypertension in terms of the reduction in exercise-induced heart rate. In addition, corresponding dosages of the two formulations demonstrated pharmacokinetic bioequivalence. ? 24-Hour DBP (primary endpoint) and SBP (measured by ambulatory blood pressure monitoring [ABPM]) were reduced to a significantly greater extent with carvedilol CR 20, 40, or 80 mg once daily than with placebo in patients with hypertension in a well designed trial. Carvedilol CR 40 or 80 mg also significantly reduced trough DBP and SBP as measured by both ABPM and office sphygmomanometry in this patient population. ? Preliminary results of a randomized comparison did not find any difference in medication compliance rates between once-daily carvedilol CR and twice-daily carvedilol IR administered over 5 months in patients with HF, which was in part due to a higher than anticipated compliance in the carvedilol IR cohort. ? Carvedilol CR was generally well tolerated in patients with hypertension, mild to severe HF, or left ventricular dysfunction following MI. Headache was the most commonly reported adverse event associated with carvedilol CR in patients with hypertension, but generally was not reported at a higher incidence in carvedilol CR than placebo recipients.     

卡维地洛与琥珀酸美托洛尔治疗慢性收缩性心力衰竭的临床观察

目的： 分析卡维地洛与琥珀酸美托洛尔治疗慢性收缩性心力衰竭的临床疗效。方法： 选取于2009年1月-2011年1月在某院心内科接受治疗的慢性收缩性心力衰竭患者,随机分为A组和B组,其中A组应用卡维地洛进行治疗,B组应用琥珀酸美托洛尔进行治疗。待治疗24个月后随访两组患者的临床治疗效果、综合超声心动图主要指标、NT-proBNP的差异。结果： 共纳入267例收缩性心力衰竭患者,分析结果显示A组和B组治疗后左室射血分数、左室舒张末期内径及NT-proBNP明显改善,具有统计学意义（P<0.01）;与B组相比,A组对左心室射血分数的改善更加显著（P<0.05）,而对左室舒张末期内径和NT-proBNP的改善两组无统计学差异（P>0.05）。结论： 卡维地洛和琥珀酸美托洛尔均可明显改善慢性收缩性心力衰竭患者的心功能指标;与琥珀酸美托洛尔相比,卡维地洛能更显著提高慢性收缩性心力衰竭患者的左室射血分数。     

Has COMET solved the controversy as to whether carvedilol is better than metoprolol in heart failure?

Carvedilol and metoprolol are beta(1)-adrenoceptor antagonists that decrease mortality in heart failure. It is not clear whether the ancillary properties, which carvedilol has but metoprolol does not have, contribute to the beneficial effect. The Carvedilol Or Metoprolol European Trial (COMET) compared metoprolol tartrate (mean daily dose 85 mg) and carvedilol (41.8 mg) in patients with heart failure. All-cause mortality was less in the carvedilol than the metoprolol group, indicating that at these doses, carvedilol has a mortality benefit over metoprolol. However, the beta(1)-adrenoceptor blocking activity of metoprolol tartrate (assessed by a decrease in heart rate) was slightly less than with carvedilol in COMET and less than that observed in previous mortality studies with metoprolol, suggesting that the use of metoprolol tartrate was not optimal in COMET.     

Beta-blockers in heart failure. The 'new wave' of clinical trials.

