Pharmacotherapy for heart failure with left ventricular dysfunction: beyond angiotensin-converting enzyme inhibitors and beta-blockers

Angiotensin-converting enzyme (ACE) inhibitors and beta-blockers make up the cornerstone of therapy for patients with heart failure involving left ventricular dysfunction. These drug classes have been proven to decrease morbidity and mortality in patients with heart failure. Unfortunately, many patients remain symptomatic and experience disease progression despite taking both an ACE inhibitor and a beta-blocker. Others may be unable to tolerate one or both of these agents. In recent years, several other drug classes have been shown to provide additional morbidity and mortality benefits in patients with heart failure. These include angiotensin II receptor blockers (ARBs), aldosterone antagonists, and the combination of isosorbide dinitrate plus hydralazine. To select the most appropriate drug therapy for patients with heart failure, clinicians should consider results from clinical trials in specific patient populations, adverse-event profiles, tolerability, cost, and dosing regimens.     

Optimising the use of beta-blockers in older patients with heart failure

Heart failure is predominantly a disease of the older person with half of all patients with the condition aged >75 years. Diuretics are the first-line symptomatic treatment for heart failure. beta-blockers should be initiated on an outpatient basis once the patient is stable, euvolaemic (by means of a diuretic) and established on an angiotensin converting enzyme (ACE) inhibitor. Large trials have demonstrated the beneficial effects of the beta-blockers carvedilol, metoprolol and bisoprolol in patients with heart failure, most of whom were also receiving ACE inhibitors. However, the mean age of patients in these trials was generally 60 to 65 years, with very few patients aged >75 years being recruited. It is, thus, not immediately clear how to apply these trial results to older patients with heart failure. Subgroup analyses from these large beta-blocker heart failure trials suggest that older patients gain similar benefit from beta-blocker treatment to younger patients. The trials, however, give no guidance as to whether older patients should receive the same target dosage or titration regimen as younger patients. It is suggested that a less aggressive titration regimen may be more appropriate for older patients while still attempting to achieve the trial target dosages. Titration can be safely achieved on an outpatient basis. In particular, a period of observation in the clinic after initiation of treatment does not appear to be necessary. The survival benefit resulting from the use of a beta-blocker in patients with heart failure is modest (months rather than years). It is, thus important not to neglect the effects of treatment on quality of life. A proportion of patients experience adverse effects with a beta-blocker. For such patients a balance needs to be made between the adverse effects on quality of life and the likely extension of life from the use of a beta-blocker. For patients who can tolerate a beta-blocker, the available evidence suggests that it can improve quality of life. The evidence currently available does not support the use of an angiotensin II receptor blocker (ARB) in addition to an ACE inhibitor and beta-blocker. For patients unable to tolerate an ACE inhibitor or beta-blocker, the use of an ARB may confer some advantage.     

Current role of beta-adrenergic blockers in the treatment of chronic congestive heart failure.

Recent findings on the use of beta-adrenergic blockers in patients with congestive heart failure (CHF) are reviewed. CHF is a progressive, debilitating disease that afflicts 4.6 million patients in the United States. Treatment has traditionally consisted of a diuretic, an angiotensin-converting-enzyme (ACE) inhibitor, and digoxin. Despite advances in ACE-inhibitor therapy, the five-year mortality rate remains nearly 50%. Overstimulation of the sympathetic nervous system is believed to contribute to mortality. Beta-blockers have recently been added to the standard of care for patients with New York Heart Association functional class II or III heart failure. Four randomized, double-blind, placebo-controlled clinical trials were recently completed that addressed the benefits of beta-blockers in CHF. The overall mortality rate was reduced 65% by carvedilol, 34% by metoprolol, and 33% by bisoprolol; all these reductions were significant compared with placebo, and the trials were ended early. Bucindolol, however, did not have a significant effect on mortality. These drugs are hepatically metabolized and may require dosage adjustment in hepatically impaired patients. Decompensation of heart failure is another consideration; a beta-blocker should be added only for patients with stable CHF. Dosages must be slowly adjusted to targeted levels. Adverse effects do not differ significantly among beta-blockers. In addition to their effect on mortality, beta-blockers reduce CHF-related morbidity, such as all-cause hospitalization. Carvedilol, metoprolol, and bisoprolol decrease the mortality and morbidity associated with CHF and can be used with limited adverse effects. The choice among these agents does not affect clinical outcomes; bucindolol, however, has proven ineffective.     

