Initial Evaluation and Therapy

Acute heart failure is defined as the rapid onset of severe symptoms of heart failure, usually within hours to several days. Acute heart failure can occur with predominant systolic or diastolic dysfunction. Acute heart failure is often life-threatening and requires urgent diagnostic and therapeutic interventions, often simultaneously.²³ Acute myocardial ischemia is a common cause and should always be considered in the differential diagnosis of this syndrome.

Several distinct clinical syndromes of acute heart failure can be identified²³ (Table 29.1).

Symptoms of acute heart failure are similar to those of chronic heart failure but are more severe. Symptoms of tissue hypoperfusion, such as fatigue, weakness, confusion, nausea, and anorexia, may be subtle but are important to recognize as they may herald impending cardiogenic shock. Chest pain may indicate acute coronary ischemia.

Physical examination often shows pulmonary rales and wheezes, an S₃ gallop, and elevation of jugular venous pressure. Peripheral pulses are weak and thready with diminished cardiac output states. A low cardiac output is reliably predicted by a low “proportional pulse pressure,” which is calculated by the pulse pressure (systolic blood pressure minus diastolic blood pressure) divided by systolic blood pressure. A ratio below 0.25 predicts a cardiac index below 2.2 L/minute/m².37,38 The skin may be cool and clammy and there may be evidence of cyanosis. Peripheral edema and ascites may indicate concomitant right ventricular failure of longer duration. Chest radiography is done urgently. An electrocardiogram (ECG) is needed to assess for signs of ischemia and infarction, and to evaluate for arrhythmia. Cardiac rhythm needs to be monitored continuously. Laboratory examination includes evaluation of hemoglobin and hematocrit, electrolytes, renal and liver function, thyroid profile, and cardiac biomarkers (troponin I or troponin T) to look for evidence of myocardial necrosis. BNP level assists in the diagnosis of heart failure in patients presenting with dyspnea, and can be followed serially to assess effectiveness of therapy. Pulse oximetry helps to assess oxygenation and pulmonary function. An arterial line is helpful in managing patients with hypotension or cardiogenic shock. Urgent two-dimensional echocardiography is essential to evaluate left ventricular size and function, right ventricular function, valve function, and the presence of pericardial effusion. Doppler echocardiographic assessment of valve stenosis and regurgitation and of hemodynamics is invaluable.

When patients are admitted to hospital with acute decompensation of chronic systolic heart failure, the specific reason for a patient’s deterioration must be searched for and corrected when possible (Box 29.2). Environmental factors such as excessive salt and fluid intake or alcohol consumption are common. Patient adherence to outpatient therapies must be assessed, as heart failure regimens often involve numerous medications. Emotional and physical stressors should be corrected when feasible.

Concomitant administration of medications for noncardiac conditions can have detrimental effects. A partial listing includes corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs). These drugs can cause fluid retention and can aggravate hypertension. NSAIDs also interfere with the beneficial renal effects of angiotensin-converting enzyme (ACE) inhibitors and can interfere with the action of loop diuretics.³⁹ The use of NSAIDs has been reported to increase the risk of hospitalization for heart failure by tenfold in patients with a history of heart failure.⁸ Metformin and thiazolindinediones can contribute to water retention and aggravate the symptoms and signs of heart failure. Cancer chemotherapies can cause myocardial damage. Cardiac toxicity due to anthracycline chemotherapy is well described. Tyrosine-kinase inhibitors, a newer class of cancer chemotherapy, are also being recognized as agents that can aggravate heart failure and cardiomyopathy.⁴⁰ Cardiac medications such as calcium channel blockers and antiarrhythmic drugs can also have direct negative effects on left ventricular contractility. Calcium channel blockers are generally contraindicated in patients admitted with acute decompensated heart failure.²³ Type 1A and 1C antiarrhythmic drugs are also contraindicated in patients with abnormal left ventricular systolic function.

Acute and chronic extracardiac conditions may also cause heart failure decompensation. Pulmonary embolus, infectious illnesses, and sepsis occur commonly. Anemia, blood loss, and thyroid disease need to be assessed and corrected. Renal failure often has etiologic factors similar to those of heart failure (e.g., hypertension, vascular disease), and worsening renal function will often aggravate heart failure. Obstructive sleep apnea can lead to exacerbation of heart failure symptoms and can be effectively treated. Influenza and pneumococcal vaccines should be administered to patients to prevent the cardiac decompensation associated with respiratory infections.

Lastly, coexistent cardiovascular illness can aggravate heart failure. Acute or chronic coronary ischemia should always be suspected, evaluated, and corrected with revascularization strategies when appropriate. Uncontrolled hypertension and cardiac arrhythmias (most commonly atrial fibrillation and ventricular arrhythmias) frequently accompany left ventricular dysfunction. Worsening valve regurgitation, endocarditis, and bilateral renal artery stenosis are other examples of conditions that can lead to heart failure exacerbations that are treatable.

There are few controlled-trial data to arrive at evidence-based guidelines for the treatment of acute heart failure. Many recommendations are based on small studies, experience, observation, and a general consensus of opinion.⁴¹ The goals of initial therapy are to improve symptoms, optimize blood pressure, lower PCWP, and improve cardiac output. Treatments to reverse or prevent myocardial injury are instituted, and a search for reversible causes of heart failure needs to occur. Optimization of other comorbid conditions is important, including hyperglycemia, renal disease, and pulmonary function.

Initial therapy includes supplemental oxygen and assessment of the need for ventilatory assistance with noninvasive positive airway pressure ventilation or endotracheal intubation. Noninvasive ventilation improves oxygenation and pulmonary compliance and decreases work of breathing. Endotracheal intubation may be required for patients with severe hypercapnia, acidosis, and respiratory muscle fatigue. The use of continuous oxygen administration alone was prospectively compared with the use of continuous positive airway pressure ventilation (CPAP) and noninvasive intermittent positive pressure ventilation (NIPPV) in 1069 patients who presented with acute cardiogenic pulmonary edema. No difference among these therapies was noted in the primary end point of death at 7 days, or in the secondary end point of death plus endotracheal intubation at 7 days. Noninvasive ventilation did result in more rapid improvement in dyspnea, tachycardia, hypercapnia, and acidosis. There was no difference in safety or efficacy between CPAP and NIPPV.⁴²

Initial medical therapy includes intravenous morphine, which acts as a vasodilator and often reduces heart rate. Intravenous loop diuretics, such as furosemide, offer rapid and effective symptom relief and are almost always prescribed. Intravenous vasodilators are very useful, especially in patients with severe hypertension; intravenous nitroglycerin and intravenous nitroprusside are used most commonly. Beta blockers should be given early to patients with heart failure and ischemic chest pain, hypertension, or tachyarrhythmias. They should be used with caution in patients with severe heart failure and should be withheld initially in the presence of hypotension, shock, bradycardia, or heart block. Calcium channel blocking agents are generally contraindicated in the acute setting.

Treatment of arrhythmias is essential. Rapid atrial fibrillation is a common problem in these patients. In the Euroheart Failure Study, 9% of patients hospitalized with acute heart failure had atrial fibrillation during the hospitalization, and 42% had a history of paroxysmal atrial fibrillation.⁴³ Other studies report atrial fibrillation in 25% to 30% of hospitalized heart failure patients.³⁶ Control of the ventricular response to atrial fibrillation is vitally important, especially in patients with diastolic heart failure. This control can be achieved rapidly with the use of intravenous beta blockers such as metoprolol or esmolol, parenteral digoxin, or intravenous amiodarone. Intravenous diltiazem can be used in patients whose left ventricular systolic function is known to be normal or near normal.

Indications for Invasive Hemodynamic Monitoring

Placement of a pulmonary artery (PA) catheter enables the clinician to accurately measure PCWP, cardiac output, and mixed venous oxygen saturation. It can also help assess the effectiveness of therapy. Whether to routinely use PA catheters to assess and manage patients with acute heart failure has been long debated. The ESCAPE trial evaluated the routine use of PA catheterization in patients hospitalized with acute exacerbation of chronic heart failure and left ventricular systolic dysfunction.⁴⁴ There was no difference in the primary end point of days alive out of the hospital during 6 months after discharge in groups managed with or without a PA catheter. There were no significant adverse effects with PA catheter use in this study. There were no subgroups identified in which use of the PA catheter was beneficial. However, there was a trend noted in improving the initial diuresis, with less deterioration of renal function, in the PA catheter group. The authors concluded that there was no indication for the routine use of PA catheters in the setting of acute heart failure.

However, a PA catheter is often essential for the management of patients with acute severe heart failure. Findings on physical examination are often insensitive indicators of hemodynamic status. Indications for PA catheter use include cardiogenic shock, differentiating pulmonary from cardiac causes of dyspnea, hemodynamic assessment if one is unsure of the diagnosis or severity of heart failure by clinical assessment, worsening renal function, guiding parenteral vasodilator therapy, and in patients who are not improving with initially prescribed therapy.³⁷ PA catheter placement is also necessary as part of the evaluation for cardiac transplantation or the implantation of a ventricular assist device (VAD) (Box 29.3).