There is now considerable clinical trial data to support the use of beta-blockers in patients with congestive heart failure (CHF) due to systolic left ventricular dysfunction. A substantial database has accumulated over the last 20 years supporting the benefits of these agents on ventricular function and clinical status. In addition, morbidity and mortality benefits have been suggested, specifically with the non-selective vasodilating agent, carvedilol. More recently, a "new wave" of clinical trials have been conducted to definitively determine the mortality benefits of beta-blockers in patients with mild to moderate CHF as well as addressing other important clinical questions. These questions include whether the beneficial effects of carvedilol on survival can be reproduced by other agents in prospective, adequately powered studies; whether the benefits of carvedilol in systolic heart failure are due to its beta-blocking properties alone or to a combination of the beta-blocking and ancillary effects of the drug; whether beta-blockers are of benefit in patients with severe New York Heart Association (NYHA) Class IIIB-IV CHF; and, whether beta-blockers are of benefit (additional to ACE inhibitors) in patients with evidence of systolic ventricular dysfunction when commenced in the immediate post-myocardial infarction period. Major studies are currently being undertaken to address the above questions. Most are still underway but 3 studies have recently reported their results: the second Cardiac Insufficiency Bisoprolol Study (CIBIS II), the Research in Left Ventricular Dysfunction Study (RESOLVD), and the Metoprolol CR/XL Randomised Intervention Trial in Heart Failure (MERIT-HF) study. These studies have demonstrated that blockade with beta1-selective, non-vasodilating agents (i.e. bisoprolol and metoprolol) improve survival in patients with CHE Comparison of relative risk reduction in these recent studies with the earlier carvedilol studies raises mechanistic questions, specifically whether non-selectivity, vasodilation and other ancillary properties of carvedilol are critical to its benefit in CHF patients. This question is currently being addressed in the Carvedilol and Metoprolol European Trial (COMET), comparing metoprolol with carvedilol. The beneficial effects of beta-blockers on mortality in patients with mild to moderate CHF have also had major implications in ongoing studies of other agents in this condition. Open-label prescribing of beta-blockers is increasing in these studies and this is having an impact on event rates and thus required duration of administration of study drug. Furthermore, it would now appear unethical to deprive suitable NYHA Class II-III CHF patients of beta-blockers as part of the design of such studies. In conclusion, beta-blockers have now become the most extensively studied class of agents in the treatment of CHF, with a database of over 6000 patients in placebo-controlled studies, and ongoing clinical and mechanistic studies. Despite this, further questions remain regarding the use of these agents in CHF, including their role in the extreme elderly, in patients with diabetes mellitus and in patients with renal impairment.     

Carvedilol in the treatment of chronic heart failure

Along with the angiotensin-converting enzyme inhibitors (ACEIs), the beta-adrenergic receptor blockers have gradually emerged to be standard in the therapy of heart failure. Individual beta-blockers that have been shown to reduce all-cause mortality in patients with heart failure include bisoprolol, metoprolol and carvedilol. Carvedilol distinguishes from the other beta-blockers as being a non-selective beta(1)- and beta(2)-receptor blocker with (1)-receptor blockade effect and anti-oxidant properties. The drug does not have sympathomimetic activity and has vasodilatory effects attributable to its (1)-receptor blockade property. Experimental and clinical studies have confirmed carvedilol's vasodilator, anti-oxidant and anti-apoptotic properties, which may contribute to its effect in reversing cardiac remodelling in animal models and patients with heart failure. These pharmacological properties render carvedilol a potentially useful agent in the treatment of patients with heart failure. Early studies of carvedilol in heart failure have reported beneficial haemodynamic effects but variable effects on exercise tolerance and clinical well being. The large-scale US Carvedilol Heart Failure Program and the Australian/New Zealand Heart Failure Collaborative Research Group reported beneficial effects of carvedilol on mortality, morbidity and clinical well being in patients with mild-to-moderate heart failure. The recently reported but yet unpublished preliminary results of the COPERNICUS study suggest that carvedilol improves mortality and morbidity in patients with advanced heart failure and severe symptoms. At this time, it is unclear whether the ancillary pharmacological properties of carvedilol can be translated to more superior clinical benefit compared to the other beta-blockers. Preliminary studies examining surrogate end points suggest that carvedilol may improve left ventricular ejection fraction (LVEF) more than metoprolol. More conclusive information regarding their relative effects of clinical outcomes will await the completion of the COMET study, which compares the effect of metoprolol and carvedilol on mortality and morbidity, expected at the end of the year 2002.     

