Cochrane Corner: Perioperative beta-blockers for preventing surgery-related mortality and morbidity

Randomized controlled trials have yielded conflicting results regarding the impact of beta-blockers on perioperative cardiovascular morbidity and mortality. This Cochrane systematic review assessed the impact of this intervention on mortality and cardiovascular events.Eighty-eight randomized controlled trials with 19 161 participants were included (53 trials on cardiac surgery and 35 trials on non-cardiac surgery).In cardiac surgery perioperative beta-blockers had a protective effect against supraventricular and ventricular arrhythmias but had no significant effect on mortality or on the occurrence of acute myocardial infarction (AMI), stroke, heart failure, hypotension or bradycardia. In non-cardiac surgery, beta-blockers had a protective effect against AMI and arrhythmias, but this was counterbalanced by an increased risk of death and stroke.In conclusion, perioperative use of beta-blockers appears overall to be beneficial in cardiac surgery. However, in non-cardiac surgery the substantial reduction in rhythm disturbances and AMI appears to be offset by an increase in mortality and stroke, and so the systematic use of beta-blockers in this setting is not recommended.     

Are beta‐blockers effective in patients who develop heart failure soon after myocardial infarction? A meta‐regression analysis of randomised trials

BACKGROUND: The great majority of post-infarction studies of beta-blockers were conducted in an era when these agents were widely held to be contra-indicated for the management of heart failure. We now know that beta-blockers are highly effective for the management of patients with chronic stable heart failure. However, there remains uncertainty about their role in the setting of post-infarction heart failure and ventricular dysfunction. AIM: the primary objective in this paper, was to investigate the extent to which heart failure or evidence of major cardiac dysfunction influenced outcome in previous trials of beta-blockers in heart failure after myocardial infarction. METHODS: We assessed the extent to which the inclusion of patients with heart failure or major cardiac dysfunction influenced outcome in randomised trials of long-term use of beta-blockade after myocardial infarction. The primary analysis was to assess the extent to which the proportion of patients included in each trial with heart failure influenced the relative odds of all-cause mortality in the trials. All randomised trials without crossover with treatment lasting more than one month and with 50 or more patients were considered. All those that provided information on the proportion of patients with heart failure or major cardiac dysfunction in the original or subsequent articles were included in the analysis. RESULTS: Overall treatment with a beta-blocker was associated with a 22.6% reduction in the odds of death (95% C1 11-32.3%). There were very few data on the effects of beta-blockers after myocardial infarction in patients with documented left ventricular systolic dysfunction. In the analysis that included heart failure as a factor, treatment with a beta-blocker was associated with a non-significant interaction with the presence of heart failure. However, because the group including heart failure patients were at higher risk, the absolute benefit of treatment with beta-blockers appeared greater in this group. CONCLUSIONS: This analysis suggests that the relative benefit of beta-blockers on mortality after a myocardial infarction is similar in the presence or absence of heart failure but that the absolute benefit may be greater in the former. However, as current clinical practice has changed radically from the time when the majority of these trials were conducted, further trial evidence would be desirable.     

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.     

The paradox of beta-adrenergic blockade for the management of congestive heart failure.

PURPOSE: To review the current data regarding the use of beta-adrenergic blockers for the treatment of congestive heart failure. MATERIAL AND METHODS: Relevant studies published between 1975 and 1991 were reviewed. Key data from each study were extracted. The significance of conclusions reached by each author(s) was identified. RESULTS: beta-adrenergic blockade, although still considered an investigational therapy for the treatment of congestive heart failure, has been proven in several studies to improve ventricular function, including myocardial contractility and relaxation. In addition, since beta-blockade up-regulates myocardial beta-receptors, the myocardium becomes more responsive to graded doses of beta-agonists. Speculation regarding the possible mechanisms of these effects is presented. In addition, since beta-blockers have been shown to reduce neurohormonal activation, they may have a beneficial effect on survival. Although small pilot studies or subgroup analysis of larger studies suggest beta-blockade therapy improves survival in heart failure, this has yet to be proven. Large prospective trials are warranted to study this issue. CONCLUSIONS: As current data suggest, beta-blockers improve ventricular function and reduce neurohormonal activation in heart failure. beta-blockers should be considered as adjunctive therapy in patients with congestive heart failure. In addition, future studies are warranted to better elucidate their effects on ventricular function and survival.     