Consecutive patients with severe heart failure were evaluated and classified according to hemodynamic measurements of PCWP and cardiac index. Patients were described as “dry” with average PCWP less than 17 mm Hg, or “wet” with PCWP reading of 29 mm Hg on average. The patients were also described as “warm” versus “cold,” based on a cardiac index of greater than 2.1 L/minute/m² versus an index of less than 1.6 L/minute/m². The severity of symptoms and findings on physical examination did not predict the hemodynamic status as defined by invasive monitoring. In addition, the hemodynamic picture did not predict the response to therapy and survival was similar in all four groups, except that patients with higher cardiac output and lower PCWP had slightly better outcomes than patients with low cardiac output and high PCWP.⁴⁵

Tailoring pharmacologic therapy to hemodynamic measurements is often helpful and necessary to determine precise measurements of cardiac output and left ventricular filling pressure, in order to guide intensive intravenous drug therapy. Aggressive therapy tailored to the response in hemodynamic measurements has been advocated as an effective method to obtain more rapid and sustained improvement in patients with the most severe heart failure.⁴⁶ When PCWP is reduced to less than 16 mm Hg, and right atrial pressure is reduced to less than 8 mm Hg, most patients will improve acutely and for the remainder of their hospitalization. Additional hemodynamic goals include reducing systemic vascular resistance to less than 1200 dynes × sec/cm⁵, raising cardiac index to greater than 2.6 L/minute/m², and maintaining systolic blood pressure over 80 mm Hg. PCWP can be lowered to a normal value of 10 to 12 mm Hg in many patients with significant left ventricular dysfunction without untoward effects.^46,47 In a group of patients referred for cardiac transplantation, a combination of aggressive parenteral therapy, targeted to optimal hemodynamics, followed by conversion to appropriate oral therapy, resulted in clinical improvement so that 30% of these patients were able to be removed from transplant lists.⁴⁶

Intravenous Diuretics

Although no randomized clinical trials exist, the use of loop diuretics is supported by a long history of clinical success. These agents increase renal excretion of salt and water. The onset of action of intravenous bolus furosemide is 30 minutes, and the drug peaks at 1 to 2 hours. The half-life of the medication is 6 hours, so twice daily dosing is usually required.³⁹ Other loop diuretics often used are bumetanide and torsemide (Tables 29.2 and 29.3). Several small clinical trials suggested that a constant infusion of a loop diuretic resulted in superior diuresis when compared to intermittent bolus dosing,^48,49 although other studies did not confirm this.⁵⁰ A large, randomized controlled study was performed in patients hospitalized with acute decompensated heart failure who were taking a high dose of furosemide prior to admission. Patients were randomized within 24 hours of admission to bolus dosing or constant infusion, and usual daily outpatient dose (given intravenously) versus high dose (2.5 times their usual daily dose). No significant differences were noted in predefined outcomes between bolus and infusion administration. However, the high-dose group had better relief of dyspnea and more fluid and weight loss than the lower-dose group; also, 23% of the high-dose group had a significant deterioration in renal function, but at 60 days there was no difference in renal function between the two groups.⁵¹

An association between high-dose loop diuretics and a worse prognosis has been observed. There is concern that this may be mediated by further activation of the renin-angiotensin-aldosterone system by loop diuretics. However, in a retrospective analysis utilizing propensity matching, hospital mortality rate was not different between low-dose and high-dose diuretic groups.⁵² It is likely that poorer outcomes associated with high-dose diuretics is not due to the drug itself but reflects a greater severity of heart failure illness with concomitant renal disease.⁵³

Whatever initial dose of diuretic is chosen, subsequent dosing should be titrated to the response of the patient’s fluid status and symptoms. Dosage reduction should be considered as the clinical status improves. Hypokalemia, alkalosis, and hypomagnesemia are frequent side effects of loop diuretics and can potentiate the occurrence of arrhythmias. Electrolyte levels must be carefully monitored during aggressive diuretic therapy.

Patients with chronic heart failure with or without renal dysfunction may exhibit resistance to loop diuretics, defined as an acute reduction in diuretic efficacy after repeated loop diuretic dosing. With chronic loop diuretic use, there is an increase in sodium reabsorption in the distal nephron and stimulation of aldosterone release. In edematous states there is delayed oral absorption of the drug. With renal dysfunction there may be reduced levels of drug delivered to the renal tubule. This resistance is associated with a poorer prognosis.²³ Diuretics that act distally in the renal tubule, such as metolazone or hydrochlorothiazide, or aldosterone blockers such as spironolactone can be added.⁴ Combination diuretic therapy induces a greater diuresis than simply increasing the dose of loop diuretic further. The response may be delayed for 48 to 72 hours. Combining diuretics often augments diuresis even in the setting of significant chronic kidney disease, and a good response can be expected in over 70% of patients. Particular attention must be given to following potassium, sodium, chloride, and magnesium levels when combination diuretic therapy is prescribed⁵⁴ (Table 29.4).

Vasopressin Inhibitors

The use of novel diuretics, vasopressin inhibitors, has been evaluated in clinical trials of treatment of acute heart failure.⁵⁵ Vasopressin is a hormone synthesized in the hypothalamus; its major effect is to control free water clearance. It acts through V1a receptors in vascular smooth muscle and myocardium, leading to peripheral and coronary vasoconstriction, myocyte hypertrophy, and positive inotropy. Vasopressin also acts through V2 receptors at the renal tubule collecting ducts to cause free water retention and hyponatremia. Levels of vasopressin are increased in patients with chronic heart failure, and higher vasopressin levels correlate with worse heart failure severity. Vasopressin release is stimulated by changes in serum osmolality and cardiac output and leads to further vasoconstriction and retention of free water.⁵⁶ Inhibition of vasopressin’s effects would have theoretic benefits in patients with heart failure.⁵⁷ In contrast to loop diuretics, inhibition of vasopressin theoretically would not cause hypotension or neurohormonal activation, and would not aggravate cardiac arrhythmias due to electrolyte depletion.

Conivaptan is a vasopressin antagonist that inhibits V1a and V2 receptors. Tolvaptan and lixivaptan are antagonists selective for the V2 receptor. These medications increase urine volume and free water excretion, with a rise in the serum sodium concentration. The use of conivaptan in patients with class III-IV heart failure was associated with increased urine output, and decreases in PCWP and right atrial pressure, without changes in cardiac output.⁸ Oral use of tolvaptan was associated with fluid loss and diuresis without change in heart rate, blood pressure, or serum creatinine.

In a large, multicenter, placebo-controlled randomized trial called EVEREST, tolvaptan was administered to patients hospitalized with heart failure. There were no adverse consequences on heart rate, blood pressure, or serum electrolytes and there was more rapid improvement in dyspnea and signs of heart failure when compared to usual therapy.⁵⁸ Hyponatremia improved. Hemodynamic effects included rapid reduction in PCWP and right atrial pressure.⁵⁹ However, at 10-months follow-up after hospitalization, there was no improvement in mortality rates or readmission rates.⁶⁰ Vasopressin inhibitors are approved for treatment of severe hyponatremic states but are not approved for use in heart failure.

Parenteral Vasodilators (Table 29.5)

Intravenous vasodilator therapy is often added to diuretic therapy to obtain more rapid improvement in severe heart failure. A clear indication for vasodilators is in patients with severe hypertension and pulmonary edema. Their use should also be considered in patients who are not responding to intravenous diuretics combined with standard oral therapies. Blood pressure response to these medications needs to be carefully monitored because hypotension is a common effect. Improvement in hemodynamics has been obtained with aggressive intravenous vasodilator therapy using intravenous nitroprusside, intravenous nitroglycerin, or nesiritide. The choice of agents depends on matching the patient’s clinical picture and hemodynamics with the predicted effects of each vasodilator.61,62

Angiotensin-Converting Enzyme Inhibitors

ACE inhibitors are of limited use as parenteral therapy in patients with acute severe heart failure in the urgent setting. Enalaprilat is an intravenous bolus formulation that can be used in patients with chronic heart failure who are taking chronic oral ACE inhibitor therapy and who are unable to take oral medication. The maximal action occurs 1 to 4 hours after administration, with a 6-hour duration of action.

Inotropic Drugs (see Table 29.5)

Vasopressors

Ultrafiltration

A new approach to the treatment of acute heart failure is venovenous ultrafiltration. This process removes iso-osmolar extracellular fluid via a convection process and is not associated with changes in serum electrolytes.⁷⁸ Anticoagulation is utilized during the process. Newer ultrafiltration systems utilize peripheral arm veins, and central venous access is not required. In a study of 40 patients admitted with heart failure, usual care for heart failure with diuretic therapy was compared with usual care combined with ultrafiltration. At 24 hours, average fluid loss with diuretic therapy was 2838 mL, compared with 4650 mL with ultrafiltration. Weight loss and improvement in dyspnea was similar with the two therapies. Ultrafiltration was not associated with significant changes in heart rate or blood pressure.⁷⁹ In another study, 20 patients with acute decompensated heart failure with renal insufficiency and diuretic resistance were treated with an 8-hour course of ultrafiltration. Over 24 hours, an average of 8650 mL of fluid was removed, with an average weight loss of 6 kg during hospitalization. Renal function remained stable, and there was no associated hypotension.⁷⁸

The UNLOAD trial investigated the use of ultrafiltration compared to intravenous diuretic therapy in 200 patients admitted with acute decompensated heart failure. Ultrafiltration was associated with more rapid weight loss and fluid loss. At 90 days, there were fewer rehospitalizations for heart failure in the ultrafiltration group, without change in mortality rates. There was no difference with respect to renal function in the two groups.⁸⁰

A trial was conducted that compared ultrafiltration with standard intravenous diuretic therapy in patients admitted to hospital with acute decompensated heart failure, persistent congestion, and worsening renal function. Fluid was removed with UF at a rate of 200 mL per hour. This trial showed worse outcomes with ultrafiltration at 96 hours of therapy. Renal function worsened with UF and did not with diuretics. Total weight loss was unchanged between the two groups. Serious adverse effects were more common in the UF group, mainly renal failure, bleeding, and catheter-related complications. There was no difference between the two groups in symptom relief, mortality, or rehospitalization at 60 days.^80a At this time, ultrafiltration is reserved for the relief of severe congestion in patients who are refractory to aggressive diuretic therapy and should not be used to replace diuretics.⁸¹ Further studies will determine if this therapy should be used more routinely in the management of acute heart failure.