The role of beta-blockers in the treatment of chronic heart failure

The introduction of beta-blockers in the treatment of cardiovascular diseases was a milestone and one of the most important contributions to clinical medicine in the 20th century. For many years, beta-blockers were considered contraindicated in patients with chronic heart failure owing to the negative inotropic action of these substances. With increasing evidence of neurohormonal activation in heart failure patients, there was a focus on the potential role of beta-blockers in the treatment of chronic heart failure. Several large randomized placebo- controlled clinical trials have shown favorable effects of beta-blockers on mortality and morbidity in heart failure patients with impaired systolic function. Beneficial effects in patients with preserved left ventricular systolic function are less clear. A reduction in heart rate is one of several mechanisms by which beta-blockers exert beneficial effects in chronic heart failure. In this article we present results from major clinical trials examining beta-blocker treatment in chronic heart failure patients and discuss heart rate as a therapeutic target in these patients.     

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.     

Metabolic profile of nebivolol, a beta-adrenoceptor antagonist with unique characteristics

beta-Adrenoceptor antagonists (beta-blockers) have historically been considered an effective and safe option for first-line treatment of hypertension. However, very recently, it has been proposed that beta-blockers should no longer be considered suitable for first-line therapy in the patient with uncomplicated hypertension because of unfavourable morbidity and mortality data. New evidence from recent clinical studies of nebivolol, a third-generation highly selective beta(1)-blocker with additional endothelial nitric oxide (NO)-mediated vasodilating activity, confirms previous findings that this drug differs from other beta-blockers. The combined mechanisms of beta-adrenoceptor antagonism and NO-mediated vasodilation may potentiate the blood pressure-lowering effect of this agent, and confer a broader favourable metabolic profile, which may be clinically relevant for hypertensive patients. The antioxidant properties of nebivolol and its neutral or even favourable effects on both carbohydrate and lipid metabolism are well documented. These properties consistently differentiate nebivolol from nonvasodilating beta-blockers such as atenolol, metoprolol or bisoprolol. Therapeutic indications for beta-blockers include a wide range of co-morbidities found in hypertensive patients, including ischaemic heart disease, tachyarrhythmias and heart failure. Given that the majority of hypertensive patients require more than one drug to control blood pressure, the multiple mechanisms of action and favourable metabolic profile of nebivolol could make it an alternative therapeutic option for hypertensive patients requiring beta-adrenoceptor therapy.     

Beta-adrenoceptor antagonists in the treatment of chronic heart failure

Beta-Adrenoceptor antagonists in the treatment of chronic heart failure The incidence of chronic heart failure is high in the developed countries (1-4/1000 per year). Treatment of chronic heart failure is a therapeutic challenge. A great improvement in mortality and morbidity of heart failure patients was achieved by the introduction of beta-adrenoceptor blockers in the treatment of chronic heart failure. However only 39% of heart failure patients are treated with a beta-adrenoceptor blocker in Europe. This review outlines pathophysiology of the beta-adrenergic system during human heart failure and its alterations induced by beta-adrenoceptor blockade. Based on the results of large clinical trials, experimental-pharmacological properties of beta-adrenoceptor blockers as well as the main aspects of its clinical use are discussed.     

Calcium antagonists in the treatment of hypertension in patients with ischaemic heart disease

Are lives saved or heart attacks prevented by antihypertensive therapy, as a result of blood pressure reduction alone, or because of other properties of the antihypertensive medications which are independent of blood pressure lowering? Long-acting calcium antagonists seem to be as effective as thiazide diuretics and angiotensin-converting enzyme (ACE) inhibitors in preventing all-cause mortality and stroke in patients with hypertension, but are probably inferior to ACE inhibitors in preventing coronary artery disease. In patients with symptomatic coronary artery disease, calcium antagonists are generally as effective as beta-blockers in relieving angina and improving exercise time-to-onset of angina or ischaemia. Unstable angina or myocardial infarction require treatment with a beta-blocker, with an ACE inhibitor added when necessary for blood pressure control or if there is significant left ventricular (LV) dysfunction. If beta-blockers are contraindicated and if there is no LV dysfunction, a non-dihydropyridine calcium antagonist can be substituted.     

Angiotensin converting enzyme inhibitors versus digoxin for the treatment of congestive heart failure.