Different intrinsic activities of bucindolol, carvedilol and metoprolol in human failing myocardium

1. Clinical studies have shown different effects of beta-blockers on the beta-adrenergic system, tolerability and outcome in patients with heart failure. 2. The study examines beta-adrenoceptor-G-protein coupling and intrinsic activity of bucindolol, carvedilol and metoprolol in human ventricular myocardium. 3. Radioligand binding studies ([(125)I]-Iodocyanopindolol) were performed in membrane preparations of human failing and nonfailing myocardium. Functional experiments were carried out in isolated muscle preparations of human left ventricular myocardium from failing hearts. 4. Bucindolol and carvedilol bound non-selectively to beta(1)- and beta(2)-adrenoceptors and exerted guanine nucleotide modulatable binding. Metoprolol was 35-fold beta(1)-selective and lacked guanine nucleotide modulatable binding. 5. All beta-blockers antagonized isoprenaline-induced enhancement of contractility. 6. In preparations in which the coupling of the stimulatory G-protein to adenylate cyclase was facilitated by forskolin, bucindolol increased force of contraction in three and decreased it in five experiments. Carvedilol increased force in one and decreased it in six experiments. Metoprolol decreased force in all experiments by 89. 4+/-2.2% (P<0.01 metoprolol vs carvedilol and bucindolol). The negative inotropic effect of metoprolol was antagonized by bucindolol. 7. It is concluded that differences in intrinsic activity can be detected in human myocardium and have an impact on cardiac contractility. In human ventricular myocardium, bucindolol displays substantially higher intrinsic activity than metoprolol and carvedilol. Bucindolol can behave as partial agonist or partial inverse agonist depending on the examined tissue. 8. Differences in intrinsic activity may contribute to differences in beta-adrenoceptor regulation and possibly to differences in tolerability and outcomes of patients with heart failure.     

卡维地洛与美托洛尔治疗慢性心力衰竭疗效比较

目的对比观察卡维地洛于美托洛尔治疗慢性心力衰竭（CHF）的疗效及对肿瘤坏死因子（TNF-α）和白细胞介素-6（IL-6）水平影响。方法94例CHF患者随机分为卡维地洛组和美托洛尔组,每组47例,比较观察两组的临床疗效及对TNF—α和IL-6水平影响。结果卡维地洛组的总有效率明显高于美托洛尔组,两组比较差异有统计学意义（P〈0．05）。两组治疗后TNF-α和IL-6水平都较治疗前明显下降,差异有统计学意义（P〈0．05）。卡维地洛组治疗后TNF-α和IL-6水平明显低于卡维地洛组,差异有统计学意义（P〈0．05）。结论卡维地洛治疗CHF的临床疗效明显高于美托洛尔,并且卡维地洛较美托洛尔更明显降低血浆TNF—α和IL-6水平,是目前治疗CHF的一种首选药物。     

Long-term effects of carvedilol on left ventricular function, remodeling, and expression of cardiac cytokines after large myocardial infarction in the rat.

Carvedilol (20 mg/kg, bid) or vehicle was given to rats surviving a myocardial infarction (MI) 24 h (n = 409). In rats with large MI, carvedilol partially preserved left ventricular (LV) function and intrinsic myocardial contractility and reactivity to beta-adrenergic stimulation. Carvedilol led to scar thickening, increased LV hypertrophy, and decreased cardiac fibrosis but did not prevent LV dilatation. Carvedilol reduced cardiac expression of interleukin-1beta but did not prevent cardiac fetal gene re-expression or modify cardiac oxidative stress. Despite these beneficial effects, carvedilol decreased survival (38.8%, versus vehicle, 50.6%) due to excessive early mortality. Thus, post-MI carvedilol has many beneficial effects, however, in this study it increased post-MI mortality, perhaps due to excessive hypotension.     

Hemodynamic characterization of left ventricular function in experimental coxsackieviral myocarditis: effects of carvedilol and metoprolol

