Beta-blocker Use in Decompensated Heart Failure

Transcription

1 Beta-blocker Use in Decompensated Heart Failure Rami Alharethi, MD, and Ray E. Hershberger, MD Corresponding author Ray E. Hershberger, MD Division of Cardiology, UHN-62, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA. Current Heart Failure Reports 2006, 3:75 80 Current Science Inc. ISSN Copyright 2006 by Current Science Inc. Despite the current advances in treatment, acute decompensated heart failure accounts for more than 1 million hospital admissions annually. Many of the patients hospitalized are already receiving long-term treatment with β-blockers. For patients who receive full dose β-blocker therapy and suffer acute decompensated heart failure, clinicians face two key questions: what to do, if anything, with the dosage of β-blocker and what is the best way to integrate inotropic and β-blocker therapies for patients who require inotropes. This article discusses these issues and reviews the available literature. Because these topics have received little systematic evaluation, we also present our clinical approaches to these problems. Introduction The use of neurohormonal antagonists such as angiotensin-converting enzyme inhibitors, aldosterone inhibitors, and β-adrenergic receptor blockers for the treatment of heart failure (HF) has led to decreased mortality and rehospitalization rates [1 4]. Despite these advances in treatment, more than 1 million patients are hospitalized annually in the United States with decompensated HF [5]. In-hospital mortality rates are reported at 4.7% to 13.9% [6,7] and mortality rates 60 days after discharge are reported at 8.5% [7]. Acute Decompensated HF The increase in left ventricular filling pressure activates the sympathetic nervous system, the renin-angiotensin-aldosterone system, and the release of nonosmotic vasopressin, which in turn affects renal hemodynamics and decreases sodium and water excretion [8]. This results in a wide range of clinical presentations for decompensated HF [9,10]. Although most patients present with progressive volume overload without acute pulmonary edema, some present with acute pulmonary edema and/ or low cardiac output [7,9]. Most patients are treated with intravenous diuretics and a few may require inotropic support or other vasoactive therapy [6,7,9]. With our current guidelines for the treatment of chronic HF [11 ], many patients with worsening heart failure are taking β-blockers. In the ADHERE [6] and the IMPACT-HF registry [7] 48% and 50%, respectively, of the patients admitted with decompensated HF were taking β-blockers. This presents a dilemma regarding the adjustment of β-blocker dosages, especially in view of the wide range of clinical presentations of worsening HF and the absence of guidelines for the treatment of acute decompensated HF. Insights into Beta-blocker Use in Acute Decompensated HF from Beta-blocker and Other Clinical Trials Long-term treatment with β-blockers in patients with HF decreases the circulating levels of vasoconstrictors such as norepinephrine, renin, endothelin, and proinflammatory cytokines [2,12 18] and may upregulate myocardial β-1-receptor density [19], which in turn may help restore the inotropic and chronotropic responsiveness of the myocardium. β-blocker use also decreases mortality and rehospitalization rates [1 4]. Despite these encouraging effects, approximately 10% of patients who were treated with metoprolol succinate (TOPROL-XL; AstraZeneca Pharmaceuticals LP, Wilmington, DE)in the MERIT-HF study [2] and 17% of patients who were treated with carvedilol in the COPERNICUS study [1] were hospitalized for worsening HF. Most of these patients were treated by an increase in the diuretic dose and adjustment of other vasoactive therapy. Few reports are available regarding possible benefits of β-blockers in acute decompensated HF. Aronson and Burger [20] reported from the PRECEDENT study that patients who were admitted with worsening HF and had been on β-blocker therapy had significantly fewer ventricular tachycardia episodes, substantially higher time

