Michael R. Bristow

The effect of carvedilol on morbidity and mortality in patients with chronic heart failure

BACKGROUND Controlled clinical trials have shown that beta-blockers can produce hemodynamic and symptomatic improvement in chronic heart failure, but the effect of these drugs on survival has not been determined. METHODS We enrolled 1094 patients with chronic heart failure in a double-blind, placebo-controlled, stratified program, in which patients were assigned to one of the four treatment protocols on the basis of their exercise capacity. Within each of the four protocols patients with mild, moderate, or severe heart failure with left ventricular ejection fractions < or = 0.35 were randomly assigned to receive either placebo (n = 398) or the beta-blocker carvedilol (n = 696); background therapy with digoxin, diuretics, and an angiotensin-converting-enzyme inhibitor remained constant. Patient were observed for the occurrence death or hospitalization for cardiovascular reasons during the following 6 months, after the beginning (12 months for the group with mild heart failure). RESULTS The overall mortality rate was 7.8 percent in the placebo group and 3.2 percent in the carvedilol group; the reduction in risk attributable to carvedilol was 65 percent (95 percent confidence interval, 39 to 80 percent; P < 0.001). This finding led the Data and Safety Monitoring Board to recommend termination of the study before its scheduled completion. In addition, as compared with placebo, carvedilol therapy was accompanied by a 27 percent reduction in the risk of hospitalization for cardiovascular causes (19.6 percent vs. 14.1 percent, P = 0.036), as well as a 38 percent reduction in the combined risk of hospitalization or death (24.6 percent vs, 15.8 percent, P < 0.001). Worsening heart failure as an adverse reaction during treatment was less frequent in the carvedilol than in the placebo group. CONCLUSIONS Carvedilol reduces the risk or death as well as the risk of hospitalization for cardiovascular causes in patients with heart failure who are receiving treatment with digoxin, diuretics, and an angiotensin-converting-enzyme inhibitor.

The Effect of Carvedilol on Morbidity and Mortality in Patients with Chronic Heart Failure

BACKGROUND Controlled clinical trials have shown that beta-blockers can produce hemodynamic and symptomatic improvement in chronic heart failure, but the effect of these drugs on survival has not been determined. METHODS We enrolled 1094 patients with chronic heart failure in a double-blind, placebo-controlled, stratified program, in which patients were assigned to one of the four treatment protocols on the basis of their exercise capacity. Within each of the four protocols patients with mild, moderate, or severe heart failure with left ventricular ejection fractions < or = 0.35 were randomly assigned to receive either placebo (n = 398) or the beta-blocker carvedilol (n = 696); background therapy with digoxin, diuretics, and an angiotensin-converting-enzyme inhibitor remained constant. Patient were observed for the occurrence death or hospitalization for cardiovascular reasons during the following 6 months, after the beginning (12 months for the group with mild heart failure). RESULTS The overall mortality rate was 7.8 percent in the placebo group and 3.2 percent in the carvedilol group; the reduction in risk attributable to carvedilol was 65 percent (95 percent confidence interval, 39 to 80 percent; P < 0.001). This finding led the Data and Safety Monitoring Board to recommend termination of the study before its scheduled completion. In addition, as compared with placebo, carvedilol therapy was accompanied by a 27 percent reduction in the risk of hospitalization for cardiovascular causes (19.6 percent vs. 14.1 percent, P = 0.036), as well as a 38 percent reduction in the combined risk of hospitalization or death (24.6 percent vs, 15.8 percent, P < 0.001). Worsening heart failure as an adverse reaction during treatment was less frequent in the carvedilol than in the placebo group. CONCLUSIONS Carvedilol reduces the risk or death as well as the risk of hospitalization for cardiovascular causes in patients with heart failure who are receiving treatment with digoxin, diuretics, and an angiotensin-converting-enzyme inhibitor.

Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy

Several small studies have suggested beneficial effects of long-term beta-blocker treatment in idiopathic dilated cardiomyopathy. Our large multicentre study aimed to find out whether metoprolol improves overall survival and morbidity in this disorder. 383 subjects with heart failure from idiopathic dilated cardiomyopathy (ejection fraction < 0.40) were randomly assigned placebo or metoprolol. 94% were in New York Heart Association functional classes II and III, and 80% were receiving background treatment. A test dose of metoprolol (5 mg twice daily) was given for 2-7 days; those tolerating this dose (96%) entered randomisation. Study medication was increased slowly from 10 mg to 100-150 mg daily. There were 34% (95% CI -6 to 62%, p = 0.058) fewer primary endpoints in the metoprolol than the placebo group; 2 and 19 patients, respectively, deteriorated to the point of needing transplantation and 23 and 19 died. The change in ejection fraction from baseline to 12 months was significantly greater with metoprolol than with placebo (0.13 vs 0.06, p < 0.0001). Pulmonary capillary wedge pressure decreased more from baseline to 12 months with metoprolol than with placebo (5 vs 2 mm Hg, p = 0.06). Exercise time at 12 months was significantly greater (p = 0.046) in metoprolol-treated than in placebo-treated patients. In patients with idiopathic dilated cardiomyopathy, treatment with metoprolol prevented clinical deterioration, improved symptoms and cardiac function, and was well tolerated.

β-Adrenergic Receptor Blockade in Chronic Heart Failure

The medical treatment of chronic heart failure has undergone a remarkable transition in the past 10 years. The approach has changed from a short-term hemodynamic/pharmacological paradigm to a more long-term, reparative strategy that aims to favorably alter the biological properties of the failing heart.1 This is dramatically illustrated by the recent success in treating mild-to-moderate chronic heart failure with β-adrenergic blocking agents. This review describes how a treatment that began as a contraindication1 2 3 became an established treatment of chronic heart failure. The failing human heart is adrenergically activated,4 5 6 which helps to maintain cardiac performance over the short term by increasing contractility and heart rate. In contrast, in the resting state there is no adrenergic support of normally functioning human left ventricles.6 Multiple lines of evidence7 8 9 indicate that it is the increase in cardiac adrenergic drive rather than an increase in circulating norepinephrine that is both initially supportive and then ultimately damaging to the failing human heart. As shown in Table 1⇓, there are 3 adrenergic receptors (β1, β2, and α1) in human cardiac myocytes coupled to a positive inotropic response and cell growth.10 11 12 β-Adrenergic receptors are coupled via the “stimulatory” G protein Gs to the effector enzyme adenylyl cyclase, which converts the substrate MgATP to cAMP. cAMP is a positively inotropic and chronotropic second messenger and is strongly growth promoting. In nonfailing human left or right ventricles, the β1/β2 ratio is 70 to 80/30 to 20, but in failing human ventricles, 35% to 40% of the total number of β-receptors are β2 because of selective downregulation in the β1 subtype.10 11 α1 Receptors are coupled via a different G protein (G …

Mechanisms and Models in Heart Failure: The Biomechanical Model and Beyond

Received August 25, 2004; revision received December 23, 2004; accepted January 19, 2005. Despite repeated attempts to develop a unifying hypothesis that explains the clinical syndrome of heart failure, no single conceptual paradigm for heart failure has withstood the test of time. Whereas clinicians initially viewed heart failure as a problem of excessive salt and water retention that was caused by abnormalities of renal blood flow (the “cardiorenal model”1), as physicians began to perform careful hemodynamic measurements, it also became apparent that heart failure was associated with a reduced cardiac output and excessive peripheral vasoconstriction. This latter realization led to the development of the “cardiocirculatory” or “hemodynamic” model for heart failure,1 wherein heart failure was thought to arise largely as a result of abnormalities of the pumping capacity of the heart and excessive peripheral vasoconstriction. However, although both the cardiorenal and cardiocirculatory models for heart failure explained the excessive salt and water retention that heart failure patients experience, neither of these models explained the relentless “disease progression” that occurs in this syndrome. Thus, although the cardiorenal models provided the rational basis for the use of diuretics to control the volume status of patients with heart failure, and the cardiocirculatory model provided the rational basis for the use of inotropes and intravenous vasodilators to augment cardiac output, these therapeutic strategies have not prevented heart failure from progressing, nor have they led to prolonged life for patients with moderate to severe heart failure.1,2⇓ In the present review we will summarize recent advances in the field of heart failure, with a focus on the new therapeutic strategies that have been developed for treating systolic heart failure. For a complete discussion on recent advances in the diagnosis and treatment of diastolic heart failure, the interested reader is referred to several …

