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Author
Wilson S Colucci, MD
Section Editor
Stephen S Gottlieb, MD
Deputy Editor
Susan B Yeon, MD, JD, FACC
INTRODUCTION — Heart failure (HF) is a common clinical syndrome representing the end-stage of a number of different cardiac diseases. It can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood. There are two mechanisms by which reduced cardiac output and HF occur: systolic dysfunction and diastolic dysfunction.
An overview of the management of HF due to systolic dysfunction, including the treatment of associated conditions, will be presented here [1-3]. Drugs that should be avoided or used with caution in patients with HF, the management of refractory HF, and therapy of HF due to diastolic dysfunction are discussed separately. (See "Drugs that should be avoided or used with caution in patients with heart failure" and "Management of refractory heart failure" and "Treatment and prognosis of diastolic heart failure".)
Chronic versus acute decompensated HF — The following discussion will emphasize the therapeutic approach to the patient with chronic HF. The management of acute decompensated HF requiring hospitalization is presented separately. Such patients typically present with dyspnea and often have rales with or without peripheral edema [4]. (See "Treatment of acute decompensated heart failure" and "Treatment of acute decompensated heart failure in acute coronary syndromes".)
Major society guidelines — Several major societies have published extensive guidelines for the treatment of HF [1,3,5,6]. These include the 2005 American College of Cardiology/American Heart Association (ACC/AHA) guidelines with 2009 focused update [1], the 2006 Canadian Cardiovascular Society consensus conference [5], and the 2006 Heart Failure Society of America guidelines [6,7], and the 2008 European Society of Cardiology (ESC) guidelines [3].
With few exceptions, these societies make similar recommendations regarding the treatment of HF due to systolic dysfunction [8]. Our approach is in broad agreement with these guidelines.
GENERAL PRINCIPLES — The management of HF begins with an accurate assessment of the etiology and severity of the disease. (See "Evaluation of the patient with suspected heart failure".)
This is followed by a therapeutic regimen aimed at the following factors:
* Correction of systemic factors (eg, thyroid dysfunction, infection, uncontrolled diabetes) (table 1).
* Lifestyle modification - There have been no randomized trials to document the benefits of lifestyle modification, all of which are based upon observational studies and physiologic rationale.
- Cessation of smoking
- Restriction of alcohol consumption
- Salt restriction to approximately 2 to 3 g (or less) of sodium per day to minimize fluid accumulation (see "Patient information: Low sodium diet")
- Weight reduction in obese subjects with goal of being within 10 percent of ideal body weight
- Daily weight monitoring to detect fluid accumulation before it becomes symptomatic
* Review of drugs that may contribute to HF (eg, nonsteroidal antiinflammatory drugs, antiarrhythmic drugs, calcium channel blockers, thiazolidinediones) (see "Drugs that should be avoided or used with caution in patients with heart failure".
* Treatment of the cause of the heart disease.
* Pharmacologic therapy directed at relieving symptoms, slowing the progression of the HF, and improving patient survival. (See 'Pharmacologic therapy of HF' below.)
* Two types of devices are recommended in selected patients with HF (table 2):
- An implantable cardioverter-defibrillator (ICD) for secondary prevention of sudden cardiac death (SCD) and for primary prevention in selected patients. The criteria for ICD implantation are discussed separately. (See "Role of implantable cardioverter-defibrillators for the primary prevention of sudden cardiac death after myocardial infarction" and "Secondary and primary prevention of sudden cardiac death in heart failure and cardiomyopathy".)
- Cardiac resynchronization therapy (CRT) with biventricular pacing can improve symptoms and survival in patients who are in sinus rhythm and have an LVEF ≤35 percent, cardiac dyssynchrony, which is currently defined as a prolonged QRS duration (≥120 msec), and moderate to severe symptoms (NYHA class III or IV HF) despite optimal medical therapy. Most patients who satisfy these criteria are also candidates for an ICD and receive a combined device. (See "Cardiac resynchronization therapy in heart failure".)
* Specialized management for HF that is refractory to maximal oral pharmacologic therapy. (See "Management of refractory heart failure".)
The goals of therapy are clinical improvement followed by stabilization and ultimately a reduction in morbidity and mortality.
TREATMENT OF THE UNDERLYING CARDIAC DISEASE — Underlying conditions that predispose to the development or exacerbation of HF should be identified and treated (table 3). (See "Epidemiology and causes of heart failure", section on 'Predisposing conditions for HF' and "Causes of dilated cardiomyopathy".)
Hypertension — Hypertension is the primary cause of HF many patients. In addition, hypertension imposes an increased hemodynamic load on the failing ventricle in patients with established HF. The goals of therapy are to reduce both preload (to diminish congestive symptoms) and afterload (to improve cardiac function).
Drug therapy — Angiotensin converting enzyme (ACE) inhibitors, beta blockers, and angiotensin II receptor blockers (ARBs) are the preferred antihypertensive agents because, as will be described below, they improve survival in patients with HF. Beta blockers can also provide anginal relief in patients with ischemic heart disease and rate control in those with atrial fibrillation. Beta blocker therapy should always be initiated at very low doses to minimize the risk of cardiac decompensation. (See 'Initiation of therapy' below.)
For patients who are still hypertensive after initiation of ACE inhibitors, beta blockers, and/or ARBs, or who cannot tolerate these drugs, appropriate agents include loop diuretics, nitrates, hydralazine, and some vasoselective calcium channel blockers (eg, amlodipine and felodipine) [9]. (See "Treatment of hypertension in heart failure".)
