Chronic Heart Failure Current Evidence,.2

REVIEW ARTICLE
Am J Cardiovasc Drugs 2011; 11 (3): 153-171 1175-3277/11/0003-0153/$49.95/0
2011 Adis Data Information BV. All rights reserved.
Chronic Heart Failure

Current Evidence, Challenges to Therapy, and Future Directions
Ryan P. Morrissey, Lawrence Czer and Prediman K. Shah
Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 2. Systolic Heart Failure (HF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 2.1 Renin-Angiotensin Inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 2.1.1 ACE Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 2.1.2 Angiotensin II Type 1 Receptor Antagonists (Angiotensin Receptor Blockers [ARBs]) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 2.2 2.3 2.4 2.1.3 Direct Renin Inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 Sympathetic Blockade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 2.2.1 b-Adrenoceptor Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 Aldosterone Blockade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 Further Afterload Reduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 2.4.1 Hydralazine and Nitrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 2.4.2 Dihydropyridine Calcium Channel Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 2.5 Managing Preload . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 2.5.1 Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 2.5.2 Ultrafiltration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 2.6 Long-Term Inotrope Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 2.6.1 Digoxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 2.6.2 Continuous Inotrope Infusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 2.6.3 Oral Inotropes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 2.7 2.8 Exogenous Erythropoietin and Iron Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 Hormone Replacement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 2.8.1 Thyroid Hormone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 2.8.2 Growth Hormone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 2.8.3 Testosterone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 2.9 3. 4. 5. 6. 7. 8. 9. 10. Vasopressin Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 164 165 165 166 166 166 167 167 167 2.10 Future Therapies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diastolic HF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dietary Supplements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drugs to Avoid in HF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Special Circumstances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Future of Ambulatory Management of HF. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abstract
Heart failure (HF) is a complex syndrome characterized by the inability of the heart to maintain a normal cardiac output without elevated intracardiac filling pressures, resulting in signs of pulmonary and peripheral edema and symptoms of dyspnea and fatigue. Central to the management of HF is a multifaceted
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pharmacological intervention to abate the harmful counter-regulatory effects of neurohormonal activation and avid salt and water retention. Whereas up to 40 years ago HF was managed with diuretics and leaf of digitalis, the cornerstones of therapy for HF patients with systolic dysfunction now include ACE inhibitors or angiotensin II type 1 receptor antagonists (angiotensin receptor blockers), b-adrenoceptor antagonists (b-blockers), and aldosterone antagonists, which have significantly improved survival. However, with the increasing number of beneficial therapies, there are challenges to implementing all of them. Specific cardiomyopathies also merit specific considerations with respect to treatment, and unfortunately there is no therapy for HF with preserved left ventricular ejection fraction that has been shown to improve survival. Although mortality has improved in HF, the biggest challenge to treatment lies in addressing the morbidity of this disease, which is now the most common reason for hospital admission in our aged population. As such, there are many therapies that may serve to improve the quality of life of HF patients. Future HF treatment regimens may include direct cellular therapy via hormone and cytokine signaling or cardiac regeneration through growth factors or cell therapy.
1. Introduction Heart failure (HF) is a syndrome of cardiac dysfunction whereby the heart cannot meet the demands of the body at normal filling pressures.[1] Short-term compensatory neurohumoral and hemodynamic changes result in long-term deleterious effects characterized by increased blood volume, increased systemic and pulmonary vascular resistance, and ultimately decreased contractility, all of which results in fluid retention, dyspnea, and fatigue. This cardiac dysfunction can be due to systolic and/or diastolic dysfunction, and signs and symptoms can be primarily left-sided, right-sided, or both. HF can also be divided into HF with low left ventricular ejection fraction (LVEF) and HF with preserved LVEF. Cardiac dysfunction can result from and perpetuate a slew of compensatory mechanisms such as cardiomyocyte hypertrophy, fibrosis and apoptosis, ventricular chamber dilatation, tachycardia, peripheral vasoconstriction, and changes in sodium/water homeostasis and renal glomerular filtration. Systemically, HF is associated with increased circulating levels of catecholamines, angiotensin II, tumor necrosis factor (TNF)-a, and other neuroendocrine hormones and inflammatory cytokines. Despite the progressive nature of HF, current pharmaceutical and device therapies can ameliorate and even reverse cardiac remodeling and other compensatory physiological changes, improving survival, lessening symptoms, and decreasing repeat hospitalizations. After the age of 40 years, one in five people in the US will develop HF.[2] Risk factors for the development of HF include hypertension, diabetes mellitus, and coronary artery disease (CAD)/myocardial infarction (MI). Indeed, current American Heart Association/American College of Cardiology (AHA/ACC) guidelines label patients at-risk for developing HF as having stage A HF (vs asymptomatic patients being stage B, and symptomatic patients being stage C through D).[3] Of course,
some etiologies of chronic HF result from an infiltrative process such as sarcoidosis, amyloidosis, or iron-overload, while others are genetically determined, e.g. Fabrys, muscular dystrophy, and left ventricular (LV) non-compaction. Previous acute cardiomyopathies such as myocarditis and peripartum cardiomyopathy can also progress to chronic HF (CHF). Lastly, not all patients with systolic or diastolic dysfunction exhibit signs or have symptoms of HF. The following is a review of the evidence behind current and potential therapies for the management of chronic, stable HF, which will be broken down into systolic HF, diastolic HF, and special considerations for distinct chronic, stable cardiomyopathies. We will address challenges to the pharmacological treatment of HF from maximizing combination therapy while minimizing side effects to improving quality of life. Not discussed in this article are the importance of implantable cardioverter defibrillators (ICDs) in the prevention of sudden cardiac death[4] and cardiac resynchronization devices in improving HF symptoms.[5] Aside from orthotopic heart transplantation, the most promising new therapy for advanced HF is mechanical support, in particular with respect to improvement in functional class.[6,7] 2. Systolic Heart Failure (HF) Much of the treatment of stable, systolic HF is aimed at impeding the bodys own regulatory mechanisms to manage a state of hypoperfusion, namely the renin-angiotensin-aldosterone and sympathetic nervous systems. Physiologically, the treatment of HF is judicious management of preload, i.e. central venous pressure, while minimizing afterload, i.e. arterial hypertension, without incurring undue hypotension and renal dysfunction. Treatment of the failing heart also involves some
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degree of reversal of maladaptive cardiac remodeling and prevention of life-threatening arrhythmias.

