Diagnosis
Stage A
The first step in the diagnosis of heart failure is to identify patients who are at risk for developing the syndrome; this concept was part of the reasoning behind the new ACC/AHA staging system.14 Patients in stage A are those with CAD, hypertension, diabetes, a history of alcohol abuse or exposure to cardiotoxic drugs (e.g., certain chemotherapeutic agents, cocaine), a history of rheumatic fever, or a family history of car-diomyopathy or sudden death. In these high-risk patients, reversible risk factors should be aggressively treated to prevent heart failure from developing.40,41
Figure 2 The evolution of heart failure by stage.
Stage b
Stage B patients have asymptomatic, structural heart disease. Echocardiography is easily the best diagnostic tool to uncover left ventricular hypertrophy or dilatation, valvular disease, or wall motion abnormalities indicative of previous myo-cardial infarction. Patients in stage B represent a significant portion of the heart failure population and constitute a key opportunity for intervention. In a community-based survey, less than half of patients with moderate or severe systolic or dia-stolic dysfunction, as defined by echocardiographic parameters, had recognized heart failure.42 At this time, the ACC/AHA guidelines do not recommend routine screening echocardiog-raphy for the large number of patients at risk for the development of heart failure. Nonetheless, a class IIa indication is given for noninvasive evaluation of left ventricular function in patients with a strong family history of cardiomyopathy or in those exposed to cardiotoxic therapies.14
Stages c and d
Stages C and D fit the traditional definition of heart failure. Patients in stage C or D usually present with decreased exercise tolerance, fluid retention, or both. Initial assessment of these patients should focus on the structural abnormality leading to heart failure, as well as evaluation of its etiology. Initial testing should include a 2-D echocardiogram with Doppler flow studies, a chest x-ray, electrocardiography, and laboratory studies, including urinalysis, complete blood count, serum chemistries, liver function studies, and thyroid-stimulating hormone measurement. These tests serve primarily to exclude other potential causes of dyspnea or fatigue.14 In patients with dyspnea, measurement of serum brain natriuretic peptide (BNP) may aid in the diagnosis; marked elevation of BNP levels suggests that the dyspnea is cardiac rather than pulmonary in origin.43 Strong consideration should be given to excluding significant CAD, because CAD is the leading cause of left ventricular dysfunc-tion.24 The ACC/AHA guidelines strongly encourage that pa-tients with heart failure be evaluated with coronary angiogra-phy rather than noninvasive testing, even if they do not have a known history of CAD; the guidelines cite the fact that nonin-vasive testing can often lead to inaccurate results in patients with cardiomyopathies (e.g., perfusion defects or wall motion abnormalities in patients with a nonischemic cardiomyopa-thy).14 Nonetheless, some argue that there is little evidence that revascularization changes outcome or prognosis in patients with left ventricular dysfunction and that it should therefore be used only to relieve angina.44
Table 3 Treatment of Heart Failure14
|
Stage A |
Treat hypertension |
|
Encourage smoking cessation |
|
|
Treat lipid disorders |
|
|
Encourage regular exercise |
|
|
Discourage alcohol intake, illicit drug use |
|
|
Prescribe ACE inhibitors if appropriate |
|
|
Stage B |
All measures used for stage A |
|
ACE inhibitors if appropriate (see text) |
|
|
Beta blockers if appropriate |
|
|
All measures used for stage A |
|
|
Drugs for routine use: |
|
|
Stage C |
ACE inhibitors |
|
Beta blockers |
|
|
Digitalis |
|
|
Dietary salt restriction |
|
|
All measures used for stages A, B, and C |
|
|
Mechanical assist devices |
|
|
Heart transplantation |
|
|
Stage D |
Continuous (not intermittent) I.V. inotropic infusions for palliation |
|
Hospice care |
ACE—angiotensin-converting enzyme
Several clinical parameters are useful for the subsequent evaluation and management of heart failure. Patients’ weights should be measured in the office, and patients should be taught to follow their weights at home to assess for fluid retention. Office evaluation of jugular venous pressure, hepatojugular reflux, the presence of a gallop rhythm, and peripheral edema can aid in initial diagnosis and can guide the need for diuresis. In addition, these signs of heart failure may be prognostically important.45
Diastolic heart failure
There is no precise definition of diastolic heart failure11; the diagnosis is usually made by a clinician who recognizes the typical signs and symptoms of heart failure despite the finding of normal systolic function (i.e., a normal LVEF) on an echocar-diogram. Doppler echocardiographic techniques can also aid in establishing the diagnosis of diastolic dysfunction.46,47
Treatment
Treatment for heart failure is keyed to the stage of the syndrome as defined by the recent ACC/AHA guidelines [see Table 3]. Treatment in all stages is aimed at preventing or palliating the remodeling process [see Pathophysiology, above]. In addition, therapy in stages C and D is intended to relieve the disabling symptoms of heart failure.
