Patricia A Howard; Judy WM Cheng; Michael A Crouch; Vincent J Colucci; James S Kalus; Sarah A Spinler and Mark Munger 

Ann Pharmacother.  2006;40(9):1607-1617.  ?2006 Harvey Whitney Books Company

Abstract and Introduction

Abstract

Objective: To review and discuss key aspects of the drug therapy recommendations in the American College of Cardiology (ACC)/American Heart Association (AHA) 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure (HF) in the Adult.
Data Sources: Data were obtained from the ACC/AHA 2005 Guideline Update for Chronic HF. English-language clinical trials, observational studies, and pertinent review articles evaluating the pharmacotherapy of chronic HF were identified, based on MEDLINE searches through January 2006.
Study Selection: Articles presenting information that impacts the evidence base for recommendations regarding the use of various drug therapies in patients with chronic HF were evaluated.
Data Synthesis: The ACC/AHA 2005 Guideline Update for HF provides revised, evidence-based recommendations for the treatment of chronic HF. The new guidelines are based on a staging system that recognizes both the development and progression of HF. Recommendations are provided for 2 stages of patients (A and B) who do not yet have clinical HF but are clearly at risk and 2 stages (C and D) that include patients with symptomatic HF. The guidelines continue to emphasize the important role of neurohormonal blockade with angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, ß-adrenergic blockers, and aldosterone antagonists. Based on recent trials, updated recommendations address the roles of combination therapy and the selective addition of hydralazine and isosorbide dinitrate. Along with specific drug recommendations, information on the practical use of various drugs is provided. Although the guidelines primarily focus on HF due to systolic dysfunction, general recommendations are also provided for patients with preserved systolic function.
Conclusions: The ACC/AHA 2005 Guideline Update provides evidence-based recommendations for healthcare professionals involved in the care of adults with chronic HF. Recent clinical trial findings have further clarified the evolving role of neurohormonal-blocking drugs in the prevention and treatment of HF.

Introduction

In August 2005, the American College of Cardiology (ACC) and American Heart Association (AHA) released the evidence-based 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult. Full text and summary documents are available on the organizations' Web sites,^[1,2] with published versions in the Journal of the American College of Cardiology^[3] and Circulation.^[4] The ACC Web site also provides a full text version, with highlighted changes, and a pocket version. The purpose of this review is to summarize, discuss, and provide perspective on key aspects of the new guidelines.

Heart failure (HF) continues to be a growing public health problem, affecting an estimated 5 million individuals in the US.^[5] Between 1979 and 2002, hospitalizations increased 157% and now approach one million annually. Frequent hospitalizations, often resulting from nonadherence to diet or medications, account for the majority of the estimated $27.9 billion in total annual treatment costs for HF in the US.

The 2005 guidelines^[1] use an HF staging system first introduced in the 2001 guidelines^[6] ( Table 1 ). This staging system emphasizes the development and progression of HF and recognizes that therapeutic intervention prior to the development of symptoms and left-ventricular (LV) dysfunction can have profound benefits. The new guidelines clarify that HF is a distinct clinical syndrome, characterized by specific signs and symptoms, and is not equivalent to LV dysfunction or cardiomyopathy. The term "congestive" has been dropped because symptoms of volume overload may not always be present. The new staging system complements but does not replace the traditional New York Heart Association (NYHA) classification scheme, which primarily measures symptoms and functional capacity in patients who would be considered stage C or D. Use of the staging system has important therapeutic implications. For example, in a patient with stage C HF, aggressive diuretic therapy could reduce symptoms temporarily, resulting in an improved NYHA functional classification. However, the patient's stage of HF would remain unchanged, and all recommendations for stage C HF would continue to apply. The format for classification of recommendations and levels of evidence is consistent with previous ACC/AHA guidelines ( Table 2 ).

Inhibitors of the Renin-Angiotensin-Aldosterone System

The new HF guidelines continue to emphasize the important role of inhibitors of the renin-angiotensin-aldosterone system, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and aldosterone antagonists.

