Beta-blockade In Heart Failure Research Articles

Systematic review of genuine versus spurious side-effects of beta-blockers in heart failure using placebo control: recommendations for patient information.

BackgroundPatients trying life-preserving agents such as beta-blockers may be discouraged by listings of harmful effects provided in good faith by doctors, drug information sheets, and media. We systematically review the world experience of side-effect information in blinded, placebo-controlled beta-blockade in heart failure. We present information for a physician advising a patient experiencing an unwanted symptom and suspecting the drug.MethodsWe searched Medline for double-blinded randomized trials of beta-blocker versus placebo in heart failure reporting side-effects. We calculated, per 100 patients reporting the symptom on beta-blockade, how many would have experienced it on placebo: the “proportion of symptoms non-pharmacological”.Results28 of the 33 classically-described side-effects are not significantly more common on beta-blockers than placebo.Of the 100 patients developing dizziness on beta-blockers, 81 (95% CI 73–89) would have developed it on placebo. For diarrhoea this proportion is 82/100 (70–95), and hyperglycaemia 83/100 (68–98). For only two side-effects is this under half (i.e. predominantly due to beta-blocker): bradycardia (33/100, CI 21–44) and intermittent claudication (41/100, 2–81).At least 6 so-called side-effects are less common on beta-blocker than placebo, including depression (reduced by 35%, p < 0.01) and insomnia (by 27%, p = 0.01).ConclusionsClinicians might reconsider whether it is scientifically and ethically correct to warn a patient that a drug might cause them a certain side-effect, when randomized controlled trials show no significant increase, or indeed a significant reduction. A better informed consultation could, in patients taking beta-blockers, alleviate suffering. In patients who might otherwise not take the drug, it might prevent deaths.

The Carvedilol's Beta-Blockade in Heart Failure and Exercise Training's Sympathetic Blockade in Healthy Athletes during the Rest and Peak Effort

In recent years, beta-blocker therapy has become a primary pharmacologic intervention in patients with heart failure by blocking the sympathetic activity. To compare the exercise training's sympathetic blockade in healthy subjects (athletes) and the carvedilol's sympathetic blockade in sedentary heart failure patients by the evaluation of the heart rate dynamic during an exercise test. A total of 26 optimized and 49 nonoptimized heart failure patients in a stable condition (for, at least, 3 months), 15 healthy athletes and 17 sedentary healthy subjects were recruited to perform a cardiopulmonary exercise test. The heart rate dynamic (rest, reserve, peak and the peak heart rate in relation to the maximum predicted for age) was analyzed and compared between the four groups. The heart rate reserve was the same between optimized (48 +/- 15) and nonoptimized (49 +/- 18) heart failure patients (P < 0.0001). The athletes (188 +/- 9) showed a larger heart rate reserve compared to sedentary healthy subjects (92 +/- 10, P < 0.0001). Athletes and healthy sedentary reached the maximum age-predicted heart ratefor their age, but none of the heart failure patients did. The carvedilol's sympathetic blockade occurred during the rest and during the peak effort in the same proportion, but the exercise training's sympathetic blockade in healthy subjects occurred mainly in the rest.

Meta-analysis: β-Blocker Dose, Heart Rate Reduction, and Death in Patients With Heart Failure

Guidelines recommend that patients with heart failure receive beta-blockers in doses used in the trials that have proven their efficacy. Although the adverse effects of beta-blockade are dose-related, it is unclear whether the benefits are. To determine whether the survival benefits of beta-blockade in heart failure are associated with the magnitude of heart rate reduction or the beta-blocker dose. MEDLINE, EMBASE, CINAHL, SIGLE, Web of Science, and the Cochrane Central Register of Controlled Trials, supplemented by hand-searches of bibliographies. Randomized, placebo-controlled heart failure trials that reported all-cause mortality. Two reviewers independently extracted data on study characteristics, beta-blocker dosing and heart rate reduction, and death. The mean left ventricular ejection fraction in the 23 beta-blocker trials ranged from 0.17 to 0.36, and more than 95% of the 19 209 patients had systolic dysfunction. The overall risk ratio for death was 0.76 (95% CI, 0.68 to 0.84); however, heterogeneity testing revealed moderate heterogeneity among trials (I (2) = 30%), which was associated with the magnitude of heart rate reduction achieved within each trial (P for meta-regression = 0.006). For every heart rate reduction of 5 beats/min with beta-blocker treatment, a commensurate 18% reduction (CI, 6% to 29%) in the risk for death occurred. No significant relationship between all-cause mortality and beta-blocker dosing was observed (risk ratio for death, 0.74 [CI, 0.64 to 0.86]) in high-dose beta-blocker trials vs. 0.78 [CI, 0.63 to 0.96] in low-dose beta-blocker trials; P for meta-regression = 0.69). The analysis is based on aggregate data and resting heart rates. Few patients in these trials had bradycardia or diastolic dysfunction at baseline. The magnitude of heart rate reduction is statistically significantly associated with the survival benefit of beta-blockers in heart failure, whereas the dose of beta-blocker is not.