Diuretics

Loop diuretics are routinely used in patients with signs or symptoms of fluid retention.⁴ Diuretics are continued once patients are euvolemic to prevent reaccumulation of fluid. A flexible dosing schedule, based on daily weights and close telephone contact with a heart failure treatment team member, can be very effective in maintaining a euvolemic state while reducing the frequency of side effects.

Furosemide is the most common loop diuretic used. Bumetanide or torsemide may be helpful in patients with suboptimal responses to furosemide, due to their more consistent absorption after oral administration. Metolazone or a thiazide diuretic can be used in addition to a loop diuretic in patients with more severe heart failure due to their synergistic effects. Patients must be periodically monitored for side effects of these agents including azotemia, hypokalemia, alkalosis, hyponatremia, and hypomagnesemia (Table 29.6).

Beta Blockers (Table 29.7)

Catecholamine levels are increased in heart failure, and higher levels correlate with worse disease severity. Catecholamines have direct negative effects on the myocardium including induction of myocyte hypertrophy and apoptosis.¹³ Clinically, these effects are evident as left ventricular dilatation, increased ischemia, increased peripheral vasoconstriction, and cardiac arrhythmia.

Beta blockers interfere with catecholamine-mediated activation of cardiac β-receptors and thereby attenuate β-receptor-mediated increases in heart rate and oxygen consumption. Sympathetic nervous system–mediated effects on remodeling can be prevented or attenuated. In addition, carvedilol blocks β-receptors and also α-receptors, which mediate vasoconstriction and increased cardiac contractility.

Multiple large trials using beta blockers in thousands of patients with chronic heart failure, or in post–myocardial infarction patients with ejection fractions below 40%, have demonstrated significant and consistent reductions in the need for repeat rehospitalization for heart failure. Mortality rates are also significantly improved. The BHAT study showed a relative 26% reduction in mortality rates at 2 years in post–myocardial infarction patients treated with propranolol.83,84 The CIBIS II trial using bisoprolol showed a 34% relative risk reduction in hospitalizations and mortality rates at 16 months of therapy.⁸⁵ The MERIT-HF study showed a relative reduction of 33% in these end points at 12 months using metoprolol succinate.⁸⁶ Patients with more severe heart failure, symptom class III-IV, with severely reduced ejection fractions below 25% were studied in the COPERNICUS trial. These patients began therapy with carvedilol during hospitalization. At mean follow-up of 10.4 months, a 35% relative mortality rate reduction was seen, with improvement in mortality rates beginning as early as 3 weeks after initiation of therapy⁸⁷ (Fig. 29.4). In these trials, beta blockers were not discontinued more frequently than placebo for perceived side effects, and there was no increased risk of heart failure exacerbation due to beta-blocker therapy when compared to placebo, even in the early phases of drug administration.⁸⁸ Several trials with carvedilol have shown an approximate 6% absolute increase in left ventricular ejection fraction after a minimum of 2 years of therapy.⁸⁹

Beta blockers should be started for treatment of heart failure and left ventricular dysfunction when patients are stable. Beta blockers should be instituted early, once patients are deemed euvolemic, and titrated up to maximal recommended doses (e.g., metoprolol succinate 200 mg daily or carvedilol 25 mg twice daily) or maximally tolerated doses. They are useful in patients with ischemic and nonischemic cardiomyopathy. Beta blockers should be instituted in patients who appear compensated and stable off this medication, as these patients have a high likelihood of disease progression to symptomatic heart failure within 12 months. Beta blockers are recommended for left ventricular dysfunction even in the absence of symptoms (stage B patients). This therapy should be combined with other recommended heart failure pharmacologic therapy. Contraindications to beta-blocker use include severe bradycardia or bronchospastic lung disease.

For patients who are already taking beta-blocker therapy and who are hospitalized with acute decompensation of heart failure, beta blockers should be continued. Withdrawal of this medication was associated with higher short-term mortality rates and more frequent rehospitalizations for heart failure in several observational studies.⁹⁰ In patients with a severe heart failure exacerbation, reduction of the chronic dose by 50% can be considered. Beta blockers should only be stopped in the presence of symptomatic hypotension, cardiogenic shock, severe bradycardia, or heart block. If beta blockers are temporarily withheld, they should be reinstituted prior to discharge unless there are ongoing specific contraindications.^91,92

Angiotensin-Converting Enzyme Inhibitors (see Table 29.7)

These agents act to counteract the effects of activation of the renin-angiotensin system by blocking the conversion of angiotensin I to angiotensin II, inhibiting the deleterious effects of angiotensin II and aldosterone. Many studies have shown benefits of ACE inhibitor therapy in post–myocardial infarction patients as well as patients with cardiomyopathy and heart failure. The SOLVD trial using enalapril in patients with class II-III heart failure and ejection fractions below 35% showed a 10% relative risk reduction in mortality rate at 3.5 years.⁹³ Enalapril given to patients less ill, with asymptomatic left ventricular dysfunction (ejection fractions under 35%) in the companion SOLVD trial showed a reduction in the clinical diagnosis of heart failure and a statistically significant reduction in heart failure hospitalizations at 3 years.⁹⁴ A meta-analysis performed of 32 trials involving 7105 patients, using captopril, enalapril, ramipril, quinapril, or lisinopril, found that ACE inhibitors reduce the risk of death and hospitalization due to heart failure.⁹⁵ These results indicate that the positive effects of ACE inhibitors are likely to be a class effect, and not specific to a particular agent.

Side effects of these agents include cough, worsening renal function in patients with underlying renal disease or renal artery stenosis, angioneurotic edema, and hyperkalemia. The dose of ACE inhibitors should be increased as renal function and blood pressure allow. Studies have shown that medium doses of ACE inhibitors, when compared to low doses, significantly reduce hospitalization rates for heart failure. However, higher doses given routinely do not significantly reduce cardiovascular events further.⁹⁶ Additional improvement in symptoms and mortality rates is thus best achieved by adding on beta blocker and other heart failure therapy rather than increasing ACE inhibitors to the highest doses.⁹⁷

In a study of class II-III chronic heart failure patients over age 65, with an ejection fraction of less than 35%, the importance of first beginning heart failure therapy with an ACE inhibitor or a beta blocker was studied. The primary end point was time to death or hospitalization for heart failure. Initiation of the beta blocker bisoprolol was not inferior to the strategy of starting therapy with the ACE inhibitor enalapril. There was also no difference in safety.⁹⁸

Angiotensin Receptor Blockers (see Table 29.7)

Angiotensin receptor blockers (ARBs) work to counter the effects of angiotensin II at the tissue level by blocking angiotensin II receptors. Multiple studies have shown benefits of these medications in patients with heart failure. Large numbers of patients in controlled trials have been studied, and these drugs have been as well studied as the ACE inhibitors. ARBs have been used as a substitute for ACE inhibitors or given in combination with ACE inhibitors and beta blockers.

The RESOLVD trial, using candesartan in heart failure patients with a mean ejection fraction of 27%, showed equivalent mortality rates and similar exercise tolerance and functional class to patients treated with enalapril at 3.5 years.⁹⁹ ELITE II, a study using losartan compared with captopril in patients with ejection fractions under 40%, showed no difference in mortality rates or congestive heart failure admissions. Losartan was better tolerated because of the lower incidence of problematic cough.¹⁰⁰ The ValHeft 2001 trial showed that valsartan as a substitute for ACE inhibitor therapy was associated with a relative 33% risk reduction in mortality rate when compared with placebo.¹⁰¹ In CHARM, candesartan was prescribed for patients with ejection fractions under 40%. A 17.5% relative risk reduction in cardiovascular death and congestive heart failure admissions was seen when this ARB was used as a substitute for ACE inhibitors.¹⁰² When candersartan was added to therapy with ACE inhibitors and beta blockers, a small 10% relative risk reduction was seen, without increased mortality rates.¹⁰³

ARBs are an appropriate choice for patients who cannot be maintained on ACE inhibitors because of side effects such as cough. Patients with angioneurotic edema during ACE inhibitor therapy have often been successfully treated with ARBs without developing this complication.104,105 Adding ARB therapy onto ACE inhibitors and beta blockers may achieve a small additional benefit, at the risk of more renal dysfunction and hyperkalemia.