Stage a
The goal of treatment in stage A is to prevent structural heart disease. This is achieved by controlling risk factors (e.g., hypertension, CAD, diabetes mellitus, hyperlipidemia, smoking, alcohol ingestion, and use of cardiotoxic drugs), which lowers the incidence of later cardiovascular events. For example, effective treatment of hypertension decreases left ventricular hypertrophy and cardiovascular mortality; it can also reduce the incidence of heart failure by 30% to 50%.40,41
Diabetes deserves particular attention because diabetes patients have a high incidence both of CAD and of heart failure in the absence of CAD; diabetes causes many detrimental biochemical and functional cardiac changes independent of is-chemia.48 ACE inhibitors and angiotensin receptor blockers (ARBs) have assumed a major role in risk reduction for diabetic patients (see below). Studies have shown that in asymptomatic high-risk patients with diabetes or vascular disease who have no history of heart failure or left ventricular dysfunction, treatment with these agents yields significant reductions in death, myocardial infarction, and stroke49-51 or delays the first hospitalization for heart failure.52
Stages b, c, and d
The goals of therapy for patients with heart failure and a low LVEF are to decrease the progression of disease and the number of hospitalizations, improve symptoms and survival, and minimize risk factors.
Table 4 Pharmacotherapy of Heart Failure
|
Category |
Drug (Trade Name) |
|
|
|
|
Initial Daily Dose |
Maximum Daily Dose |
Comment |
||
|
Loop diuretics |
Bumetanide (Bumex) Furosemide (Lasix) Torsemide (Demadex) |
0.5-1 mg q.d. or b.i.d. 20-40 mg q.d. or b.i.d. 10-20 mg q.d. or b.i.d. |
Up to 10 mg Up to 400 mg Up to 200 mg |
Titrate to achieve dry weight; carefully monitor serum potassium and creati-nine levels |
|
ACE inhibitors |
Captopril (Capoten) Enalapril (Vasotec) Fosinopril (Monopril) Lisinopril (Prinivil, Zestril) Quinapril (Accupril) Ramipril (Altace) |
6.25 mg t.i.d. 2.5 mg b.i.d. 5-10 mg 2.5-5 mg 10 mg b.i.d. 1.25-2.5 mg |
50 mg t.i.d. 10-20 mg b.i.d. 40 mg 20-40 mg 40 mg b.i.d. 10 mg |
Carefully monitor serum potassium and creatinine levels |
|
Beta blockers |
Bisoprolol (Zebeta) Carvedilol (Coreg) Metoprolol tartrate (Lopressor) Metoprolol succinate extended release (Toprol-XL) |
1.25 mg 3.125 mg b.i.d. 6.25 mg b.i.d. 12.5-25 mg |
10 mg 25 mg b.i.d. (50 mg b.i.d. for patients > 85 kg) 75 mg b.i.d. 200 mg |
Titrate dosage up over 2- to 4-week intervals, carefully monitoring for signs and symptoms of fluid overload |
|
Digitalis glycosides |
Digoxin (Lanoxin) |
0.125-0.25 mg |
0.125-0.25 mg |
Narrow therapeutic window; monitor levels carefully in older patients and those with renal insufficiency |
|
Aldosterone inhibitors |
Spironolactone (Aldactone) |
25 mg |
50 mg |
50 mg q.d. was maximum dosage used in RALES trial78; use carefully with concurrent ACE inhibitor or ARB; carefully monitor serum potassium and creatinine levels; use if potassium < 5.0 mmol/L, creatinine < 2.5 mg/dl |
|
Angiotensin receptor blockers |
Candesartan (Atacand) Irbesartan (Avapro) Losartan (Cozaar) Valsartan (Diovan) |
8 mg 75 mg 25 mg 80 mg |
32 mg 300 mg 100 mg 320 mg |
Use if patients have cough or angioede-ma on ACE inhibitor |
ACE—angiotensin-converting enzyme
ARB—angiotensin receptor blocker
RALES—Randomized Aldosterone Evaluation Study
Simple interventions can help patients control their disease. For example, basic habits of moderate sodium restriction, weight monitoring, and adherence to medication schedules serve to prevent hospitalizations for rapid fluid overload. Other frequent causes of decompensation in heart failure include anemia, arrhythmias (especially atrial fibrillation), noncompliance with medications and diet, or the use of nonsteroidal anti-inflammatory drugs (NSAIDs).52-55
Medical Therapy