Angiotensin-Converting Enzyme Inhibitors

For patients with stage A HF, the use of ACE inhibitors in those with a history of atherosclerotic vascular diseases, diabetes, or hypertension with associated cardiovascular (CV) risk factors is now a Class IIa, evidence level A recommendation (previously Class I, evidence level B).^[1] The new recommendation reflects evidence that, although conflicting, overall weighs toward efficacy. In hypertensive patients, ALLHAT (the Antihypertensives and Lipid Lowering Treatment to Prevent Heart Attack Trial) demonstrated the efficacy of ACE inhibitors for preventing HF.^[7]

In the HOPE (Heart Outcome Prevention Evaluation) study of patients at high risk for CV events and the EUROPA (European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease) study, ACE inhibitors reduced the incidence of HF and/or new-onset diabetes.^[8-10] Among diabetic patients without hypertension, ACE inhibitors prevented the development of end-organ disease, such as renal dysfunction.^[8,9,11] However, conflicting data came from the PEACE (Prevention of Events With Angiotensin-Converting Enzyme Inhibition) study, which used ACE inhibitors in patients with atherosclerotic vascular diseases.^[12] Whereas the HOPE and EUROPA studies demonstrated that ACE inhibitors significantly reduced the incidence of CV death, myocardial infarction (MI), or stroke in patients with established vascular disease or diabetes, but no evidence of HF, the PEACE study failed to show a reduction in primary composite endpoints.^[8-10,12] Differences in outcomes among these studies might be explained by the fact that patients in the PEACE study were better controlled for CV risk factors, with higher percentages receiving aspirin, ß-blockers, and antihyperlipidemic agents. Therefore, the beneficial effect of ACE inhibitors, if any, may have been diminished by the lower baseline risk of the PEACE population.

ACE inhibitors continue to be recommended for all stage B patients with history of MI, regardless of LV ejection fraction (LVEF) or presence of HF (Class I, evidence level A).^[1] The use of ACE inhibitors in patients with reduced LVEF and no HF symptoms who have not experienced MI is also now a Class I, evidence level A recommendation (previously Class I, evidence level B). This recommendation was upgraded on the basis of long-term follow-up of the SOLVD (Studies of Left Ventricular Dysfunction) population, indicating that ACE inhibitors delayed the onset of HF symptoms and decreased the combined risk of death and HF hospitalizations in asymptomatic patients with reduced LVEF, whether due to remote ischemic injury or nonischemic cardiomyopathy.^[13] In addition, ACE inhibitors are now recommended in patients with hypertension and LV hypertrophy without HF symptoms (Class IIa, evidence level B). This recommendation is based on extrapolation of results from hypertension studies demonstrating that ACE inhibitors delay the onset of HF symptoms in these patients and the fact that LV hypertrophy is now recognized as an independent CV risk factor.^[7,14] For patients with stage C HF, ACE inhibitors continue to receive a Class I, evidence level A recommendation for all patients with current or prior symptoms of HF and reduced LVEF, unless contraindicated.^[1]

The new guidelines address the practical use of ACE inhibitors.^[1] Doses should be titrated to ranges that have demonstrated mortality and morbidity benefits in clinical studies. However, if target doses cannot be achieved, intermediate doses should be used with the expectation that differences in outcomes will be small. The ATLAS (Assessment of Treatment with Lisinopril and Survival) trial compared high-dose (32.5-35 mg daily) versus low-dose (2.5-5 mg daily) lisinopril.^[15] Compared with low doses, high-dose therapy resulted in an 8% reduction in mortality (p = 0.128) and a 12% reduction in the combined endpoints of risk of death or hospitalization for any reason (p = 0.002). Failure to achieve target ACE inhibitor doses should not delay initiation of ß-blocker therapy. When using ACE inhibitors, renal function and serum potassium concentration should be assessed within 1-2 weeks of drug initiation or dosage changes, and periodically thereafter.

Retrospective analyses of large-scale clinical trials have raised concerns that aspirin might counteract the benefits of ACE inhibitors by inhibiting kinin-mediated prostaglandin synthesis.^[16] However, a comprehensive systematic overview of 22 060 patients from 6 randomized ACE inhibitor trials demonstrated significant benefit with ACE inhibitors irrespective of concomitant aspirin therapy.^[17] Clinicians who choose not to use aspirin with ACE inhibitors may consider clopidogrel as an alternative, although clopidogrel does not have an indication for primary prevention of coronary artery disease and the daily cost is approximately 50 times that of aspirin.