BACKGROUND: Carvedilol, a vasodilating nonselective beta-adrenoceptor antagonist, but not metoprolol, a selective beta1-adrenoceptor antagonist, has been shown to increase the production of cardiac antiinflammatory cytokines in experimental myocarditis. However, the hemodynamic consequences of these differences had not been investigated until today. Therefore, we determined the effects of carvedilol and metoprolol on left ventricular function in a murine model of coxsackievirus B3 (CVB3)-induced myocarditis. METHODS: BALB/c mice were inoculated with the coxsackie-B3 virus. Four and 10 days after infection, left ventricular function was investigated using a conductance micromanometer system. Additional groups were treated starting 24 h after infection using equipotent doses of carvedilol and metoprolol and studied on day 10. RESULTS: On day 4, infected mice manifested increased afterload-enhanced contractility and abnormal diastolic function. On day 10, contractile function of untreated mice was impaired. Carvedilol significantly improved cardiac index and most systolic indices, whereas metoprolol was substantially less effective. Diastolic dysfunction was not influenced by either of the beta-adrenoceptor antagonists. CONCLUSIONS: These hemodynamic data indicate that not only beta1-adrenoceptor blockade but also pleiotropic effects are involved in the cardioprotective effects of carvedilol on the pathophysiology of acute viral myocarditis.     

Has COMET solved the controversy as to whether carvedilol is better than metoprolol in heart failure?

Carvedilol and metoprolol are β₁-adrenoceptor antagonists that decrease mortality in heart failure. It is not clear whether the ancillary properties, which carvedilol has but metoprolol does not have, contribute to the beneficial effect. The Carvedilol Or Metoprolol European Trial (COMET) compared metoprolol tartrate (mean daily dose 85 mg) and carvedilol (41.8 mg) in patients with heart failure. All-cause mortality was less in the carvedilol than the metoprolol group, indicating that at these doses, carvedilol has a mortality benefit over metoprolol. However, the β₁-adrenoceptor blocking activity of metoprolol tartrate (assessed by a decrease in heart rate) was slightly less than with carvedilol in COMET and less than that observed in previous mortality studies with metoprolol, suggesting that the use of metoprolol tartrate was not optimal in COMET.     

卡维地洛治疗慢性心力衰竭的临床疗效观察

目的研究卡维地洛治疗慢性心力衰竭(CHF)患者的临床疗效及耐受性,为临床合理用药提供依据。方法108例CHF患者随机分为卡维地洛组、美托洛尔组及对照组,每组36例,所有患者治疗心力衰竭基础药物(洋地黄、利尿剂、血管紧张素转换酶抑制剂)不变,而卡维地洛组、美托洛尔组分别加用卡维地洛及美托洛尔。于治疗前及连续治疗6月后进行心功能(NY-HA)分级评估,测量心率、血压及心电图、超声心动图检测,观察LVEDD、LVESD及LVEF变化。结果2例因用药后病情恶化而退出,106例完成全程治疗及随访,结果显示,与治疗前比较,卡维地洛组及美托洛尔组均可显著改善心功能分级、LVEF,并降低血压及心率,(分别为P<0.05、P<0.01)。而对照组患者治疗前后心功能分级、LVEF、血压及心率的变化均无显著差异。卡维地洛组3例发生低血压,美托洛尔组发生低血压及心动过缓各1例,无死亡患者。对照组再次入院人数(17例)较卡维地洛组(2例)及美托洛尔组(4例)明显增加(P<0.01)。结论在心力衰竭常规药物基础上加用卡维地洛,可以明显改善心功能,降低再次入院率。     

Left ventricular diastolic function improvement by carvedilol therapy in advanced heart failure

Carvedilol treatment in chronic heart failure (CHF) patients has been demonstrated to reduce mortality by improving cardiac systolic function and reducing left ventricular adverse remodeling. However, the effects of the drug on left ventricular (LV) filling are less studied. In this study we evaluated early and long-term diastolic cardiac modifications by an echo-Doppler method during carvedilol therapy in patients with advanced CHF and pseudonormal or restrictive filling pattern. We studied 58 patients with severe but stable CHF (39 in class NYHA III and 19 in IV) having systolic and diastolic dysfunction caused by idiopathic or ischemic cardiomyopathy. Thirty-two patients were randomized to receive previous treatment plus carvedilol (group 1) and 26 continued standard therapy (group 2). In all subjects we evaluated LV volumes, LV mass, LV ejection fraction (EF), and the following transmitral filling parameters: early wave (E), atrial wave (A), E/A ratio, deceleration time (DT), and isovolumetric releasing time (IVRT). After 4 months of therapy, the carvedilol group showed a significant increase of A wave (P < 0.001), DT (P < 0.0001), IVRT (P < 0.0001), and a significant reduction of E/A ratio (P < 0.0005) with respect to group 2. Further improvement was observed at 12 months (A P < 0.0005; DT P < 0.00002; IVRT P < 0.000004; E/A P < 0.0008), although an E wave reduction was observed in group 1 with respect to controls (P < 0.001). Moreover, after 1 year of follow-up a reduction of systolic volume (P < 0.001) and pulmonary pressure (P < 0.0001) and consequent increase of EF (P < 0.001) was observed in the carvedilol group. Carvedilol treatment improved diastolic function in CHF with severe diastolic and systolic impairment at early time, converting a restrictive or pseudonormal filling pattern into an altered pattern. These changes remained significant after 1 year of therapy together with improvement in systolic function.     