Pharmacologic treatment of heart failure routinely includes diuretics, angiotensin antagonists, beta blockers, and digoxin; spironolactone or inotropes may be beneficial in some cases [see Table 4].
Diuretics In symptomatic patients in stage C and stage D, diuretics are often the first drugs prescribed to decrease fluid overload and congestive symptoms. Loop diuretics are most often given to these patients, either as maintenance therapy or on an as-needed basis. Loop diuretics can be combined with thiazides to optimize diuresis.56,57
ACE inhibitors ACE inhibitors are recommended for all patients in stages B, C, and D. By decreasing the conversion of angiotensin I to angiotensin II, ACE inhibitors minimize the multiple pathophysiologic effects of angiotensin II, such as vasoconstriction and fibrosis. ACE inhibitors (but not ARBs) also decrease the degradation of bradykinin, a substance that causes vasodilation and natriuresis. In patients with heart failure, ACE inhibitors have been shown to improve survival and cardiac performance, to decrease symptoms and hospitaliza-tions, and to decrease or slow the remodeling process.58-60
Currently, it is not clear whether all ACE inhibitors are equally effective in all forms of heart failure. There are few data from controlled trials, for example, about the efficacy of ACE inhibitors in diastolic heart failure. Moreover, although several guidelines have emphasized the need to maximize the dose of ACE inhibitor to target levels (rather than using blood pressure alone to guide dose titration), current recommendations underscore the need to add beta blockers to the regimen of patients in stage C early in the course of treatment, even if target ACE inhibitor doses have not been achieved.
Angiotensin receptor blockers What is the role of ARBs in heart failure? These agents block the effects of angiotensin II at the angiotensin II type 1 receptor site. ACC/AHA guidelines recommend the use of ARBs only in patients who cannot tolerate ACE inhibitors because of cough or angioedema14; the guidelines stress that ARBs are comparable to ACE inhibitors but are not superior.61-63 Since publication of the guidelines,however, several key trials have reported successful intervention with ARBs in stage B and C patients.64 65 The role of ARBs in patients already on beta blockers, with or without an ACE inhibitor, remains to be elucidated. Symptomatic patients who cannot tolerate ACE inhibitors or ARBs, usually because of renal insufficiency, may benefit from a combination of hy-dralazine and isosorbide dinitrate for afterload reduction.66
Beta blockers Although it was once taught that beta block-ers were contraindicated in heart failure secondary to systolic dysfunction, multiple studies have now shown an impressive effect of these drugs on many aspects of heart failure and at all stages of the syndrome. The primary action of these agents is to counteract the harmful effects of the increased sympathetic nervous system activity in heart failure. Beta blockers improve survival, ejection fraction, and quality of life; they also decrease morbidity, hospitalizations, sudden death, and the maladaptive effects of remodeling.67,68 Long-term placebo-controlled trials have shown improvement in systolic function and reversal of remodeling after 3 to 4 months of treatment with beta blockers.69-71 A recent analysis showed that even in the sickest of heart failure patients, beta-blocker therapy was well tolerated and led to a decrease in mortality and hospitalizations as early as 14 to 21 days after initiation of therapy.72 However, clinicians should be extremely cautious about starting beta blockers in patients with significant reactive airway disease, in diabetic patients with frequent episodes of hypoglycemia, or in patients with bradyarrhythmias or heart block who do not have a pacemaker implanted.