Angiotensin II Receptor Blockers

For stage A patients, ARBs now receive a Class IIa, evidence level C recommendation to prevent HF in patients who have a history of atherosclerotic vascular disease, diabetes mellitus, or hypertension with associated CV risk factors.^[1] This consensus opinion was derived from the findings of 2 trials?the Effects of Losartan on Renal and Cardiovascular Outcomes study^[18] and the Irbesartan Diabetic Nephropathy Trial^[19]?demonstrating significant reductions in the incidence of HF with ARBs in patients with diabetes and nephropathy.

For stage B patients, ARBs are recommended for post-MI patients without symptoms of HF who are intolerant to ACE inhibitors and have a low LVEF (Class I, evidence level B).^[1] ARBs are also recommended for nonischemic patients with low LVEF and no symptoms of HF who are ACE inhibitor intolerant (Class IIa, evidence level C). ARBs are a particularly appropriate alternative for patients with ACE inhibitor-induced cough. Conversely, ARBs are as likely as ACE inhibitors to cause hypotension, worsening of renal function, and hyperkalemia. Although angioedema occurs less frequently with ARBs, the potential life-threatening nature of this adverse effect necessitates extreme caution when ARBs are used in patients with a history of ACE inhibitor-induced angioedema.

While no study has specifically addressed the use of ARBs in asymptomatic patients with reduced LVEF, in the recent VALIANT (Valsartan in Acute Myocardial Infarction Trial), investigators compared the effects of captopril, valsartan, or both in 14 808 patients with low LVEF and HF at the time of MI.^[20] Target doses were valsartan 160 mg twice daily, captopril 50 mg 3 times daily, or a combination of valsartan 80 mg twice daily with captopril 50 mg 3 times daily. Results demonstrated that valsartan was as effective as captopril in reducing mortality in this patient population (HR1.0; 97.5% CI 0.90 to 1.11) and a composite endpoint of fatal and nonfatal CV events (HR 0.96; 97.5% CI 0.89 to 1.04). Combining valsartan with captopril increased adverse event rates without additional survival benefits. Extrapolating from these results in symptomatic patients, the investigators concluded that ARBs are appropriate alternatives to ACE inhibitors in stage B patients.^[1]

In stage C patients, ARBs approved for HF treatment, candesartan and valsartan, now receive a Class I, evidence level A recommendation (upgraded from Class IIa, evidence level B) for use in patients with current or prior HF symptoms and reduced LVEF who are ACE inhibitor intolerant.^[1] It is also considered reasonable to use an ARB as an alternative first-line therapy in patients with mild-to-moderate HF and reduced LVEF, especially when patients are already taking ARBs for other indications (Class IIa, evidence level A). Key studies that led to upgrading this recommendation were the Val-HeFT (Valsartan in Heart Failure Trial)^[21] and the CHARM Alternative (Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity) trials.^[22] In the Val-HeFT study, 5010 patients were randomized to receive valsartan or placebo in addition to standard therapy with digoxin, ß-blockers, and ACE inhibitors.^[21] The effect of valsartan versus ACE inhibitors in reducing the combined endpoint (cardiac arrest with resuscitation, HF hospitalizations, or administration of intravenous inotropic or vasodilator drugs for ≥4 h without hospitalization) and mortality was examined in post hoc analyses. For patients unable to tolerate ACE inhibitors because of cough or angioedema, valsartan demonstrated benefit by reducing the primary combined endpoints and mortality (valsartan vs placebo: RR 0.56; 95 % CI 0.39 to 0.81). Similarly, in 2028 patients unable to tolerate ACE inhibitors, candesartan reduced hospitalizations and mortality (HR 0.70; 95% CI 0.60 to 0.81) compared with placebo.^[22]

As with ACE inhibitors, the new guidelines stress that renal function and serum potassium concentration should be assessed within 1-2 weeks of ARB initiation or dosage changes, and periodically thereafter.^[1] For stable patients, it is reasonable to add ß-blocker therapy before full target doses of ARBs are achieved.