2 76 Treatment: Beta-blockers domain indices of the heart rate variability [21], better cardiac autonomic regulation, and lower plasma levels of norepinephrine and interleukin-6 (although the latter finding did not reach statistical significance) [22]. Beta-blocker Use in Patients with Acutely Decompensated HF not Requiring Inotropic Therapy We are unaware of studies that have systematically evaluated approaches to the adjustment of β-blocker dosages with acutely decompensated HF. We cite one expert opinion [23]. This is a concern because of the possibility that ongoing β-blocker administration might aggravate the acutely decompensated state. Although abundant evidence is available that the acute administration of a β-blocker in a patient with cardiomyopathy and compensated HF can cause an initial drop in left ventricular ejection fraction due to its acute negative inotropic effect [24], we have no published accounts of the hemodynamic effects of acute β-blocker withdrawal after long term use in decompensated HF. One might surmise that with the acute withdrawal of β-blockade cardiac function would improve, but it is also possible that other salutary effects (eg, heart rate control, anti-arrhythmic effects, beneficial metabolic and/or neurohormonal effects in the myocardium), perhaps especially important in an acutely decompensated patient, would be lost. This issue begs for critical, focused investigation. We do not adjust β-blocker dosages for the acutely volume overloaded outpatient with preserved blood pressure, good perfusion, and adequate renal function (the so-called warm and wet patient) [25 ] but attempt to quickly reestablish euvolemia over 24 to 72 hours. In otherwise stable outpatients this can be achieved with increased oral doses of loop diuretics, at times augmented by oral thiazide diuretics, or with outpatient doses of an intravenous loop diuretic. For patients who need to be hospitalized we use intravenous loop diuretics, either intermittently or with continuous infusion. Less stable outpatients or hospitalized patients on full dose β-blockade who are hypotensive with marginal perfusion or azotemia require more careful evaluation. If these patients demonstrate an initial response to intravenous diuretics and we anticipate a brief time period (eg, 1 3 days) to regain clinical stability, we usually will not consider a reduction in β-blocker dosage unless the patient s clinical response is not satisfactory. We typically reduce the β-blocker dose by 50% in patients on full dose β-blockade who are teetering toward full decompensation, that is, those who require hospitalization after failing intensive ambulatory HF management [26], those who are resistant to intravenous diuretics and/or demonstrate progressive renal dysfunction, or those who appear likely to require inotropic support. For continued deterioration we consider a further reduction to 25% of the original dose. We do not acutely stop β- blockers except for pharmacologic emergencies (eg, acute, severe, reversible airways disease) or for those committed to prolonged inotropic therapy. Patients who are hospitalized for acute noncardiac illness with decompensated HF (either before hospitalization or consequent to the medical complication) present additional complexities and need to be approached carefully. Again, we have not found any systematic studies that guide β-blocker dosing for these patients; we only provide our own clinical approach, which has not been formally evaluated. For these patients we try to avoid reducing the β-blocker dose except for an obvious indication (eg, acute reversible airways disease or status asmaticus that calls for corticosteroids or a symptomatic, new complete heart block requiring β-agonist infusion pending pacemaker implantation). We also avoid reducing the β-blocker for patients who are hemodynamically unstable as described in the previous paragraph. For patients who have decompensated HF as well as a major medical illness (such as pneumonia, urosepsis, acute cholecystitis, or gastrointestinal bleeding) complicating their HF management, we suggest that invasive hemodynamic monitoring with a pulmonary artery catheter should be strongly considered. This is particularly relevant for patients who require fluid resuscitation, multiple blood transfusions, pressors, or inotrope support. We suggest that β-blocker dose adjustments should be considered as outlined earlier. Continued Beta-blocker Use in Patients on Full Dose Beta-blockade who Require Inotropic Therapy Indications for inotropic therapy This issue is immensely complicated. Unfortunately, lack of systematic investigation provides almost no published reports upon which to base treatment recommendations. Of several thorny issues embedded within this topic, the most fundamental unresolved issue is the role and indication for the use of inotropes in patients with decompensated HF. Recent studies [6,27,28] have shown that inotropes should not be used in patients who do not require their use for the purpose of shortening the hospital stay or improving other outcomes. Based upon these and other studies, a great deal of concern has been expressed regarding inotropic therapy use under any circumstances [6,29]. Yet most clinicians know that some patients, especially those with advanced, decompensated life-threatening HF (who were not part of the aforementioned studies because of ethical concerns), are likely to die within minutes to hours without inotropic therapy to reestablish adequate blood pressure and perfusion to vital organs. These patients present a continuum of disease from advanced decompensated HF to those who are truly dependent upon inotropic therapy that is, those in