Renovascular disease — Another consideration in patients with HF and hypertension is renovascular disease, particularly in those with HF due to ischemic heart disease. Additional testing for renovascular disease is indicated only in patients in whom the history is suggestive (including severe or refractory hypertension, a sudden rise in blood pressure over a previously stable value, or repeated episodes of flash pulmonary edema) and in whom a corrective procedure will be performed if renovascular disease is detected. (See "Who should be screened for renovascular or secondary hypertension?".)
Ischemic heart disease — Coronary atherosclerosis is the most common cause of cardiomyopathy in the United States, comprising 50 to 75 percent of patients with HF. In addition, coronary disease may be present in patients with HF of other causes, and may sometimes be overlooked as a contributing factor [10].
Patients with ischemic heart disease may have HF from one or both of two mechanisms: a prior myocardial infarction (MI) followed by left ventricular dysfunction and remodeling; or hibernating myocardium due to chronic but potentially reversible ischemic dysfunction [11,12]. A separate issue is that patients with idiopathic dilated cardiomyopathy, who had a normal coronary arteriogram at diagnosis, may over time develop significant coronary atherosclerosis [13].
All patients with documented ischemic heart disease should be treated medically for relief of angina and with risk factor reduction, such as rigorous control of serum lipids. (See "Overview of the management of stable angina pectoris" and "Secondary prevention of cardiovascular disease: Risk factor reduction".)
Myocardial revascularization with angioplasty or bypass surgery may improve symptom status, exercise capacity, and prognosis in selected patients with dysfunctional yet viable (hibernating or stunned) myocardium [12]. (See "Evaluation of hibernating myocardium" and "Diagnosis and management of ischemic cardiomyopathy".) Revascularization should also be considered in patients with a history of repeated episodes of acute left ventricular dysfunction and flash pulmonary edema. (See "Evaluation of acute decompensated heart failure".)
Valvular disease — Valvular heart disease is the primary cause of HF in perhaps 10 to 12 percent of patients [2] In addition, valvular dysfunction is a secondary or superimposed phenomenon in many cases of HF. As an example, some degree of mitral and tricuspid regurgitation is almost always present in patients with severe dilated cardiomyopathy, regardless of etiology [14]. (See "Functional mitral regurgitation".)
Valvular disease imposes a hemodynamic load on the ventricles, leading to further impairment in cardiac function, regardless of whether the valvular disease is primary or secondary. Surgical correction of valvular disease, such as aortic or mitral stenosis or regurgitation or tricuspid regurgitation, can lead to improvement in cardiac function and resolution of symptoms. (See appropriate topics for the indications for surgery with various valvular lesions).
Other factors — There are a variety of other potentially reversible conditions that can impair left ventricular function and cause, or worsen, HF. These include alcohol abuse, cocaine abuse, obstructive sleep apnea, nutritional deficiencies, myocarditis, hemochromatosis, sarcoidosis, thyroid disease, and rheumatologic disorders such as systemic lupus erythematosus. The evaluation to detect these conditions should include a careful history, including a history of systemic or other noncardiac disease, and, in some cases, consideration of endomyocardial biopsy. (See "Causes of dilated cardiomyopathy" and "Evaluation of the patient with suspected heart failure" and "Endomyocardial biopsy".)
PHARMACOLOGIC THERAPY OF HF — The goals of pharmacologic therapy are to improve symptoms, slow or reverse deterioration in myocardial function, and reduce mortality. Additional pharmacologic therapy is directed at the prevention of arrhythmias and embolic events and the treatment of anemia and other possible exacerbating factors (table 1). The treatment of HF in pregnancy involves specific concern about the effects of medications on the fetus and the mother, and therefore is discussed separately. (See "Management of heart failure in pregnancy".)
A number of drugs are recommended in HF for symptom relief and improvement in outcome (table 2) [1,3]:
* Improvement in symptoms can be achieved by digoxin, diuretics, beta blockers, ACE inhibitors, and ARBs.
* Prolongation of patient survival has been documented with ACE inhibitors, beta blockers, ARBs, hydralazine/nitrates, and, in selected patients, spironolactone and eplerenone.
A review of data from the PROVED and RADIANCE trials supported the use of combination therapy with an ACE inhibitor, digoxin, and diuretics for initial management [15]. Subsequent studies showed that beta blockers, ARBs, and spironolactone provide further benefit, depending upon New York Heart Association (NYHA) class (table 4).
We recommend the following approach to the long-term management of patients with HF. This approach is generally in agreement with the 2005 ACC/AHA task force guidelines for the treatment of HF (table 2) [1]. The data supporting these summary recommendations are discussed in detail in the appropriate topic reviews.
Order of therapy — We recommend the following sequence of drugs in the typical patient, with allowance for variations depending upon clinical response:
* Loop diuretics are introduced first for fluid control in patients in overt HF. The goal is relief of signs or symptoms of volume overload, such as dyspnea and peripheral edema.
* ACE inhibitors, or if not tolerated, angiotensin II receptor blockers (ARBs) are typically initiated during or after the optimization of diuretic therapy. These drugs are usually started at low doses and then titrated to goals based upon trial data. (See 'ACE inhibitors' below.)
* Beta blockers are initiated after the patient is stable on ACE inhibitors, again beginning at low doses with titration to trial goals as tolerated. (See 'Beta blockers' below.)