Combination Therapy With Angiotensin-Converting Enzyme Inhibitors and Angiotensin-Receptor Blockers

Studies have substantiated that ARBs are reasonable alternatives to ACE inhibitors for chronic HF, with preference given to candesartan and valsartan.^[21-24] An interesting approach to further attenuate the renin-angiotensin-aldosterone system involves the addition of an ARB to concurrent ACE inhibitor therapy. Rationale for this combination is based on the fact that serum concentrations of angiotensin II remain elevated, despite the use of target ACE inhibitor doses.

Two trials addressed the combined use of an ARB and an ACE inhibitor in HF.^[21,25] In the first study, valsartan was evaluated in NYHA Class II or III HF patients (mean LVEF 27%).^[21] In the valsartan group (n = 2511) compared with the placebo group (n = 2499), background therapies included ACE inhibitors (92.6% vs 92.8%), ß-blockers (34.5% vs 35.3%), diuretics (85.5% vs 85.2%), and/or digoxin (67.1% vs 67.7%), respectively. Valsartan was initiated at 40 mg twice daily, with a target dose of 160 mg twice daily. The key findings were that valsartan, added to standard treatment, had no effect on overall mortality compared with placebo but reduced the combined endpoint (28.8% vs 32.1%; p = 0.009) of mortality and morbidity (cardiac arrest with resuscitation, HF hospitalization, and intravenous inotropic or vasodilator therapy). Although valsartan was reasonably well tolerated, adverse events leading to its discontinuation occurred more often with valsartan (9.9% vs 7.2%; p < 0.001) and included dizziness, hypotension, and renal impairment. A post hoc analysis raised concern that use of valsartan with both an ACE inhibitor and a ß-blocker might be associated with higher mortality and combined endpoint rates.

A second investigation evaluated candesartan in NYHA Class II or III HF patients (mean LVEF 28%).^[25] Patients were allocated to placebo (n = 1272) or candesartan (n = 1276), starting with 4 or 8 mg, and increased to a target dose of 32 mg daily. Background therapies in the candesartan and placebo groups included ACE inhibitors (100% vs 99.8%), diuretics (90% vs 90.1%), ß-blockers (55% vs 55.9%), spironolactone (17.4% vs 16.9%), and/or digoxin (57.6% vs 59.2%), respectively. The combined endpoint (CV death or HF hospitalization) was lower with candesartan compared with placebo (38% vs 42%; p = 0.01). Differences in total mortality were not significant (30% vs 32%; p = 0.105). Importantly, the investigators found no risk with the addition of candesartan to ACE inhibitor and ß-blocker therapy. This finding, which was an a priori objective, refutes concerns raised in the retrospective analysis of the Val-HeFT study.

As in the valsartan investigation, the addition of an ARB was associated with a higher rate of adverse events, including hypotension (p = 0.079), increased serum creatinine levels (p = 0.0001), and hyperkalemia (p < 0.0001).

Based on the above findings, the ACC/AHA guidelines state that one can consider the addition of an ARB to conventional treatment, including an ACE inhibitor, in persistently symptomatic patients with reduced LVEF.^[1] Notably, this is a Class IIb, evidence level B recommendation, meaning that its usefulness/efficacy is less well established by evidence/opinion. This fact is important, because the addition of an aldosterone antagonist to ACE inhibition is preferred in severe symptomatic HF. Triple therapy with an ACE inhibitor, an ARB, and an aldosterone antagonist is not recommended due to a lack of data and concern of hyperkalemia (Class III, evidence level C).

Aldosterone Antagonists

Data supporting the use of aldosterone antagonists in HF with advanced symptoms (stage C, NYHA Class III or IV) from LV systolic dysfunction initially came from RALES (the Randomized Aldactone Evaluation Study).^[26] The trial assessed the efficacy and safety of spironolactone in patients with NYHA Class III or IV HF from either ischemic or nonischemic causes and LVEF less than 35%. Most patients were receiving ACE inhibitors (95%), while only 10% were on ß-blockers. Compared with placebo, spironolactone reduced all-cause mortality 30% (46% vs 35%; RR 0.70; 95% CI 0.60 to 0.82; p < 0.001), while hospitalizations for worsening HF were reduced 35%.