Treatment of chronic systolic heart failure secondary to Chagas heart disease in the current era of heart failure therapy

The treatment of chronic heart failure secondary to Chagas disease has been based on extrapolation of data achieved in the treatment of non-Chagas disease heart failure. Because beta-blockers decrease the incidence of sudden cardiac death in non-Chagas disease heart failure and sudden cardiac death occurs preferentially in patients with mild Chagas disease heart failure, beta-blockers may be administered first to class I/II patients with Chagas disease heart failure. In advanced Chagas disease heart failure, angiotensin-converting enzyme inhibitor and diuretics may be given at first to compensate for congestive symptoms. After clinical status improvement, beta-blockers should be given at targeted doses, if necessary reducing angiotensin-converting enzyme inhibitor doses. Primary and secondary prevention of sudden cardiac death may be accomplished with implantable cardioverter defibrillators because of the high recurrence of life-threatening arrhythmias despite amiodarone administration. In refractory heart failure, heart transplantation is the treatment of choice.     

Cardiovascular protection using beta-blockers: a critical review of the evidence

For more than 3 decades, beta-blockers have been widely used in the treatment of hypertension and are still recommended as first-line agents by national and international guidelines. Recent meta-analyses indicate that, in patients with uncomplicated hypertension, compared with other antihypertensive agents, first-line therapy with beta-blockers was associated with an increased risk of stroke, especially in the elderly cohort with no benefit for the end points of all-cause mortality, cardiovascular morbidity, and mortality. In this review, we critically analyze the evidence supporting the use of beta-blockers in patients with hypertension and evaluate evidence for its role in other indications. The review of the currently available literature shows that in patients with uncomplicated hypertension, there is a paucity of data or absence of evidence to support use of beta-blockers as monotherapy or as first-line agents. Given the increased risk of stroke, their "pseudo-antihypertensive" efficacy (failure to lower central aortic pressure), lack of effect on regression of target end organ effects like left ventricular hypertrophy and endothelial dysfunction, and numerous adverse effects, the risk benefit ratio for beta-blockers is not acceptable for this indication. However, beta-blockers remain very efficacious agents for the treatment of heart failure, certain types of arrhythmia, hypertropic obstructive cardiomyopathy, and in patients with prior myocardial infarction.     

Cardiovascular protection using beta-blockers: a critical review of the evidence.

For more than 3 decades, beta-blockers have been widely used in the treatment of hypertension and are still recommended as first-line agents by national and international guidelines. Recent meta-analyses indicate that, in patients with uncomplicated hypertension, compared with other antihypertensive agents, first-line therapy with beta-blockers was associated with an increased risk of stroke, especially in the elderly cohort with no benefit for the end points of all-cause mortality, cardiovascular morbidity, and mortality. In this review, we critically analyze the evidence supporting the use of beta-blockers in patients with hypertension and evaluate evidence for its role in other indications. The review of the currently available literature shows that in patients with uncomplicated hypertension, there is a paucity of data or absence of evidence to support use of beta-blockers as monotherapy or as first-line agents. Given the increased risk of stroke, their "pseudo-antihypertensive" efficacy (failure to lower central aortic pressure), lack of effect on regression of target end organ effects like left ventricular hypertrophy and endothelial dysfunction, and numerous adverse effects, the risk benefit ratio for beta-blockers is not acceptable for this indication. However, beta-blockers remain very efficacious agents for the treatment of heart failure, certain types of arrhythmia, hypertropic obstructive cardiomyopathy, and in patients with prior myocardial infarction.     

