Managing heart failure is a challenge. To aid clinicians in this task, the American College of Cardiology Foundation (ACC) and the American Heart Association (AHA) publish evidence-based guidelines, most recently in 2013.¹ Since then, new drugs and devices have been shown to improve survival and reduce hospitalizations.

See related editorial

This paper reviews the ABCs of outpatient management of systolic heart failure (or heart failure with reduced ejection fraction), including the results of major trials and recommendations.

A common and serious condition

Heart failure is a debilitating syndrome that takes a significant physical and mental toll on those affected.

And it is common. An American age 40 or older faces a 20% lifetime risk of heart failure.¹ An estimated 5.1 million Americans have clinical signs and symptoms of heart failure, and 900,000 new cases are diagnosed each year.² By 2030 the prevalence of heart failure is projected to increase by 46%, and 9 million Americans will have been diagnosed with it.²

The severity of heart failure can be described using either the functional classification devised by the New York Heart Association (NYHA; Table 1) or the stages defined by the ACC and AHA.^1,3 Though survival rates have improved, there is a direct correlation between worsening symptoms and death.⁴

Heart failure is the leading cause of hospitalizations annually. It accounts for $30 billion in healthcare costs, with direct medical costs accounting for 68% and another $1.8 billion associated with clinic visits, most often with primary care providers. By 2030, the cost is projected to increase by 127% to $69.7 billion—$244 per person in the United States.²

ACE inhibitors

The renin-angiotensin-aldosterone system has been studied for over 100 years.⁵

In heart failure with reduced ejection fraction, this system is upregulated as an adaptive mechanism to maintain hemodynamic homeostasis.^6–8 However, prolonged activation of the renin-angiotensin-aldosterone system can lead to deleterious cardiovascular effects such as myocyte hypertrophy, myocardial fibrosis, sodium conservation, and fluid overload.^8,9 Angiotensin II is a potent vasoconstrictor and plays a role in cardiovascular remodeling, leading to worsening progression of heart failure.⁶

CONSENSUS (the Cooperative North Scandinavian Enalapril Survival Study) examined the effect of the angiotensin-converting enzyme (ACE) inhibitor enalapril on survival in 253 patients with NYHA class IV heart failure. Participants were randomized to receive either enalapril or placebo. At 6 months, the mortality rate was 26% in the enalapril group vs 44% in the placebo group, an 18% absolute risk reduction and a 41% relative risk reduction (P = .002). At 12 months, the relative risk reduction in mortality was 30% (P = .001).¹⁰

SOLVD (the Study of Left Ventricular Dysfunction) extended the use of ACE inhibitors to all patients with heart failure, not just those in NYHA class IV. It randomized 1,284 patients with heart failure of any NYHA class and an ejection fraction less than 35% to receive either enalapril or placebo, and demonstrated a 16% relative risk reduction in mortality in the enalapril group, with mortality rates of 36% vs 39.7% (P = .0036).¹¹

Recommendations. The benefits of ACE inhibition have been demonstrated in patients with mild, moderate, and severe heart failure. Thus, the guidelines recommend ACE inhibitors (Table 2) for all patients with heart failure with reduced ejection fraction.¹

Angiotensin II receptor blockers

Angiotensin II receptor blockers (ARBs) (Table 3) have been proven to be suitable alternatives for patients with heart failure with reduced ejection fraction who cannot tolerate ACE inhibitors.

Val-HefT (the Valsartan HF Trial)¹² randomized 5,010 patients in a double-blind fashion to receive either valsartan or placebo, with background therapy that included beta-blockers, digoxin, diuretics, and ACE inhibitors. There was a 13% reduction of the combined primary end point of mortality and morbidity and a 24% reduction in heart failure hospitalizations in the valsartan group.¹²

Subgroup analysis compared patients on the basis of use of ACE inhibitors and beta-blockers at study entry. Valsartan had a favorable effect in the subgroups using beta-blockers alone, ACE inhibitors alone, and neither drug. However, when patients received all three (a beta-blocker, an ACE inhibitor, and valsartan), the mortality rate was significantly increased (P = .009).¹² This finding conflicted with those of other studies, which found a small benefit of combining an ACE inhibitor and an ARB.

CHARM-Added (the Candesartan in HF Assessment of Reduction in Mortality and Morbidity trial)¹³ investigated whether adding the ARB candesartan to an ACE inhibitor would improve clinical outcomes. In the study, 2,548 patients in NYHA class II, III, or IV with a left ventricular ejection fraction of less than 40% who were receiving ACE inhibitors were randomized to either candesartan or placebo. The addition of candesartan resulted in a significant reduction in cardiovascular mortality and heart failure hospitalizations, but with the downside of higher rates of hyperkalemia and serum creatinine elevation.¹³

Recommendations. The 2013 guidelines recommend that ARBs be used in patients who cannot tolerate an ACE inhibitor due to cough. However, routine combined use of ARBs, ACE inhibitors, and aldosterone antagonists is not recommended and may cause harm.¹

Aldosterone receptor antagonists

Elevated levels of aldosterone lead to fluid retention, loss of magnesium and potassium, and myocardial fibrosis.

RALES (the Randomized Aldactone Evaluation Study)¹⁴ tested the hypothesis that the aldosterone receptor antagonist spironolactone (25 mg daily) would reduce deaths from all causes in patients with severe heart failure receiving standard medications including an ACE inhibitor. RALES included 1,663 patients in NYHA class III or IV with a left ventricular ejection fraction of 35% or less, randomized to receive 25 mg of spironolactone or matching placebo. This study found a 30% relative risk reduction and an 11% absolute risk reduction in all-cause mortality, a 31% relative risk reduction and a 10% absolute risk reduction in cardiac mortality, and 30% fewer cardiac-related hospitalizations in the spironolactone group.¹⁴

Eplerenone, an aldosterone receptor antagonist that lacks the antiandrogenic side effects of spironolactone, has also been shown to be beneficial. Its efficacy in patients with left ventricular systolic dysfunction was first established in postmyocardial infarction patients.¹⁵

EMPHASIS-HF (the Eplerenone in Mild Patients Hospitalized and Survival Study in Heart Failure)¹⁶ broadened the application of eplerenone (and aldosterone antagonists in general), investigating the effects of eplerenone in 2,737 NYHA class II patients, regardless of ischemic etiology. The composite end point of cardiovascular death or heart failure hospitalization occurred in 18.3% of the eplerenone group vs 25.9% of the placebo group (P < .001). A total of 12.5% of patients in the eplerenone group died, compared with 15.5% in the placebo group (P = .008). Hospitalizations were also fewer in the eplerenone group.

Recommendations. The 2013 guidelines recommend aldosterone receptor antagonists (Table 4) for patients with NYHA class II, III, or IV heart failure who have an ejection fraction of 35% or less, to reduce morbidity and mortality (class IA recommendation).¹ The guidelines also recommend that these agents not be used in patients with renal insufficiency (serum creatinine > 2.5 mg/dL in men or > 2.0 mg/dL in women; an estimated glomerular filtration rate < 30 mL/min/1.73 m²); or a serum potassium level above 5 mmol/L.¹

Angiotensin-neprilysin inhibitor (the future)

Research has identified neprilysin as another potential target in the treatment of heart failure and has sought to combine inhibition of angiotensin and neprilysin.

Neprilysin, a neutral endopeptidase, is associated with degradation of several natural vasoactive peptides such as natriuretic peptide, bradykinin, and adrenomedullin. Neprilysin inhibition increases these substances and counters the neurohormonal overactivation that leads to vasoconstriction, sodium retention, and cardiac remodeling.¹⁷

The ARB valsartan has been combined with the neprilysin inhibitor sacubitril to create the first angiotensin-neprilysin inhibitor (ARNI) (Table 5). The combination was selected to minimize the potential for angioedema.

PARADIGM-HF (the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial)¹⁷ examined whether combined angiotensin-neprilysin inhibition was superior to ACE inhibition alone with enalapril in patients with chronic heart failure.

In PARADIGM-HF, 10,521 patients with NYHA class II, III, or IV heart failure were randomized to receive either sacubitril-valsartan or enalapril. The group receiving sacubitril-valsartan had significantly fewer deaths from cardiovascular causes and heart failure hospitalizations.¹⁷ An improvement in quality of life and NYHA functional class was also observed in the sacubitril-valsartan group.¹⁷

Sacubitril-valsartan underwent priority review by the US Food and Drug Administration and has been approved. Currently, it is indicated for the treatment of heart failure with reduced ejection fraction and NYHA class II, III, or IV symptoms. It should be avoided in patients who have previously experienced angioedema with an ACE inhibitor or ARB, in patients receiving aliskiren for diabetes, and in patients with hypersensitivity reactions to either of its components. Simultaneous use of sacubitril-valsartan and an ACE inhibitor should be avoided, and a washout period is recommended when transitioning from an ACE inhibitor to this combined agent.

Beta-blockers

In heart failure, there is increased sympathetic activation and associated elevations in norepinephrine levels, which may lead to deleterious long-term effects on cardiac function and structure. Beta-adrenergic receptor blockade is now known to be cardioprotective, but it was not always so; beta-blockers used to be contraindicated in patients with heart failure.

An early experience using beta-blockers in heart failure was described in 1975.^18,19 The first study to report a survival benefit of treating systolic heart failure with a beta-blocker was published in 1979.²⁰ Later, small controlled trials demonstrated a reduction in heart failure symptoms and improvement in left ventricular function and in NYHA functional class.²¹ Larger clinical trials have demonstrated a tremendous survival benefit with beta-blockers in heart failure, specifically carvedilol, extended-release metoprolol, and bisoprolol.

The US Carvedilol Heart Failure Study Group trial²² evaluated whether beta-blocker use in heart failure patients would reduce the rates of morbidity and mortality.²² The trial included 1,094 patients with symptomatic heart failure for at least 3 months and a left ventricular ejection fraction of 35% or less on background therapy including vasodilators, ACE inhibitors, and digoxin. Patients were randomized to receive either carvedilol or placebo. Carvedilol use was associated with a dramatic 65% risk reduction in mortality (7.8% with placebo vs 3.2% with carvedilol, P < .001) and a 27% risk reduction in hospitalizations (19.6% vs 14.1%, P = .036), leading to early trial termination.

CIBIS-II (the Cardiac Insufficiency Bisoprolol Study II)²³ investigated the effects of beta-blockers on survival and morbidity. CIBIS-II included 2,647 NYHA class III or IV patients with a left ventricular ejection fraction less than 35% on background medical therapy that included diuretics and ACE inhibitors. This trial was also terminated early, after demonstrating a significant survival benefit with bisoprolol.

MERIT-HF (the Metoprolol Extended Release Randomized Intervention Trial in Congestive Heart Failure)²⁴ evaluated if once-daily metoprolol would lower mortality rates  in patients with symptomatic heart failure. The study enrolled 3,991 NYHA class II–IV patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Like the previous two beta-blocker trials, MERIT-HF was terminated early, as it demonstrated a 34% reduction in all-cause mortality (7.2% risk of death per patient-year vs 11.0%, P = .00009).

The beta-blocker trials have shown that when added to background therapy, beta-blockers improve survival and reduce hospitalizations. However, when prescribing a beta-blocker, it is important to understand that not all beta-blockers are equal in the treatment of heart failure.

COMET (the Carvedilol or Metoprolol European Trial)²⁵ was the only head-to-head randomized control trial evaluating clinical outcomes in patients receiving carvedilol or metoprolol tartrate (not metoprolol succinate). In COMET, 1,511 patients with NYHA class II, III, or IV heart failure with a left ventricular ejection fraction of 35% or less were randomized to carvedilol or metoprolol tartrate. The primary end point of all-cause mortality occurred in 34% of the carvedilol group and 40% of the metoprolol tartrate group (P = .0017). There was no significant difference with regard to the composite end point of mortality and all-cause admissions.

Recommendations. The 2013 guidelines give a class IA recommendation for starting a beta-blocker (carvedilol, bisoprolol, or metoprolol succinate, Table 6) in patients with current or prior symptoms of heart failure.¹ Beta-blockers should be initiated with caution or avoided in patients with acutely decompensated heart failure with evidence of fluid overload.

Brain-type natriuretic peptide

Brain-type natriuretic peptide (BNP) or its amino-terminal cleavage product (NT-proBNP) originates in cardiomyocytes and is released by several triggers, most commonly cardiomyocyte stretch in the setting of volume or pressure overload.²⁶ The biologic significance of BNP includes natriuresis and vasodilation, renin-angiotensin system inhibition, and sympathetic nervous system modulation.²⁶

TIME-CHF (the Trial of Intensified vs. Standard Medical Therapy in Elderly Patients With Congestive HF)²⁷ investigated whether 18-month outcomes would be better if treatment were guided by N-terminal BNP levels rather than by symptoms. The BNP-guided strategy was not associated with a reduction in hospitalization or a survival benefit.