The following drugs should be given to selected patients in the absence of a contraindication:
* The addition of the combination of hydralazine and a nitrate for patients (particularly blacks) with a reduced LVEF who have persistent symptoms despite therapy with an ACE inhibitor and beta blocker. (See 'Hydralazine plus nitrates' below.)
* The addition of an aldosterone antagonist (spironolactone or, if not tolerated, eplerenone) to improve survival in patients with New York Heart Association (NYHA) class III/IV symptoms (table 4) and a reduced left ventricular ejection fraction who can be monitored for preserved renal function and a normal plasma potassium concentration. Aldosterone antagonists also may be used to assist in the management of diuretic-induced hypokalemia (plasma potassium ≤3.8 meq/L) in patients with mild-to-moderate HF. (See 'Aldosterone antagonists' below.)
* Angiotensin II receptor blockers (ARBs) as an alternative to ACE inhibitors in patients who cannot tolerate these drugs; the addition of an ARB to an ACE inhibitor may be considered in patients who are persistently symptomatic and have a reduced left ventricular ejection fraction despite being treated with conventional therapy. (See 'Angiotensin II receptor blockers' below.)
* Digoxin to reduce hospitalization for HF or for patients with concomitant atrial fibrillation, for rate control . (See 'Digoxin' below.)
ACE inhibitors or beta blockers first — The administration of ACE inhibitors before beta blockers is largely based upon clinical trials with ACE inhibitors being performed before trials of beta blockers. Subsequent randomized trials (eg, CIBIS III) suggest that the outcomes may be similar if beta blockers are given first [16-18].
The approach we recommend is based upon the differences in time to benefit and the importance of attaining target dose between these two drug classes:
* ACE inhibitors provide rapid hemodynamic benefit and will not exacerbate heart failure in the short run [1]. (See "ACE inhibitors in heart failure due to systolic dysfunction: Therapeutic use", section on 'Effect of dose'.)
* The hemodynamic benefits of beta blockers are delayed (and there may be a transient worsening in cardiac function when therapy is initiated), but the long-term improvements in left ventricular ejection fraction (LVEF) and survival are dose-dependent in patients who can tolerate the target dose (graph 1) [19]. However, patients who cannot tolerate the target dose may derive similar benefit as those who can, if they attain the same degree of beta blockade, as assessed from the reduction in heart rate [20]. These observations suggest that some patients have higher sensitivity to beta blockers.
Given these considerations, we start with a low dose of an ACE inhibitor (eg, lisinopril 5 mg/day), increase to a moderate dose (eg, lisinopril 15 to 20 mg/day) at one to two week intervals, and then begin a beta blocker, gradually increasing toward the target dose or, if this cannot be achieved, the highest tolerated dose. When the beta blocker titration is completed, the ACE inhibitor titration is completed. In patients with low risk of adverse response to ACE inhibitors (good blood pressure, no hyponatremia, hyperkalemia or risk of intravascular depletion), higher doses of the ACE inhibitor can be started and the titration can be quicker.
Complications that develop during dose titration should be treated. For example, increasing the diuretic dose for fluid overload [1]. Hypotension rarely limits metoprolol titration, but may occur with carvedilol due to its additional vasodilator activity. If hypotension limits carvedilol titration, one should consider a change to metoprolol.
Since many patients with HF have low blood pressures, we generally alter the regimen only for symptoms or signs of underperfusion. A cardiologist should be consulted in patients who have difficulty attaining target doses.
ACE inhibitors — ACE inhibitors improve survival in patients with all severities of myocardial disease, ranging from asymptomatic left ventricular dysfunction [21] to moderate or severe HF (graph 2A-C) [22-25]. However, there is some concern about their effectiveness in blacks (graph 3) [26-28]. (See "ACE inhibitors in heart failure due to systolic dysfunction: Therapeutic use" and 'Influence of race' below.)
All patients with asymptomatic or symptomatic left ventricular dysfunction should be started on an ACE inhibitor. Beginning therapy with low doses (eg, 2.5 mg of enalapril twice daily, 6.25 mg of captopril three times daily, or 5 mg of lisinopril once daily) will reduce the likelihood of hypotension and azotemia [29]. If initial therapy is tolerated, the dose is then gradually increased at one to two week intervals to, if tolerated, a target dose of 20 mg twice daily of enalapril, 50 mg three times daily of captopril, or up to 40 mg/day of lisinopril or quinapril. Blood should be obtained in all patients one to two weeks after starting or changing a dose and periodically thereafter to assess the plasma potassium concentration and renal function.
These relatively high doses are recommended because they were used in the successful trials [1]. Although there is uncertainty if these doses are much more beneficial than lower doses, maximum dose therapy, if tolerated, is still recommended [1,30,31]. If the target doses cannot be administered or are poorly tolerated, lower doses should be used with the expectation that there are likely to be only small differences in efficacy between low and high doses [1,30]. (See "ACE inhibitors in heart failure due to systolic dysfunction: Therapeutic use", section on 'Effect of dose'.)
Impact of aspirin — Some evidence suggests that aspirin inhibits the acute hemodynamic effects of ACE inhibitors. However, most of the evidence does not support an inhibitory effect of aspirin on the long-term outcome benefits of ACE inhibitors in HF. In patients with known coronary artery disease, ASA should still be used. However, there is no evidence for using aspirin in patients without coronary artery disease. (See "ACE inhibitors in heart failure due to systolic dysfunction: Therapeutic use", section on 'Use with aspirin' and "Drugs that should be avoided or used with caution in patients with heart failure", section on 'Aspirin'.)