In the United States, two beta blockers are specifically approved for treatment of heart failure: carvedilol and long-acting metoprolol. Beta blockers should be started at the lowest possible dose and titrated up slowly at 2- to 4-week intervals. Patients should be closely monitored for worsening of symptoms or fluid retention, which can sometimes occur early in therapy with these agents. If patients do have exacerbations during initiation of beta blockade, diuretic therapy can be increased, and titration of the beta blocker can proceed more slowly.
Digoxin Digoxin has long been a mainstay in the treatment of symptomatic patients with left ventricular dysfunction, despite a lack of data from clinical trials showing benefit. A large randomized study demonstrated that digoxin was successful in decreasing hospitalization for heart failure—an important clinical end point—but did not decrease mortality.73 Recent post hoc analysis of data from this trial showed that in the patients randomized to receive digoxin therapy, mortality may have been higher in women than in men.74 It is hypothesized that the therapeutic window for digoxin may be different in men and women, with women perhaps needing a lower dose of the drug.75 Indeed, data suggest that digoxin improves morbidity as effectively at low serum concentrations (< 0.09 ng/ml) as at higher levels, and with less toxicity.76 Clinicians should carefully monitor all patients for signs and symptoms of digox-in toxicity, especially those patients who are elderly or have renal dysfunction. Physicians and patients should also keep in mind that digoxin interacts with numerous other drugs.
Spironolactone Another relatively old drug with new data to support its use in heart failure is the aldosterone antagonist spironolactone. Because of the activation of the renin-an-giotensin-aldosterone axis, which is incompletely suppressed by ACE inhibitors, patients with heart failure have increased circulating levels of aldosterone. This leads to sodium retention and potassium loss. Aldosterone also works locally within the myocardium, contributing to hypertrophy and fibrosis in the failing heart.77 A large randomized trial has shown that the addition of low-dose spironolactone (25 mg daily) to standard treatment reduces morbidity and mortality in patients with NYHA class III and IV heart failure (stage C and D patients).78
Intravenous inotropes Patients with refractory heart failure (stage D patients) often require intermittent intravenous in-otropic therapy to aid in diuresis and to improve symptoms. No survival benefit has been demonstrated with inotropic treatment. These agents have received a class IIb indication in the ACC/AHA guidelines14—that is, they are regarded as palliative.