In 2003, EPHESUS (the Eplerenone Post-Acute MI Heart Failure Efficacy and Survival Study), evaluated 6632 patients with a recent MI, LVEF less than or equal to 40%, and evidence of HF. Patients were randomized to receive the selective aldosterone blocker eplerenone or placebo.^[27] Standard therapy included an ACE inhibitor or ARB (86%) and a ß-blocker (75%). Therapy was initiated between 3 and 14 days of infarction (mean 7.3). The mean eplerenone dose was 43 mg daily over a follow-up period of 16 months. Compared with placebo, eplerenone resulted in a 2% absolute risk reduction in total mortality (14.4% vs 16.7%; p = 0.008), a 13% absolute risk reduction in the composite of CV mortality/CV hospitalizations (p = 0.002), and a 17% reduction in CV mortality (p = 0.002). Further analysis revealed that 30 day all-cause mortality was also reduced with eplerenone (4.6% vs 3.2%; absolute RR 1.4%; p = 0.004).^[28]

While these data support the use of aldosterone antagonists in selected HF patients (Class I, evidence level B), concerns have been raised regarding the increased use of these agents without appropriate serum potassium concentration and renal function monitoring.^[29,30] A Canadian population-based time-series study revealed a fourfold increase in spironolactone prescriptions following publication of the results of RALES. This increased spironolactone use was associated with a fourfold increased risk of hospitalizations for hyperkalemia and a sixfold increased risk of hyperkalemia-related mortality.^[29] Concomitant use with ACE inhibitors or ARBs can further increase the risk of hyperkalemia. Strict serum potassium monitoring criteria were observed in both RALES and EPHESUS, occurring after randomization, at 3 days, 1 week, 1 month, and every 3 months thereafter. An increase in serum potassium levels greater than 5.5 mEq/L prompted a review of current medications and diet and possible dosage reduction or discontinuation of the aldosterone antagonist. Additionally, patients with renal compromise (serum creatinine >2.5 mg/dL or creatinine clearance <30 mL/min) were excluded, and the dose was reduced in patients with mild-to-moderate renal dysfunction (creatinine clearance 30-50 mL/min). With these aggressive guidelines, the incidence of hyperkalemia (≥6 mEq/L) in the RALES population was 2% with spironolactone versus 1% with placebo and, in the EPHESUS population, 5.5% eplerenone versus 3.9% with placebo (both p < 0.05). Pharmacists can play an important role by encouraging implementation of the recommended strategies to minimize the risk of hyperkalemia ( Table 3 ).

While the ACC/AHA 2005 Guideline Update^[1] does not fully differentiate between aldosterone antagonist drugs, current data are insufficient to assume equivalence and similar benefit:risk ratios. Thus, it may be prudent to observe the regimens and indications demonstrated by the pivotal clinical trials. With selectivity for the mineralocorticoid receptor and reduced activity at androgen and progesterone receptors, eplerenone may be a rational substitution in males suffering from breast pain, gynecomastia, or impotence and in females suffering from menstrual irregularities secondary to spironolactone.

Combination Therapy with Hydralazine and Isosorbide

Hydralazine and isosorbide dinitrate was the first drug combination suggested to decrease mortality in HF.^[31] The use of hydralazine/nitrate has been superceded by ACE inhibitors, based on a comparative trial demonstrating greater survival benefit with enalapril.^[32] However, the combination of hydralazine/nitrate remains a reasonable alternative in patients who cannot be given ACE inhibitors or ARBs because of drug intolerance, hypotension, or renal insufficiency.^[1]

A retrospective analysis of earlier vasodilator trials suggested the hydralazine/nitrate combination may be particularly beneficial in African Americans.^[33,34] The presumed benefit is due to increased nitric oxide concentrations. A recent prospective trial evaluated the combination proprietary drug BiDil (hydralazine 37.5 mg/isosorbide dinitrate 20 mg/tablet).^[35,36] Therapy was titrated to 2 tablets 3 times daily in self-identified African Americans with a mean LVEF of 24%. Subjects receiving BiDil (n = 518) or placebo (n = 532) also received standard treatment, including diuretics (88% vs 91.5%), ACE inhibitors (69.4% vs 69.5%), ARBs (17.2% vs 16.5%), ß-blockers (74.1% vs 73.5%), digoxin (58.5% vs 60.7%), and spironolactone (40.2% vs 37.6%). This trial is markedly different from previous hydralazine/nitrate studies because the combination was added to rather than compared with standard treatments.