Angiotensin converting enzyme (ACE) inhibition and digoxin may be used in the management of heart failure. Digoxin increases myocardial contractility in vitro, and has a modest but durable beneficial effect in congestive heart failure due to impaired left ventricular systolic function. ACE inhibitors have clear beneficial effects in all grades of heart failure and, in addition, modify the natural history and reduce mortality. Comparative studies in mild to moderate heart failure reveal a tendency towards greater benefits and tolerability of ACE inhibitors over digoxin. ACE inhibition is indicated, in conjunction with diuretic therapy, for all grades of heart failure. Digoxin is best reserved for patients with atrial fibrillation and a rapid ventricular response, and for those whose heart failure is not controlled with an ACE inhibitor plus a diuretic. In patients with heart failure following myocardial infarction, digoxin is of modest benefit. Digoxin should be administered slowly and carefully to avoid acute vasoconstriction and toxicity. Provisional data suggest ACE inhibitors are also beneficial in these patients. However, the results of clinical trials presently in progress are required to clarify their role following myocardial infarction.     

Angiotensin II receptor antagonists in chronic heart failure: where do they fit?

Heart failure is a common and disabling condition with a dismal prognosis. Inhibition of the renin-angiotensin-aldosterone system (RAAS) with angiotensin converting enzyme (ACE) inhibitors has proven to be a valuable therapeutic strategy in this condition, with well-proven morbidity and mortality benefits. Nonetheless, ACE inhibitors provide incomplete blockade of the RAAS and also inhibit the degradation of bradykinin. Although increased levels of bradykinin may have haemodynamic advantages by contributing to vasodilatation, they may also be largely responsible for some of the adverse effects of ACE inhibitors. Angiotensin II (Ang II) receptor antagonists offer more complete blockade of the RAAS without the potentiation of bradykinin, and it was therefore hoped that they would provide even greater benefits for patients with heart failure. So far, much of the initial promise of the Ang II receptor antagonists in heart failure has not been realised. There has been no conclusive demonstration of their superiority to ACE inhibitors in their effects on morbidity and mortality, and their equivalence to ACE inhibitors has not been proven. The Ang II receptor antagonists have, however, proven to be better tolerated than ACE inhibitors and they are therefore likely to be a reasonable alternative for those patients with heart failure who cannot tolerate ACE inhibition. Recent evidence has indicated that the Ang II type 1 receptor antagonist valsartan is of value when used in patients already receiving either an ACE inhibitor or a beta-blocker, but has also suggested that giving all three drugs together is deleterious. Further evidence about the value of Ang II receptor antagonists in heart failure may be provided by further studies, of which several are currently ongoing.     

Should beta-blockers be used for the treatment of pediatric patients with chronic heart failure?

In multiple clinical trials, beta-blockers have been shown to significantly improve morbidity and mortality in adults with chronic congestive heart failure, but there is little reported experience with their use in children. Heart failure involves activation of the adrenergic nervous system and other neurohumoral systems in order to maintain cardiovascular homeostasis. These compensatory mechanisms have been shown to cause myocardial damage with chronic activation, which has been hypothesized to be a major contributing factor to the clinical deterioration of adults with heart failure. Studies have demonstrated inhibition of this neurohumoral response and concomitant clinical benefits with beta-blockers. Consequently, beta-blockers have evolved to become an important part of comprehensive medical therapy for congestive heart failure in adults. Pediatric heart failure represents an entirely different spectrum of disease, caused more commonly by congenital heart disease than cardiomyopathy. Surgical palliation and correction are important components of pediatric heart failure therapy, and residual, postsurgical cardiac lesions can lead to chronic heart failure. Although neurohumoral activation in children is similar to that in adults with heart failure, there are important differences from adults in physiology and developmental changes that are especially observed in infants. Current published clinical experience with beta-blocker use in children with heart failure is limited to case series with relatively small numbers of patients. Nevertheless, these series show consistent symptomatic improvement, and improvement in ventricular systolic function in patients with cardiomyopathies and congenital heart disease, similar to findings in adults. Adverse effects were common and many patients in these studies had adverse outcomes (death and/or need for transplantation). One study has noted differences in pharmacokinetics in children compared with adults. However, a multicenter, randomized controlled trial to evaluate carvedilol in pediatric heart failure from systolic ventricular dysfunction is currently ongoing and should help to clarify the efficacy and tolerability of carvedilol in children.     