2.1 Renin-Angiotensin Inhibition
2.1.1 ACE Inhibitors
The importance of reducing afterload, i.e. improving forward failure in the failing heart, was recognized in the 1960s with improved hemodynamics seen with the use of hydralazine, nitroprusside, nitrates, and a-adrenoceptor antagonists (a-blockers).[8] However, survival benefits would not be documented until 1986 with the use of hydralazine and isosorbide dinitrate.[9] The use of angiotensin-converting enzyme inhibitors (ACEIs) has been an accepted standard for the treatment of HF of all stages since the 1990s. In 1983, captopril was
Table I. Definitions of trial acronyms used in this article A-HeFT ATLAS CARMEN CHAMPION CHARM CHARM-Added CIBIS-II COMET CONSENSUS COPERNICUS DIG ELITE-II EMOTE EMPHASIS-HF EPHESUS ESSENTIAL GISSI Hy-C I-PRESERVE MERIT-HF OPTIMAAL PRAISE RAAM-DHF RALES SOLVD TOPCAT V-HeFT Val-HeFT VALIANT
shown to improve HF symptoms versus placebo in a small study (n = 92).[10] In 1987, the CONSENSUS (see table I for full names of trial acronyms used in this review) study was published in which 253 patients with New York Heart Association (NYHA) class IV HF were randomized to placebo versus enalapril 2.540 mg/day; the result was a 40% relative risk reduction (44% vs 26%) in all-cause mortality with enalapril at 6 months. In addition, there was improvement in functional class and LV chamber size.[11] By 1995, several much larger randomized clinical trials had demonstrated mortality benefits in class II-III HF[12] and class I HF[13] with enalapril, and in patients with ischemic cardiomyopathy due to recent MI.[14,15] In SOLVD, enalapril 2.520 mg/day versus placebo significantly reduced all-cause mortality (primary endpoint) in patients with NYHA class II-III HF (39.7% vs 35.2%, relative risk
African-American Heart Failure Trial Assessment of Treatment with Lisinopril and Survival Carvedilol and ACE-Inhibitor Remodeling Mild Heart Failure Evaluation CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Patients Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity Candesartan in Heart Failure-Added Cardiac Insufficiency Bisoprolol Study II Carvedilol Or Metoprolol European Trial Cooperative North Scandinavian Enalapril Survival Study Carvedilol Prospective Randomized Cumulative Survival Digitalis Investigation Group Losartan Heart Failure Survival Study Oral Enoximone in Intravenous Inotrope-Dependent Subjects Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure Eplerenone PostAcute Myocardial Infarction Heart Failure Efficacy and Survival Study The Studies of Oral Enoximone Therapy in Advanced HF Gruppo Italiano per lo Studio della Sopravvivenza nell_Infarto miocardico Hydralazine Captopril Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan Prospective Randomized Amlodipine Survival Evaluation Study Randomized Trial of Aldosterone Antagonism in Diastolic Heart Failure Randomized Aldactone Evaluation Study Studies of Left Ventricular Dysfunction Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Vasodilator-Heart Failure Trial Valsartan Heart Failure Trial Valsartan in Acute Myocardial Infarction
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reduction of 16%); there was also a 16% reduction in hospitalizations.[12] In addition, enalapril 20 mg/day was shown to be superior to the combination vasodilator therapy of hydralazine 300 mg/day and isosorbide dinitrate 160 mg/day, with a relative risk reduction of all-cause mortality of 28% at 2 years (over 90% were NYHA class II-III) in V-HeFT II.[16] LVEF increased for both groups, and although it was reported to be significantly different at 13 weeks, peaked at 1 year and began to converge at 2 years due to a decline in LVEF in the enalapril group. Peak oxygen consumption actually increased in the hydralazine/ isosorbide arm, while it decreased in the enalapril arm after the first year. Given that enalapril had a significantly greater effect on allcause mortality than isosorbide-hydralazine and prazosin in V-HeFT I, it stands to reason that a significant portion of this benefit was from reversal of cardiac remodeling mediated by angiotensin and not simply because of afterload reduction. In fact, in the Hy-C trial in which randomly assigned captopril or hydralazine were titrated to identical hemodynamic goals (pulmonary capillary wedge pressure <15 mmHg and systemic vascular resistance <1200 dynes/s/cm2), despite identical hemodynamic responses, there was a significant survival benefit in favor of captopril (81% vs 51% at 1 year) [nitrates could be used in either arm to achieve hemodynamic goals].[17] In mice, angiotensin II receptor activation causes cardiomyocyte hypertrophy independent of BP, with increasing stimulation resulting in interstitial fibrosis, LV chamber dilatation, and reduced LVEF;[18] however, in rats receiving infusions of angiotensin II, hydralazine ameliorated inflammatory infiltrate and myocardial fibrosis in the setting of reduced BP.[19] Probably more important is the direct activation of cardiac fibroblasts by angiotensin II, which have a higher density of receptors and are significantly upregulated in the failing heart.[20] Lastly, derivatives of angiotensin other than angiotensin II, e.g. angiotensin I-7 and I-9, may have greater effects on cardiomyocyte hypertrophy.[21] One of the challenges of HF therapy is achieving the targetdose of a medication. For ACEIs, pushing to these target doses often means risking hypotension, worsening renal function, and hyperkalemia. In the ATLAS trial, patients were randomized to either low- (2.55 mg/day) or high- (32.535 mg/day) dose lisinopril.[22] There was a significant reduction in hospitalizations (RR of 24%, p = 0.002), but a non-significant decrease in mortality (RR of 8%, p = 0.128) in the high-dose arm. Mechanistically, in addition to effects on BP, high- versus lowdose enalapril was associated with a significant decrease in IL-6, a marker of inflammation.[23] Although there was a dosedependent reduction in circulating neurohormone levels, the
incidence of mortality and repeat hospitalizations was not found to be dose dependent in one meta-analysis.[24] Thus, without further evidence, it is reasonable to titrate afterload reduction as much as possible to at least the target dose; however, if patients develop symptomatic hypotension or worsening kidney function, the medication should be kept at the dose not associated with such adverse reactions, i.e. having a patient on even a very low-dose ACEI is better than no ACEI. ACEIs are often discontinued due to intolerance. A mild (<30%) increase in serum creatinine is to be expected with ACEIs. Indeed, renal dysfunction should not immediately prohibit the use of an ACEI. In an analysis of 20 902 Medicare beneficiaries aged 65 years admitted with a diagnosis of systolic dysfunction (LVEF <40%) and started on an ACEI prior to discharge, there was a significantly greater reduction in mortality at 1 year in patients with a serum creatinine >3 mg/dL than in those with serum creatinine 3 mg/dL (37% vs 16%).[25] The most common side effect prompting discontinuation is the ACEI-induced cough, which occurs in up to 35% of patients in some series.[26] However, the clinician must be discerning in diagnosing an ACEI-associated cough that is not wheeze or cough from pulmonary congestion from HF. A potential advantage of ACEIs over ARBs, at least in vitro, is the increased bradykinin from decreased angiotensin II, which causes the ACEI cough; bradykinin induces the synthesis of nitric oxide, which has cardioprotective effects.[27] In addition, angiotensinII has direct effects on myocardial and vascular tissue independent of its effect on the kidneys.
2.1.2 Angiotensin II Type 1 Receptor Antagonists (Angiotensin Receptor Blockers [ARBs])
ARBs have not been shown to be superior to ACEIs, and with one exception (CHARM-Added), the combination of an ACEI and an ARB has not been shown to be superior to an ACEI alone. In the superiority study ELITE-II, there was no significant difference in the primary outcome of all-cause mortality (11.7% vs 10.4%) in patients aged >60 years with NYHA II-IV HF and a LVEF <40% randomized to losartan 50 mg/day or captopril 50 mg three times daily.[28] Similarly, in the OPTIMAAL study (patients aged >50 years with HF and recent acute MI), there was a non-significant decrease in mortality with captopril over losartan.[29] The CHARM trial[30] comprised three different trials with patient populations: CHARM-Alternative (candesartan in patients intolerant to ACEI),[31] CHARM-Added (candesartan in patients receiving ACEI),[32] and CHARM-Preserved (candesartan in patients with preserved LV function).[33] In CHARM, 7601 patients were randomized to candesartan 32 mg/day versus placebo.