The study was discontinued prematurely because a significantly lower mortality rate occurred in the hydralazine/nitrate group compared with the placebo group (6.2% vs 10.2%, respectively; p = 0.02). Additionally, the combination drug had a lower rate of HF exacerbation (8.7% vs 12.8%; p = 0.04). Despite producing minimal reductions in blood pressure, this potent vasodilator combination was associated with a higher rate of headache (47.5% vs 19.2%; p < 0.001) and dizziness (29.3% vs 12.3%; p < 0.001).^[35]

The ACC/AHA guidelines state that it is reasonable to add hydralazine and isosorbide dinitrate to standard therapy (including ACE inhibitors and ß-blockers) in blacks with NYHA functional Class III or IV HF and further comment that, although not yet tested, other populations may also benefit from this treatment, including patients with refractory HF and increasing renal insufficiency from ACE inhibitor therapy (Class IIa, evidence level A).^[1] Since ethnicity is a relatively imprecise term, pharmacogenomic research is needed to determine whether genetic differences, rather than race, affect a patient's response to hydralazine/nitrates.

ß-Blockers

Recommendations for the use of ß-blockers in HF are essentially unchanged.^[1] They continue to be a mainstay of HF management for patients with structural disease or symptomatic HF (stages B, C, D) without significant contraindications to their use. In addition, ß-blockers may be useful in controlling hypertension in many stage A patients. ß-Blockers are recommended for patients with cardiac structural abnormalities or remodeling who have not developed HF symptoms (stage B).^[1] A notable exception is asymptomatic patients with severe valvular disease and normal LVEF. For all patients with a recent or remote history of MI, ß-blockers are indicated, regardless of LVEF or presence of HF (Class I, evidence level A). Readers are referred to the ACC/AHA Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction for the rationale of this recommendation.^[37]

In addition, ß-blockers are indicated in all stage B patients without a history of MI who have a reduced LVEF with no HF symptoms (Class I, evidence level C).^[1] While clinical trials are lacking in this population, this consensus opinion was derived from data in 2 post-MI trials.^[38,39] Retrospective evidence from the SAVE (Survival and Ventricular Enlargement) study examining the relationship between ß-blocker use and the development of CV events, using Cox proportional hazards modeling, demonstrated a 30% risk reduction in CV death, a 21% risk reduction in the development of HF (ie, reduction in progression to new-onset HF symptoms similar to reduction achieved with ACE inhibitors), and an 11% reduction in recurrent MI, independent of ACE inhibitor use.^[38] Data from the BHAT (Beta-Blocker Heart Attack Trial) in post-MI patients, randomized to receive propranolol or placebo, showed an approximate 15% risk reduction in the development of HF symptoms in patients with history of HF prior to randomization.^[39] Together, these data suggest, and are supported by consensus opinion of the practice guideline committee, that administration of ß-blockers with proven efficacy in post-MI trials may be considered in patients with a low ejection fraction, but without symptomatic HF.

For all stable patients with current or prior HF symptoms (stage C) and a reduced LVEF, ß-blockers are recommended unless contraindicated (Class I, evidence level A).^[1] Moreover, the guidelines specifically recommend therapy with 1 of 3 ß-blockers proven to reduce mortality (bisoprolol, carvedilol, or sustained-release metoprolol succinate) but do not make further distinctions among these drugs.^[40-43] This is appropriate, given the numerous factors that may impact individual drug selection. The practical use of ß-blockers has been well described in the literature, including selection of patients, initiation and maintenance of therapy, and risks of treatment.^[43,44]

Diuretics

While little new information has become available, the 2005 guidelines reinforce the critical role that diuretics play in the management of symptomatic HF. Diuretics are recommended for all patients with symptoms of fluid retention and many with a prior history of fluid retention (Class I, evidence level C for stage C HF and Class I, evidence level B for stage D HF).^[1] In addition, the guidelines specifically state that diuretics should be used in combination with salt restriction. This subtle change is important because high dietary sodium intake can be responsible for diuretic resistance among patients with HF.