BATTLESCARRED (the NT-proBNP-Assisted Treatment to Lessen Serial Cardiac Readmissions and Death trial)²⁸ in 2009 showed that a BNP-guided management strategy significantly reduced mortality rates in patients under age 75 compared with standard medical therapy.

PROTECT (the Use of NT-proBNP Testing to Guide HF Therapy in the Outpatient Setting study)²⁹ also showed that a BNP-guided strategy was superior to usual care and was associated with reduced cardiovascular events and improved quality of life.²⁹

GUIDE IT-HF (the Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure study), currently ongoing, is designed to assess the safety, efficacy and cost-effectiveness of a biomarker-guided strategy in 1,100 high-risk patients with heart failure with reduced ejection fraction. 

Recommendations. The 2013 ACC/AHA guidelines give a class IA recommendation for the use of BNP to support clinical decision-making, particularly in cases of clinical uncertainty.¹ BNP can also be used to establish prognosis or disease severity in chronic heart failure and to achieve optimal dosage of goal-directed medical therapy for euvolemic patients followed in a structured heart failure program.¹

Heart failure clinics

Continuity of care upon discharge from the hospital is currently in a state of evolution. Those diagnosed with heart failure can now experience more comprehensive posthospital care by virtue of disease management clinics. The name may vary by institution, but whether it is called a “diuresis clinic,” “bridge clinic,” or “heart failure clinic,” the goal is to improve guideline-driven care, educate the patient, and reduce heart failure hospitalizations. Heart failure clinics are designed to provide a smooth transition from inpatient to outpatient care and to encourage patient self-accountability in health maintenance thereafter.

Studies have shown that heart failure clinics are associated with better medication dosing, fewer hospitalizations, and lower healthcare costs.^30–32

Chronotropy: I_f inhibition

An elevated resting heart rate has been shown to be associated with increased cardiovascular morbidity and mortality.³³ Studies have shown that slowing the heart rate improves myocardial contraction and energy supply and reduces energy expenditure.³⁴ Ivabradine, a selective I_f (the f is for “funny”) channel inhibitor, slows the heart rate without other known cardiovascular effects.

SHIFT (the Systolic Heart Failure Treatment With the I_f Inhibitor Ivabradine Trial)³⁵ investigated whether isolated heart rate reduction with ivabradine would reduce adverse clinical outcomes in patients with symptomatic heart failure. SHIFT randomized 6,505 patients with a left ventricular ejection fraction of 35% or less, in sinus rhythm, with a heart rate of at least 70 beats per minute, on optimal medical therapy, and hospitalized within 12 months of enrollment to receive ivabradine or placebo. The primary end point was a composite of cardiovascular mortality and hospital admission for worsening heart failure. Outcomes varied by heart rates achieved, with the best outcomes in those with the lowest heart rates at trial conclusion.

Ivabradine (Table 7) is indicated for patients with symptomatic heart failure with a left ventricular ejection fraction less than 35%, in sinus rhythm, with a resting heart rate of at least 70 beats per minute, and either on a maximally tolerated beta-blocker or with a contraindication to beta-blockers.

Ivabradine should be avoided in patients who are in acute decompensated heart failure or are hypotensive (blood pressure < 90/50 mm Hg), as well as in patients with a significant conduction abnormality (sick sinus syndrome, sinoatrial block, third-degree atrioventricular block), hepatic impairment, or bradycardia (resting heart rate < 60 beats per minute).

Digoxin

Digoxin has been used in treating systolic heart failure for more than 70 years.^36,37

DIG (Digoxin Investigative Group trial)³⁸ evaluated the long-term effect of digoxin on rates of mortality and hospitalization for heart failure over a 3-year period. In patients with  a left ventricular ejection fraction less than 45%, digoxin had no effect on overall mortality when combined with diuretics and ACE inhibitors. However, the risk of hospitalization for worsening heart failure was significantly reduced with digoxin treatment.³⁸

Recommendations. Digoxin should be considered when patients are on guideline-recommended therapy but heart failure symptoms persist. It is commonly initiated at a dose of 0.125 to 0.25 mg. The target therapeutic range for digoxin is 0.5 to 0.9 ng/mL.¹ Digoxin toxicity can occur in patients with renal impairment, hypokalemia, hypomagnesemia, and hypothyroidism.

The 2013 ACC/AHA guidelines give a class IIA recommendation (treatment is “reasonable”) for digoxin in patients with heart failure with reduced ejection fraction unless contraindicated, to decrease hospitalizations for heart failure.¹

Diuretics

Clinical manifestations of volume overload in patients with heart failure are from excess salt and water retention leading to inappropriate volume expansion in both the vascular and extravascular space. Diuretics (Table 8) are the foundation of heart failure treatment. Most patients are first initiated on a combination of a loop diuretic and a low-sodium diet to improve symptoms.

The 2013 ACC/AHA guidelines give a class I recommendation for diuretics in patients with heart failure with reduced ejection fraction who have evidence of fluid retention, unless contraindicated, to improve symptoms.¹

Devices: ICDs

Patients with heart failure are at increased risk of sudden death and ventricular arrhythmias.³⁹ Previously, antiarrhythmic drugs were considered the standard of care for nonsustained ventricular tachycardia after myocardial infarction.

MADIT (the Multicenter Automatic Defibrillator Implantation Trial) investigated whether prophylactic implantation of an internal cardiac defibrillator would improve 5-year survival rates in patients with heart failure. Eligible patients had had a Q-wave or enzyme-positive myocardial infarction within 3 weeks of study entry. They also had had an episode of asymptomatic nonsustained ventricular tachycardia unrelated to an acute myocardial infarction. Additionally, the patients had a left ventricular ejection fraction less than 35%, and inducible, sustained, nonsuppressible ventricular tachyarrhythmia on electrophysiologic testing.⁴⁰

During the study, 15 patients in the defibrillator group died vs 39 in the conventional therapy group (P = .009).⁴⁰

MADIT II evaluated the potential survival benefit of a prophylactically implanted defibrillator in the absence of electrophysiologic testing to induce arrhythmias.⁴¹ MADIT II included 1,232 patients with prior myocardial infarctions and a left ventricular ejection fracton of 30% or less. Patients were randomized to receive an implanted cardioverter-defibrillator or conventional medical therapy. The primary end point was death from any cause.⁴¹

The mortality rate was 19.8% in the conventional therapy group vs 14.2% in the defibrillator group (hazard ratio 0.69, P = .016).⁴¹ Thus, MADIT-II confirmed the benefits of prophylactic implantable cardioverter-defibrillator therapy seen in the original MADIT, and additionally eliminated the need for an electrophysiology test prior to device implantation.

SCD-HeFT (the Sudden Cardiac Death in Heart Failure Trial) evaluated whether amiodarone or a conservatively programmed shock-only, single-lead implanted cardioverter-defibrillator would decrease the risk of death (all-cause) in a population with mild to moderate heart failure with ischemic and nonischemic causes.⁴² In this trial, 2,521 patients with an ejection fraction of 35% or less, in NYHA class II or III, and with stable heart failure were randomized to receive a single-chamber implantable cardioverter-defibrillator,  amiodarone, or placebo.

There were 244 deaths in the placebo group, 240 deaths in the amiodarone group (P = .53 compared with placebo), and 182 deaths in the defibrillator group (P = .007 compared with placebo).⁴²

Recommendations. The 2013 ACC/AHA guideline¹ gives implantable defibrillator therapy a class IA recommendation for the primary prevention of sudden cardiac death in selected patients with nonischemic cardiomyopathy or ischemic cardiomyopathy at least 40 days after a myocardial infarction and 90 days after percutaneous coronary intervention or coronary artery bypass grafting; with a left ventricular ejection fraction of 35% or less; and NYHA class II or III symptoms on chronic goal-directed medical management.

This therapy receives a class IB recommendation for primary prevention of sudden cardiac death to reduce total mortality in selected patients at least 40 days after myocardial infarction with a left ventricular ejection fraction of 30% or less and NYHA class I symptoms while receiving goal-directed medical therapy.

Implantable cardioverter-defibrillators are not recommended in patients who otherwise have a life expectancy of less than 1 year.

Devices: Cardiac resynchronization therapy

From 25% to 30% of heart failure patients have an intraventricular conduction abnormality,^43,44 which can result in abnormalities of systolic and diastolic function. Biventricular pacing, in which a pacing lead is placed in the coronary sinus in addition to the right atrium and right ventricle, optimizes synchronization of ventricular contraction.^43,44

MUSTIC (the Multisite Stimulation in Cardiomyopathies study) was a randomized trial designed to assess the efficacy of biventricular pacing (also known as cardiac resynchronization therapy) in heart failure patients.⁴⁴ Entry criteria included NYHA class III heart failure for at least 1 month, left ventricular ejection fraction less than 35%, left ventricular end-diastolic diameter greater than 60 mm, and QRS duration longer than 150 ms. Patients were followed up at 9 and 12 months with 6-minute walking distance, peak oxygen consumption, changes in NYHA class, and left ventricular systolic function by echocardiography or radionuclide testing. Quality of life was assessed by the Minnesota Living With Heart Failure Questionnaire.

At 12 months, patients could walk significantly farther in 6 minutes, and their peak oxygen consumption had increased. They also reported significant improvement in quality of life, and NYHA class improved by 25%. MUSTIC was the first study to show a benefit in exercise tolerance, quality of life, improvement in cardiac performance, and reduction in heart failure symptoms with the use of biventricular pacing at 1 year.

MIRACLE (the Multicenter InSync Randomized Clinical Evaluation) validated the findings seen in MUSTIC by using a larger population size and a double-blinded method.⁴⁵ Compared with a control group, patients who underwent cardiac resynchronization therapy could walk farther in 6 minutes and scored better in NYHA class, quality of life, and left ventricular ejection fraction.⁴⁵

Recommendations. The 2013 ACC/AHA guidelines¹ give cardiac resynchronization therapy a class IA/B indication for NYHA class II, III, or IV patients on goal-directed medical therapy in sinus rhythm with left ventricular ejection fraction 35% or less, left bundle branch block, and QRS duration of 150 ms or more.¹

Devices: Implantable sensors

The future of ambulatory heart failure management may include implantable pulmonary artery pressure sensors.

The CardioMEMS is a permanently implantable pressure measurement system designed to provide daily pulmonary artery pressure measurements in an ambulatory setting with a goal of reducing heart failure-related hospitalizations. Through a transvenous delivery system, an implantable, battery-free sensor is positioned in the distal pulmonary artery.^46,47

CHAMPION (the CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Patients trial) was one of the first major trials to assess the safety and efficacy of implantable pulmonary artery pressure monitoring systems.⁴⁶ The study device was associated with a significant reduction in mean pulmonary artery pressures, fewer heart failure hospitalizations, and better quality of life. The length of stay for heart failure-related hospitalizations was also significantly shorter in the CardioMEMs group.⁴⁶

Exercise

Patients with heart failure routinely experience a decline in functional capacity. This decline manifests as reduced exercise tolerance and poor quality of life, usually resulting in a physician recommendation to rest and paradoxical deconditioning and possible progression of symptoms.

Several studies have shown that cardiac rehabilitation has improved outcomes in heart failure patients.⁴⁸ Cardiac rehabilitation is a supervised program that helps patients with exercise training, healthy living, education, and psychosocial counseling.

HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) is the largest randomized trial performed to determine whether aerobic exercise training reduces all-cause mortality or all-cause hospitalization and improves quality of life in patients with stable heart failure.⁴⁹ Although the reduction in end points was initially not statistically significant, after adjusting for highly prognostic predictors of poor outcomes (cardiopulmonary exercise time, left ventricular ejection fraction, atrial fibrillation, and depression), exercise training was found to reduce the incidence of all-cause mortality or all-cause hospitalization by 11% (P = .03).⁴⁹

Recommendations. Based on the results of HF-ACTION and several smaller studies, the ACC/AHA guidelines give exercise training a class IA recommendation as a safe and effective activity for patients with heart failure who are able to participate, to improve functional status.¹ A class IIA recommendation is given to cardiac rehabilitation for the improvement of functional capacity, exercise duration, quality of life, and mortality rates.¹

End-stage heart failure: Recognition

Despite adequate titration of goal-directed medical therapy, a portion of patients with heart failure with reduced ejection fraction ultimately progress to stage D, also termed “advanced” heart failure. The 5-year survival rate for patients with heart failure overall is 50%, but the 1-year mortality rate for those with advanced heart failure exceeds 50%.⁵⁰

Because the high rates of morbidity and mortality can potentially be lowered, recognition of heart failure disease progression is imperative so that patients can be promptly referred for therapies such as inotropic infusion, mechanical circulatory support, and cardiac transplant, as well as end-of-life care such as hospice.¹

The ACC/AHA¹ have published clinical events and findings useful in identifying patients with advanced heart failure:

• Two or more hospitalizations or emergency department visits for heart failure in the past year
• Progressive deterioration in renal function (eg, elevation in creatinine or blood urea nitrogen)
• Weight loss without other cause
• Intolerance to ACE inhibitors due to hypotension or worsening renal function
• Inability to tolerate beta-blockers due to worsening heart failure or hypotension
• Systolic blood pressure often below 90 mm Hg
• Persistent dyspnea with dressing or bathing requiring rest
• Inability to walk one block on level ground due to dyspnea or fatigue
• Recent need to escalate diuretics to maintain volume status, often reaching daily dose equivalent to furosemide more than 160 mg/day or use of supplemental metolazone
• Progressive decline in serum sodium, usually to below 133 mmol/L
• Frequent shocks from implanted cardiac defibrillator.