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Although each component trial will be discussed separately, overall there was a non-significant reduction in all-cause mortality (primary endpoint) in favor of treatment, although there was a statistically significant reduction in cardiovascular (CV) death (18% vs 20%).[30] In Val-HeFT, 5010 patients with NYHA II-IV HF symptoms and an LVEF <40% (>90% already receiving an ACEI) were randomized to valsartan or placebo.[34] Overall, there was no difference in mortality (valsartan was not superior to captopril alone). In a subgroup analysis, in those patients not receiving an ACEI or a b-blocker, mortality was significantly reduced with valsartan (although the relative risk [RR] confidence interval [CI] included the null). Interestingly, however, in those patients receiving both, valsartan was associated with an increase in mortality (with a CI not including the null). In the non-inferiority trial VALIANT, patients with recent MI and LVEF <35% by echocardiogram/angiography or 40% by radionucleotide ventriculography were randomized to valsartan, valsartan plus captopril, or captopril at a ratio of 1 : 1 : 1.[35] There was no significant difference in all-cause mortality between the three arms as well as no difference in secondary endpoints of cardiovascular morbidity and mortality. There was a significant difference in adherence in the combination arm compared with each monotherapy arm; interestingly, there were no differences in mean follow-up BPs. Adverse events including hypotension and renal dysfunction were significantly higher in both the combination arm and the valsartan arm compared with the captopril arm. In the CHARM-Added trial, 2548 patients with NYHA II-IV HF and LVEF <40% (99.9% were receiving an ACEI) were randomized to candesartan 32 mg/day or placebo. The investigators reported a statistically significant reduction in the primary combined endpoint of CV death or HF hospitalization of 15% at a mean follow-up of 41 months in favor of candesartan.[32] In a meta-analysis in patients with symptomatic LV dysfunction, combination ACEI and ARB therapy was associated with significant increases in medication discontinuation (relative risk [RR] 1.38 [95% CI 1.22, 1.55]), symptomatic hypotension (RR 1.50 [95% CI 1.09, 2.07]), worsening renal function (2.17 [95% CI 1.59,2.97]), and hyperkalemia (RR 4.87 [95% CI 2.39, 9.94]).[36] This risk was confirmed in a subsequent meta-analysis.[37] In patients with an intolerance to ACEIs (72% cough, 13% hypotension, 12% renal dysfunction, 2% angioedema), use of candesartan resulted in a significant improvement in cardiovascular death or hospitalization (covariate adjusted hazard ratio [HR] 0.70 [95% CI 0.60, 0.81], p < 0.0001), as well as for cardiovascular death alone (adjusted HR 0.80 [95% CI 0.66, 0.97], p = 0.02) in the CHARM-Alternative trial.[31] The relative
lesser effect on mortality with candesartan versus placebo compared with enalapril versus placebo in the ACEI trials may be due to the fact that patients were more likely to be receiving other HF therapy at this point such as b-blockers (55% at baseline, 6476% at final visit) and spironolactone. The discontinuation of candesartan during the trial due to intolerance was greater than for placebo, but still small (hypotension 3.7%, renal dysfunction 6%, and angioedema 0.1%). The efficacy of valsartan over placebo was shown in a subgroup of patients in Val-HeFT not concurrently receiving an ACEI (all-cause mortality 17.3% vs 27.1%, p = 0.017).[38] ACEIs and ARBs can be titrated rather quickly to achieve target BP and target doses (every 6 hours to every day depending on the specific half-life), making them an ideal medication to initiate treatment in patients with newly diagnosed HF. With both ACEIs and ARBs, one must be mindful of serum potassium concentration and check levels ideally on day 3 and day 7 as well as monthly for the first 3 months. Clinicians should also be cautious with the addition of aldosterone antagonists with respect to hyperkalemia, particularly in patients with renal insufficiency. With respect to ACEI plus ARB combination therapy, the evidence for the use of an ACEI versus an ARB as well as the combination of an ACEI and an ARB not only in HF[36,37] but also in other CV disease states or high-risk patients,[39] shows that ACEIs and ARBs are equivalent in terms of outcomes, and that the combination may actually lead to worse outcomes. A recent meta-analysis of 18 061 patients found that combination of an ACEI and an ARB reduced HF admissions, but had no effect on total hospitalizations or mortality compared with an ACEI alone.[40]
2.1.3 Direct Renin Inhibitors
A new class of agents is the direct renin inhibitors (DRIs). The first DRI was remikiren, which was never brought to market. Aliskiren has been studied mainly as an antihypertensive agent, but was evaluated for safety in patients with HF. 302 patients with class II-IV HF, hypertension, and plasma natriuretic peptide level >100 pg/mL were randomized to aliskiren 150 mg/day versus placebo with a resultant decrease in natriuretic peptide levels by 21% on treatment versus an increase of 35% in the placebo group.[41] Not surprisingly, 62% of patients were NYHA class II; the mean systolic BP was 129 17.4 mmHg. Nearly 99% of patients were receiving an ACEI or an ARB, and >30% were also receiving an aldosterone antagonist.[41] Hypotension was twice as likely in patients treated with aliskiren (3.2% vs 1.4%), and the incidence of hyperkalemia was higher in treated patients than in placebo recipients (6.4% vs 4.8%). Assessment of symptoms and echocardiographic parameters were
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not different, although the study was not powered to detect these differences.[41] No trials have demonstrated improvement in hard clinical endpoints with DRIs in patients with HF. Given the risk of hyperkalemia and the proven efficacy of ACEIs and ARBs, the only current role for aliskiren would be as an adjunctive treatment for resistant hypertension, or possibly in patients with a history of angioedema with ACEIs and/or ARBs.
2.2 Sympathetic Blockade
2.2.1 b-Adrenoceptor Antagonists
The beneficial effect of b-blockade in HF was first suggested in 1975 when seven patients experienced improvement in functional capacity and a reduction in LV chamber size with practolol (one was given atenolol).[42] The mortality benefit of b-blockade was first suggested in 1979 in a small cohort of 24 patients with NYHA III-IV HF given metoprolol, practolol, or alprenolol. Compared with 13 controls, the difference in mortality at 1 and 3 years was staggering: 83% and 52% versus 46% and 10%, respectively. However, it was not until further experiments in explanted hearts and animal models demonstrated the adverse effects of an increased adrenergic tone in chronic HF that initial concerns over the negative inotropic effects were put to rest by several multicenter, randomized, controlled trials reporting the beneficial effects of bisoprolol,[43] metoprolol,[44] and carvedilol.[45] By 2001, these three b-blockers had established themselves as a cornerstone in the management of HF. Three landmark randomized, placebo-controlled trials in patients with NYHA class II-IV HF established the use of b-blockers in the management of chronic HF due to significant reductions in mortality in addition to ACEI therapy. The US Carvedilol Heart Failure Study Group (US Carvedilol) trial randomized 1094 patients to carvedilol or placebo.[45] All patients had a run-in phase of carvedilol 6.25 mg twice daily, following which patients were given varying doses depending on severity of HF, but all had a goal dose of 2550 mg twice daily. The mean dose at follow-up was 45 27 mg/day. HF deaths were 3.2% versus 7.8% in favor of therapy. Hospitalizations were also reduced, but the results were not as impressive (14.4% vs 19.6%). Ninety-five percent of patients were also receiving an ACEI.[45] The MERIT-HF randomized 3991 patients to 25 mg (class II) or 12.5 mg (class II-IV) of metoprolol succinate (metoprolol XL/CR) versus placebo and titrated to a goal dose of 200 mg/day.[46] There was a 19% relative reduction in the combined endpoint of mortality or allcause hospitalizations in favor of therapy. There were also 32% and 39% relative reductions in death or cardiac transplantation
and cardiac death or non-fatal MI, respectively, both also in favor of metoprolol. The target dosage, 200 mg/day, was reached by 64% of the patients, and 87% received 100 mg/day or more. The mean dosage was 159 mg/day. Over 95% of patients were also receiving an ACEI or an ARB. Interestingly, patients with LVEF <25% had a better composite outcome than patients with LVEF 25%.[46] CIBIS-II randomized 2647 NYHA class III-IV patients to bisoprolol 1.25 mg/day versus placebo and showed a significantly lower mortality of 11.8% versus 17.3% in favor of bisoprolol.[47] There is often a hesitancy to initiate b-blocker therapy in patients who have symptoms of dyspnea on minimal exertion or at rest. Only 34% of patients in the US Carvedilol study and MERIT-HF had class IV symptoms, and only 17% of CIBIS-II patients were class IV. The COPERNICUS trial randomized 2289 patients with symptoms at rest or with minimal exertion (mean LVEF 20 4%) to carvedilol versus placebo.[48] Oral doses were started at 3.125 mg twice daily and, if tolerated, were increased weekly to a goal dose of 25 mg twice daily. The primary endpoint was all-cause mortality, and there was a 35% relative reduction in favor of carvedilol. Kaplan-Meier analysis revealed an 18.5% mortality at 1 year in the placebo group versus 11.4% in the carvedilol group (mean follow-up was actually 10 months). Interestingly, discontinuation rates were significantly higher in the placebo group (19% vs 15%, p = 0.02). The COPERNICUS trial teaches us that not only can a b-blocker be administered safely in patients with end-stage HF, but that doing so will improve survival akin to patients with less advanced HF. The US Carvedilol study had a much higher relative risk reduction (nearly 60%) than MERIT-HF and CIBIS-II (relative risk roughly 30% each) due to smaller absolute event rates (and it was a smaller study). In order to compare the efficacy of carvedilol versus metoprolol, 3029 patients were randomized to carvedilol (target dose 25 mg twice daily) versus metoprolol tartarate (target dose 50 mg twice daily) in COMET. Designed as a superiority trial, the endpoints were created to match MERIT-HF: all-cause mortality and the composite of all-cause mortality and all-cause admissions. Despite having two primary endpoints, the study was powered to detect a difference in all-cause mortality of 20%, and there was a statistically significant decrease in mortality in favor of carvedilol (34% vs 40%). However, there was no significant difference in the composite endpoint (74% vs 76%). Although the steering committee sought to replicate the primary endpoint of MERIT-HF, the formulation of metoprolol used in COMET was not the XL/CR succinate formulation. Pharmacologically, metoprolol tartrate is more equivalent to succinate at a three-times-daily dosing