Angiotensin II receptor blockers — ARBs for the treatment of HF appear to be as or possibly slightly less effective than ACE inhibitors when compared directly [32,33]. The CHARM-Alternative trial demonstrated benefit from candesartan in patients with class II or III HF who could not tolerate ACE inhibitors, primarily because of cough [34].
The 2005 ACC/AHA task force recommended an ARB in patients who cannot tolerate ACE inhibitors for this use and a class IIa recommendation for the use of an ARB as an alternative to ACE inhibitors, particularly in patients already taking an ARB for another indication (table 2) [1]. ARBs are more expensive than ACE inhibitors. (See "Angiotensin II receptor blockers in heart failure due to systolic dysfunction: Therapeutic use".)
A separate issue, the value of adding an ARB to appropriate doses of an ACE inhibitor, was confirmed in the CHARM-Added trial [35]. The benefit of combination therapy was also seen in a variety of subgroups including patients also treated with a beta blocker. This is an important observation since adding an ARB to an ACE inhibitor in patients treated with a beta blocker appeared to be associated with increased mortality in a post hoc subgroup analysis from the Val-HeFT trial (graph 4) [36].
We regard the CHARM-Added data as more definitive for several reasons:
* The benefits of ARBs in CHARM-Added were seen in the primary end point analysis, rather than in a post hoc analysis as in the Val-HeFT
* The duration of follow-up was longer in CHARM-Added (41 months versus 2 years)
* A greater proportion of patients in CHARM-Added were treated with a beta blocker
In addition, significant benefit was also seen in the subset of 529 patients who met the United States Food and Drug Administration (FDA) criteria for being on maximum doses of an ACE inhibitor at baseline, suggesting that similar effects could not have been achieved by increasing the dose of the ACE inhibitor [37].
The 2005 ACC/AHA guidelines concluded that the weight of evidence was less well established (class IIb) (table 2) and the 2008 European Society of Cardiology guidelines concluded that evidence and/or general agreement supported effectiveness (class Ia) for the addition of an ARB in persistently symptomatic patients with a reduced LVEF who are already being treated with conventional therapy [1,3].
We suggest the addition of an ARB, if tolerated, to HF therapy in patients who are still symptomatic on ACE inhibitors and beta blockers or are hypertensive. In patients with renal dysfunction or hyperkalemia, the addition of an ARB must be done with caution.
However, based upon the VALIANT trial, which found no increase in efficacy with the combination of valsartan and an ACE inhibitor, with or without a beta blocker in patients with HF who had had an acute MI within the preceding 10 days [38], an ARB should NOT be added to an ACE inhibitor in the immediate post-MI setting. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials".)
Beta blockers — At least certain beta blockers, particularly carvedilol, metoprolol succinate, and bisoprolol, improve overall and event-free survival in patients with New York Heart Association (NYHA) class II to III HF (table 4) [39-41] and probably in class IV HF [42,43]. Beta blockers with intrinsic sympathomimetic activity (such as pindolol and acebutolol) should be avoided [39]. (See "Rationale for and clinical trials of beta blockers in heart failure due to systolic dysfunction".)
The beta blocker trials in HF were carried out in patients receiving therapy with an ACE inhibitor; thus, the improvement in survival is additive to that induced by ACE inhibitors (graph 5) [44,45].
The magnitude of benefit was illustrated in a meta-analysis that included 22 trials involving more than 10,000 patients [39]. Compared to placebo, beta blockers significantly reduced mortality at one year (odds ratio 0.65) and two years (odds ratio 0.72). During the first year, it was estimated that beta blocker therapy saved 3.8 lives per 100 patients treated and was associated with four fewer hospitalizations per 100 patients treated.
The controlled trials, which evaluated the role of beta blockers in HF, excluded patients with relative contraindications to beta blocker therapy. Relative contraindications in patients with HF include:
- Heart rate <60 bpm
- Symptomatic hypotension
- Greater than minimal evidence of fluid retention
- Signs of peripheral hypoperfusion
- PR interval >0.24 sec
- Second- or third-degree atrioventricular block
- History of asthma or reactive airways
- Peripheral arterial disease with resting limb ischemia
Choice of agent — We recommend use of carvedilol, bisoprolol or extended release metoprolol succinate since these beta blockers have been shown to reduce all-cause mortality and decrease hospitalization in patients with HF and left ventricular systolic dysfunction (LVEF ≤ 35-40 percent) in randomized controlled trials.
Limited data are available on the comparative efficacy of these three beta blockers. Indirect evidence suggests that carvedilol may produce greater improvement in LVEF than metoprolol. Patients with low blood pressure may be less likely to tolerate carvedilol because of its vasodilatory activity. Conversely, carvedilol may be preferred in patients with higher blood pressure. (See "Rationale for and clinical trials of beta blockers in heart failure due to systolic dysfunction", section on 'Comparison with other beta blockers',Retrospective data suggest that some beta blockers other than those with proven benefit in randomized trials (eg, atenolol but not short-acting metoprolol tartrate) may be beneficial in HF. However these observations are not sufficient to support a recommendation for use of beta blockers without benefit established by randomized studies.
Patients with low blood pressure may tolerate metoprolol better than carvedilol. Conversely, those with high blood pressure may have a greater lowering of blood pressure with carvedilol. In MERIT-HF, metoprolol succinate resulted in a higher blood pressure than placebo, presumably because of improved cardiac function.