Tips and tricks on outpatient initiation and uptitration of beta-blockade in heart failure

beta-blockade has a therapeutic role across the continuum of patients with heart failure (HF), with a demonstrated mortality benefit in stage II and III HF. Concerns regarding initiation and uptitration linger as patients with resting bradycardia, pulmonary, or vascular disease are often unnecessarily excluded from receiving therapy. We will review the risk data on beta-blockade and offer therapeutic strategies to help overcome residual barriers to the initiation and uptitration of this important therapy in patients with HF.

Carvedilol Reduces Aldosterone Release in Systolic Heart Failure

Treatment of advanced systolic heart failure (HF) with the aldosterone antagonist spironolactone on the background of angiotensin converting enzyme inhibition (ACEI) is well established. However, the only large prospective trial to investigate this therapy (RALES) predated the routine use of beta-blockade in HF. The widespread practice of combining ACEI, beta-blockers and spironolactone in HF management has led to serious concerns regarding hyperkalemia. Beta-blockade has been shown to reduce circulating angiotensin (Ang) II levels in HF patients established on ACEI therapy, possibly by renin suppression. To measure the effects of addition of the beta-blocker carvedilol to optimal ACEI therapy on aldosterone release in HF. Seventeen patients with NYHA Class II-III HF, left ventricular ejection fraction <35%, were stabilised on diuretic and ACEI therapy. Plasma was collected for measurement of Ang II, Ang I, aldosterone and amino-terminal-pro-B-type natriuretic peptide (NT-proBNP). A 24h urine collection was obtained for measurement of aldosterone/creatinine ratio. Carvedilol was then commenced and up titrated over the next 6-8 weeks and all samples were again obtained. Plasma Ang II levels decreased from 8.6 (0.8-94.6)fmol/mL, geometric mean (95% confidence interval) to 2.0 (0.1-61.9)fmol/mL, P=0.001, Ang I levels decreased from 96 (13-702)fmol/mL to 23 (0-1050)fmol/mL, P=0.002, and urine aldosterone/creatinine ratio decreased from 3.7 (0.9-14.8)nmol/mmol to 1.8 (0.4-8.9)nmol/mmol, P=0.01, with addition of carvedilol therapy. It is concluded that carvedilol suppresses aldosterone production in HF patients receiving ACEI therapy. However, the clinical importance of this finding needs to be further tested from the point of view both of the likelihood of clinical benefit from aldosterone antagonists as well as the risk of hyperkalemia and whether aldosterone levels are of predictive value.

Vagal heart rate responses to chronic beta‐blockade in human heart failure relate to cardiac norepinephrine spillover

We have documented a pre-junctional beta-2 adrenoceptor mediated reduction in cardiac norepinephrine spillover (CNES) in heart failure patients receiving chronic beta-blockade. Our present objective was to ascertain the consequence of this decrease for vagal heart rate (HR) regulation by determining CNES, arterial baroreflex sensitivity for HR (BRS) and arterial baroreflex modulation of muscle sympathetic nerve activity (MSNA) before and upon 4 months of beta-blockade with either carvedilol or metoprolol. In 19 heart failure patients in sinus rhythm (age: 55+/-2 [mean+/-S.E.]; ejection fraction: 20+/-2%), beta-blockade increased BRS from 4.8+/-0.9 to 7.9+/-1.3 ms/mm Hg (P<0.005) but had no effect on arterial baroreflex modulation of MSNA. Changes in CNES and BRS were inversely related (r=-0.52; n=16, P<0.05). Chronic beta-blockade in heart failure augments reflex vagal control of HR at an efferent site of interaction involving blockade of cardiac sympathetic pre-junctional beta-2 adrenoceptors that facilitate NE release.