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interval.[49] Secondly, the target dose in COMET for metoprolol was 50 mg twice daily, substantially less than the target dose of 200 mg/day in MERIT-HF. The equivalent succinate formulation of metoprolol should be roughly the sum total of the twice daily tartrate dosing,[50] i.e. a more appropriate target dose in COMET (although still with a shorter half-life), would have been metoprolol tartrate 100 mg twice daily. Furthermore, metoprolol tartrate has never been shown in a large randomized control trial to improve mortality in HF. For this latter reason, only the XL/CR formulation of metoprolol succinate is recommended for the treatment of chronic HF in the current guidelines. However, in a meta-analysis of 22 b-blocker trials (including eight metoprolol, two bisoprolol, and eight carvedilol trials), non-selective b-blockers were associated with a greater reduction in mortality (odds ratio [OR] 0.52 [95% CI 0.28, 0.89]) than selective b-blockers [OR 0.67 (95% CI 0.570.79)].[51] A challenge often encountered is the co-management of atrial fibrillation or indeed any tachycardia and HF. Balancing nodal-blocking agents and afterload-reducing agents can be frustrating. We find that, given the lack of overwhelming evidence for the superiority of carvedilol over metoprolol XL, it is reasonable to use the cardioselective metoprolol in patients with concomitant tachycardia in order to maximize heart rate control without as much effect on BP. In addition, if a patient experiences marked hypotension with the lowest dose of carvedilol, we have successfully used metoprolol tartrate (relying on a shorter half-life to prevent excessive hypotension) and then converted to metoprolol succinate. Another reason to consider metoprolol over the non-selective carvedilol is severe obstructive pulmonary disease. In a crossover study of 51 patients (NYHA class I-III), forced expiratory volume in 1 second (FEV1) was lowest with carvedilol, although there were no changes in functional capacity or 6-minute walk test.[52] In general, non-selective b-blockers are well tolerated by patients with reactive airway disease, but a trial of b1-selective blockers is warranted if reactive airway worsens on a non-selective b-blocker such as carvedilol. As discussed with ACEIs and ARBs, guidelines recommend titrating b-blockers to target dosing. However, a recent metaanalysis of 23 b-blocker trials found that there was no significant difference in effect on mortality between low- and high- dose trials (with high defined as >50% of patients achieving target dose): RR 0.78 and 0.74, respectively.[53] Perhaps congruent with common sense, there was a strong association between achieved heart rate and mortality, with every reduction of 5 beats/min conferring an 18% reduction in risk of death.
Lastly, for newly diagnosed systolic dysfunction, which therapy to initiate first: an ACEI/ARB or a b-blocker? Acutely, ACEIs/ARBs help to decrease the work of the left ventricle by reducing afterload and thereby improving cardiac output. On the other hand, and particularly in patients with significant volume overload, b-blockers will lessen stroke volume by decreasing HR and can precipitate a worsening in pulmonary edema. In the long term, both medications improve survival, but in meta-analysis, the relative reduction in mortality is slightly better with b-blockers with an OR of 0.65 (95% CI 0.53, 0.80)[51] versus ACEIs, OR 0.77 (95% CI 0.670.88)[54] [however, this is confounded by the fact that in all of the above b-blocker trials, almost all patients were receiving concurrent treatment with an ACEI and/or an ARB]. Most of the time, however, both classes can be safely started simultaneously, in particular in less advanced cases of HF. In the CARMEN trial, 572 patients were randomized to carvedilol 25 mg twice daily, enalapril 10 mg/day, or both.[55] There were no differences in mortality, hospitalizations, or safety at 18 months; furthermore, the combination arm resulted in a greater reduction in end-systolic volume (followed next by carvedilol). CIBIS-III randomized (non-blinded) patients to bisoprolol (65% at a target dose of 10 mg twice daily) or enalapril (84% at a target dose of 10 mg twice daily) for 6 months followed by combination treatment for 24 months.[56] The primary endpoint of death or hospitalization was non-significantly reduced further in the bisoprolol group. The fact that fewer patients reached the target dose of bisoprolol is also reflected in a non-significant trend in worsening of HF symptoms in the bisoprolol arm. Regardless of which therapy is initiated first, b-blockers should be titrated more slowly than ACEIs/ARBs (e.g. ever 12 weeks, unless in a monitored setting) to prevent decompensation of cardiac function.
2.3 Aldosterone Blockade
Natriuresis is the bodys own counterbalance to the sodiumavid/water-avid state in congestive HF, and it follows that augmenting this process would improve signs and symptoms of HF. The mineralocorticoid aldosterone increases sodium reabsorption (and the efflux of potassium) in the distal tubules of the nephron, which increases water reabsorption in the collecting duct, thereby increasing BP. Angiotensin II induces the production of aldosterone from the adrenal glands, as does an elevated serum concentration of potassium. The use of aldosterone antagonists for the management of HF has been evaluated in three clinical trials: RALES,[57] EPHESUS,[58] and EMPHASIS-HF.[59]
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In RALES, 1663 patients with current or a history of NYHA class IV HF symptoms (at least NYHA class III at enrollment) were randomized to placebo or spironolactone 25 mg/day (which could be increased to 50 mg after 8 weeks).[57] Patients with serum creatinine concentrations >2.5 mg/dL or potassium >5 mmol/L were excluded; 95% of patients were receiving an ACEI at enrollment. The trial was halted early at 2 years after a 30% relative reduction in all-cause mortality was observed (primary endpoint) in the spironolactone-treated group. Cardiac hospitalizations were also significantly less in the spironolactone group. Interestingly, there were no differences in BP between the two groups at follow-up. A similar decrease in mortality was seen at 16 months in patients randomized to eplerenone 25 mg/day 314 days post-MI in the EPHESUS trial.[58] In RALES, all patients had at least a history of NYHA class IV symptoms in the preceding 6 months, and in EPHESUS, there were no inclusion criteria based on functional class; however, all were post-acute MI. The ACC/AHA and the Heart Failure Society of America (HFSA) guideline recommendations for aldosterone antagonists are stringently based on these inclusion criteria. However, the recent completion and publication of the EMPHASIS-HF trial has confirmed what most had suspected, i.e. that aldosterone antagonists are also beneficial in patients with NYHA class II HF.[59] EMPHASISHF randomized 2737 patients aged >55 years with a LVEF 35% and a HF hospitalization within the preceding 6 months or plasma brain natriuretic peptide (BNP) 250 pg/mL (or proBNP 500 pg/mL in men and 750 pg/mL in women) plus NYHA class II symptoms. The primary endpoint was a composite of CV death or HF hospitalization, which occurred in 19.8% of treated patients versus 27.4% of placebo recipients. This composite was largely driven by HF hospitalizations; however, CV deaths were also significantly less in the treated group. In addition, total mortality was significantly reduced in favor of eplerenone: 12.5% versus 15.5%. Although EPHESUS and EMPHASIS-HF used eplerenone, we believe that the benefit is a class effect of mineralocorticoid blockade, and at our center we usually start with spironolactone and only change to eplerenone if a patient develops gynecomastia. In RALES, the median creatinine and potassium concentrations increased in the spironolactone group by 0.050.1 mg/dL and 0.30 mmol/L, respectively;[57] similar increases were seen in EPHESUS and EMPHASIS-HF. Serum potassium concentrations >5.5 mmol/L were observed in significantly more patients in the eplerenone group than in the placebo group in EMPHASIS-HF (11.8% vs 7.2%, p < 0.001).[59] Although these are small increases, clinical trials represent very controlled environments with close follow-up and scrutiny of aberrant
laboratory results and patient complaints. In the real world, the incidence of acute or subacute worsening of renal function and hyperkalemia is likely much higher, with hospitalizations for hyperkalemia increasing 3-fold after the publication of the RALES trial results.[60] Rates of hyperkalemia are likely to increase in the light of the results of EMPHASIS-HF. Caution must be exercised when starting an aldosterone antagonist, in particular since patients will already be receiving an ACEI or an ARB. Ideally, serum potassium should be checked on day 3, day 7, and every month for the first 3 months after initiating therapy. Lastly, current HFSA guidelines specifically recommend against therapy consisting of an ACEI plus an ARB and an aldosterone antagonist.[1]
2.4 Further Afterload Reduction
2.4.1 Hydralazine and Nitrates
The combination of hydralazine and isosorbide dinitrate was the first therapy for afterload reduction that was studied in a large, randomized, placebo-controlled manner. Published in 1986, the V-HeFT I trial randomized 642 men with mild to severe HF receiving digoxin to placebo, prazosin 20 mg/day, or the combination of hydralazine (300 mg/day) plus isosorbide dinitrate (160 mg/day). Whereas mortality in the prazosin group was similar to placebo, those in the isosorbide dinitrate/hydralazine arm had a 34% risk reduction at 2 years and a 36% risk reduction at 3 years in all-cause mortality.[9] However, as discussed previously, the results of V-HeFT II in which 804 men were randomized to isosorbide dinitrate/hydralazine versus enalapril 20 mg/day established the efficacy of the ACEI in reducing mortality.[16] On the basis of observational studies that Blacks/African Americans on average have a less active renin-angiotensin system, A-HeFT randomized 1050 Black men and women to placebo versus a fixed dose of hydralazine 37.5 mg plus isosorbide dinitrate 20 mg (BiDil, NitroMed, Charlotte, NC, USA).[61] The starting dose was one tablet three times daily and was titrated to two tablets. The endpoint was a composite score comprising weighted values for death, hospitalization for HF, and change in quality of life at 6 months. Enrollees had to have had NYHA class II-IV HF for at least 3 months and be on optimal medical therapy; 74% of patients were receiving a b-blocker, 70% of patients were receiving an ACEI, and over 15% were receiving an ARB. The trial was halted early due to greater mortality in the placebo group (10.2% vs 6.2%). There was a statistically significant decrease in the primary composite score endpoint, and all subgroups also favored the isosorbide dinitrate/hydralazine group.