Carvedilol Inhibits Clinical Progression in Patients With Mild Symptoms of Heart Failure

BACKGROUND We tested the hypothesis that carvedilol inhibits clinical progression in patients with mildly symptomatic heart failure due to left ventricular (LV) systolic dysfunction. METHODS AND RESULTS Patients (n = 366) who had mildly symptomatic heart failure with an LV ejection fraction (LVEF) < or = 0.35, had minimal functional impairment (defined as the ability to walk 450 to 550 m on a 6-minute walk test), and were receiving optimal standard therapy, including ACE inhibitors, were randomized double-blind to carvedilol (n = 232) or placebo (n = 134) and followed up for 12 months. The primary end point was clinical progression, defined as death due to heart failure, hospitalization for heart failure, or a sustained increase in heart failure medications. Clinical progression of heart failure occurred in 21% of placebo patients and 11% of carvedilol patients, reflecting a 48% (P = .008) reduction in the primary end point of heart failure progression (relative risk, 0.52; CI, 0.32 to 0.85). This effect of carvedilol was not influenced by sex, age, race, cause of heart failure, or baseline LVEF. Carvedilol also significantly improved several secondary end points, including LVEF, heart failure score, NYHA functional class, and the physician and patient global assessments. Carvedilol reduced all-cause mortality but had no effects on the Minnesota Living With Heart Failure scale, the distance walked in 9 minutes on a self-powered treadmill, or cardiothoracic index. The drug was well tolerated. CONCLUSIONS Carvedilol, when added to standard therapy, including an ACE inhibitor, reduces clinical progression in patients who are only mildly symptomatic with well-compensated heart failure.

Assessment of the beta-adrenergic receptor pathway in the intact failing human heart: progressive receptor down-regulation and subsensitivity to agonist response.

We developed methods for identifying beta-adrenergic receptors in human right ventricular endomyocardial biopsy tissue with the radioligand (-)[125I]iodocyanopindolol (ICYP). Specific ICYP binding in a crude, high-yield membrane preparation derived from endomyocardial biopsy tissue was high (specificity greater than 90%), of high affinity (KD around 20 pM), saturable and stereospecific for the (-) vs the (+) isomer of isoproterenol. Subjects with mild-moderate and severe biventricular dysfunction had respective decreases in beta-adrenergic receptor density of 38.2% and 57.7% when normalization methods were averaged, with no significant differences in ICYP dissociation constant. A subgroup of subjects was subdivided by left ventricular ejection fraction (LVEF) into those with mild cardiac dysfunction (LVEF less than 0.50 greater than 0.40) and severe heart failure (LVEF less than 0.20) and given graded sequential infusions of dobutamine and calcium gluconate. Those with severe cardiac dysfunction had marked impairment of the dobutamine dP/dt and stroke work index response, whereas these responses to calcium did not differ in the two groups. These data indicate that in the intact human heart endomyocardial biopsy may be used for direct analysis of beta-adrenergic receptors, heart failure-associated myocardial beta-adrenergic down-regulation begins with mild-moderate ventricular dysfunction, reduction in myocardial beta-receptor density is related to degree of heart failure, and beta-receptor down-regulation is associated with pharmacologically specific impairment of the beta-agonist-mediated contractile response.

Medical Therapy Can Improve the Biological Properties of the Chronically Failing Heart: A New Era in the Treatment of Heart Failure

Myocardial failure has been considered to be an irreversible and progressive process characterized by ventricular enlargement, chamber geometric alterations, and diminished pump performance. However, more recent evidence has suggested that certain types of medical therapy may lead to retardation and even reversal of the cardiomyopathic process. In the failing heart, long-term neurohormonal/autocrine-paracrine activation results in abnormalities in myocyte growth, energy production and utilization, calcium flux, and receptor regulation that produce a progressively dysfunctional, mechanically inefficient heart. Interventions such as ACE inhibition and beta-blockade result in a reduction in the harmful long-term consequences of neurohormonal/autocrine-paracrine effects and retard the progression of left ventricular dysfunction or ventricular remodeling. Furthermore, in subjects with idiopathic dilated or ischemic cardiomyopathy, antiadrenergic therapy with beta-blocking agents appears to be able to partially reverse systolic dysfunction and ventricular remodeling. Although the precise mechanisms underlying this latter effect have not yet been elucidated, the general mechanism appears to be via improvement in the biological function of the cardiac myocyte. Such an improvement in the intrinsic defect(s) responsible for myocardial failure will likely translate into important clinical benefits.