Guidelines and recommendation — The ACC/AHA guidelines recommend use of one of the beta blockers proven to reduce mortality (carvedilol, extended release metoprolol succinate, and bisoprolol) in all stable patients with current or prior symptoms of HF and reduced LVEF, unless contraindicated (table 2) [1]. The 2006 HFSA guidelines included a similar recommendation for patients with HF and LVEF ≤40 percent [7]. (See "Use of beta blockers in heart failure due to systolic dysfunction".)
In the absence of a contraindication, our recommendation is to offer carvedilol, metoprolol succinate, or bisoprolol to patients with NYHA class II, III, or stable class IV HF with left ventricular ejection fraction less than 40 percent.
Initiation of therapy — Because of the need for careful attention to initial dosing and the risk of transient worsening of symptoms, it is recommended that beta blocker therapy be initiated under the consultative guidance of an experienced HF center. Among inpatients, initiation of therapy prior to hospital discharge improves beta blocker use without an increase in side effects or drug discontinuation [46]. Prior to initiation of therapy, the patient should have no or minimal evidence of fluid retention and should not have required recent intravenous inotropic therapy.
The patient should be informed that beta blockers may lead to an increase in symptoms for 4 to 10 weeks before any improvement is noted. Therapy should be begun at very low doses and the dose doubled every two weeks until the target dose is reached or symptoms become limiting [47]. Initial and target doses are:
* For carvedilol, 3.125 mg twice daily initially and 25 to 50 mg twice daily ultimately (the higher dose being used in subjects over 85 kg)
* For extended-release metoprolol (metoprolol succinate), 12.5 mg daily in patients with NYHA class III or IV or 25 mg daily in patients with NYHA II, and ultimately 200 mg/day. If patients receive short acting metoprolol for cost reasons, dosing is not well established, but we recommend 6.25 mg twice daily initially and 50 to 100 mg twice daily ultimately.
* For bisoprolol, 1.25 mg once daily initially and 5 to 10 mg once daily ultimately.
Even lower starting doses should be given to patients with recent decompensation or a systolic pressure below 85 mmHg.
Every effort should be made to achieve the target dose since the improvement appears to be dose-dependent. The proportion of patients who reach the target dose is higher in clinical trials than in the general population in which the patients are older and have more comorbid disease. However, although not optimal, even low doses appear to be of benefit and should be used when higher doses are not tolerated [20].
What may be most important is the degree of beta blockade [20]. However, aiming for a particular resting heart rate or a particular reduction in heart rate is not of proven value [48].
The patient should weigh himself or herself daily and call the physician if there has been a 1 to 1.5 kg weight gain. Weight gain alone may be treated with diuretics, but resistant edema or more severe decompensation may require dose reduction or cessation (possibly transient) of the beta blocker. (See "Use of beta blockers in heart failure due to systolic dysfunction".)
Although data about the duration of beta blocker therapy in HF are lacking, it has been suggested that patients who are doing well should not have the beta blocker withdrawn, since clinical deterioration and sudden death or death from progressive HF has been observed.
Hydralazine plus nitrates — Hydralazine plus nitrate therapy may provide symptomatic and mortality benefit in selected patients with heart failure (HF) due to systolic dysfunction.
Data supporting the efficacy of hydralazine plus nitrates in patients with HF due to systolic dysfunction are discussed separately (see "Hydralazine plus nitrate therapy in patients with heart failure due to systolic dysfunction".
We recommend hydralazine plus nitrate therapy for patients with persistent NYHA class III to IV HF and LVEF <40 percent despite optimal therapy including a beta blocker, ACEI inhibitor (or ARB), and diuretics, we recommend the addition of the combination of hydralazine and an oral nitrate. Although there is no clear evidence of racial differences in response to treatment with hydralazine plus nitrate (since tests for interaction between race and treatment were not significant), some have interpreted the data to indicate that hydralazine and nitrate therapy is of greater proven benefit in black than white patients.
We suggest treatment with a combination of hydralazine plus nitrate in patients with HF and reduced LVEF who are unable to take both ACE inhibitor and ARB due to drug intolerance (including hyperkalemia), hypotension, or renal insufficiency. ARB intolerance can be presumed in patients who develop hyperkalemia or renal insufficiency on ACE inhibitor therapy.
Dosing — Starting doses of hydralazine 25 mg three times daily and isosorbide dinitrate 20 mg three times daily are recommended. Uptitration of dose should be considered every 2 to 4 weeks. The dose should not be increased if symptomatic hypotension develops. The target dose is hydralazine 75 mg three times daily and isosorbide dinitrate (40 mg three times daily). Although direct evidence of efficacy is lacking, isosorbide mononitrate (40 to 120 mg daily) may be used in place of isosorbide dinitrate to improve compliance.
TREATMENT OF SUBGROUPS
Influence of gender — Meta-analyses have defined the role of ACE inhibitors and beta blockers in women with HF. A meta-analysis of ACE inhibitor trials suggested that the benefit from these drugs may not apply to women [49]. Among trials of ACE inhibitor therapy in symptomatic HF, the relative mortality risk with an ACE inhibitor was significantly reduced in men at 0.80 (95% CI 0.68-0.93) but showed only a trend toward significance in women at 0.90 (95 0.78-1.05). Until more definitive data are provided, ACE inhibitors should continue to be used in women with HF.