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Although the isosorbide dinitrate/hydralazine fixed-dose combination proved efficacious in Blacks/African Americans, it is often overlooked that most of these patients were already receiving an agent to inhibit the renin-angiotensin system, and 40% were also receiving an aldosterone antagonist. For this reason, both guidelines prudently recommend this combination only after achieving target doses of an ACEI or an ARB (if tolerated). Although not studied in non-Blacks/non-African Americans, for those patients who still require afterload reduction despite optimal dosing of an ACEI or an ARB, or for those who are intolerant due to renal dysfunction or hyperkalemia, we do use the combination of isosorbide dinitrate plus hydralazine. Although no randomized trial has evaluated the non-fixed-dose isosorbide dinitrate plus hydralazine, we find this to be adequate, although more cumbersome due to the number of pills: the real challenge to the use of combination nitrates and hydralazine is the three-times-a-day dosing totaling at least six pills every day. Consideration can be made to use isosorbide mononitrate with its once-a-day dosing, but, again, the efficacy of this in combination with thrice- or twice-daily hydralazine has not been prospectively evaluated in a randomized trial. Alternatively, twice-daily combination therapy can be considered.
2.4.2 Dihydropyridine Calcium Channel Antagonists
indicated for the treatment of hypertension in HF patients, but should be used with caution.
2.5 Managing Preload
2.5.1 Diuretics
The evaluation of other afterload-reducing agents such as dihydropyridine calcium channel antagonists (calcium channel blockers [CCBs]) has been evaluated in two larger randomized trials. VHeFT III randomized patients to felodipine versus placebo (n = 450), with significant improvements in hypertension and LVEF, but not quality of life, functional class, or hospitalizations.[62] PRAISE[63] randomized 1153 patients in NYHA class IIIb-IV and an LVEF <30% to amlodipine 5 mg/day (uptitrated to 10 mg/day if tolerated) or placebo; almost all patients were already receiving an ACEI. The primary endpoint was death and hospitalization for cardiovascular events, and there was a non-significant relative decrease of 9% in the primary endpoint in favor of amlodipine. Peripheral edema (27% vs 18%) and pulmonary edema (15% vs 10%) were much more common in the amlodipine group, which can make differentiating HF exacerbation from adverse medication effect difficult. It is worth mentioning that in a small study (n = 28), the dihydropyridine CCB nifedipine was associated with more HF hospitalizations than isosorbide dinitrate,[64] while another small study (n = 20) showed a significant improvement in hemodynamics and LV end-diastolic diameter with nifedipine.[65] In our opinion, nifedipine should probably be avoided in patients with HF. Thus, amlodipine and nifedipine are only
There are few trials evaluating the efficacy and safety of diuretics in the management of HF. However, two challenges in the management of volume status in chronic HF warrant mention: the use of combination loop and thiazide-type diuretics, and the bioavailability of the various loop diuretics. Although evidence is scant, being based on very small observational studies, the rationale for the addition of thiazide-type diuretics to standard loop diuretics to treat diuretic-resistant HF is that thiazide-type diuretics will block reabsorption of sodium in the distal convoluted tubules after it has already been blocked upstream by the loop diuretics. In a review of the observational and randomized trials in patients with HF, the combination of a thiazide-type diuretic (most commonly metolazone) resulted in a doubling of urinary sodium loss resulting in a greater weight loss compared with loop diuretics alone; however, hypokalemia was more common in patients receiving the combination.[66] In patients with persistent overload despite stringent control of salt and water intake and escalating doses of loop diuretics, we found that the addition of metolazone or chlorothiazide is effective, with the caveat that serum potassium must be monitored frequently and if a patient already requires supplementation with potassium chloride, that this be increased a priori. The relative efficacy of furosemide versus bumetanide in the management of edema secondary to HF has been an area of interest since the 1970s, and the introduction of the newest loop diuretic torsemide in 1993 has resulted in a renewed interest in the efficacy of loop diuretics. Bumetanide is roughly 50-fold more potent than furosemide on a milligram per milligram basis, something that is only worth considering when continuous infusions are necessary due to volume. There is no clinically significant difference in potassium loss between bumetanide and furosemide.[67] In a study of 20 patients with chronic HF, both bumetanide and furosemide had prolonged absorption compared with healthy controls, but bumetanide had a better bioavailability than furosemide in both patients and healthy controls. However, with respect to elimination, the half-lives of both loop diuretics were doubled in patients with HF, but furosemide lasted twice as long as bumetanide.[68] In a randomized but open-label trial comparing furosemide and torsemide in 234 patients with HF, there was a statistically significant decrease in HF hospitalizations (32% vs 17%) in favor of torsemide but not in total hospitalizations (76% vs
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71%), nor was there a significant difference in dyspnea scores compared with baseline;[69] taken together, this implies that the difference in HF hospitalizations may have been due to random chance. Other open-label studies with similar numbers of patients have also reported a reduction in HF hospitalizations[70] as well as a trend towards greater improvement in functional class[71] with torsemide; however, definitive conclusions cannot be made until double-blinded, randomized trials are conducted. In summary, the pharmacokinetic differences of the various loop diuretics are minimal, and we do not believe that clinically relevant differences exist with respect to the desired effect of diuresis.
2.5.2 Ultrafiltration
Although typically used in the setting of acute, decompensated HF, intermittent ultrafiltration (UF) in diuretic-resistant or hyponatremic ambulatory patients has been used, reducing inotrope dependence in one series (n = 19),[72] and reducing hospitalizations in another (n = 13).[73] Data for acute decompensated HF shows that UF is associated with significantly fewer rehospitalizations for HF at 90 days, while being equivalent to continuous intravenous diuretics in terms of fluid removal, weight loss, and changes in serum creatinine.[74] In addition, UF has the advantage of less potassium and magnesium loss than loop diuretics. Intermittent UF for chronic, stable HF has not been studied in a randomized clinical trial; however, anecdotally, outpatient UF is of benefit in patients severely refractory to diuretics.
2.6 Long-Term Inotrope Therapy
2.6.1 Digoxin
reduction of almost 30%);[77] both of these findings have since been confirmed in a Cochrane review of patients with HF in sinus rhythm.[80] However, a post hoc analysis of DIG revealed that women who received digoxin had an increased risk of death compared with men (absolute increased risk of 4.2%, relative risk of almost 20%).[81] The serum digoxin concentration at 1 month was 0.8 ng/mL in women and 0.9 ng/mL in men, which was statistically significant, and, given the difference in volume of distributions, on average, between men and women, was also possibly clinically significant. One-year follow-up serum digoxin concentrations were 0.6 ng/mL in both men and women. Although we do routinely use digoxin for the treatment of NYHA class II-IV patients, keeping in mind that there has not been a proven mortality benefit, we are mindful of creatinine clearance and like to keep serum digoxin levels below 0.8 ng/mL in both men and women; furthermore, we do not titrate to a target serum digoxin level and in general we do not use doses in excess of 0.125 mg/day. In patients at risk for renal dysfunction, such as those with frequent decompensations or requiring high-dose or combination diuretics, we adjust the digoxin dose to every other day.
2.6.2 Continuous Inotrope Infusions
Along with diuretics, the use of digoxin as an inotrope was the standard treatment for congestive HF until the 1970s. In fact, it was 200 years before the use of vasodilators for the management of congestive HF that in 1776 Dr William Withering published his 10-year experience in treating 163 patients with cardiac dropsy.[75] However, the use of digitalis as therapy for supraventricular tachycardia versus management of congestive HF regardless of rhythm would occupy the next two centuries,[76] and would not be settled until 1997 with the publication of the DIG trial.[77] It had already been shown that withdrawal of digoxin in patients with stable NYHA class II-III HF resulted in a worsening of functional class[78,79] when the DIG trial randomized 6801 patients to digoxin (median dose 0.25 mg) or placebo. Although there was no difference in the primary endpoint of all-cause mortality, there was a significant decrease in hospitalizations in the treated group of 6% (relative