A study on the cardiodepressant action of a beta-blocking agent carteolol in heart-lung preparation of the dog

Direct cardiodepressant activities of three beta-blockers, carteolol, pindolol and propranolol, were estimated using heart-lung preparation of the dog. Beta-blocking doses of these drugs to inhibit the positive chronotropic effect of isoproterenol by 50% were 2.2 micrograms for carteolol, 4.0 micrograms for pindolol and 21 micrograms for propranolol. Cardiac performance of the preparation was not influenced by up to 1 mg of these three beta-blockers. After 10 mg of these drugs, the cardiac function curves were shifted rightward and downward indicating the heart failure. It was doubtful, however, that this result indicated the cardiodepressant action of beta-blockers, for the preparation showed spontaneous deterioration without beta-blocker treatment. The influences of these beta-blockers on the compromised heart-lung preparations showed essentially similar results. In conclusion, direct cardiodepressant activity of the beta-blocker, if any, was exerted with far more large doses than their beta-blocking doses. The implication of the results in clinical use of beta-blockers, especially in relation to heart failure, was discussed.     

Beta-blockers: the new standard of therapy for mild heart failure

Many physicians are reluctant to prescribe beta-blockers to patients with mild heart failure, especially when standard therapy (diuretics and an angiotensin-converting enzyme inhibitor, with or without digitalis glycosides) seems to be effective at relieving symptoms. However, current first-line medications for heart failure either ignore or incompletely inhibit adrenergic activation, one of the primary contributors to progressive left ventricular systolic dysfunction. Thus, even effective standard "triple" therapy does not safeguard the patient against further catastrophic deterioration of cardiac performance. Clinical trials have shown that the use of beta-blockers in addition to standard therapy improves left ventricular function, reduces hospitalizations, and-in the cases of bisoprolol, long-acting metoprolol, and carvedilol-improves survival in patients with chronic heart failure. In addition, carvedilol has been found to significantly slow disease progression even in mildly symptomatic patients. Though achieving beta-blockade in patients with heart failure requires extra effort by the clinician (appropriate patient selection, optimization of background therapy, initiating drug treatment at low doses, and titrating slowly with careful vigilance for early signs of clinical instability), the cost is small compared with the consequence of postponing adrenergic intervention. The educational objective of this article is to provide the primary care physician with a review of the current understanding of the pathophysiological characteristics underlying chronic systolic heart failure, the clinical benefits of administering beta-blockers during the early stages of heart failure, and the practical considerations of initiating therapy.     

How useful are beta-blockers in cardiovascular disease?

Recent studies have shown that beta-blockers in patients with hypertension is associated with an increased risk of cardiovascular events, in particular stroke, leading to headlines speculating the end of the beta-blocker era. The objective of this review is to critically examine the usefulness of beta-blockers in cardiovascular diseases. We reviewed the currently available evidence for the usefulness of beta-blockers in patients with hypertension and also assessed the efficacy of its use for other indications, like, chronic heart failure, stable angina, myocardial infarction, arrhythmias etc. The review of the currently available literature shows that for patients with uncomplicated hypertension, there is paucity of data or absence of evidence to support use of beta-blockers as monotherapy or as first line agent. Given the risk of stroke and numerous unacceptable adverse effects, the risk benefit ratio for beta-blockers is not acceptable for this indication. However, beta-blockers are very efficacious agents for the treatment of heart failure, certain types of arrhythmia, and post myocardial infarction. The various guideline committees should seriously reconsider their decision about their endorsement of beta-blockers as first line therapy for uncomplicated hypertension. However, this is applicable for hypertension and beta-blockers continue to be efficacious for other indications.     