In contrast, women appear to benefit from beta blockers to the same degree as men [49,50]. A pooled analysis from MERIT-HF, COPERNICUS, CIBIS II, and the United States Carvedilol Heart Failure trials found that the mortality benefit from beta blocker therapy was the same in men and women (relative risk 0.66 and 0.63, respectively) [49].
Influence of race — Race may affect the response to ACE inhibitors, hydralazine plus isosorbide dinitrate, and beta blockers in patients with HF.
ACE inhibitors — The V-HeFT trial and a matched cohort study from the SOLVD trial suggested that there were important differences between blacks and whites in the response to ACE inhibitors [26-28]. Two major findings were noted:
* Blacks had higher rates of both progressive HF and overall mortality. In the SOLVD analysis, the respective values were 13 versus 8 per 100 patient-years in whites for hospitalization for HF and 12 versus 10 per 100 patient-years for overall mortality [26].
* Blacks had a lesser response than whites to ACE inhibition with enalapril despite receiving similar doses. In the SOLVD matched cohort study, enalapril therapy in whites was associated with a significant 44 percent reduction in hospitalization for HF compared to placebo; in contrast there was no significant reduction among blacks (graph 3) [26].
The apparent lack of response in blacks has some biologic plausibility since similar findings have been noted in patients with hypertension. Blacks respond less well to ACE inhibitors than to most other antihypertensive drugs (graph 6) [51]. In the matched cohort study from SOLVD, there were significant reductions in systolic and diastolic pressure with enalapril in whites (5/3.6) but not blacks [26]. (See "Treatment of hypertension in blacks".) In addition to genetic disparities, environmental differences (such as diet) could contribute to the varying response.
In contrast to these findings, another analysis of the SOLVD trials using mortality as the end point found that the relative risk (RR) of death was reduced to the same degree in both blacks and whites (RR for blacks 0.89, 95% CI 0.74-1.06; RR for whites 0.89, 95% CI 0.82-0.97) [49]. The risk reduction was significant in whites but not blacks, an observation that is likely to be explained by the smaller number of blacks in the trials (800 versus 5718). Thus, ACE inhibitors should continue to be used in black patients with HF.
Beta blockers — There are conflicting data on the efficacy of beta blockers in black patients. In the carvedilol trials, the benefit of beta blockade was of similar magnitude in blacks and nonblack patients [52]. In comparison, it appeared that blacks derived no benefit with bucindolol in the BEST trial [53].
A meta-analysis of beta blocker trials in HF confirmed this distinction, finding different results depending upon whether or not the BEST data were included [49]. In the COPERNICUS, MERIT-HF, and United States Carvedilol Heart Failure trials, the reduction in all-cause mortality with beta blockers was the same for blacks and whites (relative risk 0.67 and 0.63 respectively). With inclusion of the data from BEST, the benefit of beta blockers remained significant for whites but was no longer significant in blacks (relative risk 0.69 and 0.97, respectively).
These observations demonstrate that bucindolol, a beta blocker with partial beta agonist activity [54], is not effective in reducing mortality in blacks. The reasons for this difference are not clear, but (as speculated by the authors of BEST) may include race-specific differences in the beta adrenergic pathway [53].
Hydralazine with nitrates — In the V-HeFT trials, blacks had a lesser benefit from ACE inhibition than whites, while the benefit of the hydralazine-nitrate combination was more pronounced [28]. This observation led to the design of the A-HeFT trial (African-American Heart Failure Trial), in which black patients with class III to IV HF on standard heart failure therapy (including an ACE inhibitor if tolerated) were randomly assigned to a fixed combination of hydralazine and isosorbide dinitrate or placebo. (See 'Hydralazine plus nitrates' above.)
Influence of diabetes — Diabetic patients with HF are treated in the same fashion as nondiabetics. Data supporting this approach are available for both beta blockers and ACE inhibitors. (See "Heart failure in diabetes mellitus", section on Drug therapy.)
The thiazolidinediones and metformin, which are often used in type 2 diabetics, are relatively contraindicated in patients with HF. (See "Drugs that should be avoided or used with caution in patients with heart failure".)
Digoxin — Digoxin is given to patients with HF and systolic dysfunction to control symptoms (such as fatigue, dyspnea, and exercise intolerance) and, in patients with atrial fibrillation, to control the ventricular rate. As demonstrated in the DIG trial, digoxin therapy was associated with a significant reduction in hospitalization for HF but no benefit in terms of overall mortality [55].
However, subsequent subgroup analyses suggest that digoxin may have an effect on survival that varies with the serum digoxin concentration (SDC). Compared to placebo, survival was significantly improved when the SDC was between 0.5 and 0.8 ng/mL in men and significantly worsened when the SDC was ≥1.2 ng/mL (graph 7) [56]. A similar relationship was seen in women with a nonsignificant trend toward improved survival when the SDC was between 0.5 and 0.9 ng/mL and significantly worse survival when the SDC was ≥1.2 ng/mL [57]. (See "Use of digoxin in heart failure due to systolic dysfunction", section on 'Optimal digoxin level'.)
The use of digoxin for the treatment of symptoms in patients with left ventricular dysfunction was given a class I recommendation by 2005 ACC/AHA guidelines (table 2) [1]. We recommend starting digoxin in patients with left ventricular systolic dysfunction (left ventricular ejection fraction [LVEF] <40 percent) who continue to have NYHA functional class II, III, and IV symptoms (table 4) despite appropriate therapy including an ACE inhibitor, beta blocker, and, if necessary for fluid control, a diuretic. The usual daily dose is 0.125 mg or less, based upon renal function. Based upon the data from the DIG trial mentioned above correlating serum digoxin concentration and survival, we recommend maintaining the SDC between 0.5 and 0.8 ng/mL (graph 7) [56].