Continuous infusions of inotropes such as dobutamine and milrinone have not been shown to improve survival. However, continuous inotropes offer improvement in functionality and dyspnea, with stage D patients in at least one study becoming ambulatory.[82] There is no difference in mortality or rehospitalizations between dobutamine and milrinone.[83] Early reports of increased mortality on inotropes[84] may have been due to the fact that those patients were without ICDs; however, this is purely speculation based on anecdotal experience. The late 2000s have seen a renewed interest in inotropes with a novel class, the calcium sensitizers, which increase intracellular calcium, ostensibly augmenting contraction. Levosimendan, one of the most-studied calcium sensitizers, offers a myriad of theoretical, pleiotropic effects,[85] and initial reports were positive with greater improvement in hemodynamics in acute, decompensated HF as well as a suggestion of improved mortality over dobutamine.[86] However, in a large, randomized trial again, of decompensated patients levosimendan had no significant effect on mortality, CV death, number of days alive and out of the hospital, or patient symptom assessment compared with dobutamine.[87] However, as discussed in section 2.6.3, levosimendan has the advantage of an oral formulation.
2.6.3 Oral Inotropes
Oral inotropes such as amrinone, a precursor of milrinone, which is also a phosphodiestease-3 (PDE-3) inhibitor, increasing
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available cAMP, were not US FDA-approved in the late 1980searly 1990s due excessive toxicity, particularly ventricular arrhythmias, in addition to having an unclear benefit.[88] There has been a renewed interest in PDE-3 inhibition, with phase III clinical trials of the PDE-3 inhibitor enoximone currently on-going.[89] Looking past the safety issues with higher doses of enoximone, the current efficacy results do not leave much room for hope. In the EMOTE trial, there was no clear benefit of its use in weaning patients off chronic intravenous inotropic support.[90] More recently, the ESSENTIAL I & II trials evaluated enoximone in 1854 patients with a LVEF 30%, NYHA class III-IV HF, and one hospitalization or two outpatient visits for decompensated HF in the preceding 6 months.[91] These patients were randomized to low-dose enoximone and continued on b-blocker therapy. There was no significant difference compared with placebo in mortality, HF rehospitalizations, 6-minute walk test, or assessment of symptoms.[91] An oral formulation of the calcium sensitizer levosimendan was evaluated in a randomized trial in 307 patients with NYHA class III-IV HF (1 mg once or twice daily vs placebo). Despite significant improvements in plasma NTproBNP concentrations and quality of life, there was no improvement in the composite of symptom assessment, hospitalizations and mortality.[92] However, we believe that oral calcium sensitizers may be a safer alternative to chronic intravenous infusions of inotropes for palliation as patients will not need in-dwelling central venous access.
2.7 Exogenous Erythropoietin and Iron Therapy
There was a significant increase in functional class by selfreported assessment and physician assessment (primary endpoint), with no significant differences in adverse events. Currently, we do not routinely treat HF patients with exogenous erythropoietin in the absence of chronic renal insufficiency; however, we do treat patients with iron-deficiency anemia with iron supplementation. There is recent evidence that iron deficiency, independent of anemia, may be a significant risk factor of death or transplantation in HF patients with systolic dysfunction.[97]
2.8 Hormone Replacement
2.8.1 Thyroid Hormone
Observational reports point toward worse outcomes in HF patients with concurrent anemia.[93,94] However, data regarding the routine treatment of anemia with exogenous erythropoietin and supplementation of iron-deficient patients with iron have not uniformly shown benefit. In HF patients randomized to darbepoetin-alfa or placebo (n = 319), there was no difference in exercise duration at 27 weeks (primary endpoint) despite a significant increase in hemoglobin (Hb) concentration of 1.8 g/dL versus a decrease of 0.2 g/dL in the placebo group (baseline median Hb 11.4). There was also no difference in functional class or quality-of-life score, although there was a trend towards lower mortality and HF hospitalizations with darbepoetinalfa.[95] A phase III trial of darbepoetin with a primary endpoint of death or first HF hospitalization is currently enrolling patients.[96] The use of intravenous iron sucrose in the treatment of iron deficiency (ferritin <100 mg) has been evaluated in one blinded, randomized trial in 459 patients with NYHA class II-III HF.
It is interesting that signs and symptoms of hypothyroidism edema, pulmonary effusions, dyspnea, and fatigue are similar to those with HF; indeed, patients with hypothyroidism have both low cardiac output and increased systemic vascular resistance.[98] Triiodothyronine (T3) is an inotrope directly influencing calcium homeostasis within the sarcoplasmic reticulum, expression of b-adrenoceptors, and production of myosin chains.[98] Epidemiologically, elevated thyroid stimulating hormone (TSH) [with or without overt hypothyroidism] is associated with the development of cardiovascular disease, and patients with HF and concurrent hypothyroidism have worse outcomes.[99] Interestingly, improvement in cardiac output and systemic vascular resistance seems to be related to suppression of norepinephrine and aldosterone by thyroid hormone.[100] Clinical trials evaluating the effects of T3 supplementation in patients with HF are small, with hemodynamic changes being the primary outcomes. In the largest placebo-controlled trial to date, 86 patients with ischemic, class II-IV HF were treated with the thyroid hormone analog 3,5-diiodothyropropionic acid for 6 months.[101] Therapy was associated with improvement in cardiac index and systemic vascular resistance (as well as lipid profile and weight), but was not associated with improvement in functional class or symptoms. Interestingly, patients treated with the T3 analog were much more likely to report dyspnea and to present with hypotension, tachycardia, and elevated blood urea nitrogen (BUN), all of which are signs/symptoms of decompensated HF. Currently, there is insufficient evidence to support the administration of thyroid hormone in the absence of clinically overt hypothyroidism.
2.8.2 Growth Hormone
HF is an active process characterized by a hostile milieu of inflammatory cytokines, the end result of which is cardiac cachexia and premature somatopause. HF patients are more
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likely to have low baseline serum levels of both growth hormone (GH) and insulin-like growth factor (IGF) compared with matched controls,[102] with serum IGF levels corresponding to both adiponectin, BNP, and functional class.[103] In a recent series, serum IGF level was significantly lower in NYHA class III-IV patients compared with those in class I-II, and low IGF levels were associated with all-cause mortality and rehospitalization.[103] However, whether supplementing GH in patients with low GH or IGF is beneficial has not been extensively studied. In a larger single-blinded trial of 56 patients with NYHA class II-IV HF and GH deficiency, replacement of GH resulted in a significant improvement in quality of life and exercise duration as well as a reduction in plasma BNP levels.[104] Although supplementation or replacement of GH is a promising area, in particular in advanced HF, the safety and efficacy of GH with respect to hard clinical outcomes is currently unknown.
2.8.3 Testosterone
As many as 40% of men with HF have low serum testosterone levels, with levels inversely related to worsening functional class.[102] In a randomized trial in 20 patients, intramuscular administration of testosterone over 12 weeks was associated with a significant increase in 6-minute walk test from baseline; there was no effect on weight, BP, muscle mass, or LV size.[105] In a larger trial of 76 men randomized to topical testosterone gel (only 24% testosterone-deficient at baseline), there was a significant improvement in exercise capacity as well as functional class (35% vs 8%, p = 0.01), although, again, there was no change in muscle mass or strength.[106] Interestingly, a recent placebo-controlled, randomized study has shown that even in women (n = 36), administration of testosterone via transdermal patch was associated with significant improvements in 6-minute walk test, peak oxygen consumption, and muscle strength.[107] Although perhaps too vague in defining cardiovascular adverse events, a recent trial of testosterone in elderly men to improve muscle mass has raised concerns over testosterone safety.[108] Larger trials in patients with HF are needed to confirm or refute safety concerns in this population, as well as elicit whether testosterone has any effect on mortality or re-hospitalization.
2.9 Vasopressin Antagonists