Applying standard therapies to new targets: the use of ACE inhibitors and B-blockers for heart failure in adults with congenital heart disease

Increasingly, patients and clinicians are being confronted with congestive heart failure (CHF) as a late complication of congenital heart disease. However, medical management of heart failure in this patient group represents a challenge because of complex hemodynamics and a lack of evidence from large randomized controlled trials to guide therapy. This article will review the evidence of the use angiotensin converting enzyme inhibitors (ACEIs) and beta-blockers (BBs) in left heart failure, discuss the mechanisms of heart failure as they pertain to congenital heart disease and review the limited literature of the use of neurohormonal antagonists in congenital heart disease. Some recommendations for use of angiotensin converting enzyme inhibitors and beta-blockers in heart failure due various congenital heart lesions are offered. Well-designed clinical trials are urgently needed to extend the impressive reductions in morbidity and mortality achieved with neurohormonal blockade in left ventricular (LV) heart failure to adults with congenital heart disease.     

Diuretic window hypothesis in cirrhosis: Changing the point of view

Since the 1970s,non-selective beta-blockers(NSBB)have been used to prevent variceal upper bleeding in advanced cirrhotic patients.However,several recent studies have raised the doubt about the benefit of NSBB in end-stage cirrhotic patients.In fact,they suggested a detrimental effect in these patients that even reduced survival.All of these studies have been assembled to compose the“window therapy hypothesis”,in which NSBB would have traditional indication to be initiated to prevent variceal upper bleeding;however,treatment should be stopped(or not be initiated)in patients with end-stage cirrhosis.NSBB would reduce the cardiac reserve of these patients,worsening systemic perfusion and prognosis.However,it should be emphasized that these studies present important bias issues,and their results also suggested that diuretic treatment may also be behind the effects observed.In this opinion review,we changed the point of view from NSBB to diuretic treatment,based on a physiopathogenic approach of circulatory parameters of cirrhotic patients studied,and based on diuretic effect in blood pressure lowering and in other hypervolemic disease,as heart failure.We suggest a“diuretic window hypothesis”,composed by an open window in hypervolemic phase,an attention window when patient present in a normal plasma volume phase,and a closed window during the plasma hypovolemic phase.     

Early use of beta-blockers is associated with attenuation of serum C-reactive protein elevation and favorable short-term prognosis after acute myocardial infarction

BACKGROUND: We have reported that a marked elevation in serum C-reactive protein (CRP) level is a predictor for infarct expansion and cardiac rupture after AMI. Although beta-blockers prevent cardiac rupture after AMI, their effect on serum CRP elevation has not been determined. METHODS: We studied a total of 154 patients with first Q-wave AMI. Patients complicated by pump failure were excluded from this study. Eighty-two patients received beta-blocker treatment within 24 h of the onset of AMI, while 72 patients received no beta-blocker treatment. Peak serum creatine kinase (CK) and CRP levels were determined by serial measurements. RESULTS: There was no difference between the groups according to age, sex, coronary risk factors, pre-infarction angina, infarct site, prior use of cardiovascular drugs, use of revascularization therapy, and prevalence of multivessel disease. Beta-blocker treatment was associated with a lower peak CRP level (6.9 +/- 6.1 vs.10.8 +/- 9.3 mg/dl, p = 0.002), a shorter duration from the onset to the peak CRP level (2 +/- 1 vs. 3 +/- 2 days, p < 0.0001), a lower incidence of cardiac rupture (p = 0.03) and lower in-hospital cardiac mortality (p = 0.02), despite similar peak CK levels. CONCLUSION: The early use of beta-blockers is associated with decreased serum CRP level and a favorable clinical outcome after first Q-wave AMI, suggesting some beneficial effects of beta-blockers on infarct healing after AMI.     