406 Cardiopulmonary effects of beta-blockade in heart failure: differences between carvedilol and bisoprolol

406 Cardiopulmonary effects of beta-blockade in heart failure: differences between carvedilol and bisoprolol

The Role of Beta Blockade in Heart Failure

Beta-blocker therapy remains one of the most fascinating issues in heart failure (HF) clinical practice. These agents, once absolutely contraindicated in patients with HF, have been shown to have the greatest beneficial effects on the patients' prognosis. They have radically changed the clinical course of HF, more than any other agent previously introduced, and are now the cornerstone of current HF treatment.1-3 Beta-blocker therapy contradicted most of the hypotheses on which the treatment of HF was based.

The Role of Beta Blockade in Heart Failure

Beta-blocker therapy remains one of the most fascinating issues in heart failure (HF) clinical practice. These agents, once absolutely contraindicated in patients with HF, have been shown to have the greatest beneficial effects on the patients' prognosis. They have radically changed the clinical course of HF, more than any other agent previously introduced, and are now the cornerstone of current HF treatment.1-3 Beta-blocker therapy contradicted most of the hypotheses on which the treatment of HF was based.

Betablocker in der Therapie der chronischen Herzinsuffizienz

Once contraindicated, beta-blockers have become an established, evidence-based, recommended treatment concept in chronic heart failure during the last years. The increased activation of the adrenergic system in heart failure syndrome, which leads to transmission of several adverse biological signals to myocytes through adrenergic receptors, provides the rationale for the use of beta-blockers in patients with chronic heart failure. Long-term treatment with different types of beta-blockers addictive to an ACE-inhibitor and diuretics results in normalization of left ventricular shape, an improvement of left ventricular function, and a reduction of hospitalization rate for heart failure. Hemodynamic and clinical improvement is independent of etiology and severity of left ventricular dysfunction. THERAPEUTICAL RECOMMENDATIONS ACCORDINGS TO STUDIES: Adequately powered clinical trials (CIBIS II, MERIT-HF, COPERNICUS) testing different types of beta-blockers (bisoprolol, metoprolol, carvedilol) clearly demonstrated that total mortality and the incidence of sudden cardiac death were significantly reduced in heart failure patients by each of these agents. On the basis of all available evidence, all patients with chronic, stable heart failure (NYHA class II-IV) and with impaired left ventricular function (LVEF < 45%) should receive one of the three above mentioned beta-blockers. Protective effects of beta-blockers in heart failure comprise decrease in heart rate, a decrease of energy consumption, antifibrillatory effects, protection against adrenergic overactivation, and hence, inhibition of myocardial cell necrosis. Moreover, several beta-blockers induce an up-regulation of beta-receptors leading to an improvement of contractility during long-term treatment. It should be mentioned that even a low dosage of beta-blockers exert negative inotropic effects and may lead to a deterioration of hemodynamics and heart failure symptoms in patients with heart failure. The patients treated should be informed that the success of the "paradoxical intervention" will be obvious until 2-3 months after initiation of additional beta-blocker therapy. Beta-blocker treatment for heart failure should be started in stable patients with a very low initial dosage and then up-titrated to the maximal tolerated dosage and should be continued indefinitely. Mortality reduction by beta-blockade in heart failure is no class effect. So far, beneficial effects could only be demonstrated for lipophilic agents. Whether the non-selective beta-blocker carvedilol with additional properties has advantages over the beta-1-selective metoprolol is currently investigated in the COMET (Carvedilol or Metoprolol European Trial) study. Despite the impressive effects in terms of morbidity and mortality reduction, the transfer of these benefits to the clinical practice setting is difficult, with international data showing only 10% of patients with heart failure being treated.

β-blockers, angiotensin II, and ACE inhibitors in patients with heart failure

Blood concentrations of angiotensin II are often raised in patients with heart failure, despite treatment with angiotensin-converting-enzyme (ACE) inhibitors. We compared concentrations of angiotensin II in two groups of matched patients, receiving ACE inhibitor therapy with or without concomitant administration of beta-blockers. Concentrations of angiotensin II were lower in individuals taking beta-blockers than in those who were not (geometric mean 1.1 [95% CI 0.4-2.7] vs 15.5 [4.6-52.6] fmol/mL, 95% CI for difference 3-59). Our findings indicate that a reduction in angiotensin II concentrations might contribute to the therapeutic benefits of beta-blockade in heart failure, especially in patients who simultaneously receive ACE inhibitor treatment.