End-stage heart failure: Left ventricular assist devices

For patients with refractory heart failure despite optimal medical management, advanced therapies such as heart transplant or ventricular assist devices have been proven to be durable options. These mechanical circulatory support devices “unload” the diseased ventricle and maintain cardiac output to vital organs.⁵¹ They were initially designed as temporary support to allow ventricular recovery or as a bridge to cardiac transplant. However, they have also evolved into permanent (“destination”) therapy.⁵²

REMATCH (the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive HF trial) was the landmark study that showed that left ventricular assist device implantation resulted in a survival benefit and an improved quality of life in patients with advanced heart failure ineligible for cardiac transplant, compared with medical management.⁵⁰ Implantation of a left ventricular assist device was associated with a 27% absolute reduction in the 1-year mortality rate.⁵⁰

Since the National Institutes of Health’s artificial heart program was launched in 1964, there has been tremendous progress in the development of mechanical circulatory devices.⁵⁰ The results of REMATCH were promising, but the 2-year survival rate was still only 23%, leaving a lot to be desired.

The HeartMate II (Thoratec) trial compared an axial continuous-flow device vs the previously established pulsatile left ventricular assist device, and noted a 2-year survival of 58% with the continuous flow device vs  24% with the pulsatile device (P = .008).⁵³

ADVANCE (Evaluation of the HeartWare Left Ventricular Assist Device for the Treatment of Advanced Heart Failure) showed similar efficacy of the HVAD (Heartware), a centrifugal continuous-flow LVAD currently in use.⁵⁴

The next generation of continuous-flow left ventricular assist devices are currently in clinical trials in the United States and include the axial flow MVAD (Heartware) and centrifugal flow Heartmate III (Thoratec).

We emphasize the importance of early identification of patients with advanced disease who may qualify for and benefit from such therapies.

The management of heart failure is evolving. In the 1960s, the standard heart failure medical regimen included digoxin, diuretics, and the recommendation of rest. This contrasts with the current era, in which medical regimens include neurohormonal blockade, diuretics, and the promotion of physical activity.⁵⁵ Since the publication of the 2013 heart failure guidelines, new medical and device options have emerged that have been proven to either improve survival or reduce hospitalizations. The development of clinical guidelines promotes evidence-based practice and overcomes the inertia of practice patterns based on anecdotal evidence.

Several approaches to the management of heart failure have been recommended. A major effort should be made to identify those at risk for heart failure (stage A) and to implement risk factor modification. Treatment of hypertension, diabetes mellitus, and dyslipidemia decreases the risk of heart failure.¹

For patients with evidence of structural heart disease with and without symptoms, Figure 1 summarizes a guideline approach to the management of heart failure. It should be stressed that guidelines are meant to guide management, but do not serve as a substitute for sound clinical judgment.

Heart failure is the common final pathway of all cardiac pathology, and understanding the neurohormonal response and maladaptive physiology has led to the development of novel therapeutics and devices. At present, the field of cardiology may not be able to remove the “failure” from heart failure, but we can make every effort to prevent failure of treatment delivery and reduce resource utilization and morbidity associated with this syndrome.

Acknowledgments: We would like to thank Chankya Dahagam and Cynthia Obenwa for their valuable contribution in the preparation of this manuscript.

Managing heart failure is a challenge. To aid clinicians in this task, the American College of Cardiology Foundation (ACC) and the American Heart Association (AHA) publish evidence-based guidelines, most recently in 2013.¹ Since then, new drugs and devices have been shown to improve survival and reduce hospitalizations.

See related editorial

This paper reviews the ABCs of outpatient management of systolic heart failure (or heart failure with reduced ejection fraction), including the results of major trials and recommendations.

A common and serious condition

Heart failure is a debilitating syndrome that takes a significant physical and mental toll on those affected.

And it is common. An American age 40 or older faces a 20% lifetime risk of heart failure.¹ An estimated 5.1 million Americans have clinical signs and symptoms of heart failure, and 900,000 new cases are diagnosed each year.² By 2030 the prevalence of heart failure is projected to increase by 46%, and 9 million Americans will have been diagnosed with it.²

The severity of heart failure can be described using either the functional classification devised by the New York Heart Association (NYHA; Table 1) or the stages defined by the ACC and AHA.^1,3 Though survival rates have improved, there is a direct correlation between worsening symptoms and death.⁴

Heart failure is the leading cause of hospitalizations annually. It accounts for $30 billion in healthcare costs, with direct medical costs accounting for 68% and another $1.8 billion associated with clinic visits, most often with primary care providers. By 2030, the cost is projected to increase by 127% to $69.7 billion—$244 per person in the United States.²

ACE inhibitors

The renin-angiotensin-aldosterone system has been studied for over 100 years.⁵

In heart failure with reduced ejection fraction, this system is upregulated as an adaptive mechanism to maintain hemodynamic homeostasis.^6–8 However, prolonged activation of the renin-angiotensin-aldosterone system can lead to deleterious cardiovascular effects such as myocyte hypertrophy, myocardial fibrosis, sodium conservation, and fluid overload.^8,9 Angiotensin II is a potent vasoconstrictor and plays a role in cardiovascular remodeling, leading to worsening progression of heart failure.⁶

CONSENSUS (the Cooperative North Scandinavian Enalapril Survival Study) examined the effect of the angiotensin-converting enzyme (ACE) inhibitor enalapril on survival in 253 patients with NYHA class IV heart failure. Participants were randomized to receive either enalapril or placebo. At 6 months, the mortality rate was 26% in the enalapril group vs 44% in the placebo group, an 18% absolute risk reduction and a 41% relative risk reduction (P = .002). At 12 months, the relative risk reduction in mortality was 30% (P = .001).¹⁰

SOLVD (the Study of Left Ventricular Dysfunction) extended the use of ACE inhibitors to all patients with heart failure, not just those in NYHA class IV. It randomized 1,284 patients with heart failure of any NYHA class and an ejection fraction less than 35% to receive either enalapril or placebo, and demonstrated a 16% relative risk reduction in mortality in the enalapril group, with mortality rates of 36% vs 39.7% (P = .0036).¹¹

Recommendations. The benefits of ACE inhibition have been demonstrated in patients with mild, moderate, and severe heart failure. Thus, the guidelines recommend ACE inhibitors (Table 2) for all patients with heart failure with reduced ejection fraction.¹

Angiotensin II receptor blockers

Angiotensin II receptor blockers (ARBs) (Table 3) have been proven to be suitable alternatives for patients with heart failure with reduced ejection fraction who cannot tolerate ACE inhibitors.

Val-HefT (the Valsartan HF Trial)¹² randomized 5,010 patients in a double-blind fashion to receive either valsartan or placebo, with background therapy that included beta-blockers, digoxin, diuretics, and ACE inhibitors. There was a 13% reduction of the combined primary end point of mortality and morbidity and a 24% reduction in heart failure hospitalizations in the valsartan group.¹²

Subgroup analysis compared patients on the basis of use of ACE inhibitors and beta-blockers at study entry. Valsartan had a favorable effect in the subgroups using beta-blockers alone, ACE inhibitors alone, and neither drug. However, when patients received all three (a beta-blocker, an ACE inhibitor, and valsartan), the mortality rate was significantly increased (P = .009).¹² This finding conflicted with those of other studies, which found a small benefit of combining an ACE inhibitor and an ARB.

CHARM-Added (the Candesartan in HF Assessment of Reduction in Mortality and Morbidity trial)¹³ investigated whether adding the ARB candesartan to an ACE inhibitor would improve clinical outcomes. In the study, 2,548 patients in NYHA class II, III, or IV with a left ventricular ejection fraction of less than 40% who were receiving ACE inhibitors were randomized to either candesartan or placebo. The addition of candesartan resulted in a significant reduction in cardiovascular mortality and heart failure hospitalizations, but with the downside of higher rates of hyperkalemia and serum creatinine elevation.¹³

Recommendations. The 2013 guidelines recommend that ARBs be used in patients who cannot tolerate an ACE inhibitor due to cough. However, routine combined use of ARBs, ACE inhibitors, and aldosterone antagonists is not recommended and may cause harm.¹

Aldosterone receptor antagonists

Elevated levels of aldosterone lead to fluid retention, loss of magnesium and potassium, and myocardial fibrosis.

RALES (the Randomized Aldactone Evaluation Study)¹⁴ tested the hypothesis that the aldosterone receptor antagonist spironolactone (25 mg daily) would reduce deaths from all causes in patients with severe heart failure receiving standard medications including an ACE inhibitor. RALES included 1,663 patients in NYHA class III or IV with a left ventricular ejection fraction of 35% or less, randomized to receive 25 mg of spironolactone or matching placebo. This study found a 30% relative risk reduction and an 11% absolute risk reduction in all-cause mortality, a 31% relative risk reduction and a 10% absolute risk reduction in cardiac mortality, and 30% fewer cardiac-related hospitalizations in the spironolactone group.¹⁴

Eplerenone, an aldosterone receptor antagonist that lacks the antiandrogenic side effects of spironolactone, has also been shown to be beneficial. Its efficacy in patients with left ventricular systolic dysfunction was first established in postmyocardial infarction patients.¹⁵

EMPHASIS-HF (the Eplerenone in Mild Patients Hospitalized and Survival Study in Heart Failure)¹⁶ broadened the application of eplerenone (and aldosterone antagonists in general), investigating the effects of eplerenone in 2,737 NYHA class II patients, regardless of ischemic etiology. The composite end point of cardiovascular death or heart failure hospitalization occurred in 18.3% of the eplerenone group vs 25.9% of the placebo group (P < .001). A total of 12.5% of patients in the eplerenone group died, compared with 15.5% in the placebo group (P = .008). Hospitalizations were also fewer in the eplerenone group.

Recommendations. The 2013 guidelines recommend aldosterone receptor antagonists (Table 4) for patients with NYHA class II, III, or IV heart failure who have an ejection fraction of 35% or less, to reduce morbidity and mortality (class IA recommendation).¹ The guidelines also recommend that these agents not be used in patients with renal insufficiency (serum creatinine > 2.5 mg/dL in men or > 2.0 mg/dL in women; an estimated glomerular filtration rate < 30 mL/min/1.73 m²); or a serum potassium level above 5 mmol/L.¹

Angiotensin-neprilysin inhibitor (the future)

Research has identified neprilysin as another potential target in the treatment of heart failure and has sought to combine inhibition of angiotensin and neprilysin.

Neprilysin, a neutral endopeptidase, is associated with degradation of several natural vasoactive peptides such as natriuretic peptide, bradykinin, and adrenomedullin. Neprilysin inhibition increases these substances and counters the neurohormonal overactivation that leads to vasoconstriction, sodium retention, and cardiac remodeling.¹⁷

The ARB valsartan has been combined with the neprilysin inhibitor sacubitril to create the first angiotensin-neprilysin inhibitor (ARNI) (Table 5). The combination was selected to minimize the potential for angioedema.

PARADIGM-HF (the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial)¹⁷ examined whether combined angiotensin-neprilysin inhibition was superior to ACE inhibition alone with enalapril in patients with chronic heart failure.

In PARADIGM-HF, 10,521 patients with NYHA class II, III, or IV heart failure were randomized to receive either sacubitril-valsartan or enalapril. The group receiving sacubitril-valsartan had significantly fewer deaths from cardiovascular causes and heart failure hospitalizations.¹⁷ An improvement in quality of life and NYHA functional class was also observed in the sacubitril-valsartan group.¹⁷

Sacubitril-valsartan underwent priority review by the US Food and Drug Administration and has been approved. Currently, it is indicated for the treatment of heart failure with reduced ejection fraction and NYHA class II, III, or IV symptoms. It should be avoided in patients who have previously experienced angioedema with an ACE inhibitor or ARB, in patients receiving aliskiren for diabetes, and in patients with hypersensitivity reactions to either of its components. Simultaneous use of sacubitril-valsartan and an ACE inhibitor should be avoided, and a washout period is recommended when transitioning from an ACE inhibitor to this combined agent.