Carvedilol versus other beta-blockers in heart failure

Carvedilol is a beta-blocker with ancillary properties. Pilot clinical studies with carvedilol, added to the standard therapy of digoxin, diuretics and ACE inhibitors, showed beneficial effects in mild, moderate and severe heart failure. Patients consistently showed improvement in LV ejection fraction and NYHA functional class. Subsequently large clinical trials showed decreased morbidity and mortality with carvedilol in mild and moderate and more recently, severe heart failure. However, there is little or no improvement in exercise tolerance with carvedilol. The beneficial effects of carvedilol in heart failure are associated with cardiac remodelling. Metoprolol and bisoprolol are selective beta(1)-blockers without ancillary properties. Early studies showed benefits with metoprolol and bisoprolol in heart failure. Large clinical trials established that metoprolol and bisoprolol decreased mortality and morbidity in heart failure. In contrast no benefit has been shown with celiprolol, a selective beta(1)-blocker and beta(2)-stimulant in heart failure. There is a debate as to whether the ancillary properties of carvedilol contribute to its beneficial effect in heart failure, making it a better drug to use than metoprolol. Short-term studies suggested that carvedilol and metoprolol were equivalent in heart failure but short-term is probably not an appropriate way to compare the drugs. A recent long-term study and study in poor responders to metoprolol, suggest that carvedilol may be better than metoprolol in heart failure.     

Beta-adrenoceptor genotype influences the response to carvedilol in patients with congestive heart failure

Although the widespread introduction of beta-adrenoceptor antagonists into the management of congestive heart failure (CHF) has led to significant improvements in morbidity and mortality, it is also apparent that clinical responses to this therapy vary substantially. With the recognition that functionally significant genetic polymorphisms of the beta2-adrenoceptor exist with clinically relevant allelic frequency, we hypothesized that beta2-adrenoceptor genotype may affect the response to carvedilol. The clinical response, influence on left ventricular function and beta2-adrenoceptor (beta2AR) genotype was determined in 80 patients treated with carvedilol. A clinically significant improvement in left ventricular function (good responder) was defined as an absolute improvement of 10% in the left ventricular ejection fraction or 5% in the fractional shortening. Consistent with studies performed in vitro on the influence of beta2AR genotype and receptor desensitization, subjects who were homozygous for the allele encoding the Gln27 polymorphism displayed a significantly lower proportion of good responders than patients who were homozygous or heterozygous for the Glu27 polymorphism (26% versus 63%, P=0.003). These data demonstrate a significant influence of beta2AR genotype in the response to carvedilol in CHF patients. Accordingly, determination of beta2AR status may be of value in the tailoring of individual therapy in patients with CHF.     

卡维地洛与比索洛尔治疗慢性心力衰竭疗效比较

目的 比较卡维地洛、比索洛尔治疗慢性心力衰竭（CHF）的疗效.方法 80例CHF患者分为卡维地洛组（40例）、比索洛尔组（40例）,两组在常规治疗基础上分别加用卡维地洛和比索洛尔,观察治疗前后心率（HR）、血压（BP）、左心室舒张末径（LVEDD）、左心室收缩末径（LVESD）、左心室射血分数（LVEF）、6 min步行试验距离（6 min walk）等指标.结果 卡维地洛组和比索洛尔组总有效率分别为82.5%和87.5%,两组差异无统计学意义（χ2=2.18,P＞0.05）;治疗后两组HR、SBP、DBP、LVEDD、LVESD均低于治疗前（均P＜0.05）;LVEF和6 min walk均高于治疗前（均P＜0.05）.结论 比索洛尔和卡维地洛疗效相似,均能显著改善心力衰竭患者的心功能.     