Selective beta‐1 blockade improves left ventricular energy status, systolic and diastolic function in the rats with postinfarct heart failure

Background: The mechanisms for the beneficial effects of beta-blockade in heart failure are incompletely understood. The aim of this study was to investigate the effects of betal-blockade on cardiac bioenergetics and function in rats during early postinfarct remodeling phase. Methods: Large myocardial infarction (MI) was induced in male Sprague-Dawley rats. Two different groups were studied: rats with MI treated with metoprolol (5 mg!kg/b; n = 9) during 4 weeks and rats with MI placebo treated (n = 9). All rats were investigated with 31P MRS and transthoracic echocardiography (ECHO) 3 days after induction of MI and 4 weeks later. Volume-selective 31P MRS was performed on 2.35 T Bruker Biospec magnet. Results: Trentrnent with metoprolol increased myocardial PCr/ATP ratio indicating improved myocardial energy reserve which was associated with improvement in systolic and diastolic function.

Beta-blockade in heart failure: A comparison of carvedilol with metoprolol

OBJECTIVESThis study was performed to compare the long-term clinical efficacy of treatment with metoprolol versus carvedilol in patients with chronic heart failure.BACKGROUNDBeta-adrenergic blockade is of proven value in chronic heart failure. Metoprolol, a selective beta-blocker, is widely used, but recent trials suggest carvedilol, a nonselective beta-blocker with alpha-1-receptor antagonist activity and antioxidant activities, is also effective. It is uncertain, however, if these additional properties of carvedilol provide further clinical benefit compared with metoprolol.METHODSIn this randomized double-blind control trial, 51 patients with chronic heart failure and mean left ventricular (LV) ejection fraction of 26% ± 1.8% were randomly assigned treatment with metoprolol 50 mg twice daily or carvedilol 25 mg twice daily in addition to standard therapy after a four-week dose titration period for a total of 12 weeks. Response was assessed by a quality of life questionnaire, New York Heart Association class, exercise capacity (6-min walk test), radionucleotide ventriculography for LV ejection fraction, two-dimensional echocardiography measurement of LV dimensions and diastolic filling and 24-h electrocardiograph monitoring to assess heart rate variability.RESULTSBoth carvedilol and metoprolol produced highly significant improvement in symptoms (p < 0.001), exercise capacity (p < 0.05) and LV ejection fraction (p < 0.001), and there were no significant differences between the two drugs. Carvedilol had a significantly greater effect on sitting and standing blood pressure, LV end-diastolic dimension and normalized the mitral E wave deceleration time.CONCLUSIONSBoth metoprolol and carvedilol were equally effective in improving symptoms, quality of life, exercise capacity and LV ejection fraction, although carvedilol lowers blood pressure more than metoprolol.

Bisoprolol Beneficial in Heart Failure

The beneficial effect of beta-blockade in heart failure is now widely accepted; in particular, the beta-blocker carvedilol has been marketed for this

Beta-adrenergic blocking agents: past, present, and future perspectives.

The 'proof of concept' of beta-blockade for heart failure (i.e. that the pharmacologic actions of beta-blockers are beneficial) is now firmly established, as the treatment of heart failure has progressed from using positive inotropic stimulation, via drugs with no direct effect on cardiac function, to beta-blockers with negative intropic effects. This review addresses some remaining issues regarding beta-blockade in heart failure. The mechanism of action of beta-blockers in heart failure is more likely to be improved intrinsic cardiac myocyte function and prevention or reversal of remodeling, than restoration of beta-adrenergic signal transduction. The role of the differentiating characteristics of beta-blockers is not clear at this time, and there is no compelling evidence to select one agent over another on the basis of individual drug properties. Recent reports suggest that beta-blockers reduce the combined risk of all-cause mortality and hospitalizations by about 30-35%. These results are heavily influenced by experience with carvedilol, but other agents tested include metoprolol, bucindolol, bisoprolol, and nebivolol. Responsiveness to beta-blockers is not related to patients' age, sex, or race, or to the etiology or severity of heart failure. Beta-blockers are currently recommended as adjunctive treatment in patients who remain mildly to moderately symptomatic while receiving added digitalis, diuretics, and angiotensin-converting enzyme inhibitors. Existing gaps in our knowledge must be filled in order to achieve optimal clinical application of beta-blockers. Ongoing studies will provide much of the information required. The role of beta-blockers will probably expand as we improve our understanding of the pathophysiology of heart failure, and especially of the remodeling process.