Angiotensin Antagonism in Patients with Heart Failure

Chronic heart failure (CHF) is a major cause of morbidity and mortality in western society. It is now widely accepted that the renin-angiotensin-aldosterone system (RAAS) and, in particular, angiotensin II (A-II) play a key role in the pathophysiology of CHF. Large-scale clinical trials have demonstrated that inhibitors of angiotensin-converting enzyme (ACE), the principal enzyme responsible for A-II production, improve symptoms and survival in patients with CHF. This enzyme is also responsible for the breakdown of the vasodilator hormone bradykinin. Administration of ACE inhibitors is associated with increased plasma bradykinin levels and this is thought to contribute to the vascular changes associated with ACE inhibitor therapy. However, RAAS inhibition with ACE inhibitors remains incomplete because ACE inhibitors do not block the non-ACE-mediated conversion of angiotensin I to A-II. Angiotensin receptor antagonists (angiotensin receptor blockers; ARBs) antagonize the action of A-II at the A-II type 1 (AT(1)) receptor, whilst allowing the potentially beneficial actions of A-II mediated via the A-II type 2 (AT(2)) receptor. Evidence that the clinical benefit demonstrated with ACE inhibitors in patients with CHF may extend to ARBs has only emerged recently. Combination therapy with both an ACE inhibitor and an ARB has a number of potential advantages and has been investigated in several large-scale clinical trials recently. In patients with CHF, first-line therapy should include an ACE inhibitor and a beta-adrenoceptor antagonist. The addition of an ARB provides symptomatic relief but has not been shown to improve survival. Where an ACE inhibitor is not tolerated, treatment with an ARB would seem an appropriate alternative. There is insufficient data to support the routine use of ARBs as first-line therapy in the management of CHF.     

Effects of ACE Inhibitors or ↓-Blockers in Patients Treated with the Fixed-Dose Combination of Isosorbide Dinitrate/Hydralazine in the African-American Heart Failure Trial

BACKGROUND: In the A-HeFT (African-American Heart Failure Trial), treatment of African-American patients with New York Heart Association (NYHA) class III/IV heart failure (HF) with fixed-dose combination (FDC) of isosorbide dinitrate/hydralazine (I/H) reduced mortality and morbidity and improved patient reported functional status compared with standard therapy alone. OBJECTIVE: To examine the benefit of FDC I/H in subgroups based on baseline drug therapy and to investigate whether ACE inhibitors and/or angiotensin receptor antagonists (angiotensin receptor blockers) [ARBs] or beta-adrenoceptor antagonists (beta-blockers) provided additional benefit in FDC I/H-treated African-American patients with HF. STUDY DESIGN: The A-HeFT was a double-blind, placebo-controlled study enrolling 1050 patients stabilized on optimal HF therapies and with NYHA class III/IV HF with systolic dysfunction conducted during the years 2001-4 with up to 18 months follow-up. The primary endpoint was a composite of mortality, first HF hospitalization, and improvement of quality of life at 6 months. Secondary endpoints included mortality, hospitalizations, and change in quality of life. Prospective Kaplan-Meier survival analyses were used for differences between FDC I/H and placebo groups and retrospective analyses were conducted within FDC I/H-treated and placebo groups. RESULTS: Subgroup analysis for mortality, event-free survival (death or first HF hospitalization), and HF hospitalization showed that FDC I/H, compared with placebo, was effective with or without ACE inhibitors or beta-blockers or other standard medications with all-point estimates favoring the FDC I/H group. Within the placebo-treated group, beta-blockers or ACE inhibitors and/or ARBs were efficacious in improving survival (hazard ratio [HR] 0.33; p<0.0001 for [beta]-blocker use and HR 0.39; p=0.01 for ACE inhibitor and/or ARB use). However, within the FDC I/H-treated group, use of beta-blockers, but not ACE inhibitors and/or ARBs, provided additional significant benefit for survival (HR 0.44; p=0.029 and HR 0.60; p=0.34, respectively), event-free survival (HR 0.62; p=0.034 and HR 0.72; p=0.29, respectively) and the composite score of death, HF hospitalization and change in quality of life (p=0.016 and p=0.13, respectively). CONCLUSION: Based on the analysis of baseline medication use in the A-HeFT, FDC I/H was superior to placebo with or without beta-blockers or ACE inhibitor. However, beta-blockers but not ACE inhibitors and/or ARBs provided additional significant benefit in African-Americans with HF treated with FDC I/H. These analyses are hypotheses generating and their confirmation in clinical trials needs to be considered.     