Digoxin is NOT indicated as primary therapy for the stabilization of patients with acutely decompensated HF. Such patients should first receive appropriate treatment for HF, usually with intravenous medications. Digoxin may be initiated at the same time as part of a long-term treatment strategy.
Diuretics — Sodium and water retention lead to the common congestive symptoms of pulmonary and peripheral edema. Fluid overload can typically be controlled and symptoms improved by diuretic therapy. Improvement in symptoms can occur within hours to days. In comparison, the clinical effects of digoxin, ACE inhibitors, and beta blockers may require weeks or months to become fully apparent.
Appropriate diuretic usage can also affect the success of other drugs given for the treatment of HF. Inappropriately low doses will result in fluid retention, which can diminish the response to ACE inhibitors and ARBs and increase the risk of decompensation with the use of beta blockers. Conversely, excessive diuresis will lead to volume contraction, which can increase the risk of hypotension and renal insufficiency with ACE inhibitors, ARBs, and beta blockers.
A loop diuretic should be given to control pulmonary and/or peripheral edema. The most commonly used loop diuretic for the treatment of HF is furosemide, but some patients respond better to bumetanide or torsemide because of superior and more predictable absorption. (See "Use of diuretics in heart failure".)
The usual starting dose in outpatients with HF is 20 to 40 mg of furosemide or its equivalent. Subsequent dosing is determined by the diuretic response. In patients who are volume overloaded, a reasonable goal is weight reduction of 1.0 kg/day. If a patient does not respond, the diuretic dose should initially be increased to find the single effective dose, rather than giving the same dose twice a day.
Intravenous diuretics (either as a bolus or a continuous infusion) are more potent than their equivalent oral doses, and may be required for unstable or severe disease. Thiazide diuretics can be added for a synergistic effect. (See "Use of diuretics in heart failure".)
The fall in intracardiac filling pressure that results from diuretic-induced fluid removal may lower the cardiac output via the Frank-Starling relationship. This effect is usually minor and does not interfere with therapy. However, an otherwise unexplained rise in BUN and serum creatinine should be viewed as a sign of a potentially important reduction in tissue perfusion. Further diuresis should be performed only with careful monitoring for signs and symptoms attributable to hypoperfusion. (See "Use of diuretics in heart failure".)
Over the long term, diuretic therapy should be maintained to prevent recurrent edema. In many cases, this adjustment can be facilitated by having the patient record his or her weight each day and allowing him or her to make changes in dose if the weight increases or decreases beyond a specified range.
Aldosterone antagonists — Spironolactone and eplerenone, which compete with aldosterone for the mineralocorticoid receptor, prolong survival in selected patients with HF. The endocrine side effects of spironolactone result from nonselective binding to androgen and progesterone receptors; eplerenone has greater specificity for the mineralocorticoid receptor and therefore has a lower incidence of endocrine side effects (1 versus 10 percent in the respective trials cited below). (See "Use of diuretics in heart failure", section on Improved survival with aldosterone antagonism.)
The 2005 ACC/AHA guidelines concluded that the weight of evidence is in favor of efficacy of an aldosterone antagonist (class IIa) in selected patients with moderate to severe HF and reduced LVEF who can be carefully monitored for preserved renal function and a normal plasma potassium concentration (table 2) [1].
The role of aldosterone blockade in mild-to-moderate HF has not been defined and its use was not recommended in such patients [1]. One exception would be in patients with mild-to-moderate HF who have diuretic-induced hypokalemia (plasma potassium ≤3.8 meq/L) that cannot be controlled with potassium replacement.
The efficacy of an aldosterone antagonist in patients treated with both an ACE inhibitor and an ARB, as in CHARM-Added, is uncertain [35]. The 2005 ACC/AHA guidelines on chronic heart failure concluded that an aldosterone antagonist should not be used in such patients (table 2) [1].
Despite these recommendations, spironolactone appears to be used more broadly, without regard to NYHA class, without optimization of background therapy with an ACE inhibitor and beta blocker, and without appropriate follow-up [58]. Such use has been associated with an increased rate of complications.
Although eplerenone is associated with fewer endocrine side effects than spironolactone (1 versus 10 percent in the respective trials), this advantage must be weighed against the marked difference in cost between the two drugs. It may be reasonable to begin with spironolactone (25 to 50 mg/day), and switch to eplerenone (25 and after four weeks 50 mg/day) if endocrine side effects occur. To the degree that blockade of a deleterious effect of aldosterone on the heart is important, a similar benefit would not be expected with other potassium-sparing diuretics (such as amiloride).
It is essential that serum potassium and creatinine be checked one to two weeks after starting spironolactone or eplerenone and periodically thereafter. Patients with poor renal function are particularly at risk for hyperkalemia.