Successes and failures of current treatment of heart failure

Successes and failures of current treatment of heart failure

The sympathetic nervous system in chronic heart failure

The sympathetic nervous system plays a pivotal role in the natural history of chronic heart failure (CHF). There is early activation of cardiac adrenergic drive, which is followed by an increasing magnitude of generalized sympathetic activation, with worsening heart failure. The adverse consequences predominate over the short-term compensatory effects and are mediated through downregulation of beta-receptor function and harmful biological effects on the cardiomyocyte. beta-blockers exert a beneficial effect on the natural history of CHF by attenuating the negative biological effects, restoring homogeneity of contractile/relaxant mechanisms, and reducing the risk of myocardial ischemia and arrhythmias. After pioneering work conducted over 20 years ago, numerous studies have shown the beneficial effects of beta-blockade on left ventricular function, and survival, morbidity, and mortality rates in CHF. Large-scale trials are underway to determine the overall benefits of beta-blockade in heart failure.

Nebivolol in the treatment of cardiac failure: A double-blind controlled clinical trial

Background: Nebivolol is a highly cardioselective long-acting beta-blocker with vasodilating properties, which acts in part via the endothelial l-arginine/nitric oxide pathway. As an antihypertensive drug it is effective in once-daily dosage. Nebivolol has previously been shown to improve left ventricular function in patients with cardiac impairment. Methods and Results: This paper reports a double-blind randomized trial comparing, in patients with heart failure, once-daily nebivolol 2.5 or 5.0 mg (initiated in all at 2.5 mg) with placebo on a constant background of digitalis plus diuretic. There was with nebivolol no overall deterioration of cardiac function or cardiac symptoms, and especially not of exercise capacity, in comparison with placebo. One patient on nebivolol 2.5 mg developed hypotension and pulmonary edema, and one patient on nebivolol 5 mg, bradycardia. All the remaining patients continued with unchanged diuretic and digitalis dosage. Nebivolol was accompanied by a trend toward clinical and functional improvement; rather better results were obtained with 2.5 than 5.0 mg. Conclusions: In view of increasing interest in beta-blockade in heart failure, nebivolol merits further study in this context. The capacity of nebivolol to enhance endothelial nitric oxide production appears potentially attractive.

Beta-blockers in heart failure. Future directions.

The rationale for beta-blockade in heart failure is now well established. Heart failure mortality, which is predicted by neurohormonal activation, remains high despite modern treatment including ACE inhibition, and additional neurohormonal blockade has further therapeutic potential. Previous clinical trial experience in heart failure, most of which has been in patients with idiopathic cardiomyopathy, indicates consistent improvement in ventricular function although variable changes in symptoms and exercise performance. However, the major burden of heart failure occurs in patients with ischaemic heart disease and in this respect it is notable that beta-blockade following myocardial infarction confers significant mortality benefit in subgroups with heart failure. The Australia and New Zealand carvedilol heart failure study is the largest completed study of beta-blocker treatment in patients with heart failure of ischaemic aetiology, including 415 patients randomized to carvedilol or placebo and indicating excellent tolerability of a titrated dose regimen and improved ventricular function after 6 months of treatment. An overview of all currently available randomized clinical trials of beta-blockade in heart failure, which includes more than 1600 patients, indicates a mortality risk reduction of approximately 20% but with wide confidence intervals. A large scale trial with several thousand patients is required to detect reliably a plausible 15-20% mortality reduction with beta-blockade in heart failure. The dissociation of clinical and mortality effects demonstrated with other heart failure treatments indicates the necessity for an appropriately powered mortality study which could define a major improvement in heart failure therapy for the future.

Beta blockers in heart failure

The rationale for beta blockade in heart failure is now well established. Heart failure mortality, which is predicted by neurohormonal activation, remains high despite modern treatment, including angiotensin-converting enzyme (ACE) inhibition, and additional neurohormonal blockade has further therapeutic potential. Previous clinical trial experience in heart failure, most of which has been in patients with idiopathic cardiomyopathy, indicates consistent improvement in ventricular function, although variable changes in symptoms and exercise performance. However, the major burden of heart failure occurs in patients with ischemic heart disease, and in this respect it is notable that beta blockade following myocardial infarction confers a significant mortality benefit in subgroups with heart failure. An overview of all currently available randomized clinical trials of beta blockade in heart failure, which includes more than 1600 patients, indicates a mortality risk reduction of approximately 20%, but with wide confidence intervals. A large scale trial with several thousand patients is required to confirm reliably a plausible 20% mortality reduction with beta blockade in heart failure. The dissociation of clinical and mortality effects demonstrated with other heart failure treatments indicates the necessity for an appropriately powered mortality study that could define a major improvement in heart failure therapy for the future. The response to beta blockade will vary according to heart failure severity. A cautious dosetitration approach is required in all cases. In severe heart failure, symptomatic improvement may result, but for the large group of patients with moderate and stable heart failure, the principal aim of treatment is improved longevity.