Beta-blockers

In heart failure, there is increased sympathetic activation and associated elevations in norepinephrine levels, which may lead to deleterious long-term effects on cardiac function and structure. Beta-adrenergic receptor blockade is now known to be cardioprotective, but it was not always so; beta-blockers used to be contraindicated in patients with heart failure.

An early experience using beta-blockers in heart failure was described in 1975.^18,19 The first study to report a survival benefit of treating systolic heart failure with a beta-blocker was published in 1979.²⁰ Later, small controlled trials demonstrated a reduction in heart failure symptoms and improvement in left ventricular function and in NYHA functional class.²¹ Larger clinical trials have demonstrated a tremendous survival benefit with beta-blockers in heart failure, specifically carvedilol, extended-release metoprolol, and bisoprolol.

The US Carvedilol Heart Failure Study Group trial²² evaluated whether beta-blocker use in heart failure patients would reduce the rates of morbidity and mortality.²² The trial included 1,094 patients with symptomatic heart failure for at least 3 months and a left ventricular ejection fraction of 35% or less on background therapy including vasodilators, ACE inhibitors, and digoxin. Patients were randomized to receive either carvedilol or placebo. Carvedilol use was associated with a dramatic 65% risk reduction in mortality (7.8% with placebo vs 3.2% with carvedilol, P < .001) and a 27% risk reduction in hospitalizations (19.6% vs 14.1%, P = .036), leading to early trial termination.

CIBIS-II (the Cardiac Insufficiency Bisoprolol Study II)²³ investigated the effects of beta-blockers on survival and morbidity. CIBIS-II included 2,647 NYHA class III or IV patients with a left ventricular ejection fraction less than 35% on background medical therapy that included diuretics and ACE inhibitors. This trial was also terminated early, after demonstrating a significant survival benefit with bisoprolol.

MERIT-HF (the Metoprolol Extended Release Randomized Intervention Trial in Congestive Heart Failure)²⁴ evaluated if once-daily metoprolol would lower mortality rates  in patients with symptomatic heart failure. The study enrolled 3,991 NYHA class II–IV patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Like the previous two beta-blocker trials, MERIT-HF was terminated early, as it demonstrated a 34% reduction in all-cause mortality (7.2% risk of death per patient-year vs 11.0%, P = .00009).

The beta-blocker trials have shown that when added to background therapy, beta-blockers improve survival and reduce hospitalizations. However, when prescribing a beta-blocker, it is important to understand that not all beta-blockers are equal in the treatment of heart failure.

COMET (the Carvedilol or Metoprolol European Trial)²⁵ was the only head-to-head randomized control trial evaluating clinical outcomes in patients receiving carvedilol or metoprolol tartrate (not metoprolol succinate). In COMET, 1,511 patients with NYHA class II, III, or IV heart failure with a left ventricular ejection fraction of 35% or less were randomized to carvedilol or metoprolol tartrate. The primary end point of all-cause mortality occurred in 34% of the carvedilol group and 40% of the metoprolol tartrate group (P = .0017). There was no significant difference with regard to the composite end point of mortality and all-cause admissions.

Recommendations. The 2013 guidelines give a class IA recommendation for starting a beta-blocker (carvedilol, bisoprolol, or metoprolol succinate, Table 6) in patients with current or prior symptoms of heart failure.¹ Beta-blockers should be initiated with caution or avoided in patients with acutely decompensated heart failure with evidence of fluid overload.

Brain-type natriuretic peptide

Brain-type natriuretic peptide (BNP) or its amino-terminal cleavage product (NT-proBNP) originates in cardiomyocytes and is released by several triggers, most commonly cardiomyocyte stretch in the setting of volume or pressure overload.²⁶ The biologic significance of BNP includes natriuresis and vasodilation, renin-angiotensin system inhibition, and sympathetic nervous system modulation.²⁶

TIME-CHF (the Trial of Intensified vs. Standard Medical Therapy in Elderly Patients With Congestive HF)²⁷ investigated whether 18-month outcomes would be better if treatment were guided by N-terminal BNP levels rather than by symptoms. The BNP-guided strategy was not associated with a reduction in hospitalization or a survival benefit.

BATTLESCARRED (the NT-proBNP-Assisted Treatment to Lessen Serial Cardiac Readmissions and Death trial)²⁸ in 2009 showed that a BNP-guided management strategy significantly reduced mortality rates in patients under age 75 compared with standard medical therapy.

PROTECT (the Use of NT-proBNP Testing to Guide HF Therapy in the Outpatient Setting study)²⁹ also showed that a BNP-guided strategy was superior to usual care and was associated with reduced cardiovascular events and improved quality of life.²⁹

GUIDE IT-HF (the Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure study), currently ongoing, is designed to assess the safety, efficacy and cost-effectiveness of a biomarker-guided strategy in 1,100 high-risk patients with heart failure with reduced ejection fraction. 

Recommendations. The 2013 ACC/AHA guidelines give a class IA recommendation for the use of BNP to support clinical decision-making, particularly in cases of clinical uncertainty.¹ BNP can also be used to establish prognosis or disease severity in chronic heart failure and to achieve optimal dosage of goal-directed medical therapy for euvolemic patients followed in a structured heart failure program.¹

Heart failure clinics

Continuity of care upon discharge from the hospital is currently in a state of evolution. Those diagnosed with heart failure can now experience more comprehensive posthospital care by virtue of disease management clinics. The name may vary by institution, but whether it is called a “diuresis clinic,” “bridge clinic,” or “heart failure clinic,” the goal is to improve guideline-driven care, educate the patient, and reduce heart failure hospitalizations. Heart failure clinics are designed to provide a smooth transition from inpatient to outpatient care and to encourage patient self-accountability in health maintenance thereafter.

Studies have shown that heart failure clinics are associated with better medication dosing, fewer hospitalizations, and lower healthcare costs.^30–32

Chronotropy: I_f inhibition

An elevated resting heart rate has been shown to be associated with increased cardiovascular morbidity and mortality.³³ Studies have shown that slowing the heart rate improves myocardial contraction and energy supply and reduces energy expenditure.³⁴ Ivabradine, a selective I_f (the f is for “funny”) channel inhibitor, slows the heart rate without other known cardiovascular effects.

SHIFT (the Systolic Heart Failure Treatment With the I_f Inhibitor Ivabradine Trial)³⁵ investigated whether isolated heart rate reduction with ivabradine would reduce adverse clinical outcomes in patients with symptomatic heart failure. SHIFT randomized 6,505 patients with a left ventricular ejection fraction of 35% or less, in sinus rhythm, with a heart rate of at least 70 beats per minute, on optimal medical therapy, and hospitalized within 12 months of enrollment to receive ivabradine or placebo. The primary end point was a composite of cardiovascular mortality and hospital admission for worsening heart failure. Outcomes varied by heart rates achieved, with the best outcomes in those with the lowest heart rates at trial conclusion.

Ivabradine (Table 7) is indicated for patients with symptomatic heart failure with a left ventricular ejection fraction less than 35%, in sinus rhythm, with a resting heart rate of at least 70 beats per minute, and either on a maximally tolerated beta-blocker or with a contraindication to beta-blockers.

Ivabradine should be avoided in patients who are in acute decompensated heart failure or are hypotensive (blood pressure < 90/50 mm Hg), as well as in patients with a significant conduction abnormality (sick sinus syndrome, sinoatrial block, third-degree atrioventricular block), hepatic impairment, or bradycardia (resting heart rate < 60 beats per minute).

Digoxin

Digoxin has been used in treating systolic heart failure for more than 70 years.^36,37

DIG (Digoxin Investigative Group trial)³⁸ evaluated the long-term effect of digoxin on rates of mortality and hospitalization for heart failure over a 3-year period. In patients with  a left ventricular ejection fraction less than 45%, digoxin had no effect on overall mortality when combined with diuretics and ACE inhibitors. However, the risk of hospitalization for worsening heart failure was significantly reduced with digoxin treatment.³⁸

Recommendations. Digoxin should be considered when patients are on guideline-recommended therapy but heart failure symptoms persist. It is commonly initiated at a dose of 0.125 to 0.25 mg. The target therapeutic range for digoxin is 0.5 to 0.9 ng/mL.¹ Digoxin toxicity can occur in patients with renal impairment, hypokalemia, hypomagnesemia, and hypothyroidism.

The 2013 ACC/AHA guidelines give a class IIA recommendation (treatment is “reasonable”) for digoxin in patients with heart failure with reduced ejection fraction unless contraindicated, to decrease hospitalizations for heart failure.¹

Diuretics

Clinical manifestations of volume overload in patients with heart failure are from excess salt and water retention leading to inappropriate volume expansion in both the vascular and extravascular space. Diuretics (Table 8) are the foundation of heart failure treatment. Most patients are first initiated on a combination of a loop diuretic and a low-sodium diet to improve symptoms.

The 2013 ACC/AHA guidelines give a class I recommendation for diuretics in patients with heart failure with reduced ejection fraction who have evidence of fluid retention, unless contraindicated, to improve symptoms.¹

Devices: ICDs

Patients with heart failure are at increased risk of sudden death and ventricular arrhythmias.³⁹ Previously, antiarrhythmic drugs were considered the standard of care for nonsustained ventricular tachycardia after myocardial infarction.

MADIT (the Multicenter Automatic Defibrillator Implantation Trial) investigated whether prophylactic implantation of an internal cardiac defibrillator would improve 5-year survival rates in patients with heart failure. Eligible patients had had a Q-wave or enzyme-positive myocardial infarction within 3 weeks of study entry. They also had had an episode of asymptomatic nonsustained ventricular tachycardia unrelated to an acute myocardial infarction. Additionally, the patients had a left ventricular ejection fraction less than 35%, and inducible, sustained, nonsuppressible ventricular tachyarrhythmia on electrophysiologic testing.⁴⁰

During the study, 15 patients in the defibrillator group died vs 39 in the conventional therapy group (P = .009).⁴⁰

MADIT II evaluated the potential survival benefit of a prophylactically implanted defibrillator in the absence of electrophysiologic testing to induce arrhythmias.⁴¹ MADIT II included 1,232 patients with prior myocardial infarctions and a left ventricular ejection fracton of 30% or less. Patients were randomized to receive an implanted cardioverter-defibrillator or conventional medical therapy. The primary end point was death from any cause.⁴¹

The mortality rate was 19.8% in the conventional therapy group vs 14.2% in the defibrillator group (hazard ratio 0.69, P = .016).⁴¹ Thus, MADIT-II confirmed the benefits of prophylactic implantable cardioverter-defibrillator therapy seen in the original MADIT, and additionally eliminated the need for an electrophysiology test prior to device implantation.

SCD-HeFT (the Sudden Cardiac Death in Heart Failure Trial) evaluated whether amiodarone or a conservatively programmed shock-only, single-lead implanted cardioverter-defibrillator would decrease the risk of death (all-cause) in a population with mild to moderate heart failure with ischemic and nonischemic causes.⁴² In this trial, 2,521 patients with an ejection fraction of 35% or less, in NYHA class II or III, and with stable heart failure were randomized to receive a single-chamber implantable cardioverter-defibrillator,  amiodarone, or placebo.

There were 244 deaths in the placebo group, 240 deaths in the amiodarone group (P = .53 compared with placebo), and 182 deaths in the defibrillator group (P = .007 compared with placebo).⁴²

Recommendations. The 2013 ACC/AHA guideline¹ gives implantable defibrillator therapy a class IA recommendation for the primary prevention of sudden cardiac death in selected patients with nonischemic cardiomyopathy or ischemic cardiomyopathy at least 40 days after a myocardial infarction and 90 days after percutaneous coronary intervention or coronary artery bypass grafting; with a left ventricular ejection fraction of 35% or less; and NYHA class II or III symptoms on chronic goal-directed medical management.

This therapy receives a class IB recommendation for primary prevention of sudden cardiac death to reduce total mortality in selected patients at least 40 days after myocardial infarction with a left ventricular ejection fraction of 30% or less and NYHA class I symptoms while receiving goal-directed medical therapy.

Implantable cardioverter-defibrillators are not recommended in patients who otherwise have a life expectancy of less than 1 year.