Life-threatening hyperkalemia can also occur in the setting of other risk factors. These include:
* Increasing age
* More severe HF
* Diabetes mellitus
* Underlying renal dysfunction
* Volume depletion
* Higher baseline plasma potassium concentration
* Spironolactone dose ≥50 mg/day
* Higher ACE inhibitor or angiotensin II receptor blocker dose
* Combined use of ACE inhibitors and angiotensin II receptor blockers
* Concomitant beta blocker use
* Use of potassium supplements or potassium-containing salt substitutes
* Use of nonsteroidal antiinflammatory drugs
Renal dysfunction, which is an important risk factor for hyperkalemia in this setting, may be underestimated by the serum creatinine concentration, especially in elderly patients and other patients with reduced lean body mass in whom creatinine production is reduced. Formulas are available to estimate glomerular filtration rate from a stable serum creatinine that take into account age and body mass. (See "Assessment of kidney function: Serum creatinine; BUN; and GFR", section on 'Estimation equations'.)
Calcium channel blockers — Some initial studies suggested a possible deleterious effect of calcium channel blockers in patients with HF, while later trials with vasoselective calcium channel blockers amlodipine and felodipine showed a neutral effect on mortality (graph 8 and graph 9) [9]. Thus, there is NO direct role for these drugs in the management of HF. However, amlodipine and felodipine appear to be safe in patients with HF and can be used if treatment with a calcium channel blocker is necessary for another indication, such as angina or hypertension. (See "Calcium channel blockers in heart failure due to systolic dysfunction".)
Statins — Intensive lipid lowering with statin therapy is recommended for the secondary prevention of atherosclerotic cardiovascular disease, independent of the presence of HF. (See "Intensity of lipid lowering therapy in secondary prevention of coronary heart disease" and "Treatment of lipids (including hypercholesterolemia) in secondary prevention".)
Clinical trials have evaluated the efficacy of statins on mortality in patients with both ischemic and nonischemic systolic HF. The supportive data and statin therapy in patients with diastolic HF are discussed separately. (See "Statin therapy in patients with heart failure".)
Suumarized briefly, there is no good evidence that statin therapy is beneficial in patients with HF without coronary artery disease and it is unclear how useful they are in patients with coronary disease whose primary problem is severe heart failure. Limited data suggest that statins may benefit patients with diastolic dysfunction.
N-3 polyunsaturated fatty acids — Evidence from a randomized trial indicates that supplementation with N-3 polyunsaturated fatty acids (PUFA) in patients with HF can reduce mortality. The GISSI-HF investigators randomly assigned 6975 class II-IV chronic HF patients to 1 g/day n-3 PUFA or placebo with a median follow-up of 3.9 years [59]. Death from any cause was reduced with n-3 PUFA compared to placebo from 29 to 27 percent (adjusted hazard ratio 0.91, 95.5% CI 0.833-0.998) and the endpoint of death or admission to the hospital for cardiovascular reasons was also reduced (59 to 57 percent, adjusted hazard ratio 0.92, 99 percent CI 0.849-0.999).
The potential role of supplementation with N-3 polyunsaturated fatty acids for prevention of HF is discussed separately. (See "Fish oil and marine omega-3 fatty acids".)
Drugs to avoid — A variety of drugs should be avoided or used with caution in patients with HF. This issue is presented separately. (See "Drugs that should be avoided or used with caution in patients with heart failure".)
EXERCISE TRAINING — Both chronic hypoperfusion and a reduction in physical activity lead to skeletal muscle dysfunction and exercise intolerance in patients with chronic HF. (See "Skeletal muscle dysfunction and exercise intolerance in heart failure".)
Randomized controlled trials have shown that exercise training can lessen symptoms, increase exercise capacity, improve the quality of life, reduce hospitalization, and increase survival in patients with chronic HF. These improvements are additive to the benefits of ACE inhibitors and beta blockers. These issues are discussed in detail separately. (See "Cardiac rehabilitation in patients with heart failure" and "Components of cardiac rehabilitation and exercise prescription".)
The 2005 ACC/AHA guidelines recommend exercise training as an adjunctive approach to improve clinical status in patients with reduced LVEF and HF [1]. Based upon the available data, we recommend that cardiac rehabilitation be offered to patients with stable NYHA class II to III HF (table 4) who do not have advanced arrhythmias and who do not have other limitations to exercise [1]. Exercise training should be used in conjunction with drug therapy. The beneficial effects of exercise are seen with high or low levels of training, and are apparent as early as three weeks after training. There are not enough data at present to recommend cardiac rehabilitation for patients with advanced HF.
SERIAL ASSESSMENT — Patients with HF should be evaluated serially to assess status, the response to therapy, and potential need for changes in management. The 2005 ACC/AHA guidelines on the management of chronic HF recommend that each visit should include assessment of ability to perform activities of daily living, volume status and weight, current use of alcohol, tobacco, illicit drugs, alternative therapies, and chemotherapy drugs, as well as diet and sodium intake (table 5) [1].
It was also considered reasonable to repeat measurement of left ventricular ejection fraction and structural remodeling in patients who have a change in clinical status, have experienced or recovered from a clinical event, or have received treatment that might significantly change these parameters. The efficacy of serial measurement of serum brain natriuretic peptide was considered less well established.
MANAGEMENT OF REFRACTORY HF — Although the majority of patients with HF due to systolic dysfunction respond to optimal medical therapy, some patients do not improve or experience rapid recurrence of symptoms. These patients have symptoms at rest or on minimal exertion and often require repeated prolonged hospitalizations for intensive management. Specialized strategies are generally considered for these patients, including continuous intravenous positive inotropic therapy, cardiac resynchronization therapy, extracorporeal ultrafiltration via hemofiltration, mechanical circulatory support, surgery, or cardiac transplantation (table 6) [1].
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