Combination Hydralazine/Isosorbide Dinitrate

Combination therapy with the vasodilators hydralazine and isosorbide dinitrate (ISDN) was associated with improvement in mortality rate when compared to placebo in one study in the era prior to the advent of ACE inhibitors and beta-blocker therapy for heart failure.¹¹⁰ A retrospective analysis of this study suggested that African-American patients may have benefited preferentially. To evaluate this finding prospectively, the A-Heft study enrolled over 1000 self-described African-American patients with class II-IV heart failure and ejection fractions below 45%. The use of the combination of hydralazine with ISDN, titrated to a dose of 75 mg hydralazine plus 40 mg ISDN given three times daily, was associated with a 40% relative risk reduction in mortality at 10 months and a 33% relative risk reduction in first hospitalization for heart failure. This therapy was added on to treatment with beta blockers, ACE inhibitors, and spironolactone.¹¹¹ Hydralazine-ISDN is approved for treatment of African-American patients with heart failure and left ventricular systolic dysfunction.

Digoxin

Digoxin works by inhibiting the myocyte sodium-potassium pump, leading to increased intracellular calcium levels and increased inotropy. It also has vagotonic effects. However, digoxin is a relatively weak inotropic agent. The use of digoxin in heart failure was studied in large numbers of patients in the Digitalis Investigation Group (DIG) trial. A decreased need for rehospitalization for heart failure was seen with this therapy. However, there was no improvement in overall mortality rate.¹¹² A post-hoc analysis of this data concluded that patients with lower serum digoxin levels (0.5-0.9 ng/dL) did have lower mortality rates and lower rates of heart failure hospitalization when compared to those with levels greater than 0.9 ng/mL.¹¹³

Digoxin is indicated only for patients with symptomatic heart failure, stages C and D.⁴ It is also useful in heart failure patients with atrial fibrillation to help control the ventricular rate. Digoxin is not useful in the setting of acute heart failure, and it should be avoided in patients with hyopkalemia, bradycardia, or heart block.

Acute Heart Failure Following Myocardial Infarction

In a large registry of 5573 consecutive patients with acute myocardial infarction, 42% of patients had heart failure or left ventricular systolic dysfunction during hospitalization.¹¹⁶ These patients tended to be older, were more commonly women, and were more likely to have had previous myocardial infarction or coronary bypass surgery. Comorbid conditions were present more commonly, including peripheral arterial disease, hypertension, diabetes mellitus, or previous stroke. In-hospital mortality rate for these patients was 13%, versus 2.3% for patients with acute myocardial infarction but without heart failure or left ventricular dysfunction. Mortality rate ranged 13% to 21% for patients with lung congestion and left ventricular ejection fraction below 40%. Other complications also occurred more commonly in these patients, including atrial and ventricular arrhythmias, reinfarction, and stroke (Figs. 29.6 and 29.7).

In patients with acute heart failure due to acute myocardial infarction, rapid reperfusion is the cornerstone of therapy and may be achieved with thrombolytic therapy, acute coronary angioplasty, or urgent coronary artery bypass surgery. In the GRACE Study, revascularization therapies were associated with a lower mortality rate in patients with ACS and acute heart failure.¹¹⁵

In patients who develop heart failure or significant left ventricular systolic dysfunction following myocardial infarction, a number of pharmacologic therapies have been shown in large placebo-controlled randomized studies to improve mortality rate and reduce repeat hospitalization. Beta blockers should be part of standard post–myocardial infarction therapy in these patients. In the CAPRICORN study, the use of carvedilol led to a significant 23% relative risk reduction.¹¹⁷ SAVE was the first trial to show that the use of an ACE inhibitor, captopril, was beneficial in post–myocardial infarction patients with ejection fractions below 40%.¹¹⁸ There was a 5% absolute mortality rate reduction after 42 months of follow-up. In AIRE, treatment with the ACE inhibitor ramipril, started 3 to 10 days after myocardial infarction in patients with heart failure, resulted in a significant mortality rate benefit at an average of 15 months of follow-up.¹¹⁹ Another trial showed that treatment with the ACE inhibitor trandolapril following myocardial infarction and an ejection fraction below 35% resulted in a significantly improved survival at 2 to 4 years of follow-up.¹²⁰ In VALIANT, a high dose of the ARB valsartan was as effective as an ACE inhibitor in improving survival and reducing cardiovascular morbidity.¹²¹

Therefore beta blockers and ACE inhibitors should be started early and continued long term in patients with reduced left ventricular ejection fraction following acute myocardial infarction. ARBs are recommended in those patients who are intolerant to ACE inhibitors.

Aldosterone blockers have also been shown to be effective in improving prognosis in patients with heart failure or left ventricular dysfunction following myocardial infarction and are recommended for these patients. The EPHESUS study showed that eplerenone significantly reduced all-cause mortality rates and repeat hospitalizations at 16-month follow-up.¹²² Reduction in mortality rate and sudden cardiac death was noted as early as 30 days after initiation of eplerenone.¹²³

Implanted Cardioverter-Defibrillator Therapy

The ICD was compared to antiarrhythmic drugs for secondary prevention of sudden cardiac death in the AVID study. These patients had been resuscitated from cardiac arrest or survived ventricular tachycardia associated with syncope and had ejection fractions under 40%. In the study 1016 patients were randomized to receive an ICD or antiarrhythmic drugs (over 90% received amiodarone). There was a statistically improved survival rate with ICD therapy at 1, 2, and 3 years of follow-up.¹⁵² In two other studies of similar patients, a nonsignificant reduction in rates of all-cause mortality and arrhythmic death was seen with the ICD when compared to amiodarone,^153,154 and increased mortality rate was seen with propafenone therapy (a class IC antiarrhythmic).¹⁵⁴ Published guidelines recommend ICDs as first-line therapy, in preference to antiarrhythmic drugs, in patients with ischemic and nonischemic cardiomyopathy who have survived a cardiac arrest or an episode of sustained ventricular tachycardia.⁸²

ICD therapy has also been evaluated as primary prevention of arrhythmic death in patients with coronary heart disease and previous myocardial infarction with left ventricular dysfunction, without symptomatic clinical arrhythmias, and also in patients with nonischemic cardiomyopathy. In MADIT I, post–myocardial infarction patients with ejection fractions below 35% and asymptomatic nonsustained ventricular tachycardia on monitoring were studied with electrophysiologic testing. Patients were enrolled in this study if they had inducible ventricular tachycardia not suppressed with antiarrhythmic therapy. At 2 years of follow-up, total mortality rate was significantly reduced from 39% in the medically treated group (standard medical therapy with or without amiodarone) to 15% in the ICD group.¹⁵⁵ In the MUSTT study, a similar cohort of patients showed an improvement in mortality rate from 55% in patients treated with medication to 24% in patients treated with ICDs at 5 years.¹⁵⁶ In MADIT II, the patient population was extended to include patients with a history of myocardial infarction and ejection fractions of less than 30%. Importantly, in this study, neither ventricular arrhythmias seen on monitoring nor those induced at electrophysiologic study were necessary for inclusion. A statistically significant improvement in total mortality rate was seen in patients treated with ICDs, from 19.8% to 14.2% at 4 years¹⁵⁷. It should be noted that class IV heart failure patients were not included in any of these studies.

The Sudden Cardiac Death Heart Failure Trial (SCD-HeFT) enrolled patients with functional class II and III heart failure with left ventricular ejection fractions under 35%. This study differed from MADIT I and II in that a greater number of patients (48%) had nonischemic cardiomyopathy. Primary prevention of sudden cardiac death was compared among standard heart failure pharmacologic therapy, standard therapy combined with amiodarone, and standard therapy plus an ICD. After a mean follow-up of 45.5 months, mortality rate was improved from 29% in the medical group and 28% in the amiodarone group to 22% in the ICD group, which was statistically significant. This improvement was particularly notable in class II heart failure patients.¹⁵⁸ Benefits of ICD therapy were seen in patients with both ischemic and nonischemic cardiomyopathy. In the DEFINITE study, the use of the ICD as primary prevention was evaluated in 458 patients with nonischemic cardiomyopathy who had ventricular arrhythmia seen on routine monitoring. After a mean follow-up of 29 months, total mortality rate was not significantly reduced (17.5% with placebo vs. 12% in ICD, P = 0.08) but prevention of sudden death was significantly reduced.¹⁵⁹ A meta-analysis of all studies in which ICDs were used as primary prevention in patients with nonischemic cardiomyopathy indicated a statistically significant 31% relative risk reduction in favor of ICDs.¹⁶⁰

Thus, the approved use of ICD therapy for prevention of sudden cardiac death has been extended to prophylactic primary prevention therapy in patients with symptomatic heart failure, class II-III and left ventricular ejection fractions under 35% due to both ischemic as well as nonischemic cardiomyopathy.⁸²

Cardiac Resynchronization Therapy

In many patients with heart failure, there is abnormal timing and coordination of systolic motion of the intraventricular septum and left ventricular free wall, termed dyssynchrony. This often coexists with His-Purkinje conduction system disease, with marked QRS prolongation on ECG.¹⁶¹ In fact, left bundle branch block pattern with long QRS duration is associated with an increase in all-cause mortality rate in heart failure patients. Pacemaker therapies have been developed to correct left ventricular dyssynchrony, delivering timed pacing to both intraventricular septum and left ventricular free wall. This is termed biventricular pacing or cardiac resynchronization therapy (CRT). Standard dual-chamber transvenous leads are placed in the right atrium (in the absence of chronic atrial fibrillation) and right ventricle. The left ventricular free wall is paced via a third electrode passed through the coronary sinus into an epicardial lateral cardiac vein. Alternatively, a left ventricular lead can be placed directly on the epicardium of the lateral wall of the left ventricle via thoracoscopy. The pacemaker is programmed to coordinate timing of septal stimulation via the right ventricle with left ventricular lateral wall stimulation^161,162 (Fig. 29.8).