Devices: Cardiac resynchronization therapy

From 25% to 30% of heart failure patients have an intraventricular conduction abnormality,^43,44 which can result in abnormalities of systolic and diastolic function. Biventricular pacing, in which a pacing lead is placed in the coronary sinus in addition to the right atrium and right ventricle, optimizes synchronization of ventricular contraction.^43,44

MUSTIC (the Multisite Stimulation in Cardiomyopathies study) was a randomized trial designed to assess the efficacy of biventricular pacing (also known as cardiac resynchronization therapy) in heart failure patients.⁴⁴ Entry criteria included NYHA class III heart failure for at least 1 month, left ventricular ejection fraction less than 35%, left ventricular end-diastolic diameter greater than 60 mm, and QRS duration longer than 150 ms. Patients were followed up at 9 and 12 months with 6-minute walking distance, peak oxygen consumption, changes in NYHA class, and left ventricular systolic function by echocardiography or radionuclide testing. Quality of life was assessed by the Minnesota Living With Heart Failure Questionnaire.

At 12 months, patients could walk significantly farther in 6 minutes, and their peak oxygen consumption had increased. They also reported significant improvement in quality of life, and NYHA class improved by 25%. MUSTIC was the first study to show a benefit in exercise tolerance, quality of life, improvement in cardiac performance, and reduction in heart failure symptoms with the use of biventricular pacing at 1 year.

MIRACLE (the Multicenter InSync Randomized Clinical Evaluation) validated the findings seen in MUSTIC by using a larger population size and a double-blinded method.⁴⁵ Compared with a control group, patients who underwent cardiac resynchronization therapy could walk farther in 6 minutes and scored better in NYHA class, quality of life, and left ventricular ejection fraction.⁴⁵

Recommendations. The 2013 ACC/AHA guidelines¹ give cardiac resynchronization therapy a class IA/B indication for NYHA class II, III, or IV patients on goal-directed medical therapy in sinus rhythm with left ventricular ejection fraction 35% or less, left bundle branch block, and QRS duration of 150 ms or more.¹

Devices: Implantable sensors

The future of ambulatory heart failure management may include implantable pulmonary artery pressure sensors.

The CardioMEMS is a permanently implantable pressure measurement system designed to provide daily pulmonary artery pressure measurements in an ambulatory setting with a goal of reducing heart failure-related hospitalizations. Through a transvenous delivery system, an implantable, battery-free sensor is positioned in the distal pulmonary artery.^46,47

CHAMPION (the CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Patients trial) was one of the first major trials to assess the safety and efficacy of implantable pulmonary artery pressure monitoring systems.⁴⁶ The study device was associated with a significant reduction in mean pulmonary artery pressures, fewer heart failure hospitalizations, and better quality of life. The length of stay for heart failure-related hospitalizations was also significantly shorter in the CardioMEMs group.⁴⁶

Exercise

Patients with heart failure routinely experience a decline in functional capacity. This decline manifests as reduced exercise tolerance and poor quality of life, usually resulting in a physician recommendation to rest and paradoxical deconditioning and possible progression of symptoms.

Several studies have shown that cardiac rehabilitation has improved outcomes in heart failure patients.⁴⁸ Cardiac rehabilitation is a supervised program that helps patients with exercise training, healthy living, education, and psychosocial counseling.

HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) is the largest randomized trial performed to determine whether aerobic exercise training reduces all-cause mortality or all-cause hospitalization and improves quality of life in patients with stable heart failure.⁴⁹ Although the reduction in end points was initially not statistically significant, after adjusting for highly prognostic predictors of poor outcomes (cardiopulmonary exercise time, left ventricular ejection fraction, atrial fibrillation, and depression), exercise training was found to reduce the incidence of all-cause mortality or all-cause hospitalization by 11% (P = .03).⁴⁹

Recommendations. Based on the results of HF-ACTION and several smaller studies, the ACC/AHA guidelines give exercise training a class IA recommendation as a safe and effective activity for patients with heart failure who are able to participate, to improve functional status.¹ A class IIA recommendation is given to cardiac rehabilitation for the improvement of functional capacity, exercise duration, quality of life, and mortality rates.¹

End-stage heart failure: Recognition

Despite adequate titration of goal-directed medical therapy, a portion of patients with heart failure with reduced ejection fraction ultimately progress to stage D, also termed “advanced” heart failure. The 5-year survival rate for patients with heart failure overall is 50%, but the 1-year mortality rate for those with advanced heart failure exceeds 50%.⁵⁰

Because the high rates of morbidity and mortality can potentially be lowered, recognition of heart failure disease progression is imperative so that patients can be promptly referred for therapies such as inotropic infusion, mechanical circulatory support, and cardiac transplant, as well as end-of-life care such as hospice.¹

The ACC/AHA¹ have published clinical events and findings useful in identifying patients with advanced heart failure:

• Two or more hospitalizations or emergency department visits for heart failure in the past year
• Progressive deterioration in renal function (eg, elevation in creatinine or blood urea nitrogen)
• Weight loss without other cause
• Intolerance to ACE inhibitors due to hypotension or worsening renal function
• Inability to tolerate beta-blockers due to worsening heart failure or hypotension
• Systolic blood pressure often below 90 mm Hg
• Persistent dyspnea with dressing or bathing requiring rest
• Inability to walk one block on level ground due to dyspnea or fatigue
• Recent need to escalate diuretics to maintain volume status, often reaching daily dose equivalent to furosemide more than 160 mg/day or use of supplemental metolazone
• Progressive decline in serum sodium, usually to below 133 mmol/L
• Frequent shocks from implanted cardiac defibrillator.

End-stage heart failure: Left ventricular assist devices

For patients with refractory heart failure despite optimal medical management, advanced therapies such as heart transplant or ventricular assist devices have been proven to be durable options. These mechanical circulatory support devices “unload” the diseased ventricle and maintain cardiac output to vital organs.⁵¹ They were initially designed as temporary support to allow ventricular recovery or as a bridge to cardiac transplant. However, they have also evolved into permanent (“destination”) therapy.⁵²

REMATCH (the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive HF trial) was the landmark study that showed that left ventricular assist device implantation resulted in a survival benefit and an improved quality of life in patients with advanced heart failure ineligible for cardiac transplant, compared with medical management.⁵⁰ Implantation of a left ventricular assist device was associated with a 27% absolute reduction in the 1-year mortality rate.⁵⁰

Since the National Institutes of Health’s artificial heart program was launched in 1964, there has been tremendous progress in the development of mechanical circulatory devices.⁵⁰ The results of REMATCH were promising, but the 2-year survival rate was still only 23%, leaving a lot to be desired.

The HeartMate II (Thoratec) trial compared an axial continuous-flow device vs the previously established pulsatile left ventricular assist device, and noted a 2-year survival of 58% with the continuous flow device vs  24% with the pulsatile device (P = .008).⁵³

ADVANCE (Evaluation of the HeartWare Left Ventricular Assist Device for the Treatment of Advanced Heart Failure) showed similar efficacy of the HVAD (Heartware), a centrifugal continuous-flow LVAD currently in use.⁵⁴

The next generation of continuous-flow left ventricular assist devices are currently in clinical trials in the United States and include the axial flow MVAD (Heartware) and centrifugal flow Heartmate III (Thoratec).

We emphasize the importance of early identification of patients with advanced disease who may qualify for and benefit from such therapies.

The management of heart failure is evolving. In the 1960s, the standard heart failure medical regimen included digoxin, diuretics, and the recommendation of rest. This contrasts with the current era, in which medical regimens include neurohormonal blockade, diuretics, and the promotion of physical activity.⁵⁵ Since the publication of the 2013 heart failure guidelines, new medical and device options have emerged that have been proven to either improve survival or reduce hospitalizations. The development of clinical guidelines promotes evidence-based practice and overcomes the inertia of practice patterns based on anecdotal evidence.

Several approaches to the management of heart failure have been recommended. A major effort should be made to identify those at risk for heart failure (stage A) and to implement risk factor modification. Treatment of hypertension, diabetes mellitus, and dyslipidemia decreases the risk of heart failure.¹

For patients with evidence of structural heart disease with and without symptoms, Figure 1 summarizes a guideline approach to the management of heart failure. It should be stressed that guidelines are meant to guide management, but do not serve as a substitute for sound clinical judgment.

Heart failure is the common final pathway of all cardiac pathology, and understanding the neurohormonal response and maladaptive physiology has led to the development of novel therapeutics and devices. At present, the field of cardiology may not be able to remove the “failure” from heart failure, but we can make every effort to prevent failure of treatment delivery and reduce resource utilization and morbidity associated with this syndrome.

Acknowledgments: We would like to thank Chankya Dahagam and Cynthia Obenwa for their valuable contribution in the preparation of this manuscript.

Managing heart failure is a challenge. To aid clinicians in this task, the American College of Cardiology Foundation (ACC) and the American Heart Association (AHA) publish evidence-based guidelines, most recently in 2013.¹ Since then, new drugs and devices have been shown to improve survival and reduce hospitalizations.

See related editorial

This paper reviews the ABCs of outpatient management of systolic heart failure (or heart failure with reduced ejection fraction), including the results of major trials and recommendations.

A common and serious condition

Heart failure is a debilitating syndrome that takes a significant physical and mental toll on those affected.

And it is common. An American age 40 or older faces a 20% lifetime risk of heart failure.¹ An estimated 5.1 million Americans have clinical signs and symptoms of heart failure, and 900,000 new cases are diagnosed each year.² By 2030 the prevalence of heart failure is projected to increase by 46%, and 9 million Americans will have been diagnosed with it.²

The severity of heart failure can be described using either the functional classification devised by the New York Heart Association (NYHA; Table 1) or the stages defined by the ACC and AHA.^1,3 Though survival rates have improved, there is a direct correlation between worsening symptoms and death.⁴

Heart failure is the leading cause of hospitalizations annually. It accounts for $30 billion in healthcare costs, with direct medical costs accounting for 68% and another $1.8 billion associated with clinic visits, most often with primary care providers. By 2030, the cost is projected to increase by 127% to $69.7 billion—$244 per person in the United States.²

ACE inhibitors

The renin-angiotensin-aldosterone system has been studied for over 100 years.⁵

In heart failure with reduced ejection fraction, this system is upregulated as an adaptive mechanism to maintain hemodynamic homeostasis.^6–8 However, prolonged activation of the renin-angiotensin-aldosterone system can lead to deleterious cardiovascular effects such as myocyte hypertrophy, myocardial fibrosis, sodium conservation, and fluid overload.^8,9 Angiotensin II is a potent vasoconstrictor and plays a role in cardiovascular remodeling, leading to worsening progression of heart failure.⁶

CONSENSUS (the Cooperative North Scandinavian Enalapril Survival Study) examined the effect of the angiotensin-converting enzyme (ACE) inhibitor enalapril on survival in 253 patients with NYHA class IV heart failure. Participants were randomized to receive either enalapril or placebo. At 6 months, the mortality rate was 26% in the enalapril group vs 44% in the placebo group, an 18% absolute risk reduction and a 41% relative risk reduction (P = .002). At 12 months, the relative risk reduction in mortality was 30% (P = .001).¹⁰

SOLVD (the Study of Left Ventricular Dysfunction) extended the use of ACE inhibitors to all patients with heart failure, not just those in NYHA class IV. It randomized 1,284 patients with heart failure of any NYHA class and an ejection fraction less than 35% to receive either enalapril or placebo, and demonstrated a 16% relative risk reduction in mortality in the enalapril group, with mortality rates of 36% vs 39.7% (P = .0036).¹¹

Recommendations. The benefits of ACE inhibition have been demonstrated in patients with mild, moderate, and severe heart failure. Thus, the guidelines recommend ACE inhibitors (Table 2) for all patients with heart failure with reduced ejection fraction.¹

Angiotensin II receptor blockers

Angiotensin II receptor blockers (ARBs) (Table 3) have been proven to be suitable alternatives for patients with heart failure with reduced ejection fraction who cannot tolerate ACE inhibitors.

Val-HefT (the Valsartan HF Trial)¹² randomized 5,010 patients in a double-blind fashion to receive either valsartan or placebo, with background therapy that included beta-blockers, digoxin, diuretics, and ACE inhibitors. There was a 13% reduction of the combined primary end point of mortality and morbidity and a 24% reduction in heart failure hospitalizations in the valsartan group.¹²

Subgroup analysis compared patients on the basis of use of ACE inhibitors and beta-blockers at study entry. Valsartan had a favorable effect in the subgroups using beta-blockers alone, ACE inhibitors alone, and neither drug. However, when patients received all three (a beta-blocker, an ACE inhibitor, and valsartan), the mortality rate was significantly increased (P = .009).¹² This finding conflicted with those of other studies, which found a small benefit of combining an ACE inhibitor and an ARB.