Carvedilol: a new candidate for reversal of MDR1/P-glycoprotein-mediated multidrug resistance

In 1983, carvedilol [1-[carbazolyl-(4)-oxy]-3-[(2-methoxyphenoxyethyl)amino]-2-propanol] was designed and developed as a beta-adrenoceptor antagonist with vasodilating activity for efficacious and safe treatment of hypertension and coronary artery disease. Carvedilol belongs to the 'third generation' of beta-adrenoceptor antagonists and shows selectivity for the beta1- rather than beta2-adrenoceptor. Carvedilol is also an alpha1-blocking agents, with around 2- to 3-fold more selectivity for beta1- than alpha1-adrenoceptors. This degree of alpha1-blockade is responsible for the moderate vasodilator properties of carvedilol, being different from other beta-adrenoceptor antagonists. In addition, carvedilol is a potent antioxidant, with a 10-fold greater activity than vitamin E. Some carvedilol metabolites found in human plasma also exhibit antioxidative activity approximately 50- to 100-fold greater than carvedilol and other antioxidants. These unique properties of carvedilol, i.e. adrenergic (beta1, beta2 and alpha1) blockade and antioxidative activity, may be important in preventing progressive deterioration of left ventricular dysfunction and chronic heart failure. Recently, carvedilol has been demonstrated to reverse multidrug resistance (MDR) to anticancer drugs in tumor cells in vitro and its reversal effects were comparable with verapamil, which has been used in the first clinical trial for the reversal of MDR. This review introduces the reversal activity and usefulness against MDR, as well as an overview of the pharmacological and pharmacokinetic properties, of carvedilol.     

卡维地洛及美托洛尔对慢性心力衰竭合并糖尿病患者的心功能及胰岛素抵抗的影响

目的 观察卡维地洛和美托洛尔对慢性心力衰竭（chronicheart failure,CHF）合并2型糖尿病（type2 diabetesmellitus,T2DM）患者的心功能及胰岛素抵抗的影响。方法CHF合并T2DM患者130例,根据常规治疗基础上加用卡维地洛与美托洛尔分为卡维地洛组（65例）和美托洛尔组（65例）。治疗12个月。结果（1）卡维地洛组及美托洛尔组心功能均较治疗前改善（P〈0．05）。LVEF均高于治疗前（P〈0．05）,舒张末期内径（LVEDd）、舒张末期容积指数（LVEDVI）、收缩末期容积指数（LVESVI）均低于治疗前（P〈0．05）。卡维地洛组疗效优于美托洛尔组（P〈0．05）。（2）卡维地洛组的胰岛素抵抗指数显著低于治疗前（P〈0．05）,而美托洛尔治疗前后无明显变化（P〉0．05）。结论卡维地洛和美托洛尔均能明显改善CHF合并T2DM患者的心功能,卡维地洛可改善胰岛素抵抗。     