In the MIRACLE trial, 453 patients with ejection fractions under 35% and class III-IV heart failure and QRS duration greater than 130 ms were treated with standard medical therapy or resynchronization therapy plus medical therapy. At 6 months of follow-up, CRT resulted in a statistically significant improvement in 6-minute walking distance, quality of life score, and functional class, with fewer hospitalizations for recurrent heart failure.¹⁶¹ No significant mortality rate improvement was noted during a relatively short follow-up period. There was an 8% rate of unsuccessful left ventricular lead placement and a 1.2% incidence of serious complications of implantation of the pacemaker device, including coronary sinus dissection or perforation. A meta-analysis of three major resynchronization trials in 1634 patients concluded that chronic resynchronization therapy was associated with a statistically significant 51% reduction in death from progressive heart failure.¹⁶³

In the CARE-HF study, resynchronization therapy (without ICD) was evaluated in 813 patients with class III-IV heart failure due to left ventricular systolic dysfunction, with ejection fraction under 35% and QRS duration greater than 150 ms or QRS duration greater than 120 ms with signs of dyssynchrony on echocardiography. The primary end point of all-cause mortality rate plus unplanned hospitalization from cardiovascular causes was reduced from 55% in medically treated patients to 39% in resynchronization patients (P < 0.001). All-cause mortality rate was reduced from 30% to 20% with resynchronization therapy (P < 0.002). Mean follow-up was 29.4 months. Measures of quality of life were improved, and ejection fractions improved.¹⁶⁴ Thus, resynchronization therapy alone, without an ICD, can reduce mortality rates as well as improve symptoms in chronic heart failure patients.

Devices combining biventricular pacing and ICD capabilities were evaluated in patients with systolic heart failure and low ejection fraction. These patients often have indications for both devices. The rationale is to decrease morbidity and mortality rates associated with progressive heart failure as well as decrease mortality rates associated with sudden life-threatening ventricular arrhythmia. Biventricular pacing does not interfere with appropriate ICD detection and termination of ventricular arrhythmias.¹⁶⁵ The COMPANION trial enrolled 1520 patients with advanced heart failure, functional class III-IV, in sinus rhythm, who had the ECG finding of QRS duration greater than 120 ms. Therapies compared were best pharmacologic heart failure therapy, best therapy along with biventricular pacing, and best therapy along with combination biventricular pacing and ICD. Successful implantation occurred in 87% to 91% of patients in the latter two groups, with a procedural mortality rate of 0.5% to 0.8%. The primary end points of death from any cause or hospitalization for any cause, followed over 12 months, were 68% in the drug therapy group and 56% in both device groups, a significant difference. One-year rates of death or hospitalization due to cardiovascular cause were 60% in the drug group, with a relative risk reduction of 25% in the biventricular pacing group and 28% in the biventricular pacing/ICD group. The authors concluded that there was a significant reduction in heart failure hospitalizations with biventricular pacing, and there was an additional significant reduction in mortality rate when ICD therapy was added. Improvement occurred in both patients with ischemic and those with nonischemic cardiomyopathy.¹⁶⁶

CRT was then studied in class II and III heart failure patients with ejection fraction below 30%; 1798 patients with QRS duration greater than 120 ms during native conduction, or 200 ms during ventricular pacing, were treated with an ICD alone or with ICD plus CRT. At a mean follow-up of 40 months, there was a significant improvement with CRT in the primary end point of all-cause mortality rate plus hospitalization for heart failure (33.2% with CRT-ICD versus 40.3% with CRT alone, P < 0.001). Therefore, CRT has been successfully extended to class II heart failure patients with low ejection fraction.¹⁶⁷

Currently, devices combining CRT with ICD are recommended for patients with left ventricular systolic dysfunction with ejection fraction under 35%, QRS duration 120 ms or greater on ECG, in sinus rhythm, and class II-IV heart failure symptoms despite optimal medical therapy. These devices provide both symptomatic benefit and improve survival in patients with heart failure.

1. VADs can be used as a bridge to cardiac transplantation. A mortality rate of 30% has been reported in patients listed for and awaiting heart transplantation, so VADs may enable many patients to survive to obtain transplantation.

2. VADs can be used as a “bridge to decision.” These patients have urgent need for support but have severe medical conditions exacerbated by heart failure that make transplantation an initial poor option. These medical conditions may improve after a period of improved circulation with a VAD so that transplantation may become feasible.

3. VADs may be used as a bridge to definitive surgical therapy, such as in patients with severe ischemic heart disease who require coronary revascularization, which may lead to recovery of myocardial function.

4. A small minority of patients may require VAD therapy as a bridge to recovery, when improvement in cardiac function with nonsurgical approaches is expected. An example of this is patients with acute fulminant myocarditis.¹⁴⁸ In addition, there have been case reports of patients with subacute cardiomyopathy and severe heart failure who received VAD support for months and had improvement in left ventricular function such that the VAD was removed and patients survived without cardiac transplantation.¹⁷² However, only 5% to 10% of patients with chronic heart disease will improve sufficiently for VAD removal.

5. Finally, current VADs have a low incidence of pump failure and can be used as long-term support, or “destination therapy.”

1. Weintraub, NL, Collins, SP, Pang, PS, et al. Acute heart failure syndromes: Emergency department presentation, treatment, and disposition: Current approaches and future aims. A scientific statement from the American Heart Association. on behalf of the American Heart Association Council on Clinical Cardiology and Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation. Circulation. 2010; 122:1975–1996.

2. Roger, VL, Go, AS, Lloyd-Jones, DM, et al. AHA statistical update. Heart disease and stroke statistics—2011 update. on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2011; 123:e18–e209.

3. Jessup, M, Brozena, S. Heart failure. N Engl J Med. 2003; 348:2007–2018.

4. Jessup, M, Abraham, WT, Casey, DE, et al. 2009 focused update: ACCF/AHA guidelines for the diagnosis and management of heart failure in the adult. J Am Coll Cardiol. 2009; 53:1343–1382.

5. Chen, J, Normand, ST, Wang, Y, Krumholz, HM. National and regional trends in heart failure hospitalization and mortality rates for Medicare beneficiaries, 1998-2008. JAMA. 2011; 306:1669–1678.

6. Gheorghiade, M, Zannad, F, Sopko, G. Acute heart failure syndromes. Current state and framework for future research. Circulation. 2005; 112:3958–3968.

7. Rudiger, T, Harjola, V, Muller, A, et al. Acute heart failure: Clinical presentation. One year mortality and prognostic factors. Eur J Heart Fail. 2005; 7:662–670.

8. Sharma, M, Teerlink, JR. A rational approach for the treatment of acute heart failure: Current strategies and future options. Curr Opin Cardiol. 2004; 19:254–263.

9. Fadel, BM, Ellahham, S, Ringe, MD. Hyperthyroid heart disease. Clin Cardiol. 2000; 23:402–408.

10. Asbun, J, Villarreal, F. The pathogenesis of myocardial fibrosis in the setting of diabetic cardiomyopathy. J Am Coll Cardiol. 2006; 47:693–700.

11. Alpert, MA. Obesity cardiomyopathy: Pathophysiology and evolution of the clinical syndrome. Am J Med Sci. 2001; 321:225–236.

12. Wu, A, Cody, R. Medical and surgical treatment of chronic heart failure. Curr Probl Cardiol. 2003; 28:225–260.

13. Packer, M. Current role of beta-adrenergic blockers in the management of chronic heart failure. Am J Med. 2001; 110(7A):81S–84S.

14. Pang, P. Acute heart failure syndromes: Initial management. Emerg Med Clin North Am. 2011; 29:675–688.

15. Cowie, M, Mendez, G. B-natriuretic peptide and congestive heart failure. Curr Probl Cardiol. 2003; 44:264–311.

16. McCullough, PA, Nowack, PM, McCord, J, et al. B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: Analysis from breathing not properly (BNP) multinational study. Circulation. 2002; 106:416–422.

17. Morrison, LK, Harrison, A, Krishnaswamy, P, et al. Utility of a rapid BNP assay in differentiating congestive heart failure from lung disease in patients presenting with dyspnea. J Am Coll Cardiol. 2002; 39:202–209.

18. Muller, C, Scholer, A, Lawle-Kilian, K, et al. Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N Engl J Med. 2004; 350:647–654.

19. Maisel, A. B-type natriuretic peptide levels. Diagnosis and prognosis in congestive heart failure: What’s next? Circulation. 2002; 105:2328–2331.

20. Logeart, D, Thabut, G, Jourdian, P, et al. Predischarge B-type natriuretic peptide assay for identifying patients at high risk of readmission after decompensated heart failure. J Am Coll Cardiol. 2004; 43:635–641.