CHARM-Added (the Candesartan in HF Assessment of Reduction in Mortality and Morbidity trial)¹³ investigated whether adding the ARB candesartan to an ACE inhibitor would improve clinical outcomes. In the study, 2,548 patients in NYHA class II, III, or IV with a left ventricular ejection fraction of less than 40% who were receiving ACE inhibitors were randomized to either candesartan or placebo. The addition of candesartan resulted in a significant reduction in cardiovascular mortality and heart failure hospitalizations, but with the downside of higher rates of hyperkalemia and serum creatinine elevation.¹³

Recommendations. The 2013 guidelines recommend that ARBs be used in patients who cannot tolerate an ACE inhibitor due to cough. However, routine combined use of ARBs, ACE inhibitors, and aldosterone antagonists is not recommended and may cause harm.¹

Aldosterone receptor antagonists

Elevated levels of aldosterone lead to fluid retention, loss of magnesium and potassium, and myocardial fibrosis.

RALES (the Randomized Aldactone Evaluation Study)¹⁴ tested the hypothesis that the aldosterone receptor antagonist spironolactone (25 mg daily) would reduce deaths from all causes in patients with severe heart failure receiving standard medications including an ACE inhibitor. RALES included 1,663 patients in NYHA class III or IV with a left ventricular ejection fraction of 35% or less, randomized to receive 25 mg of spironolactone or matching placebo. This study found a 30% relative risk reduction and an 11% absolute risk reduction in all-cause mortality, a 31% relative risk reduction and a 10% absolute risk reduction in cardiac mortality, and 30% fewer cardiac-related hospitalizations in the spironolactone group.¹⁴

Eplerenone, an aldosterone receptor antagonist that lacks the antiandrogenic side effects of spironolactone, has also been shown to be beneficial. Its efficacy in patients with left ventricular systolic dysfunction was first established in postmyocardial infarction patients.¹⁵

EMPHASIS-HF (the Eplerenone in Mild Patients Hospitalized and Survival Study in Heart Failure)¹⁶ broadened the application of eplerenone (and aldosterone antagonists in general), investigating the effects of eplerenone in 2,737 NYHA class II patients, regardless of ischemic etiology. The composite end point of cardiovascular death or heart failure hospitalization occurred in 18.3% of the eplerenone group vs 25.9% of the placebo group (P < .001). A total of 12.5% of patients in the eplerenone group died, compared with 15.5% in the placebo group (P = .008). Hospitalizations were also fewer in the eplerenone group.

Recommendations. The 2013 guidelines recommend aldosterone receptor antagonists (Table 4) for patients with NYHA class II, III, or IV heart failure who have an ejection fraction of 35% or less, to reduce morbidity and mortality (class IA recommendation).¹ The guidelines also recommend that these agents not be used in patients with renal insufficiency (serum creatinine > 2.5 mg/dL in men or > 2.0 mg/dL in women; an estimated glomerular filtration rate < 30 mL/min/1.73 m²); or a serum potassium level above 5 mmol/L.¹

Angiotensin-neprilysin inhibitor (the future)

Research has identified neprilysin as another potential target in the treatment of heart failure and has sought to combine inhibition of angiotensin and neprilysin.

Neprilysin, a neutral endopeptidase, is associated with degradation of several natural vasoactive peptides such as natriuretic peptide, bradykinin, and adrenomedullin. Neprilysin inhibition increases these substances and counters the neurohormonal overactivation that leads to vasoconstriction, sodium retention, and cardiac remodeling.¹⁷

The ARB valsartan has been combined with the neprilysin inhibitor sacubitril to create the first angiotensin-neprilysin inhibitor (ARNI) (Table 5). The combination was selected to minimize the potential for angioedema.

PARADIGM-HF (the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial)¹⁷ examined whether combined angiotensin-neprilysin inhibition was superior to ACE inhibition alone with enalapril in patients with chronic heart failure.

In PARADIGM-HF, 10,521 patients with NYHA class II, III, or IV heart failure were randomized to receive either sacubitril-valsartan or enalapril. The group receiving sacubitril-valsartan had significantly fewer deaths from cardiovascular causes and heart failure hospitalizations.¹⁷ An improvement in quality of life and NYHA functional class was also observed in the sacubitril-valsartan group.¹⁷

Sacubitril-valsartan underwent priority review by the US Food and Drug Administration and has been approved. Currently, it is indicated for the treatment of heart failure with reduced ejection fraction and NYHA class II, III, or IV symptoms. It should be avoided in patients who have previously experienced angioedema with an ACE inhibitor or ARB, in patients receiving aliskiren for diabetes, and in patients with hypersensitivity reactions to either of its components. Simultaneous use of sacubitril-valsartan and an ACE inhibitor should be avoided, and a washout period is recommended when transitioning from an ACE inhibitor to this combined agent.

Beta-blockers

In heart failure, there is increased sympathetic activation and associated elevations in norepinephrine levels, which may lead to deleterious long-term effects on cardiac function and structure. Beta-adrenergic receptor blockade is now known to be cardioprotective, but it was not always so; beta-blockers used to be contraindicated in patients with heart failure.

An early experience using beta-blockers in heart failure was described in 1975.^18,19 The first study to report a survival benefit of treating systolic heart failure with a beta-blocker was published in 1979.²⁰ Later, small controlled trials demonstrated a reduction in heart failure symptoms and improvement in left ventricular function and in NYHA functional class.²¹ Larger clinical trials have demonstrated a tremendous survival benefit with beta-blockers in heart failure, specifically carvedilol, extended-release metoprolol, and bisoprolol.

The US Carvedilol Heart Failure Study Group trial²² evaluated whether beta-blocker use in heart failure patients would reduce the rates of morbidity and mortality.²² The trial included 1,094 patients with symptomatic heart failure for at least 3 months and a left ventricular ejection fraction of 35% or less on background therapy including vasodilators, ACE inhibitors, and digoxin. Patients were randomized to receive either carvedilol or placebo. Carvedilol use was associated with a dramatic 65% risk reduction in mortality (7.8% with placebo vs 3.2% with carvedilol, P < .001) and a 27% risk reduction in hospitalizations (19.6% vs 14.1%, P = .036), leading to early trial termination.

CIBIS-II (the Cardiac Insufficiency Bisoprolol Study II)²³ investigated the effects of beta-blockers on survival and morbidity. CIBIS-II included 2,647 NYHA class III or IV patients with a left ventricular ejection fraction less than 35% on background medical therapy that included diuretics and ACE inhibitors. This trial was also terminated early, after demonstrating a significant survival benefit with bisoprolol.

MERIT-HF (the Metoprolol Extended Release Randomized Intervention Trial in Congestive Heart Failure)²⁴ evaluated if once-daily metoprolol would lower mortality rates  in patients with symptomatic heart failure. The study enrolled 3,991 NYHA class II–IV patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Like the previous two beta-blocker trials, MERIT-HF was terminated early, as it demonstrated a 34% reduction in all-cause mortality (7.2% risk of death per patient-year vs 11.0%, P = .00009).

The beta-blocker trials have shown that when added to background therapy, beta-blockers improve survival and reduce hospitalizations. However, when prescribing a beta-blocker, it is important to understand that not all beta-blockers are equal in the treatment of heart failure.

COMET (the Carvedilol or Metoprolol European Trial)²⁵ was the only head-to-head randomized control trial evaluating clinical outcomes in patients receiving carvedilol or metoprolol tartrate (not metoprolol succinate). In COMET, 1,511 patients with NYHA class II, III, or IV heart failure with a left ventricular ejection fraction of 35% or less were randomized to carvedilol or metoprolol tartrate. The primary end point of all-cause mortality occurred in 34% of the carvedilol group and 40% of the metoprolol tartrate group (P = .0017). There was no significant difference with regard to the composite end point of mortality and all-cause admissions.

Recommendations. The 2013 guidelines give a class IA recommendation for starting a beta-blocker (carvedilol, bisoprolol, or metoprolol succinate, Table 6) in patients with current or prior symptoms of heart failure.¹ Beta-blockers should be initiated with caution or avoided in patients with acutely decompensated heart failure with evidence of fluid overload.

Brain-type natriuretic peptide

Brain-type natriuretic peptide (BNP) or its amino-terminal cleavage product (NT-proBNP) originates in cardiomyocytes and is released by several triggers, most commonly cardiomyocyte stretch in the setting of volume or pressure overload.²⁶ The biologic significance of BNP includes natriuresis and vasodilation, renin-angiotensin system inhibition, and sympathetic nervous system modulation.²⁶

TIME-CHF (the Trial of Intensified vs. Standard Medical Therapy in Elderly Patients With Congestive HF)²⁷ investigated whether 18-month outcomes would be better if treatment were guided by N-terminal BNP levels rather than by symptoms. The BNP-guided strategy was not associated with a reduction in hospitalization or a survival benefit.

BATTLESCARRED (the NT-proBNP-Assisted Treatment to Lessen Serial Cardiac Readmissions and Death trial)²⁸ in 2009 showed that a BNP-guided management strategy significantly reduced mortality rates in patients under age 75 compared with standard medical therapy.

PROTECT (the Use of NT-proBNP Testing to Guide HF Therapy in the Outpatient Setting study)²⁹ also showed that a BNP-guided strategy was superior to usual care and was associated with reduced cardiovascular events and improved quality of life.²⁹

GUIDE IT-HF (the Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure study), currently ongoing, is designed to assess the safety, efficacy and cost-effectiveness of a biomarker-guided strategy in 1,100 high-risk patients with heart failure with reduced ejection fraction. 

Recommendations. The 2013 ACC/AHA guidelines give a class IA recommendation for the use of BNP to support clinical decision-making, particularly in cases of clinical uncertainty.¹ BNP can also be used to establish prognosis or disease severity in chronic heart failure and to achieve optimal dosage of goal-directed medical therapy for euvolemic patients followed in a structured heart failure program.¹

Heart failure clinics

Continuity of care upon discharge from the hospital is currently in a state of evolution. Those diagnosed with heart failure can now experience more comprehensive posthospital care by virtue of disease management clinics. The name may vary by institution, but whether it is called a “diuresis clinic,” “bridge clinic,” or “heart failure clinic,” the goal is to improve guideline-driven care, educate the patient, and reduce heart failure hospitalizations. Heart failure clinics are designed to provide a smooth transition from inpatient to outpatient care and to encourage patient self-accountability in health maintenance thereafter.

Studies have shown that heart failure clinics are associated with better medication dosing, fewer hospitalizations, and lower healthcare costs.^30–32

Chronotropy: I_f inhibition

An elevated resting heart rate has been shown to be associated with increased cardiovascular morbidity and mortality.³³ Studies have shown that slowing the heart rate improves myocardial contraction and energy supply and reduces energy expenditure.³⁴ Ivabradine, a selective I_f (the f is for “funny”) channel inhibitor, slows the heart rate without other known cardiovascular effects.

SHIFT (the Systolic Heart Failure Treatment With the I_f Inhibitor Ivabradine Trial)³⁵ investigated whether isolated heart rate reduction with ivabradine would reduce adverse clinical outcomes in patients with symptomatic heart failure. SHIFT randomized 6,505 patients with a left ventricular ejection fraction of 35% or less, in sinus rhythm, with a heart rate of at least 70 beats per minute, on optimal medical therapy, and hospitalized within 12 months of enrollment to receive ivabradine or placebo. The primary end point was a composite of cardiovascular mortality and hospital admission for worsening heart failure. Outcomes varied by heart rates achieved, with the best outcomes in those with the lowest heart rates at trial conclusion.

Ivabradine (Table 7) is indicated for patients with symptomatic heart failure with a left ventricular ejection fraction less than 35%, in sinus rhythm, with a resting heart rate of at least 70 beats per minute, and either on a maximally tolerated beta-blocker or with a contraindication to beta-blockers.

Ivabradine should be avoided in patients who are in acute decompensated heart failure or are hypotensive (blood pressure < 90/50 mm Hg), as well as in patients with a significant conduction abnormality (sick sinus syndrome, sinoatrial block, third-degree atrioventricular block), hepatic impairment, or bradycardia (resting heart rate < 60 beats per minute).

Digoxin

Digoxin has been used in treating systolic heart failure for more than 70 years.^36,37

DIG (Digoxin Investigative Group trial)³⁸ evaluated the long-term effect of digoxin on rates of mortality and hospitalization for heart failure over a 3-year period. In patients with  a left ventricular ejection fraction less than 45%, digoxin had no effect on overall mortality when combined with diuretics and ACE inhibitors. However, the risk of hospitalization for worsening heart failure was significantly reduced with digoxin treatment.³⁸

Recommendations. Digoxin should be considered when patients are on guideline-recommended therapy but heart failure symptoms persist. It is commonly initiated at a dose of 0.125 to 0.25 mg. The target therapeutic range for digoxin is 0.5 to 0.9 ng/mL.¹ Digoxin toxicity can occur in patients with renal impairment, hypokalemia, hypomagnesemia, and hypothyroidism.