beta-blockers in heart failure: recently completed and ongoing clinical trials

beta-Blockers have emerged as an important therapy in patients with symptomatic left ventricular systolic dysfunction. Early studies demonstrated that beta-blocker therapy improved left ventricular function, reduced neurohumoral activity and reduced heart failure symptoms in these patients. While none of these small studies demonstrated a significant benefit in terms of overall survival, several meta-analyses suggested that beta-blocker therapy could, in fact, reduce mortality in patients with left ventricular systolic dysfunction and mild to moderate heart failure symptoms (New York Heart Association class II or III). Three large, recently completed, trials have confirmed the benefit of beta-blockade in these patients. This report reviews some of the initial clinical studies of beta-blockade in heart failure, examines the findings of the three large multicentre trials and other relevant research. Finally, ongoing trials designed to assess the relative efficacy of different beta-blockers and evaluate the utility of beta-blockade in specific subsets of patients with heart failure are discussed.     

The renin-angiotensin system: the role of inhibitors, blockers, and genetic polymorphisms in the treatment and prevention of heart failure

The renin-angiotensin system (RAS) plays an important role in the pathogenesis and worsening of heart failure (HF). Blocking this system with angiotensin converting enzyme (ACE) inhibitors in patients with HF and left ventricular dysfunction reduces mortality and morbidity and these drugs are currently recommended as standard therapy. A more recently developed class of drug, angiotensin receptor blockers (ARBs) block the RAS at the receptor level, and may therefore provide more complete blockade. ARBs, either singly or in combination with ACE inhibitors, are currently being compared to either ACE inhibitor therapy alone or to placebo in randomized trials of patients with or at high risk of developing HF. With respect to large trials published to date directly comparing ARB versus ACE inhibitor therapy, neither the Losartan Heart Failure Survival Study (ELITE II) nor the Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) found differences in mortality or morbidity between the treatment groups. As regards combination ARB/ACE inhibitor therapy versus ACE inhibitor therapy alone, one completed study, the Valsartan Heart Failure Trial (Val-HeFT), found no differences in mortality but a decrease in HF-related hospitalizations in the combined therapy group. Four additional long-term trials (VALIANT, CHARM, ONTARGET, and TRANSCEND) should complete the totality of evidence regarding the role of ARBs in the treatment of HF. Since genetic polymorphisms affecting drug metabolizing enzymes or drug receptors are known to influence responses to drugs, exploration of these effects on treatment responses to ARBs and ACE inhibitors may provide for more targeted treatment of HF.     

Enalapril. A reappraisal of its pharmacology and therapeutic use in hypertension.

Enalapril, an angiotensin converting enzyme (ACE) inhibitor usually administered orally once daily, decreases blood pressure by lowering peripheral vascular resistance without increasing heart rate or output. It is effective in lowering blood pressure in all grades of essential and renovascular hypertension. Patients not responding adequately to enalapril monotherapy usually respond with the addition of a thiazide diuretic (or a calcium antagonist or beta-blocker), and rarely require a third antihypertensive agent. Enalapril is at least as effective as other established and newer ACE inhibitors, and members of other antihypertensive drug classes including diuretics, beta-blockers, calcium antagonists and alpha-blockers, but therapy with enalapril may be less frequently limited by serious adverse effects or treatment contraindications than with other drug classes. The most frequent adverse effect limiting all ACE inhibitor therapy in clinical practice is cough. This favourable profile of efficacy and tolerability, and the substantial weight of clinical experience, explain the increasing acceptance of enalapril as a major antihypertensive treatment and supports its use as logical first-line therapeutic option.     

Perspectives of I(f) inhibition by ivabradine in cardiology

High heart rates predict cardiovascular morbidity and mortality in the healthy population, in hypertensive patients, and in those with coronary heart disease (CHD) or heart failure. I(f) channel inhibition with ivabradine is an effective approach to reduce heart rate pharmacologically, with the prospect of preventing complications. The antianginal effects of heart rate-lowering with ivabradine have been shown to be similar to those with beta-adrenoceptor antagonists (beta-blockers) in patients with CHD. The BEAUTIfUL and SHIfT trials will provide evidence on whether I(f) channel inhibition with ivabradine is able to reduce mortality and morbidity in patients with CHD with impaired left ventricular function and heart failure. Future perspectives for additional study are potential roles of ivabradine in the treatment of hypertension and atherosclerosis, and their complications. Further clinical and mechanistic studies to clarify the pathophysiological background are needed to fully define the role of heart rate reduction in the broad spectrum of cardiovascular interventions.     