21. Januzzi, JL, van Kimmenade, R, Lainchbury, J, et al. NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: An international pooled analysis of 1256 patients. The International Collaborative of NT-proBNP Study. Eur Heart J. 2006; 27:330–337.

22. O’Donoghue, M, Chen, A, Baggish, AL, et al. The effects of ejection fraction on N-Terminal ProBNP and BNP levels in patients with acute CHF: Analysis from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study. J Card Fail (Suppl). 2005; 11:S9–S14.

23. Nieminen, MS, Bohm, M, Cowie, MR, et al. Executive summary of the guidelines on the diagnosis and treatment of acute heart failure. The Task Force on Acute Heart Failure of the European Society of Cardiology. Eur Heart J. 2005; 26:384–416.

24. Fonarow, GC, Adams, KF, Abraham, WT, et al. Risk stratification for in-hospital mortality in acutely decompensated heart failure. JAMA. 2005; 293:572–580.

25. O’Connor, CM, Abraham, WT, Albert, NM, et al. Predictors of mortality after discharge in patients hospitalized with heart failure: An analysis from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF). Am Heart J. 2008; 156:662–673.

26. Rose, E, Gelijns, A, Moskowitz, A, et al. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med. 2001; 345:1435–1443.

27. Collins, SP, Lindsell, CJ, Storrow, AB, et al. Early changes in clinical characteristics after emergency department therapy for acute heart failure syndromes: Identifying patients who do not respond to standard therapy. Heart Fail Rev. 2012; 17:387–394.

28. Hochman, J, Sleeper, L, Webb, J, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK investigators: SHould we emergently revascularize Occluced Coronaries for cardiogenic shocK? N Engl J Med. 1999; 341:625–634.

29. Jemtel, TH, Alt, EU. Are hemodynamic goals viable in tailoring heart failure therapy? Hemodynamic goals are outdated. Circulation. 2006; 113:1027–1032.

30. Chin, M, Goldman, L. Correlates of major complications or death in patients admitted to the hospital with congestive heart failure. Arch Intern Med. 1996; 156:1814–1820.

31. Fonarow, GC, Peacock, WP, Phillips, CO, et al. Admission B-type natriuretic peptide levels and in-hospital mortality in acute decompensated heart failure. for the ADHERE Scientific Advisory Committee and Investigators. J Am Coll Cardiol. 2007; 49:1943–1950.

32. Peacock, WF, DeMarco, T, Fonarow, GC, et al. Cardiac troponin and outcome in acute heart failure. N Engl J Med. 2008; 358:2117–2126.

33. Stevenson, LW. Are hemodynamic goals viable in tailoring heart failure therapy? Hemodynamic goals are relevant. Circulation. 2006; 113:1020–1027.

34. Damman, K, van Deursen, VM, Navis, G, et al. Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease. J Am Coll Cardiol. 2009; 53:582–588.

35. Mullens, W, Abrahams, Z, Francis, GS, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol. 2009; 53:589–596.

36. Smith, GL, Lichtman, JH, Bracken, MB, et al. Renal impairment and outcomes in heart failure. Systematic review and meta-analysis. J Am Coll Cardiol. 2006; 47:1987–1996.

37. Harinstein, ME, Flaherty, JD, Fonarow, GC, et al. Clinical assessment of acute heart failure syndromes: Emergency department through the early post-discharge period. Heart. 2011; 97:1607–1618.

38. Thomas, SS, Nohria, A. Hemodynamic classifications of acute heart failure and their clinical application. An update. Circ J. 2012; 76:278–286.

39. Jain, P, Massie, B, Gattis, W, et al. Current medical treatment for the exacerbation of chronic heart failure resulting in hospitalization. Am Heart J. 2003; 145:S3–17.

40. Floyd, JD, Nguyen, DT, Lobins, RL, et al. Cardiotoxicity of cancer therapy. J Clin Oncol. 2005; 23:7685–7696.

41. Gheorghiade, M, Pang, PS. Acute heart failure syndromes. J Am Coll Cardiol. 2009; 53:557–573.

42. Gray, A, Goodcare, S, Newby, DE, et al. Noninvasive ventilation in acute cardiogenic pulmonary edema. N Engl J Med. 2008; 359:142–151.

43. Nieminen, MS, Brutsaert, D, Dickstein, K, et al. EuroHeart Failure Survey II (EHFS II): A survey on hospitalized acute heart failure patients: Description of population. Eur Heart J. 2006; 27:2725–2736.

44. The ESCAPE Investigators and ESCAPE Study Coordinators. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness. JAMA. 2005; 294:1625–1633.

45. Stevenson, L. Tailored therapy for hemodynamic goals for advanced heart failure. Eur J Heart Fail. 1999; 1:251–257.

46. Steimle, A, Stevenson, L, Chelimsky-Fallick, C, et al. Sustained hemodynamic efficacy of therapy tailored to reduce filling pressures in survivors with advanced heart failure. Circulation. 1997; 96:1165–1172.

47. Stevenson, L, Tillisch, J. Maintenance of cardiac output with normal filling pressures in patients with dilated heart failure. Circulation. 1986; 74:1303–1308.

48. Dormans, T, van Meyel, J, Gerlag, P, et al. Diuretic efficacy of high dose furosemide in severe heart failure: Bolus injection versus continuous infusion. J Am Coll Cardiol. 1996; 28:376–382.

49. Thompson, MR, Nappi, JM, Dunn, JP, et al. Continuous versus intermittent infusion of furosemide in acute decompensated heart failure. J Card Fail. 2010; 16:188–193.

50. Allen, LA, Turer, AT, DeWald, T, et al. Continuous versus bolus dosing of furosemide for patients hospitalized with heart failure. Am J Cardiol. 2010; 105:1794–1797.

51. Felker, GM, Lee, KL, Bull, DA, et al. Diuretic strategies in patients with acute decompensated heart failure. for the NHLBI Heart Failure Clinical Research Network. N Engl J Med. 2011; 364:797–805.

52. Yilmaz, MB, Gayat, E, Salem, R, et al. Impact of diuretic dosing on mortality in acute heart failure using a propensity-matched analysis. Eur J Heart Fail. 2011; 13:1244–1252.

53. Testani, JM, Cappola, TP, Brensinger, CM, et al. Interaction between loop diuretic-associated mortality and blood urea nitrogen concentration in chronic heart failure. J Am Coll Cardiol. 2011; 58:375–382.

54. Jentzer, JC, DeWald, TA, Hernandez, AF. Combination of loop diuretics with thiazide-type diuretics in heart failure. J Am Coll Cardiol. 2010; 56:1527–1534.

55. Gheorghiade, M, Gattis, W, O’Connor, CM, et al. Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure. JAMA. 2004; 291:1963–1971.

56. Goldsmith, SR, Gheorghiade, M. Vasopressin antagonism in heart failure. J Am Coll Cardiol. 2005; 46:1785–1791.

57. Orlandi, C, Zimmer, CA, Gheroghiade, M. Role of vasopressin antagonists in the management of acute decompensated heart failure. Curr Heart Fail Rep. 2005; 2:131–139.

58. Gheorghiade, M, Konstam, MA, Burnett, JC, et al. Short term clinical effects of tolvaptan, an oral vasopressin antagonist in patients hospitalized for heart failure: Results of the EVEREST clinical status trials. JAMA. 2007; 297:1332–1343.

59. Udelson, JE, Orlandi, C, Ouyang, J, et al. Acute hemodynamic effects of tolvaptan, a vasopressin V2 receptor blocker, in patients with symptomatic heart failure and systolic dysfunction: An international, multicenter, randomized, placebo-controlled trial. J Am Coll Cardiol. 2008; 52:1540–1545.

60. Konstam, MA, Gheorghiade, M, Burnett, JC, et al. JAMA. 2007; 297:1319–1331.

61. Publication Committee for the VMAC Investigators. Intravenous nesiritide versus nitroglycerin for treatment of decompensated congestive heart failure: A randomized controlled trial. JAMA. 2000; 287:1531–1540.

62. Colucci, W, Elkayam, U, Horton, D, et al. Intravenous nesiritide, a natriuetic in the treatment of decompensated congestive heart failure. N Engl J Med. 2002; 343:246–253.

63. Silver, M, Horton, D, Ghali, J, et al. Effect of nesiritide versus dobutamine on short-term outcomes in the treatment of patients with acute decompensated heart failure. J Am Coll Cardiol. 2002; 39:798–803.

64. Burger, A, Horton, D, LeGemtel, T, et al. Effect of neseritide (B-type natriuretic peptide) and dobutamine on ventricular arrhythmias in the treatment of patients with acutely decompensated congestive heart failure: The PRECEDENT Study. Am Heart J. 2002; 144:1102–1108.

65. Sackner-Bernstein, JD, Kowalski, M, Fox, M, Aaronson, K. Short-term risk of death after treatment with nesiritide for decompensated heart failure. JAMA. 2005; 293:1900–1905.

66. Sackner-Bernstein, JD, Skopicki, HA, Aarronson, KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation. 2005; 111:1487–1491.

67. Abraham, WT, Adams, KF, Fonarow, GC, et al. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications. J Am Coll Cardiol. 2005; 4:57–64.

68. O’Connor, CM, Starling, RC, Hernandez, AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med. 2011; 365:32–43.

69. Chattergee, K, DeMarco, T. Role of nonglycosidic inotropic agents. Indications, ethics, and limitations. Med Clin North Am. 2003; 87:391–418.