The guidelines note that periodic weight and symptom assessment should direct diuretic dosage adjustment, based on the patient's fluid status.^[1] In a nurse-driven telephone follow-up program, recently discharged HF patients were contacted at least weekly. Nurses assessed patients for symptoms of HF exacerbation and adjusted diuretic doses as appropriate. After one year, this intervention resulted in a 30% reduction in emergency department visits (p = 0.029) and readmissions (p = 0.045).^[45] In another study, a patient-driven sliding-scale diuretic protocol in patients with NYHA Class II-IV HF resulted in a 90% reduction in emergency department visits (p = 0.015).^[46] Diuretic dose adjustment was based on a 6 point questionnaire that evaluated signs (daily weights) and symptoms (dyspnea, peripheral edema) of HF. These data suggest that a flexible dosing strategy could enhance diuretic effectiveness.

The relationship between diuretic use and the efficacy and safety of other HF therapies is also important. Symptoms of volume overload can arise upon initiation or dose escalation of a ß-blocker. Some ß-blocker clinical trials managed this complication by increasing the diuretic dose to regain a euvolemic state and improve tolerance of the increased ß-blocker dose.^[40,43] Diuretic-induced volume depletion can negatively impact titration of both ACE inhibitors and ß-blockers by increasing the risk of hypotension. In the absence of fluid overload, diuretic dosage reduction should be considered.

Cyclooxygenase (COX) inhibitors (both COX-2 selective and nonselective) can cause fluid retention and congestive symptoms, which may attenuate diuretic efficacy.^[47] Thus, these agents should be used cautiously or avoided entirely in HF patients. The renal effects of COX inhibitors, along with diuretic-associated volume depletion, may result in additive risks of renal dysfunction. Diuretic resistance may develop in patients taking COX inhibitors, as well as in those with significant renal impairment or excess sodium intake. As outlined in the guidelines, potential strategies for overcoming diuretic resistance include continuous infusions of loop diuretics, combination diuretic regimens, or the addition of positive inotropic agents to improve renal blood flow.^[1]

Digoxin

Recommendations for digoxin use in patients with HF have changed only slightly with the 2005 guidelines.^[1] The primary change was to reclassify the recommendation for use from Class I, evidence level A to Class IIa, evidence level B. The primary role of digoxin is to reduce hospitalizations in patients with current or past symptoms of systolic HF. The only long-term study to support the use of digoxin in HF was the DIG (Digitalis Investigation Group) trial.^[48] In this trial, 6800 patients with primarily NYHA Class II or III HF symptoms were treated with digoxin or placebo for approximately 3 years. While there was no impact on mortality, digoxin reduced HF hospitalizations 30% (p < 0.001). Consequently, the newly reclassified guideline for digoxin is better aligned with current trial evidence.

Digoxin is often a good choice for rate control in patients with atrial fibrillation and HF because use of calcium-channel blockers with negative inotropic effects is generally discouraged, and rapid titration of ß-blockers to higher doses for rate control may not be tolerated.^[1] When digoxin is used in the HF patient with atrial fibrillation, a loading dose may achieve faster rate control; conversely, there is little reason to use a loading dose for symptomatic HF alone.

Evidence suggests that the beneficial effects of digoxin in HF occur throughout the therapeutic range.^[49] However, digoxin toxicity occurs with higher drug concentrations, and hypokalemia may increase the risk even at lower ranges. Overall, aggressive digoxin dosing (serum concentrations >1.0 mg/L) does not significantly improve efficacy and may increase toxicity risk.

Heart Failure with Preserved Left-Ventricular Function

Perhaps as many as 50% of patients with symptomatic HF have normal systolic function or only minimally reduced LVEF.^[50,51] Currently, most clinicians appreciate that there is less than complete understanding of underlying mechanisms and that the diagnosis of diastolic HF is often one of exclusion. Nonetheless, most will accept that there exists impaired ventricular relaxation, increased passive stiffness, and an abnormal ventricular end-diastolic pressure-volume relation, resulting in increased LV diastolic pressures.^[52-54] Epidemiologic studies that have attempted to characterize HF patients with preserved systolic function clinically have identified various associated characteristics, including female gender, history of hypertension, history of atrial fibrillation, and advanced age. Only one randomized, prospective trial has evaluated drug therapy.^[55] The CHARM-Preserved (Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity) trial evaluated the effects of the ARB candesartan in patients with HF and preserved LVEF (mean 54%) on the composite outcome of CV mortality or hospitalization for worsening HF.^[55] The trial randomized 3023 patients to treatment or placebo, with a median follow-up of 36 months. There was a nonsignificant 11% RR reduction in the primary outcome with candesartan compared with placebo (HR 0.89; 95% CI 0.77 to 1.03; p = 0.118). CV death did not differ, but fewer patients in the candesartan group were hospitalized for HF (15.2% vs 18.5%; p = 0.017). The ACC/AHA 2005 Guideline Update focuses on the absence of data for preserved LV function and stresses ameliorating symptoms and reducing or controlling risk factors ( Table 4 ).^[1]