beta-Blocker therapy in heart failure

Heart failure is an important public health problem and one for which morbidity and mortality remain high despite treatment with angiotensin converting enzyme (ACE) inhibitors. A large number of clinical trials examining the effects of beta-blockers in the treatment of heart failure have now been performed. Two large-scale clinical trials have recently confirmed significant survival benefits with these agents, with effects that are additive to those achieved with ACE inhibitor therapy. These trials have now established beta-blocker therapy as an important part of standard heart failure treatment. The clinical use of beta-blockers in patients with heart failure requires careful translation of the randomized controlled trials into everyday clinical practice. Patient selection is key to the safe use of beta-blockers. Patients who may be suitable for beta-blockade therapy include those with mild-moderate heart failure due to left ventricular systolic impairment, those who are receiving adequate dose of diuretics and ACE inhibitors and those whose clinical condition is stable at the time of initiation of the beta-blocker. Survival benefits have been demonstrated with bisoprolol, carvedilol and metoprolol. Whether different beta-blockers have important clinical differences with regard to clinical end-points is as yet uncertain. beta-Blockers should be initiated at low dose, with titration of dose over several weeks and careful clinical monitoring for potential adverse effects, such as hypotension or worsening congestion. This careful application of the clinical trials into clinical practice will allow the safe use of this effective treatment for patients with chronic heart failure.     

Causes and consequences of increased sympathetic activity in renal disease

Much evidence indicates increased sympathetic nervous activity (SNA) in renal disease. Renal ischemia is probably a primary event leading to increased SNA. Increased SNA often occurs in association with hypertension. However, the deleterious effect of increased SNA on the diseased kidney is not only caused by hypertension. Another characteristic of renal disease is unbalanced nitric oxide (NO) and angiotensin (Ang) activity. Increased SNA in renal disease may be sustained because a state of NO-Ang II unbalance is also present in the hypothalamus. Very few studies have directly compared the efficacy of adrenergic blockade with other renoprotective measures. Third-generation beta-blockers seem to have more protective effects than traditional beta-blockers, possibly via stimulation of NO release. Although it has been extensively documented that muscle SNA is increased in chronic renal failure, data on renal SNA and cardiac SNA are not available for these patients before end-stage renal disease. It is also unknown whether additional treatment with third-generation beta-blockers can delay the progression of renal injury and prevent cardiac injury in chronic renal failure more efficiently than conventional treatment with angiotensin-converting enzyme inhibitors only.     

Forecasting the impact of a clinical practice guideline for perioperative beta-blockers to reduce cardiovascular morbidity and mortality.

BACKGROUND: Beta-blockers reduce morbidity and mortality when administered to high-risk patients undergoing major noncardiac surgery, yet little is known about how often they are being prescribed. Clinical practice guidelines are tools that can be used to speed the translation of research into practice and may be one method to improve the use of beta-blockers. Before implementing any guideline, it is important to forecast its potential clinical and financial impact. METHODS: We conducted a retrospective cohort study, using administrative and medical record review data, of all adult patients undergoing major noncardiac surgery at Baystate Medical Center, Springfield, Mass, during a 1-month period in 1999. Patients with 2 or more cardiac risk factors or with documented coronary artery disease were classified as high risk and were considered eligible for treatment with a beta-blocker if they had no obvious contraindications to its use. We estimated the potential clinical benefit of treating eligible patients with a beta-blocker by extrapolating the treatment effect observed in a previously reported randomized clinical trial. RESULTS: Of 158 patients undergoing major noncardiac surgery, 67 (42.4%) seemed to be ideal candidates for treatment with perioperative beta-blockers. Of these 67 patients, 25 (37%) received a beta-blocker at some time perioperatively. During the course of a year, we estimate that between 560 and 801 patients who do not receive beta-blockers might benefit from treatment with these medications. Full use of beta-blockers among eligible patients at our institution could result in 62 to 89 fewer deaths each year at an overall cost of $33 661 to $40 210. CONCLUSIONS: There seems to be a large opportunity to improve the quality of care of patients undergoing major noncardiac surgery by increasing the use of beta-blockers in the perioperative period. A clinical practice guideline may be one method to achieve these goals at little cost.     