Treatment of heart failure in patients with diabetes mellitus

Patients with diabetes mellitus have an increased morbidity and mortality from cardiovascular disease. Both coronary artery disease and congestive heart failure (CHF) are largely responsible for the increased cardiovascular adverse events in patients with diabetes. This review discusses the pathophysiology of CHF, the mechanisms of left ventricular (LV) dysfunction and the neurohormonal mechanisms involved in both LV dysfunction and CHF. Diabetes with and without hypertension is an important cause of LV dysfunction and CHF. Diabetes may be responsible for the metabolic and ultrastructural causes of LV dysfunction, while hypertension may be responsible for the marked fibrotic changes that are found. Experimental induction of diabetes in animals has shed light on the biochemical and ultrastructural changes seen. The role of insulin to reverse both metabolic and structural changes is reviewed both from experimental data and with the limited amount of clinical data available. The therapy of CHF in patients with diabetes is similar to that of patients without diabetes, with therapy directed toward the use of beta-blockers and angiotensin converting enzyme (ACE) inhibitors. As the morbidity and mortality are higher in patients with diabetes, several studies have pointed out the importance of this subgroup where the opportunity to make a significant clinical impact exists. A significant opportunity exists to reduce morbidity and mortality with beta-blockers and ACE inhibitors when ischaemia and CHF are both present. However, studies in patients diabetes have been limited to post hoc subgroup analyses and rarely as predefined subgroups. Clinical trials involving patients with diabetes with and without hypertension and LV dysfunction are clearly needed in the future to adequately address the needs of this high risk subgroup.     

Tolerability of beta-blockers in outpatients with refractory heart failure who were receiving continuous milrinone

STUDY OBJECTIVE: To investigate the dosing, tolerability, and outcomes associated with the use of concomitant beta-blockers and inotropic therapy in patients with refractory heart failure during the first 6 months of their therapy. DESIGN: Retrospective review. SETTING: University-based, tertiary care heart failure and transplant center. PATIENTS: Sixteen inotrope-dependent outpatients with end-stage refractory heart failure who were receiving continuous intravenous milrinone. Of these patients, 12 also received an oral beta-blocker; the remaining four patients who did not receive beta-blockers served as the comparator group. MEASUREMENTS AND MAIN RESULTS: For each patient, the initial and final study drug doses of continuous intravenous milrinone and oral beta-blocker treatment, when applicable, were recorded over the 6-month period. Mean heart rate, blood pressure, ejection fraction, and oxygen consumption were measured, and 95% confidence intervals were calculated. Serum sodium and creatinine concentrations, as well as the creatinine clearance, were measured. In the 12 patients who received concomitant milrinone and beta-blockers, the mean baseline ejection fraction was approximately 18%, and they received milrinone for 18.6 weeks. Seven patients received carvedilol for 16.1 weeks, and five received metoprolol tartrate for 17.6 weeks. Dosages of the beta-blockers were titrated. Final daily doses were carvedilol 42.8 mg (95% confidence interval 20.3-65.4) and metoprolol 42.5 mg (95% confidence interval 28.0-57.2). Patients continued to receive other standard oral drug therapy for heart failure. One patient discontinued metoprolol and one discontinued carvedilol because of hypotension and/or worsening heart failure. Cardiac adverse events in the concomitant milrinone plus beta-blocker group were heart failure requiring hospitalization in 10 patients and ventricular arrhythmias in one. CONCLUSION: Inotrope-dependent patients with refractory end-stage heart failure tolerated continuous intravenous milrinone plus beta-blockers in addition to diuretics and vasodilators for the 6-month observation period. Beta-blocker dosages were titrated, and three patients achieved the target beta-blocker dosage established for stage A-C heart failure. Additional studies are needed to determine the optimal selection and dosing of drug combinations in this population.     

Heart failure drugs: what's new?

Heart failure is common, causes major disability and often shortens life. In the past, drugs such as diuretics and digoxin formed the mainstay of treatment. More recently, angiotensin-converting enzyme (ACE) inhibitors have become a standard part of management. New developments in the drug treatment of heart failure include the possible addition of beta-blockers or spironolactone to diuretic and ACE inhibitor therapy. Also, angiotensin-II receptor antagonists have been proposed both as an alternative and as additional therapy to ACE inhibitors. Here, we discuss the place of these new approaches in the treatment of patients with heart failure due to left ventricular dysfunction.