Carvedilol in the treatment of chronic heart failure

Along with the angiotensin-converting enzyme inhibitors (ACEIs), the β-adrenergic receptor blockers have gradually emerged to be standard in the therapy of heart failure. Individual β-blockers that have been shown to reduce all-cause mortality in patients with heart failure include bisoprolol, metoprolol and carvedilol. Carvedilol distinguishes from the other β-blockers as being a non-selective ₁- and ₂-receptor blocker with ₁-receptor blockade effect and anti-oxidant properties. The drug does not have sympathomimetic activity and has vasodilatory effects attributable to its ₁-receptor blockade property. Experimental and clinical studies have confirmed carvedilol’s vasodilator, anti-oxidant and anti-apoptotic properties, which may contribute to its effect in reversing cardiac remodelling in animal models and patients with heart failure. These pharmacological properties render carvedilol a potentially useful agent in the treatment of patients with heart failure. Early studies of carvedilol in heart failure have reported beneficial haemodynamic effects but variable effects on exercise tolerance and clinical well being. The large-scale US Carvedilol Heart Failure Program and the Australian/New Zealand Heart Failure Collaborative Research Group reported beneficial effects of carvedilol on mortality, morbidity and clinical well being in patients with mild-to-moderate heart failure. The recently reported but yet unpublished preliminary results of the COPERNICUS study suggest that carvedilol improves mortality and morbidity in patients with advanced heart failure and severe symptoms. At this time, it is unclear whether the ancillary pharmacological properties of carvedilol can be translated to more superior clinical benefit compared to the other β-blockers. Preliminary studies examining surrogate end points suggest that carvedilol may improve left ventricular ejection fraction (LVEF) more than metoprolol. More conclusive information regarding their relative effects of clinical outcomes will await the completion of the COMET study, which compares the effect of metoprolol and carvedilol on mortality and morbidity, expected at the end of the year 2002.     

Disparate effects of carvedilol versus metoprolol treatment of stroke-prone spontaneously hypertensive rats on endothelial function of resistance arteries

In human hypertension, blockade of beta-adrenoceptors does not improve resistance artery structure or endothelial dysfunction. We tested in hypertensive rats the hypothesis that carvedilol, a beta-blocker with antioxidant properties, would improve endothelial dysfunction, whereas the beta1-selective blocker, metoprolol, would not. Twenty-week-old SHRSP were treated orally for 10 weeks with carvedilol (50 mg/kg/day) or metoprolol (100 mg/kg/day), with or without hydralazine (25 mg/kg/day), the latter because neither beta-blocker was a very effective blood pressure-lowering agent in this model. Mesenteric arteries (lumen, <300 microm) were studied on a pressurized myograph. After 10 weeks, untreated SHRSP had a systolic blood pressure (mm Hg) of 239+/-3 that was unaffected by carvedilol or metoprolol treatment but decreased (p < 0.05) by hydralazine (187+/-4), carvedilol + hydralazine (221+/-3), and metoprolol + hydralazine (197+/-3). Carvedilol alone improved endothelium-dependent relaxation of resistance arteries, as elicited by the lowest concentration of acetylcholine studied (10(-7) M), whereas metoprolol had no effect. Hydralazine improved endothelial function as elicited by acetylcholine at a dose of 10(-6) M, also found under cotreatment with carvedilol but attenuated by cotreatment with metoprolol. Carvedilol or metoprolol alone had no significant effect on endothelium-independent relaxation produced by a nitric oxide donor (sodium nitroprusside). However, vessels from rats treated with carvedilol + hydralazine exhibited significantly greater relaxation than those from rats treated with metoprolol + hydralazine. These data suggest that carvedilol may have favorable effects on hypertension-related endothelial dysfunction not observed with metoprolol. Neither drug corrected small artery structure in SHRSP.     

Assuming the worst may not be bad at all Carvedilol in heart failure treatment

Objective: Carvedilol, a β-adrenoceptor blocking agent with additional α₁-adrenoceptor blocking properties, has been shown to improve left ventricular function in chronic heart failure (CHF). However, its effect on mortality has recently been the subject of controversial discussion. The aim of this meta-analysis is to review the data on mortality from two large study programs (the US Carvedilol Heart Failure Study and the study by the Australia/New Zealand Heart Failure Research Collaborative Group) on additional carvedilol treatment in CHF standard therapy and to analyse the design and limitations of the individual studies. Methods and Results: For determination of overall, mortality, all patients who died and all patients who were withdrawn for other reasons during the open run-in phase of the studies were assigned to the carvedilol group to create a “worst-case analysis.” Meta-analysis of mortality data using the random effects model shows a significantly reduced relative risk of 0.55 × 95%-confidence interval 0.325–0.924; p < 0.05 of death in patients treated with carvedilol compared with patient on standard treatment only. Conclusion: Treatment of CHF using carvedilol significantly reduces mortality in patients with CHF, even if the “worst case” is assumed by assigning all deaths in the open run-in phase to carvedilol. Received: 6 October 1997 / Accepted in revised form: 18 February 1998