70. Teerlink, JR, Metra, M, Zaca, V, et al. Agents with inotropic properties for the management of acute heart failure syndromes. Traditional agents and beyond. Heart Fail Rev. 2009; 14:243–253.

71. Shah, M, Hasselblad, V, Stinnett, S, et al. Hemodynamic profiles of advanced heart failure: Association with clinical characteristics and long-term outcomes. J Card Fail. 2001; 7:105–113.

72. Jaski, B, Fifer, M, Wright, R, et al. Positive inotropic and vasodilator actions of milrinone in patients with severe congestive heart failure. J Clin Inves. 1985; 75:643–649.

73. Colucci, W, Wright, R, Jaski, B, et al. Milrinone and dobutamine in severe heart failure: Differing hemodynamic effects and individual patient responsiveness. Circulation. 1986; 73:175–183.

74. Cuffe, M, Califf, R, Adams, K, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: A randomized controlled trial. JAMA. 2002; 287:1541–1547.

75. O’Connor, C, Gattis, W, Uretsky, B, et al. Continuous intravenous dobutamine is associated with an increased risk of death in patients with advanced heart failure: Insights from the Flolan International Randomized Survival Trial (FIRST). Am Heart J. 1999; 138:78–86.

76. Hershberger, RE, Nauman, D, Walter, TL, et al. Care processes and clinical outcomes of Continuous Outpatient Support with Inotropes (COSI) in patients with refractory end stage heart failure. J Card Fail. 2003; 9:180–187.

77. De Backer, D, Biston, P, Devriendt, J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. for the SOAP II Investigators. N Engl J Med. 2010; 362:779–789.

78. Jaski, BE, Ha, J, Denys, BG, et al. Peripherally inserted veno-venous ultrafiltration for rapid treatment of volume overloaded patients. J Card Fail. 2003; 9:227–231.

79. Bart, BA, Boyle, A, Bank, AJ, et al. Ultrafiltration versus usual care for hospitalized patients with heart failure. J Am Coll Cardiol. 2005; 46:2043–2053.

80. Constanzo, MK, Guglin, ME, Saltzberg, MT, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol. 2007; 49:675–683.

80a. Bart, BA, Goldsmith, SR, Lee, KL, et al. Ultrafiltration in decompensated heart failure with vardiorenal syndrome. for the Heart Failure Clinical Research Network. N Engl J Med. 2012; 367:2296–2304.

81. Fiaccadori, E, Regolisti, G, Maggiore, M, et al. Ultrafiltration in heart failure. Am Heart J. 2011; 161:439–449.

82. Lindenfeld, J, Albert, NM, Boehmer, JP, et al. Executive summary: HFSA 2010 comprehensive heart failure practice guideline. J Card Fail. 2010; 16:475–539.

83. BHAT Trial Research Group. A randomized trial of propranolol in patients with acute myocardial infarction. I: Mortality results. JAMA. 1982; 747:1707–1714.

84. BHAT Trial Research Group. A randomized trial of propranolol in patients with acute myocardial infarction. II: Morbidity results. JAMA. 1983; 250:2814–2819.

85. CIBIS II Investigators. The Cardiac Insufficiency Bisoprolol Study II: A randomized trial. Lancet. 1999; 353:9–13.

86. The MERIT-HF Study Group. Effects of controlled release metoprolol on total mortality, hospitalizations and well-being in patients with heart failure. JAMA. 2000; 283:1295–1302.

87. Packer, M, Coats, A, Fowler, M, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001; 344:1651–1658.

88. Krum, H, Roecker, E, Mohacsi, P, et al. Effects on initiating carvedilol in patients with severe chronic heart failure. Results from the COPERNICUS Study. JAMA. 2003; 289:712–718.

89. Bristow, M, Gilbert, E, Abraham, W, et al. Carvedilol produces dose related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation. 1996; 94:2807–2816.

90. Yilmaz, MB, Laribi, S, Mebazaa, A. Managing beta-blockers in acute heart failure: When to start and when to stop? Curr Heart Fail Rep. 2010; 7:110–115.

91. Bohm, M, Link, A, Cai, D, et al. Beneficial association of beta-blocker therapy on recovery from severe acute heart failure treatment: Data from the Survival of Patients with Acute Heart Failure in Need of Intravenous Inotropic Support Trial. Crit Care Med. 2011; 39:940–944.

92. Ginsberg, FL. Beta-blockers: Essential heart failure therapy. Crit Care Med. 2011; 39:1198–1199.

93. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991; 325:293–302.

94. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fraction. N Engl J Med. 1992; 327:685–691.

95. Garg, R, Yusuf, S. Overview of randomized trials of angiotensin converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA. 1995; 273:1450–1456.

96. Packer, M, Poole-Wilson, PA, Armstrong, PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor lisinopril on morbidity and mortality in chronic heart failure. Atlas Study Group. Circulation. 1999; 100:2312–2318.

97. Aronow, WS. Epideminology, pathophysiology, prognosis, and treatment of systolic and diastolic heart failure. Card Rev. 2006; 14:108–124.

98. Willenheimer, R, van Veldhuisen, DJ, Silke, B, et al. Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite sequence. Circulation. 2005; 112:2426–2435.

99. The RESOLVD Pilot Study Investigators. Comparison of candesartan, enalapril, and their combination in congestive heart failure. Circulation. 1999; 100:1056–1064.

100. Pitt, B, Poole-Wilson, P, Segal, R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: Randomized trial—The Losartan Heart Failure Survival Study (ELITE II). Lancet. 2000; 355:1582–1587.

101. Cohn, J, Tognoni, G. A randomized trial of the angiotensin receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001; 345:1667–1675.

102. Granger, C, McMurray, J, Yusuf, S, et al. Effects of candesartan in patients with chronic heart failure and reduced left ventricular systolic function intolerant to angiotensin-converting enzyme inhibitors. The CHARM Alternative Trial. Lancet. 2003; 362:772–776.

103. McMurray, J, Ostergren, J, Swedberg, K, et al. Effects of candesartan in patients with chronic heart failure and reduced left ventricular systolic function taking angiotensin-converting enzyme inhibitors. The CHARM-Added Trial. Lancet. 2003; 362:759–766.

104. Manohair, P, Pina, I. Therapeutic role of angiotensin II receptor blockers in the treatment of heart failure. Mayo Clin Proc. 2003; 78:334–338.

105. Sharma, D, Buyse, M, Pitt, B, et al. Meta-analysis of observed mortality data from all controlled double-blind multiple dose studies of losartan in heart failure. Am J Cardiol. 2000; 85:187–192.

106. Pitt, B, Zannad, F, Remme, W, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999; 341:709–717.

107. Juurlink, DN, Mamdani, NM, Lee, DS, et al. Rates of hyperkalemia after publication of the randomized aldactone study. N Engl J Med. 2004; 351:543–551.

108. Zannad, F, McMurray, JJV, Krum, H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. for the EMPHASIS-HF Study Group. N Engl J Med. 2011; 364:11–21.

109. Rossignol, P, Ménard, J, Fay, R, et al. Eplerenone survival benefits in heart failure patients post-myocardial infarction are independent from its diuretic and potassium-sparing effects: Insights from an EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) substudy. J Am Coll Cardiol. 2011; 58:1958–1966.

110. Cohn, J, Archibald, D, Ziesche, S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veteran Administration Cooperative Study. N Engl J Med. 1986; 314:1547–1552.

111. Taylor, AL, Zieche, S, Yancy, C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004; 351:2049–2057.

112. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997; 336:525–533.

113. Ahmed, A, Rich, MW, Love, TE, et al. Digoxin and reduction in mortality and hospitalization in heart failure: A comprehensive post hoc analysis of the DIG trial. Eur Heart J. 2006; 27:178–186.

114. Velazquez, EJ, Pfeffer, MA. Acute heart failure complicating acute coronary syndromes. Circulation. 2004; 109:440–442.

115. Steg, PG, Dabbous, DH, Feldman, LJ, et al. Determinants and prognostic impact of heart failure complicating acute coronary syndromes. Circulation. 2004; 109:494–499.

116. Velazquez, EJ, Francis, GS, Armstrong, PW, et al. An international perspective on heart failure and left ventricular systolic dysfunction complicating myocardial infarction: The VALIANT registry. Eur Heart J. 2004; 25:1911–1919.

117. The CAPRICORN Investigators. Effect of carvedilol on outcome after myocardial infarction in patients with left ventricular dysfunction: The CAPRICORN Randomized Trial. Lancet. 2001; 357:1385–1390.

118. Pfeffer, M, Braunwald, E, Moye, L, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 1992; 327:669–677.

119. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet. 1993; 342:821–828.

120. Kober, L, Torp-Pedersen, C, Carlsen, JE, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 1995; 333:670–676.

121. Pfeffer, MA, McMurray, JJ, Velazquez, EJ. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003; 349:1893–1903.

122. Pitt, B, Remme, W, Zannad, F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 348:1309–1321.

123. Pitt, B, White, H, Nicolau, J. Eplerenone reduces mortality 30 days after randomization following acute myocardial infarction in patients with left ventricular systolic dysfunction and heart failure. J Am Coll Cardiol. 2005; 46:424–430.