A rationale for the use of beta-blockers as standard treatment for heart failure

BACKGROUND: Cardiac sympathetic activation is one of the major and earlier changes observed in patients with heart failure. Its relation to the severity of the disease and its independent prognostic value show that it may directly contribute to the progression of heart failure. beta-Blockers are the most effective tool to counteract the untoward effects of sympathetic activation on the cardiovascular system. METHODS AND RESULTS: We reviewed the results of the placebo-controlled, double-blind studies about the effects of beta-blockers in patients with heart failure. These studies have involved almost 10,000 patients to date and have consistently shown that the long-term administration of beta-blockers is associated with a highly significant improvement in both left ventricular function and prognosis of the patients with heart failure. The evidence supporting the use of beta-blockers now equals or even surpasses that of angiotensin-converting enzyme inhibitors; therefore beta-blockers should be considered part of standard therapy. Issues that remain unclarified include the mechanisms through which beta-blockers may improve cardiac function and their tolerability and efficacy in specific groups of patients (such as those with asymptomatic left ventricular dysfunction, severe heart failure, the elderly, or those with left ventricular diastolic dysfunction). It is not currently clear whether the pharmacologic differences between individual beta-blockers are clinically relevant. If they are, the potential for even greater benefit with certain agents exists. It is hoped that these issues will be clarified by the results of ongoing multicenter trials.     

Current thinking regarding the use of diuretics in heart failure

The majority of therapies used in the contemporary management of chronic heart failure (CHF) have been rigorously evaluated by means of large-scale clinical trials to assess their beneficial effects on quality of life and prognosis. Such therapies include angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and cardiac resynchronization therapy (CRT). Diuretics are the most commonly prescribed class of drugs in CHF patients and in the short term they remain the most efficacious treatment for relief from fluid congestion. There is, however, scant evidence to suggest that they confer any long term benefit in terms of disease progression or prognosis to the CHF sufferer. Injudicious use of diuretics has been demonstrated to be potentially harmful and consideration should be paid to avoiding dietary salt indiscretion as well as the pharmacokinetic properties of individual diuretics to achieve optimal diuretic response. In this article, we explore the current insight into the use of diuretics in CHF.     

Sudden Cardiac Death in Dilated Cardiomyopathy – Therapeutic Options

BACKGROUND: Despite routine use of angiotensin-converting enzyme (ACE) inhibitors, beta-blockers and spironolactone in patients with heart failure due to dilated cardiomyopathy (DCM), these patients still have a considerable annual mortality rate of 5-10%. Sudden unexpected death accounts for up to 50% of all deaths and is most often due to rapid ventricular tachycardia or ventricular fibrillation and less often due to bradyarrhythmias or asystole. THERAPEUTIC OPTIONS: The use of beta-blockers in patients with heart failure has been shown to improve overall mortality considerably. This survival benefit has been demonstrated for bisoprolol, metoprolol and carvedilol. Therefore, one of these three beta-blocking agents should be administered routinely starting with low doses in all patients with New York Heart Association (NYHA) class II or III heart failure in addition to ACE inhibitors, unless there is a contraindication to beta-blocker use. In addition, NYHA class IV heart failure patients have been shown to benefit from carvedilol therapy, if tolerated. The conflicting results of GESICA and CHF-STAT studies do not support a strategy of "prophylactic" amiodarone therapy in patients with DCM in order to prevent sudden cardiac death. Despite growing evidence that implantable cardioverter defibrillator (ICD) therapy results in improved overall survival py preventing sudden cardiac death in patients at high risk for serious arrhythmic events, arrhythmia risk stratification with regard to prophylactic ICD implantation remains highly controversial in patients with DCM. CONCLUSION: This review describes potential arrhythmia mechanisms in DCM and summarizes the results of antiarrhythmic drug trials and of prophylactic ICD trials in patients with heart failure as well as our knowledge concerning arrhythmia risk stratification in patients with DCM.     

Use of carvedilol in daily practice

Studies conducted over recent years have definitively confirmed beta-blockers as the major treatment for heart failure. However, they are difficult to use and, to date, only carvedilol has been granted a Marketing Authorisation for this indication. The practical aspects of treatment with carvedilol in these patients are reviewed.