tensin II, and adrenergic stimuli.[109] Although most trial data[110,111] and clinical experience with antagonism of arginine vasopressin comes from the treatment of acute decompensated HF complicated by hyponatremia, there may also be a role in patients with end-stage stable HF. Patients with class III-IV HF (n = 142) were randomized to conivaptan 1040 mg or placebo in one trial.[112] There was a significant improvement in hemodynamic parameters and increase in urine output with conivaptan; however, follow-up was limited to 6 hours.[112] Patients with stable class I-III HF (n = 254) were randomized to tolvaptan 3060 mg or placebo taken for 25 days in another study;[113] although there was a significant decrease in bodyweight after day 1, there was no further change (there were also significant increases in urine output with tolvaptan, but this was only monitored on day 1).[113] In a trial analyzing effect on LV dimensions, 240 patients were randomized to tolvaptan 30 mg/day or placebo, and at 1 year, there was a non-significant reduction in LV volume. Although not the primary endpoint, there were fewer deaths and HF hospitalizations with tolvaptan than with placebo (5% vs 9%, and 18% vs 28%, respectively).[114] Vasopressin antagonists may find a niche role in the treatment of patients with advanced HF who are refractory to diuretics and in those with persistent volume overload and significant hyponatremia. Currently tolvaptan is the only oral vasopressin antagonist approved by the FDA for the treatment of hyponatremia. Further trials are underway to define the role, if any, of vasopressin antagonists in the treatment of advanced HF with hyponatremia.[115]
2.10 Future Therapies
Vasopressin, or antidiuretic hormone, plays a central role in water homeostasis, and patients with HF have elevated serum vasopressin levels in order to maintain high intracardiac filling pressures via plasma osmolality, natriuretic peptides, angio 2011 Adis Data Information BV. All rights reserved.
The future therapy of dilated cardiomyopathy may be direct cellular repair through stem cell implantation or cytokine administration. Cell therapy has been used in small studies with varying success,[116] but recently a fairly large cohort (n = 191) of patients with LVEF <35% who received intracoronary bone marrow-derived progenitor cells were compared with matched controls and were found to have significant improvement in LVEF and cardiac index as well as preserved functional capacity and reduced mortality compared with controls.[117] However, the exact mechanism of improvement is unknown, and may in fact be related to cytokines released by transferred cells. Gene transfer using cardiomyocyte-specific adenovirus (AAV 8 and 9) shows promise. Several growth factors have been evaluated in animal models as well as human trials and show some promise, including vascular endothelial growth factor (VEGF), granulocyte colony-stimulating factor (GCSF), granulocytemacrophage colony-stimulating factor (GMCSF), hepatocyte
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growth factor, and fibroblast growth factor.[118] VEGF and GCSF are the most-studied growth factors in clinical trials of HF (and acute MI); however, clinical improvements compared with control have been marginal at best, with the most promising result being increased perfusion.[118] Transgenic therapy aimed at increasing b-adrenoceptor signaling and calciummodulating proteins such as sarcoplasmic endoreticulum Ca-ATPase (SERCA) and decreasing calcium cycling protein inhibitors such as type-1 phosphatase have been evaluated in animal models, with trials in humans underway.[119] Intracoronary transfer of SERCA2a in a swine model of HF resulted in significantly higher LVEF, significant improvement in LV dilatation, and stable plasma BNP levels,[120] and is currently being evaluated in phase II clinical trials.[121] Targeting modulators of actin also shows promise, for example thymosin beta4, which is essential for activation of epicardial progenitor cells[122] and enhanced cardiomyocyte survival both ex vivo and in vivo after artery coronary artery ligation.[123] Typically used for pulmonary arterial hypertension, phosphodiesterase (PDE) inhibitors such as sildenafil may have an added mechanistic benefit in HF by inhibiting cyclic nucleotide PDE activity, thereby increasing cGMP and cAMP and resulting in increased contractility.[124] Pentoxifylline, a xanthine derivative indicated for the treatment of intermittent claudication, acts as a PDE inhibitor, increasing cAMP and decreasing TNF-a, as well as a non-selective adenosine antagonist, garnering interest as a new therapeutic agent for HF. Several small, randomized, placebo-controlled trials have shown significant benefits with respect to NYHA class and LVEF, as well as non-significant reductions in mortality.[125] Although promising, the efficacy and safety of pentoxifylline in the management of HF needs to be evaluated in larger trials. Peroxisome proliferator-activated receptors (PPARs), which regulate glucose and lipid metabolism (the target of fibrates) via transcriptional activators, may play a role in the development of LV hypertrophy and dilated cardiomyopathy;[126] however, it remains to be seen whether pharmacological alterations of the PPAR pathway will lead to any benefit in patients with HF. 3. Diastolic HF No specific therapy has been shown to improve outcomes in patients with preserved LV function, also known as diastolic dysfunction. In the CHARM-Preserved trial, 3023 patients were randomized to candesartan 32 mg/day (NYHA class II-IV, LVEF >40%) or placebo with a primary endpoint of all-cause mortality or rehospitalization.[33] There was a trend towards improvement in the composite outcome in favor of can 2011 Adis Data Information BV. All rights reserved.
desartan, which was driven by a significant reduction in HF hospitalizations. However, in the I-PRESERVE trial, which randomized 4128 patients with NYHA class II-IV HF and LVEF >45%, there was no effect of irbesartan on the primary endpoint (death or CV hospitalization) or on HF hospitalizations.[127] In the RAAM-DHF trial,[128] echocardiographic parameters of diastolic function and plasma levels of procollagen type I N-terminal propeptide (secondary endpoints) improved from baseline, but there was no change in 6-minute walk test (primary endpoint) after 24 weeks in 46 patients randomized to eplerenone 25 mg/day uptitrated to 50 mg/day.[128] Results of the much larger TOPCAT trial will address the effect on hard clinical endpoints. A small study of patients (n = 97) with LVEF >40% randomized to carvedilol did not show consistent improvement in diastolic parameters (primary endpoint).[129] The effect of a b-blocker (metoprolol succinate) on clinical outcomes in patients with preserved LV function will be addressed in the multicenter beta-PRESERVE study.[130] Currently, treatment of diastolic HF should focus on managing predisposing and exacerbating conditions (such as hypertension and atrial fibrillation) and volume status (see section 2.5, Managing Preload). 4. Dietary Supplements Population studies suggest that moderate fish consumption (12 servings per week)[131] is associated with a lower incidence of HF (both systolic and diastolic); however, this has not been consistently reported.[132] The GISSI-HF trial randomized 6975 patients with NYHA class II-IV HF (regardless of LV function) to omega-3 fatty acid 1 g/day or placebo.[133] After a median of 3.9 years of follow-up, there were statistically significant, although numerically small, reductions in mortality of 27% versus 29% and death plus hospitalization of 57% versus 59% (co-primary endpoints) in favor of omega-3 therapy. Although omega-3 supplementation seemed to improve cardiovascular death, there were no significant differences in lipid profiles and there was no difference in the incidence of sudden cardiac death between groups. Likewise, a meta-analysis of ICD trials found no correlation between ICD discharges and omega-3 fatty acid use.[134] Thus, the etiology for benefit, if truly present, may be due to cardiac or vascular remodeling (there was slightly less worsening of HF as a cause of death, and a trend towards less HF hospitalizations in GISSI-HF) or antithrombotic effects (although there were less MIs, there were more strokes with omega-3 fatty acids in GISSI-HF).[133] Indeed, small studies suggest that supplementation with omega-3 fatty acids is associated with a reduction in plasma BNP
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levels.[135,136] Even less studied registry data suggest that moderate chocolate consumption (13 servings per month and 12 servings per week) is associated with a lower rate of HF hospitalization or death; however, there was no benefit observed with greater intake (36 servings per week), and a trend towards harm with daily consumption.[137] 5. Drugs to Avoid in HF It is worthwhile iterating that several classes of medications should be avoided in patients with HF. Non-steroidal antiinflammatory drugs (NSAIDs) [not inclusive of aspirin] should be contraindicated in HF patients because they lead to salt and water retention and an increase in systemic vascular resistance;[138] furthermore, all NSAIDs, including COX-2 selective NSAIDs, are associated with an increased incidence of MI, stroke, and CV death.[21] Caution should also be exercised with corticosteroids, as they can also cause salt and water retention. Although the topic of antiarrhythmics in HF is deserving of its own review, all class I agents and the class III agents sotalol, dronedarone, and ibutilide are contraindicated in HF.[138] Class I agents have greater negative inotropic and proarrhythmic effects in patients with HF. Sotalol and ibutilide are also associated with increased risk of ventricular arrhythmias in HF patients. Dronedarone is associated with a worsening of HF symptoms in NYHA class III and IV patients, resulting in an increased incidence of death.[139] The thiazolidinediones (pioglitizone and rosiglitazone) should be avoided in patients with class III or IV HF, and patients should be monitored closely for HF symptoms and weight gain, in which case the agent should be discontinued. Metformin should also be avoided in patients with class III/IV HF or frequent exacerbations with cardiorenal syndrome due to a risk of lactic acidosis.[138] Non-dihydropyridine CCBs, e.g. verapamil and diltiazem, are contraindicated in patients with systolic HF due to their negative inotropic effect and neurohormonal activation resulting in worsening of HF.[138] 6. Special Circumstances There are several specific cardiomyopathies that merit mention regarding pharmacotherapy. Patients with cardiac amyloid light chain (AL) amyloidosis should not receive digoxin because of the risk of light chains adherent to myocardium co-binding digoxin, thereby increasing myocyte exposure to digoxin and resulting in toxicity. Patients with hypertrophic obstructive cardiomyopathy benefit with b-blockers to allow increased LV end-diastolic volume to relieve outflow tract ob 2011 Adis Data Information BV. All rights reserved.