Comparative hemodynamic, left ventricular functional, and antiadrenergic effects of chronic treatment with metoprolol versus carvedilol in the failing heart

BACKGROUND The basic pharmacology of the third-generation beta-blocking agent carvedilol differs considerably from second-generation compounds such as metoprolol. Moreover, carvedilol may produce different, ie, more favorable, clinical effects in chronic heart failure. For these reasons, we compared the effects of carvedilol and metoprolol on adrenergic activity, receptor expression, degree of clinical beta-blockade, hemodynamics, and left ventricular function in patients with mild or moderate chronic heart failure. METHODS AND RESULTS The effects of carvedilol versus metoprolol were compared in two concurrent placebo-controlled trials with carvedilol or metoprolol that had common substudies focused on adrenergic, hemodynamic, and left ventricular functional measurements. All subjects in the substudies had chronic heart failure resulting from idiopathic dilated cardiomyopathy. Carvedilol at 50 to 100 mg/d produced reductions in exercise heart rate that were similar to metoprolol at 125 to 150 mg/d, indicating comparable degrees of beta-blockade. Compared with metoprolol, carvedilol was associated with greater improvement in New York Heart Association functional class. Although there were no significant differences in hemodynamic effects between the carvedilol and metoprolol active-treatment groups, carvedilol tended to produce relatively greater improvements in left ventricular ejection fraction, stroke volume, and stroke work compared with changes in the respective placebo groups. Carvedilol selectively lowered coronary sinus norepinephrine levels, an index of cardiac adrenergic activity, whereas metoprolol did not lower coronary sinus norepinephrine and actually increased central venous norepinephrine levels. Finally, metoprolol was associated with an increase in cardiac beta-receptor density, whereas carvedilol did not change cardiac beta-receptor expression. CONCLUSIONS The third-generation beta-blocking agent carvedilol has substantially different effects on left ventricular function, hemodynamics, adrenergic activity, and beta-receptor expression than dose the second-generation compound metoprolol. Some or all of these differences may explain the apparent differences in clinical results between the two compounds.

Selection and Treatment of Candidates for Heart Transplantation A Statement for Health Professionals From the Committee on Heart Failure and Cardiac Transplantation of the Council on Clinical Cardiology, American Heart Association

Improved outcome of heart failure in response to medical therapy, coupled with a critical shortage of donor organs, makes it imperative to restrict heart transplantation to patients who are most disabled by heart failure and who are likely to derive the maximum benefit from transplantation. Hemodynamic and functional indexes of prognosis are helpful in identifying these patients. Stratification of ambulatory heart failure patients by objective criteria, such as peak exercise oxygen consumption, has improved ability to select appropriate adult patients for heart transplantation. Such patients will have a poor prognosis despite optimal medical therapy. When determining the impact of individual comorbid conditions on a patients candidacy for heart transplantation, the detrimental effects of each condition on posttransplantation outcome should be weighed. Evaluation of patients with severe heart failure should be done by a multidisciplinary team that is expert in management of heart failure, performance of cardiac surgery in patients with low left ventricular ejection fraction, and transplantation. Potential heart transplant candidates should be reevaluated on a regular basis to assess continued need for transplantation. Long-term management of heart failure should include continuity of care by an experienced physician, optimal dosing in conventional therapy, and periodic reevaluation of left ventricular function and exercise capacity. The outcome of high-risk conventional cardiovascular surgery should be weighed against that of transplantation in patients with ischemic and valvular heart disease. Establishment of regional specialized heart failure centers may improve access to optimal medical therapy and new promising medical and surgical treatments for these patients as well as stimulate investigative efforts to accelerate progress in this critical area.