The 2013 ACC/AHA guidelines give a class IIA recommendation (treatment is “reasonable”) for digoxin in patients with heart failure with reduced ejection fraction unless contraindicated, to decrease hospitalizations for heart failure.¹

Diuretics

Clinical manifestations of volume overload in patients with heart failure are from excess salt and water retention leading to inappropriate volume expansion in both the vascular and extravascular space. Diuretics (Table 8) are the foundation of heart failure treatment. Most patients are first initiated on a combination of a loop diuretic and a low-sodium diet to improve symptoms.

The 2013 ACC/AHA guidelines give a class I recommendation for diuretics in patients with heart failure with reduced ejection fraction who have evidence of fluid retention, unless contraindicated, to improve symptoms.¹

Devices: ICDs

Patients with heart failure are at increased risk of sudden death and ventricular arrhythmias.³⁹ Previously, antiarrhythmic drugs were considered the standard of care for nonsustained ventricular tachycardia after myocardial infarction.

MADIT (the Multicenter Automatic Defibrillator Implantation Trial) investigated whether prophylactic implantation of an internal cardiac defibrillator would improve 5-year survival rates in patients with heart failure. Eligible patients had had a Q-wave or enzyme-positive myocardial infarction within 3 weeks of study entry. They also had had an episode of asymptomatic nonsustained ventricular tachycardia unrelated to an acute myocardial infarction. Additionally, the patients had a left ventricular ejection fraction less than 35%, and inducible, sustained, nonsuppressible ventricular tachyarrhythmia on electrophysiologic testing.⁴⁰

During the study, 15 patients in the defibrillator group died vs 39 in the conventional therapy group (P = .009).⁴⁰

MADIT II evaluated the potential survival benefit of a prophylactically implanted defibrillator in the absence of electrophysiologic testing to induce arrhythmias.⁴¹ MADIT II included 1,232 patients with prior myocardial infarctions and a left ventricular ejection fracton of 30% or less. Patients were randomized to receive an implanted cardioverter-defibrillator or conventional medical therapy. The primary end point was death from any cause.⁴¹

The mortality rate was 19.8% in the conventional therapy group vs 14.2% in the defibrillator group (hazard ratio 0.69, P = .016).⁴¹ Thus, MADIT-II confirmed the benefits of prophylactic implantable cardioverter-defibrillator therapy seen in the original MADIT, and additionally eliminated the need for an electrophysiology test prior to device implantation.

SCD-HeFT (the Sudden Cardiac Death in Heart Failure Trial) evaluated whether amiodarone or a conservatively programmed shock-only, single-lead implanted cardioverter-defibrillator would decrease the risk of death (all-cause) in a population with mild to moderate heart failure with ischemic and nonischemic causes.⁴² In this trial, 2,521 patients with an ejection fraction of 35% or less, in NYHA class II or III, and with stable heart failure were randomized to receive a single-chamber implantable cardioverter-defibrillator,  amiodarone, or placebo.

There were 244 deaths in the placebo group, 240 deaths in the amiodarone group (P = .53 compared with placebo), and 182 deaths in the defibrillator group (P = .007 compared with placebo).⁴²

Recommendations. The 2013 ACC/AHA guideline¹ gives implantable defibrillator therapy a class IA recommendation for the primary prevention of sudden cardiac death in selected patients with nonischemic cardiomyopathy or ischemic cardiomyopathy at least 40 days after a myocardial infarction and 90 days after percutaneous coronary intervention or coronary artery bypass grafting; with a left ventricular ejection fraction of 35% or less; and NYHA class II or III symptoms on chronic goal-directed medical management.

This therapy receives a class IB recommendation for primary prevention of sudden cardiac death to reduce total mortality in selected patients at least 40 days after myocardial infarction with a left ventricular ejection fraction of 30% or less and NYHA class I symptoms while receiving goal-directed medical therapy.

Implantable cardioverter-defibrillators are not recommended in patients who otherwise have a life expectancy of less than 1 year.

Devices: Cardiac resynchronization therapy

From 25% to 30% of heart failure patients have an intraventricular conduction abnormality,^43,44 which can result in abnormalities of systolic and diastolic function. Biventricular pacing, in which a pacing lead is placed in the coronary sinus in addition to the right atrium and right ventricle, optimizes synchronization of ventricular contraction.^43,44

MUSTIC (the Multisite Stimulation in Cardiomyopathies study) was a randomized trial designed to assess the efficacy of biventricular pacing (also known as cardiac resynchronization therapy) in heart failure patients.⁴⁴ Entry criteria included NYHA class III heart failure for at least 1 month, left ventricular ejection fraction less than 35%, left ventricular end-diastolic diameter greater than 60 mm, and QRS duration longer than 150 ms. Patients were followed up at 9 and 12 months with 6-minute walking distance, peak oxygen consumption, changes in NYHA class, and left ventricular systolic function by echocardiography or radionuclide testing. Quality of life was assessed by the Minnesota Living With Heart Failure Questionnaire.

At 12 months, patients could walk significantly farther in 6 minutes, and their peak oxygen consumption had increased. They also reported significant improvement in quality of life, and NYHA class improved by 25%. MUSTIC was the first study to show a benefit in exercise tolerance, quality of life, improvement in cardiac performance, and reduction in heart failure symptoms with the use of biventricular pacing at 1 year.

MIRACLE (the Multicenter InSync Randomized Clinical Evaluation) validated the findings seen in MUSTIC by using a larger population size and a double-blinded method.⁴⁵ Compared with a control group, patients who underwent cardiac resynchronization therapy could walk farther in 6 minutes and scored better in NYHA class, quality of life, and left ventricular ejection fraction.⁴⁵

Recommendations. The 2013 ACC/AHA guidelines¹ give cardiac resynchronization therapy a class IA/B indication for NYHA class II, III, or IV patients on goal-directed medical therapy in sinus rhythm with left ventricular ejection fraction 35% or less, left bundle branch block, and QRS duration of 150 ms or more.¹

Devices: Implantable sensors

The future of ambulatory heart failure management may include implantable pulmonary artery pressure sensors.

The CardioMEMS is a permanently implantable pressure measurement system designed to provide daily pulmonary artery pressure measurements in an ambulatory setting with a goal of reducing heart failure-related hospitalizations. Through a transvenous delivery system, an implantable, battery-free sensor is positioned in the distal pulmonary artery.^46,47

CHAMPION (the CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Patients trial) was one of the first major trials to assess the safety and efficacy of implantable pulmonary artery pressure monitoring systems.⁴⁶ The study device was associated with a significant reduction in mean pulmonary artery pressures, fewer heart failure hospitalizations, and better quality of life. The length of stay for heart failure-related hospitalizations was also significantly shorter in the CardioMEMs group.⁴⁶

Exercise

Patients with heart failure routinely experience a decline in functional capacity. This decline manifests as reduced exercise tolerance and poor quality of life, usually resulting in a physician recommendation to rest and paradoxical deconditioning and possible progression of symptoms.

Several studies have shown that cardiac rehabilitation has improved outcomes in heart failure patients.⁴⁸ Cardiac rehabilitation is a supervised program that helps patients with exercise training, healthy living, education, and psychosocial counseling.

HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) is the largest randomized trial performed to determine whether aerobic exercise training reduces all-cause mortality or all-cause hospitalization and improves quality of life in patients with stable heart failure.⁴⁹ Although the reduction in end points was initially not statistically significant, after adjusting for highly prognostic predictors of poor outcomes (cardiopulmonary exercise time, left ventricular ejection fraction, atrial fibrillation, and depression), exercise training was found to reduce the incidence of all-cause mortality or all-cause hospitalization by 11% (P = .03).⁴⁹

Recommendations. Based on the results of HF-ACTION and several smaller studies, the ACC/AHA guidelines give exercise training a class IA recommendation as a safe and effective activity for patients with heart failure who are able to participate, to improve functional status.¹ A class IIA recommendation is given to cardiac rehabilitation for the improvement of functional capacity, exercise duration, quality of life, and mortality rates.¹

End-stage heart failure: Recognition

Despite adequate titration of goal-directed medical therapy, a portion of patients with heart failure with reduced ejection fraction ultimately progress to stage D, also termed “advanced” heart failure. The 5-year survival rate for patients with heart failure overall is 50%, but the 1-year mortality rate for those with advanced heart failure exceeds 50%.⁵⁰

Because the high rates of morbidity and mortality can potentially be lowered, recognition of heart failure disease progression is imperative so that patients can be promptly referred for therapies such as inotropic infusion, mechanical circulatory support, and cardiac transplant, as well as end-of-life care such as hospice.¹

The ACC/AHA¹ have published clinical events and findings useful in identifying patients with advanced heart failure:

• Two or more hospitalizations or emergency department visits for heart failure in the past year
• Progressive deterioration in renal function (eg, elevation in creatinine or blood urea nitrogen)
• Weight loss without other cause
• Intolerance to ACE inhibitors due to hypotension or worsening renal function
• Inability to tolerate beta-blockers due to worsening heart failure or hypotension
• Systolic blood pressure often below 90 mm Hg
• Persistent dyspnea with dressing or bathing requiring rest
• Inability to walk one block on level ground due to dyspnea or fatigue
• Recent need to escalate diuretics to maintain volume status, often reaching daily dose equivalent to furosemide more than 160 mg/day or use of supplemental metolazone
• Progressive decline in serum sodium, usually to below 133 mmol/L
• Frequent shocks from implanted cardiac defibrillator.

End-stage heart failure: Left ventricular assist devices

For patients with refractory heart failure despite optimal medical management, advanced therapies such as heart transplant or ventricular assist devices have been proven to be durable options. These mechanical circulatory support devices “unload” the diseased ventricle and maintain cardiac output to vital organs.⁵¹ They were initially designed as temporary support to allow ventricular recovery or as a bridge to cardiac transplant. However, they have also evolved into permanent (“destination”) therapy.⁵²

REMATCH (the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive HF trial) was the landmark study that showed that left ventricular assist device implantation resulted in a survival benefit and an improved quality of life in patients with advanced heart failure ineligible for cardiac transplant, compared with medical management.⁵⁰ Implantation of a left ventricular assist device was associated with a 27% absolute reduction in the 1-year mortality rate.⁵⁰

Since the National Institutes of Health’s artificial heart program was launched in 1964, there has been tremendous progress in the development of mechanical circulatory devices.⁵⁰ The results of REMATCH were promising, but the 2-year survival rate was still only 23%, leaving a lot to be desired.

The HeartMate II (Thoratec) trial compared an axial continuous-flow device vs the previously established pulsatile left ventricular assist device, and noted a 2-year survival of 58% with the continuous flow device vs  24% with the pulsatile device (P = .008).⁵³

ADVANCE (Evaluation of the HeartWare Left Ventricular Assist Device for the Treatment of Advanced Heart Failure) showed similar efficacy of the HVAD (Heartware), a centrifugal continuous-flow LVAD currently in use.⁵⁴

The next generation of continuous-flow left ventricular assist devices are currently in clinical trials in the United States and include the axial flow MVAD (Heartware) and centrifugal flow Heartmate III (Thoratec).

We emphasize the importance of early identification of patients with advanced disease who may qualify for and benefit from such therapies.

The management of heart failure is evolving. In the 1960s, the standard heart failure medical regimen included digoxin, diuretics, and the recommendation of rest. This contrasts with the current era, in which medical regimens include neurohormonal blockade, diuretics, and the promotion of physical activity.⁵⁵ Since the publication of the 2013 heart failure guidelines, new medical and device options have emerged that have been proven to either improve survival or reduce hospitalizations. The development of clinical guidelines promotes evidence-based practice and overcomes the inertia of practice patterns based on anecdotal evidence.

Several approaches to the management of heart failure have been recommended. A major effort should be made to identify those at risk for heart failure (stage A) and to implement risk factor modification. Treatment of hypertension, diabetes mellitus, and dyslipidemia decreases the risk of heart failure.¹

For patients with evidence of structural heart disease with and without symptoms, Figure 1 summarizes a guideline approach to the management of heart failure. It should be stressed that guidelines are meant to guide management, but do not serve as a substitute for sound clinical judgment.

Heart failure is the common final pathway of all cardiac pathology, and understanding the neurohormonal response and maladaptive physiology has led to the development of novel therapeutics and devices. At present, the field of cardiology may not be able to remove the “failure” from heart failure, but we can make every effort to prevent failure of treatment delivery and reduce resource utilization and morbidity associated with this syndrome.

Acknowledgments: We would like to thank Chankya Dahagam and Cynthia Obenwa for their valuable contribution in the preparation of this manuscript.