Diastolic heart failure
Despite the large number of patients with primarily diastolic heart failure, few clinical trials have addressed the management of these cases. Physiologic principles used to guide treatment in these patients include control of blood pressure, heart rate, myocardial ischemia, and blood volume.14
Revascularization and surgical therapy
Patients in all stages of heart failure must be evaluated for CAD. Angioplasty and surgical revascularization improve is-chemic symptoms and can lead to improved ejection fraction and decreased incidence of sudden death.79
Clinical trials to investigate the role of surgical interventions in halting or reversing the remodeling process are now under way. Such interventions include mitral valve repair or replacement, mechanical devices to reduce wall stress, and surgical excision of infarcted tissue.80-83
Cardiac transplantation remains the only definitive treatment for stage D patients, but it is available only to roughly 2,500 patients a year in the United States.84 Left ventricular assist devices are available to support patients waiting for heart transplant. There is growing evidence supporting the use of these devices as destination therapy for stage D patients, many of whom are not eligible for cardiac transplantation.85
Implanted devices
Biventricular Pacing Systems
Many heart failure patients have intraventricular conduction delays that may contribute to altered myocardial contractility or dyssynchrony. Biventricular pacing is a novel therapy for patients with left ventricular systolic dysfunction, particularly those with a left bundle branch block. The goal of this therapy is to restore the usual pattern of electrical activation of the left ventricle and thereby restore ventricular synchrony. Pacing leads are placed in the right atrium and the right ventricle and into a cardiac vein in the lateral wall of the left ventricle via the coronary sinus. There is evidence that with restored ventricular synchrony from a biventricular pacing system, the remodeling process is halted and reversed. Trials have shown that implantation of a biventricular pacer results in decreased ventricular size and volumes, improved ventricular function, and less mitral regurgitation. This has led to improved exercise tolerance, decreased hospitalizations, and improved quality of life.86-88 Although individual randomized trials have not shown a mortality benefit for biventricular pacing, a recent meta-analysis of four of the largest trials to date showed a 51% decrease in death from progressive heart failure.89 In addition, a large clinical trial of biventricular pacing in patients with heart failure was stopped early because resynchronization therapy was found to confer a statistically significant benefit regarding the combined end point of mortality and hospitalization.90
Figure 3 Data from the Framingham Heart Study indicate a steady upward trend since the 1950s in age-adjusted survival after the onset of heart failure.96 Estimates shown are for patients 65 to 74 years of age.
Cardioverter-Defibrillators
The use of implantable cardioverter-defibrillators (ICDs) for the primary prevention of sudden death in patients with left ventricular dysfunction has grown enormously in recent years. There is increasing evidence that ICD placement reduces mortality in patients with ischemic cardiomyopathy, regardless of whether they have nonsustained ventricular arrhythmias.91 The role of these devices in patients with heart failure of a nonischemic cause has yet to be elucidated and is the subject of several ongoing trials.
Prognosis
Despite many advances in the management of heart failure, this disorder remains life-threatening. Symptomatic heart failure continues to confer a worse prognosis than the majority of cancers in the United States, with 1-year mortality averaging 45%.12,13 Nonetheless, it is difficult to discuss the prognosis of heart failure as a whole, because an individual patient’s likelihood of survival is related to the cause of the heart failure, as well as multiple other clinical factors. For example, given the same severity of heart failure symptoms, an 85-year-old woman with ischemic cardiomyopathy would have a lower likelihood of survival than a 45-year-old man with idiopathic cardiomyopathy. One study of 1,230 patients with cardiomy-opathy found that survival was significantly worse in patients with cardiomyopathy from ischemia, infiltrative disease, car-diotoxic chemotherapy, HIV infection, or connective tissue disease than in patients with idiopathic cardiomyopathy.92
There are conflicting data about the prognosis of diastolic heart failure. However, recent studies have shown that mortality in these cases may be as high as in systolic heart failure, and hospitalization rates are equal.
It is also important for clinicians to remember that a low LVEF is not universally predictive of poor outcome. In patients referred for transplantation, survival has correlated more closely with other variables—notably, peak exercise oxygen con-sumption.94 One prospectively validated model for predicting survival in patients with severe heart failure incorporates LVEF with six other clinical factors: presence of coronary disease, resting heart rate, mean arterial blood pressure, presence of in-traventricular conduction delays, serum sodium concentration, and peak exercise oxygen consumption.95 These tools can be used to stratify patients according to risk and to make the most appropriate use of modern therapies and treatment modalities.
How can we improve the prognosis of patients with heart failure? A recent report from the Framingham Heart Study has shown promising evidence of increasing survival after the diagnosis of heart failure [see Figure 3].96 To further this trend, we must work toward widespread implementation of the therapies known to decrease morbidity and mortality in heart failure. We must also investigate more completely the impact of medical therapy on the survival of patients with diastolic heart failure. There should be continued efforts to increase the number of traditionally underrepresented patients (e.g., women and minorities) enrolled in heart failure trials. Finally, in keeping with the emphasis of the ACC/AHA guidelines, we must concentrate on identifying and treating those patients at greatest risk for heart failure to prevent it from occurring.