End-Stage Heart Failure

The mortality rate from chronic HF exceeds 70% at 8 years.^[5] Heart transplant is the only known cure, but less than 5% of patients are eligible candidates.^[1] Palliative care, a growing approach to the management of chronic stage D HF, uses an interdisciplinary approach to identify patient, family, and caregiver goals in conjunction with symptomatic, psychosocial, and spiritual needs, to prepare an individualized care plan.^[56] Hospice care, a form of palliative care available when a chronic HF patient has decided to forgo certain measures that prolong life, while seemingly appropriate, is currently underutilized.^[56] HF is the leading noncancer diagnosis of patients in hospice care, comprising 12.2% of all hospice patients in 2004.^[57] Symptoms reported by patients with chronic HF in their final weeks of life include anxiety, pain, dyspnea, edema, fatigue, depressed mood, anorexia, incontinence, and constipation.^[58,59] Therefore, pharmacotherapy of palliative and hospice care includes oxygen, anxiolytics, morphine or other narcotics, and antidepressants, as well as diuretics, digoxin, ACE inhibitors, ARBs, and ß-blockers.^[56]

Small doses of morphine sulfate, such as 2-3 mg taken orally, may relieve dyspnea and pain. Doses may be titrated upwards as needed.^[60] Medications such as nonsteroidal antiinflammatory drugs should be avoided, as they may lead to fluid retention. Selective serotonin reuptake inhibitors are commonly prescribed for depressive symptoms that include poor sleep, anorexia, and feelings of guilt or worthlessness. HF patients should have their serum sodium concentrations checked periodically, if appropriate, to monitor for selective serotonin receptor uptake inhibitor-associated hyponatremia.^[61] Tricyclic antidepressants should be avoided, as they may cause orthostatic hypotension and ventricular arrhythmias.^[60] Continuous positive airway pressure has been used to improve sleep-disordered breathing and LV function.^[62]

Perhaps the most controversial recommended drug therapy for palliative care is outpatient continuous inotrope infusions of either milrinone or dobutamine (Class IIb, evidence level C).^[1] While the increased risk of sudden death with inotrope infusions is well known,^[63] the benefits of intermittent or continuous inotrope infusions for palliation or hospice care are not well described.^[60,64-66] Typically, outpatient continuous inotrope infusions are administered as a bridge to transplant in patients who have implantable cardioverter defibrillators (ICDs).^[67,68] However, in patients who elect hospice care, ICDs are usually deactivated. Most studies of inotropes for palliative or hospital care have been small case series or observational open-label studies of intermittent inotrope therapy (rather than continuous infusion therapy), describing success as clinical improvement.^[60,64-66] There have been no reports of outcomes in hospice patients nor systematic analysis of specific symptom improvement in patients prescribed inotropes for the stated purpose of palliative care. Unfortunately, few hospices currently provide dobutamine or milrinone continuous infusions.^[61] While commonly used in clinical practice for palliative care, intermittent infusions of inotropes are not recommended for management of chronic HF in the 2005 guidelines (Class III, evidence level B).^[1]

Summary

The ACC/AHA 2005 Guideline Update for Chronic HF emphasizes the importance of risk factor modification, early detection, and therapies proven to prevent and/or reduce morbidity and mortality.^[1] Because HF cannot be cured with drug therapy, lifelong follow-up and patient education are needed to promote adherence to diet and medications. Importantly, the new guidelines recognize the necessity of a team approach in the care of patients with HF. At every step along the continuum, from the development of CV risk factors through the various stages of symptomatic HF, numerous opportunities exist for pharmacists to use their expertise to delay disease progression and improve patient outcomes.

CLICK HERE for more information about this journal.