124. Owan, TE, Redfield, MM. Epideminology of diastolic heart failure. Prog Cardiovasc Dis. 2005; 47:320–332.

125. Leite-Moreira, AF. Current perspectives in diastolic dysfunction and diastolic heart failure. Heart. 2006; 92:712–718.

126. Gaasch, WH. Diagnosis and treatment of heart failure based on left ventricular systolic or diastolic dysfunction. JAMA. 1994; 271:1276–1280.

127. Vasan, RS, Benjamin, EJ, Levy, D. Prevalence, clinical features and prognosis of diastolic heart failure: An epidemiologic perspective. J Am Coll Cardiol. 1995; 26:1565–1574.

128. Aurigemma, GP, Zile, MR, Gaasch, WH. Contractile behavior of the left ventricle in diastolic heart failure. Circulation. 2006; 113:296–304.

129. Owan, TE, Hodge, DO, Herges, RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006; 355:251–259.

130. Parissis, JT, Ikonomidis, I, Rafouli-Stergiou, P, et al. Clinical characteristics and predictors of in-hospital mortality in acute heart failure with preserved left ventricular ejection fraction. Am J Cardiol. 2011; 107:79–84.

131. Klapholz, M, Maurer, M, Lowe, AM, et al. Hospitalization for heart failure in the presence of a normal left ventricular ejection fraction. J Am Coll Cardiol. 2004; 43:1432–1438.

132. Devereux, RB, Roman, MJ, Liu, JE, et al. Congestive heart failure despite normal left ventricular systolic function in a population-based sample: The strong heart study. Am J Cardiol. 2000; 86:1090–1096.

133. Philbin, EF, Rocco, TA, Jr., Lindenmuth, NW. Systolic versus diastolic heart failure in community practice: Clinical features, outcomes, and the use of angiotensin-converting enzyme inhibitors. Am J Med. 2000; 1009:605–613.

134. Yancy, CW, Lopatin, M, Stevenson, LW, et al. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function. J Am Coll Cardiol. 2006; 47:76–84.

135. Bhatia, RS, Tu, JV, Lee, DL, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med. 2006; 355:260–269.

136. Franklin, KM, Aurigemma, GP. Prognosis in diastolic heart failure. Prog Cardiovasc Dis. 2005; 47:333–339.

137. Yusuf, S, Pfeffer, MA, Swedberg, K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: The CHARM-Preserved Trial. Lancet. 2003; 362:777–781.

138. Massie, BM, Carson, PE, McMurray, JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008; 359:2456–2467.

139. Little, WC, Brucks, S. Therapy for diastolic heart failure. Prog Cardiovasc Dis. 2005; 47:380–388.

140. Zile, M, Baica, CF. Alterations in ventricular function: Diastolic heart failure. In: Mann DL, et al, eds. Heart Failure. A Companion to Braunwald’s Heart Disease. Philadelphia: WB Saunders; 2004:222–227.

141. Feldman, A, McNamara, D. Myocarditis. N Engl J Med. 2000; 19:1388–1398.

142. Parrillo, JE. Inflammatory cardiomyopathy (myocarditis): Which patients should be treated with anti-inflammatory therapy? Circulation. 2001; 104:4–6.

143. Nelson, KH, Li, T, Afonso, L. Diagnostic approach and the role of MRI in the assessment of acute myocarditis. Cardiol Rev. 2009; 17:24–30.

144. Friedrich, MG, Sechtem, U, Shulz-Menger, J, et al. Cardiovascular magnetic resonance in myocarditis: A JACC white paper. J Am Coll Cardiol. 2009; 53:1475–1487.

145. Parrillo, JE, Cunnion, R, Epstein, S, et al. A prospective randomized controlled trial of prednisone for dilated cardiomyopathy. N Engl J Med. 1989; 321:1061–1068.

146. Wojnicz, R, Nowalany-Kozielska, E, Wojciechowska, C, et al. Randomized, placebo-controlled study for immunosuppressive treatment of inflammatory dilated cardiomyopathy: Two-year follow-up results. Circulation. 2001; 104:39–45.

147. Mason, J, O’Connell, J, Herskowitz, A, et al. A clinical trial of immunosuppressive therapy for myocarditis. N Engl J Med. 1995; 333:269–275.

148. McCarthy, R, Boehmer, J, Hrubianr, F, et al. Long-term outcome of fulminant myocarditis as compared with acute (non-fulminant) myocarditis. N Engl J Med. 2002; 342:690–695.

149. The Cardiac Arrhythmia Suppression Trial Investigators Preliminary Report. Effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med. 1989; 321:406–412.

150. Singh, S, Fletcher, R, Fisher, S, et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. N Engl J Med. 1995; 333:77–82.

151. Julian, D, Camm, A, Frangin, G, et al. Randomized trial of effect of amiodarone on mortality in patients with left ventricular dysfunction after recent myocardial infarction: EMIAT. Lancet. 1997; 349:667–674.

152. The AVID Investigators. A comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med. 1997; 337:1576–1583.

153. Connoly, S, Gent, M, Roberts, R, et al. Canadian Implantable Defibrillator Study (CIDS): A randomized trial of the implantable cardioverter-defibrillator against amiodarone. Circulation. 2000; 101:1297–1302.

154. Kuck, K, Cappato, R, Siebels, J, et al. Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest: The Cardiac Arrest Study Hamburg (CASH). Circulation. 2000; 102:748–754.

155. MADIT Investigators. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. N Engl J Med. 1995; 335:1933–1940.

156. Buxton, A, Lee, K, Fisher, J, et al. A randomized study of the prevention of sudden death in patients with coronary artery disease. N Engl J Med. 1999; 341:1882–1890.

157. MADIT II Investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2001; 346:877–883.

158. Bardy, GH, Lee, KL, Mark, DB, et al. Amiodarone or an implantable cardioverter defibrillator for congestive heart failure (SCD-HeFT). N Engl J Med. 2005; 352:225–237.

159. Kadish, A, Dyer, A, Daubert, JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Eng J Med. 2004; 350:2151–2158.

160. Desai, AS, Farg, JC, Maisel, WH, Baughman, KL. Implantable defibrillators for the prevention of mortality in patients with non-ischemic cardiomyopathy. A meta-analysis of randomized controlled trials. JAMA. 2004; 292:2874–2879.

161. Abraham, W, Fisher, W, Smith, A, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002; 346:1845–1853.

162. Jarcho, JA. Biventricular pacing. N Engl J Med. 2006; 355:288–294.

163. Bradley, D, Bradley, E, Baughman, K, et al. Cardiac resynchronization and death from progressive heart failure. A meta-analysis of randomized controlled trials. JAMA. 2003; 289:730–740.

164. Cleland, JAF, Danbert, J, Erdmann, E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005; 352:1539–1549.

165. Young, J, Abraham, W, Smith, A, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure. The MIRACLE ICD trial. JAMA. 2003; 289:2685–2694.

166. Bristow, MR, Saxon, LA, Boehmer, J, et al. Comparison of medical therapy, pacing and defibrillation in heart failure (COMPANION). N Engl J Med. 2004; 350:2140–2150.

167. Tang, ASL, Wells, GA, Talajic, M, et al. Cardiac-resynchronization therapy for mild-to-moderate heart failure. for the Resynchronization-Defibrillation for Ambulatory Heart failure Trial (RAFT) Investigators. N Engl J Med. 2010; 363:2385–2395.

168. Wilson, SR, Mudge, GH, Jr., Stewart, JC, et al. Evaluation for a ventricular assist device: Selecting the appropriate candidate. Circulation. 2009; 119:2225–2232.

169. Stevenson, LW, Rose, EA. Left ventricular assist devices: Bridges to transplantation, recovery and destination therapy for whom? Circulation. 2003; 108:3059–3063.

170. Felker, GM, Rogers, JG. Same bridge, new destinations. Rethinking paradigms for mechanical cardiac support in heart failure. J Am Coll Cardiol. 2006; 47:930–932.

171. Mancini, D, Burkoff, D. Mechanical device-based methods of managing and treating heart failure. Circulation. 2005; 12:438–448.

172. Muller, J, Wallukat, G, Weng, Y, et al. Weaning from mechanical cardiac support in patients with idiopathic dilated cardiomyopathy. Circulation. 1997; 96:542–549.

173. Terraciano, CM, Miller, LW, Yacoub, MH. Contemporary use of ventricular assist devices. Ann Rev Med. 2010; 24:184–189.

174. Slaughter, MS, Rogers, JG, Milano, CA, et al. Advanced heart failure treated with continuous-flow left ventricular assist device. for the HeartMate II Investigators. N Engl J Med. 2009; 361:2241–2251.

175. Shreenivas, SS, Rame, JE, Jessup, M. Mechanical circulatory support as a bridge to transplantation or for destination therapy. Curr Heart Fail Rep. 2010; 7:159–166.

176. Rose, E, Gelijas, A, Moskowitz, A, et al. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med. 2001; 345:1435–1443.

177. Stevenson, LW, Pagani, FD, Young, JB, et al. INTERMACS profiles of advanced heart failure: The current picture. J Heart Lung Transplant. 2009; 28:535–541.

178. Kirklin, JK, Naftel, DC, Formos, RL, et al. The 24th INTERMACS Annual Report. 4,000 implants and counting. J Heart Lung Transplant. 2012; 31:117–126.