struction, and reduction of afterload can theoretically worsen the gradient.[140] In addition to b-blocker therapy, patients with hypertrophic obstructive cardiomyopathy benefit with respect to gradient and function class from the negative inotrope disopyramide.[141] We recommend screening for sarcoidosis in African Americans with non-ischemic dilated cardiomyopathy as early initiation of treatment for sarcoidosis can improve HF symptoms.[142] Similarly, early recognition of Fabrys cardiomyopathy namely, LV hypertrophy in middleaged patients without a history of hypertension and early replacement of a-galactosidase A deficiency can also potentially improve outcomes.[143] Elderly patients with HF are probably undertreated, and should be treated with guidelinerecommended therapies as with any other patient; however, the clinician must be mindful of decreased drug clearance and the increased risk of polypharmacy and drug-drug interactions given the increased likelihood of other concurrent medical conditions. 7. Other Considerations In treating HF, it is important to not lose sight of the fact that not only are these patients at increased risk of death, but their quality of life is also significantly impacted. As such, screening for depression and addressing sexual dysfunction is quick and non-invasive, and can improve morbidity. Patients with post-CAD depression are more likely to develop HF,[144] and the prevalence of depression among HF patients ranges from 20% to 34%, with depression being reported in almost half of NYHA class IV patients.[145] Small studies show that depressed HF patients have higher plasma levels of TNF-a[146] and BNP.[147] Meta-analysis suggests that patients with depression have worse outcomes, with a two-fold increase in risk of death, heart transplantation, or other cardiac events.[145] Although intervention trials specific to HF are scant, depression can be managed safely with antidepressants;[148] however, there is no evidence that doing so affects mortality or morbidity. Sexual dysfunction may be significantly under-reported in HF patients; however, fear of exertion during intercourse may be more common than erectile dysfunction, with patients being much less likely to participate in sexual intercourse after a diagnosis of HF is made;[149] however, the physical demands of intercourse are usually well tolerated by class I-III patients, representing less than four metabolic equivalents (METs).[150] A significant degree of erectile dysfunction and sexual dysfunction in general may be iatrogenic, with every class of therapy associated with some degree of dysfunction.[151] The treatment of erectile dysfunction with PDE-5 inhibitors in patients with
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HF (NYHA class I-III) is efficacious and safe,[152] and should be offered to patients who are not receiving nitrate therapy. 8. The Future of Ambulatory Management of HF The management of pre- and afterload in HF patients may be facilitated in the future with ambulatory pulmonary artery (PA) and left atrial (LA) pressure monitors. These devices are placed percutaneously and continually record intracardiac pressure, which can be downloaded to a handheld device and uploaded to a physicians office. Both the LA and PA pressure monitors have been tested in clinical trials. The LA pressure monitoring device (HeartPOD, Savacor, Inc., a subsidiary of St Jude Medical, Inc., Minneapolis, MN, USA) has been evaluated as a physician-directed self-management tool whereby based upon LA pressure trends (five LA pressure readings), patients (n = 40) were prompted to adjust their medication dosing, activity level, or salt and water intake. The device was associated with significant improvements in NYHA class and LVEF. Dosages of ACEIs and b-blockers were also significantly increased, while, interestingly, dosages of loop diuretics decreased (non-significant).[153] PA-pressure sensor-guided therapy (using the Champion heart sensor [CardioMEMS, Inc., Atlanta, GA, USA]) has been compared with standard medical therapy (n = 550) in the CHAMPION trial.[154] All patients received the wireless heart failure sensor as a permanent PA implant and were then randomized to the treatment or control group before discharge. Patients receiving PA pressureguided therapy had significantly reduced HF hospitalizations at 6 months (RR reduction of 30%) as well as a significant improvement in symptoms by questionnaire.[154] Although PA catheters have not been shown to change clinical outcomes in patients with decompensated HF, these preliminary results seem promising, and it will interesting to see if improvement in hospitalization trends persist, and if mortality is affected. 9. Recommendations We recommend starting HF therapy with an ACEI instead of a b-blocker initially because of the immediate effect of afterload reduction and long-term mortality benefit versus the immediate negative inotropic effect and long-term mortality benefit with a b-blocker. However, hypertensive patients can often tolerate starting both an ACEI and a b-blocker immediately. Heart failure medications should be titrated to achieve goal afterload reduction (BP) as well as minimize fluid accumulation. Ideally, patients with a history of systolic dysfunction should receive an ACEI and a b-blocker indefinitely. Patients with current systolic
dysfunction should also be treated with an aldosterone antagonist and patients with recurrent hospitalizations may benefit from the addition of digoxin. Serum potassium concentrations should be monitored frequently and serum digoxin level should be maintained at <0.8 ng/mL. The combination of an ACEI plus an ARB should be avoided. For patients with hypertension despite a maximal dose of an ACEI or an ARB, we recommend initiation of hydralazine and isosorbide dinitrate regardless of ethnicity or race before, for example, use of dihydropyridine CCBs, clonidine, or combination treatment with an ACEI plus an ARB. Managing patients with diastolic dysfunction can be difficult and necessitates strict management of volume and associated dysrhythmias to prevent symptoms and hospitalizations. All patients with HF should also be offered fish oil supplementation and screened for hypothyroidism and anemia. For patients with cardiac cachexia, it is reasonable to initiate testosterone supplementation in deficient patients after first obtaining a prostate-specific antigen and hemoglobin/hematocrit. In order to improve quality of life in patients with HF, we recommend screening for and treating depression and sexual dysfunction. Not discussed in this review is the importance of aggressive treatment of hypertension and primary and secondary prevention of MI, the two most common risk factors for HF,[2] in reducing the incidence of ischemic cardiomyopathy and subsequent systolic HF. Indeed, patients who are at risk for HF (AHA stage A), including patients with diabetes, hypertension, and hyperlipidemia and patients who are obese, physically inactive, and who smoke,[1] should be counseled about their risk not only of CHD and stroke, but also of HF, and the mortal and morbid impact that diagnosis portends. 10. Summary Of paramount importance is a multidisciplinary approach to the treatment of chronic HF with a focus on salt and fluid restriction and medication adherence. Early referral to Advanced Heart Failure and Heart Transplantation specialists should also be done for consideration for transplantation or ventricular assist devices. With an optimal medication regimen, in particular, use of an ACEI/ARB, a b-blocker, and an aldosterone antagonist, mortality can be significantly reduced in patients with systolic HF; combined with the judicious use of diuretics and digoxin, morbidity can also be substantially reduced. Treatment of co-morbid conditions such as hypothyroidism, anemia, depression, and sexual dysfunction are also important. Future therapies for HF will most likely focus on molecular signaling to either promote new cell formation or retard maladaptive cardiac remodeling.
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Acknowledgments
The authors would like to acknowledge Dr Michelle Kittleson, MD, PhD and Dr Michele Hamilton, MD for their assistance with the manuscript content. The authors have no conflicts of interest relevant to the content of this review, and no funding was received for the preparation of this manuscript.
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Correspondence: Lawrence Czer, MD, Medical Director, Heart Transplant Program, Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Rm 6215, Los Angeles, CA 90048, USA. E-mail: lawrence.czer@cshs.org

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Am J Cardiovasc Drugs 2011; 11 (3): 153-171 1175-3277/11/0003-0153/$49.95/0

2011 Adis Data Information BV. All rights reserved.

Chronic Heart Failure

Pharmacotherapy for Chronic Heart Failure

degree of reversal of maladaptive cardiac remodeling and prevention of life-threatening arrhythmias.

Am J Cardiovasc Drugs 2011; 11 (3)

Pharmacotherapy for Chronic Heart Failure

Pharmacotherapy for Chronic Heart Failure

Pharmacotherapy for Chronic Heart Failure

Pharmacotherapy for Chronic Heart Failure

Pharmacotherapy for Chronic Heart Failure

Pharmacotherapy for Chronic Heart Failure

Pharmacotherapy for Chronic Heart Failure

Pharmacotherapy for Chronic Heart Failure

2011 Adis Data Information BV. All rights reserved.

Am J Cardiovasc Drugs 2011; 11 (3)

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