3 Beta-blocker Use in Decompensated Heart Failure Alharethi and Hershberger 77 whom inotrope withdrawal will lead to imminent demise [30,31,32 ]. We advise the use of inotropes only for patients who require their use. Short of systematic and standardized measures to define such a patient population, clinicians will need to continue to rely on their clinical judgment to define this population. In our experience the number of patients in this group are few, and we hospitalize these patients only after they have failed multiple stages of outpatient disease management tactics in our HF treatment program [26]. Choice of an inotropic drug In contrast to the indications for inotrope use, the choice of an inotropic drug for patients receiving metoprolol or carvedilol has received greater attention [33 35,36,37 ]. In patients not receiving β-blockers, the most commonly used inotropes are dobutamine, a β-1- and β-2-adrenergic receptor agonist that increases the production of intracellular cyclic adenosine monophosphate, and milrinone, a phosphodiesterase III (PDE III) inhibitor that decreases the degradation of cyclic adenosine monophosphate [38]. The use of these inotropes in patients receiving long term β-blockade was evaluated in several small studies. However, these patients did not have acute decompensated HF. Lowes et al. [34] showed that patients who are treated with carvedilol long term respond less favorably to dobutamine than to milrinone, requiring higher doses of dobutamine (15 20 µg/kg/min) to increase the cardiac index. Metra et al. [35] noted different responses to dobutamine in patients treated long term with the β-1-selective antagonist metoprolol versus the nonselective β-blocker carvedilol, which blocks both β-1- and β-2-adrenergic receptors. Patients receiving metoprolol showed no difference between baseline (before initiation of β-blockade) and after 9 to 12 months of metoprolol therapy for cardiac index (Fig. 1), heart rate, and systemic vascular resistance, and only a modest change in responsiveness in the decrease in the pulmonary artery and systemic arterial pressures. In contrast, substantial differences were observed in the dobutamine dose response curve after long-term carvedilol therapy. The improvement of cardiac index, the increase in systemic pressure, the decrease in systemic vascular resistance, and the decrease in pulmonary artery pressure were markedly blunted, and the heart rate responsiveness was blunted to a lesser degree. In particular, with carvedilol the pulmonary artery pressure actually increased with dobutamine, an effect that was suggested to result from the blockade of vascular β-2-receptors and other pharmacological properties of the drug. Notably, the use of either β-blocker did not affect the response to intravenous enoximone, an investigational PDE III inhibitor with properties similar to those of milrinone, and metoprolol even augmented the response to enoximone. The study by Bollano et al. [33] also showed differential responses to dobutamine for metoprolol or carvedilol. These results suggest that the choice of inotropic therapy in a patient receiving long-term β-blocker therapy may be important. Dobutamine appears to be nearly as effective in the presence of the β-1-antagonist metoprolol, but this is not the case with full dose carvedilol. However, the use of a PDE III inhibitor in patients treated long term with β-blockers appears to be as efficacious as it is in patients not receiving β- blockers [36,37 ]. Beta-blocker dosing for patients receiving inotropic therapy A third issue is the best approach to β-blocker dosing for a patient who has been treated long term with β-blockers once inotropic therapy has been initiated. Again, we have been unable to find a systematic evaluation in the literature examining β-blocker dosage once a patient has been started on inotropic therapy. (However, the use of PDE III inhibitors to facilitate the initiation and uptitration of β-blockers in patients with advanced HF has been examined [39 41]). We again offer only our own clinical experience: for patients treated with carvedilol we decrease the dose by 50% and decrease it by another 50% (to 25% of the original dose) within 2 or 3 days if the patient continues to require intravenous inotropic therapy. For patients treated with metoprolol, we take a less aggressive position on the urgency, frequency, and degree of dose reductions, particularly if the patient has responded clinically to inotropic therapy (eg, effective diuresis, improved perfusion, blood pressure, and renal function). We have not formally evaluated these aspects of our clinical experience. Well designed studies are needed to evaluate these issues. Conclusions β-blockers are currently standard therapy for HF, and the number of patients already on long-term β-blocker therapy who are admitted with decompensated HF will increase. These patients present a challenging dilemma to clinicians regarding the most appropriate strategy for β-blocker use, with the concern that some patients may further deteriorate after the withdrawal of β-blockers [42,43]. In the absence of guidelines for the treatment of acute decompensated HF and recognizing a wide range of the clinical presentations and causes of these decompensations, we recommend the following for adjusting β-blockers. For outpatients, we emphasize increased doses of diuretics to reestablish euvolemia as quickly as possible without a change in β-blocker dosing. For patients requiring hospitalization (having failed intensive ambulatory outpatient management), we propose considering the reduction of β-blocker doses if the patient is unresponsive to diuretic and/or vasodilator therapy.

4 78 Treatment: Beta-blockers Figure 1. Absolute changes (mean ± SEM) from baseline in cardiac index after dobutamine (A,C) or enoximone (B,D) administration, before (open symbols) and after (closed symbols) long-term β-blocker treatment with metoprolol (A,B) or carvedilol (C,D). Asterisks immediately above or below the standard error bars indicate significance of dose-specific differences from baseline. Asterisks between the dose-response curves indicate significance of dose-specific differences from baseline between, before, and after β-blocker therapy. P values at the bottom of each graph indicate differences between the slopes of the dose-response curves before and after metoprolol or carvedilol treatment. *P < 0.05; **P < 0.01; ***P < (Adapted from Metra et al. [35]; with permission.) For patients requiring inotropic therapy, we suggest considering the reduction of β-blocker doses as outlined earlier, particularly for patients receiving carvedilol. Although dobutamine appears nearly as efficacious in patients receiving metoprolol, the use of a PDE III inhibitor should be considered in patients on high dose carvedilol, particularly for those with significant cardiogenic shock and other signs of advanced decompensation. Clinical Trial Acronyms ADHERE Acute Decompensated Heart Failure National Registry; COPERNICUS Carvedilol Prospective Randomized Cumulative Survival; IMPACT-HF Initiation Management Pre-discharge Assessment of Carvedilol Heart Failure; MERIT-HF Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure; PRECEDENT Prospective Randomized Evaluation of Cardiac Ectopy with Dobutamine or Nesiritide Therapy.

5 Beta-blocker Use in Decompensated Heart Failure Alharethi and Hershberger 79 References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Packer M, Coats AJ, Fowler MB, et al.: Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001, 344: Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999, 353: Brophy JM, Joseph L, Rouleau JL: Beta-blockers in congestive heart failure. A Bayesian meta-analysis. Ann Intern Med 2001, 134: Packer M, Bristow MR, Cohn JN, et al.: The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996, 334: American Heart Association: Heart Disease and Stroke Statistics 2005 Update. 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