To the Editor: Thanks for the concise review of obstructive sleep apnea (OSA) in the January 2016 issue.¹ I offer the following comments and questions:

1. Risk factors for OSA include large neck circumference, which in Table 1 is defined as larger than 40 cm (15.75 inches), which would include shirt collar sizes 16 and above. In the second paragraph of the text, large neck circumference is defined as greater than 17 inches in men, which would include collar sizes above 17. The definition of a large neck as larger than 40 cm must obviously be more sensitive for predicting OSA, and the definition of greater than 17 inches more specific. Which do the authors use in clinical practice?

2. The American Academy of Sleep Medicine is quoted as recommending home OSA screening “if direct monitoring of the response to non-[continuous positive airway pressure] treatments for sleep apnea is needed.”² However, the need for direct monitoring would seem to be a contraindication to home testing rather than an indication. If this statement is correct as written, would the authors explain why and how specific non-CPAP treatments for OSA are more amenable to monitoring at home than in the sleep lab?

3. Patients with Parkinson disease are at risk for both OSA and hypotension, making them generally an exception to the association of OSA with hypertension.³

4. The home overnight OSA test often consists of a pulse oximeter worn for 8 hours at night, taped to a finger.⁴ This simple, inexpensive test for OSA detects episodes of apnea or hypopnea that result in arterial desaturation. Is it beneficial to also document episodes of apnea or hypopnea that do not result in arterial desaturation? These episodes are included in the 17% false-negative rate for home OSA testing mentioned in the text. Are these episodes important clinically, other than for prognosis in patients who may go on to develop apneic episodes severe enough to cause desaturation?

5. Lastly, the authors may wish to comment on the importance of diagnosing and treating OSA in patients who plan to have elective surgery under general anesthesia, which can lead to profound sleep apnea in the recovery room, with associated morbidity and death.⁵

To the Editor: Thanks for the concise review of obstructive sleep apnea (OSA) in the January 2016 issue.¹ I offer the following comments and questions:

1. Risk factors for OSA include large neck circumference, which in Table 1 is defined as larger than 40 cm (15.75 inches), which would include shirt collar sizes 16 and above. In the second paragraph of the text, large neck circumference is defined as greater than 17 inches in men, which would include collar sizes above 17. The definition of a large neck as larger than 40 cm must obviously be more sensitive for predicting OSA, and the definition of greater than 17 inches more specific. Which do the authors use in clinical practice?

2. The American Academy of Sleep Medicine is quoted as recommending home OSA screening “if direct monitoring of the response to non-[continuous positive airway pressure] treatments for sleep apnea is needed.”² However, the need for direct monitoring would seem to be a contraindication to home testing rather than an indication. If this statement is correct as written, would the authors explain why and how specific non-CPAP treatments for OSA are more amenable to monitoring at home than in the sleep lab?

3. Patients with Parkinson disease are at risk for both OSA and hypotension, making them generally an exception to the association of OSA with hypertension.³

4. The home overnight OSA test often consists of a pulse oximeter worn for 8 hours at night, taped to a finger.⁴ This simple, inexpensive test for OSA detects episodes of apnea or hypopnea that result in arterial desaturation. Is it beneficial to also document episodes of apnea or hypopnea that do not result in arterial desaturation? These episodes are included in the 17% false-negative rate for home OSA testing mentioned in the text. Are these episodes important clinically, other than for prognosis in patients who may go on to develop apneic episodes severe enough to cause desaturation?

5. Lastly, the authors may wish to comment on the importance of diagnosing and treating OSA in patients who plan to have elective surgery under general anesthesia, which can lead to profound sleep apnea in the recovery room, with associated morbidity and death.⁵

To the Editor: Thanks for the concise review of obstructive sleep apnea (OSA) in the January 2016 issue.¹ I offer the following comments and questions:

1. Risk factors for OSA include large neck circumference, which in Table 1 is defined as larger than 40 cm (15.75 inches), which would include shirt collar sizes 16 and above. In the second paragraph of the text, large neck circumference is defined as greater than 17 inches in men, which would include collar sizes above 17. The definition of a large neck as larger than 40 cm must obviously be more sensitive for predicting OSA, and the definition of greater than 17 inches more specific. Which do the authors use in clinical practice?

2. The American Academy of Sleep Medicine is quoted as recommending home OSA screening “if direct monitoring of the response to non-[continuous positive airway pressure] treatments for sleep apnea is needed.”² However, the need for direct monitoring would seem to be a contraindication to home testing rather than an indication. If this statement is correct as written, would the authors explain why and how specific non-CPAP treatments for OSA are more amenable to monitoring at home than in the sleep lab?

3. Patients with Parkinson disease are at risk for both OSA and hypotension, making them generally an exception to the association of OSA with hypertension.³

4. The home overnight OSA test often consists of a pulse oximeter worn for 8 hours at night, taped to a finger.⁴ This simple, inexpensive test for OSA detects episodes of apnea or hypopnea that result in arterial desaturation. Is it beneficial to also document episodes of apnea or hypopnea that do not result in arterial desaturation? These episodes are included in the 17% false-negative rate for home OSA testing mentioned in the text. Are these episodes important clinically, other than for prognosis in patients who may go on to develop apneic episodes severe enough to cause desaturation?

5. Lastly, the authors may wish to comment on the importance of diagnosing and treating OSA in patients who plan to have elective surgery under general anesthesia, which can lead to profound sleep apnea in the recovery room, with associated morbidity and death.⁵

Longtime scientific advisors to the AT (Ataxia Telangiectasia) Children’s Project Nathaniel Heintz, PhD, and Michael Kastan, MD, PhD, have been elected to the National Academy of Sciences.

Longtime scientific advisors to the AT (Ataxia Telangiectasia) Children’s Project Nathaniel Heintz, PhD, and Michael Kastan, MD, PhD, have been elected to the National Academy of Sciences.

Longtime scientific advisors to the AT (Ataxia Telangiectasia) Children’s Project Nathaniel Heintz, PhD, and Michael Kastan, MD, PhD, have been elected to the National Academy of Sciences.

Kerri Nelson, a graduate student in the Department of Nursing at Pennsylvania State University and mother of a child with a rare disorder, is conducting a survey with NORD to learn how patients and families find rare disease information that is helpful to them.

“When I began my Doctorate of Nursing Practice, I found the National Organization for Rare Disorders (NORD) and felt that this organization would have been beneficial two years prior when my son was diagnosed with a rare disorder,” she wrote on the NORD blog. As a result, Ms. Nelson got the idea to help those with newly diagnosed children find the NORD website. She has designed a toolkit to be distributed to patients and families at Penn State’s Milton S. Hershey Medical Center. She also developed a brief survey that is posted on the NORD website.

Kerri Nelson, a graduate student in the Department of Nursing at Pennsylvania State University and mother of a child with a rare disorder, is conducting a survey with NORD to learn how patients and families find rare disease information that is helpful to them.

“When I began my Doctorate of Nursing Practice, I found the National Organization for Rare Disorders (NORD) and felt that this organization would have been beneficial two years prior when my son was diagnosed with a rare disorder,” she wrote on the NORD blog. As a result, Ms. Nelson got the idea to help those with newly diagnosed children find the NORD website. She has designed a toolkit to be distributed to patients and families at Penn State’s Milton S. Hershey Medical Center. She also developed a brief survey that is posted on the NORD website.

Kerri Nelson, a graduate student in the Department of Nursing at Pennsylvania State University and mother of a child with a rare disorder, is conducting a survey with NORD to learn how patients and families find rare disease information that is helpful to them.

“When I began my Doctorate of Nursing Practice, I found the National Organization for Rare Disorders (NORD) and felt that this organization would have been beneficial two years prior when my son was diagnosed with a rare disorder,” she wrote on the NORD blog. As a result, Ms. Nelson got the idea to help those with newly diagnosed children find the NORD website. She has designed a toolkit to be distributed to patients and families at Penn State’s Milton S. Hershey Medical Center. She also developed a brief survey that is posted on the NORD website.

Erythema multiforme

Erythema multiforme (EM) is a hypersensitivity reaction.  Cutaneous lesions generally occur symmetrically on the extensor surfaces of the acral extremities and spread centripetally.  Lesions are polymorphous and may be macular, papular, or bullous, with or without mucosal involvement.  Classic targetoid lesions have a dusky central area, a paler edematous ring, and an erythematous outermost ring. EM can be triggered by multiple causes.  90% of cases are infectious, with herpes simplex virus infection most common and mycoplasma pneumoniae second.  Medications (sulfonamides, anticonvulsants, etc), malignancy, autoimmune disease, immunizations, radiation, and sarcoidosis may also cause EM. 

The differential diagnosis for EM includes urticaria, Stevens-Johnson syndrome, fixed drug eruption, bullous pemphigoid, paraneoplastic pemphigus, acute febrile neutophilic dermatosis (Sweet's syndrome), polymorphous light eruption (PMLE), and cutaneous small vessel vasculitis. The lesions of EM are fixed and all arise within 72 hours of onset, which can help distinguish between urticaria. The distribution of the lesions can help rule out Stevens-Johnson syndrome, which classically begins centrally and spreads distally and often will involve mucosal surfaces. Fixed drug eruption generally presents with fewer lesions and a preceding medication history. Bullous pemphigoid and paraneoplastic pemphigus are both chronic in their course and have distinguishing histopathologic characteristics that will not be present in erythema multiforme.  Sweet's syndrome is also associated with infection; however, histology reveals a dense neutrophilic infiltrate with dermal edema on biopsy.  History can be useful in distinguishing EM from PMLE: preceding infection strongly suggests EM, while ultraviolet radiation exposure is more likely to result in PMLE. Lastly, EM differs from cutaneous small vessel vasculitis through both histopathologic examination and direct immunofluorescence.

EM is usually a self-limited condition of about two weeks without significant sequelae, however, it may vary in both the length and severity of its course. A small subset of patients may experience episodic eruptions over a period of years, in what is known as recurrent EM. An even smaller subset of patients may continuously suffer from the lesions for months or even years, which is termed persistent EM.  Treatment is aimed at the underlying condition or cause.  Offending medications should be discontinued. Patients with mild cases of EM generally fare well with symptomatic treatment alone; however, more severe cases may require hospitalization for hydration, analgesia, and antiviral therapy. The use of systemic corticosteroids for EM is controversial and is generally reserved for severe cases with mucosal involvement.   Prophylactic antiviral therapy is indicated for those with recurrent erythema multiforme of viral origin who suffer from six or more episodes per year. Very rarely, erythema multiforme may include ocular involvement leading to serious long-term sequelae, so patients with ocular symptoms should be immediately referred to an ophthalmologist for evaluation.

The patient's biopsy revealed necrotic keratinocytes and exocytosis of lymphocytes and was consistent with EM.  She improved with oral antiviral therapy and topical steroid cream. 

Erythema multiforme

Erythema multiforme (EM) is a hypersensitivity reaction.  Cutaneous lesions generally occur symmetrically on the extensor surfaces of the acral extremities and spread centripetally.  Lesions are polymorphous and may be macular, papular, or bullous, with or without mucosal involvement.  Classic targetoid lesions have a dusky central area, a paler edematous ring, and an erythematous outermost ring. EM can be triggered by multiple causes.  90% of cases are infectious, with herpes simplex virus infection most common and mycoplasma pneumoniae second.  Medications (sulfonamides, anticonvulsants, etc), malignancy, autoimmune disease, immunizations, radiation, and sarcoidosis may also cause EM. 

The differential diagnosis for EM includes urticaria, Stevens-Johnson syndrome, fixed drug eruption, bullous pemphigoid, paraneoplastic pemphigus, acute febrile neutophilic dermatosis (Sweet's syndrome), polymorphous light eruption (PMLE), and cutaneous small vessel vasculitis. The lesions of EM are fixed and all arise within 72 hours of onset, which can help distinguish between urticaria. The distribution of the lesions can help rule out Stevens-Johnson syndrome, which classically begins centrally and spreads distally and often will involve mucosal surfaces. Fixed drug eruption generally presents with fewer lesions and a preceding medication history. Bullous pemphigoid and paraneoplastic pemphigus are both chronic in their course and have distinguishing histopathologic characteristics that will not be present in erythema multiforme.  Sweet's syndrome is also associated with infection; however, histology reveals a dense neutrophilic infiltrate with dermal edema on biopsy.  History can be useful in distinguishing EM from PMLE: preceding infection strongly suggests EM, while ultraviolet radiation exposure is more likely to result in PMLE. Lastly, EM differs from cutaneous small vessel vasculitis through both histopathologic examination and direct immunofluorescence.

EM is usually a self-limited condition of about two weeks without significant sequelae, however, it may vary in both the length and severity of its course. A small subset of patients may experience episodic eruptions over a period of years, in what is known as recurrent EM. An even smaller subset of patients may continuously suffer from the lesions for months or even years, which is termed persistent EM.  Treatment is aimed at the underlying condition or cause.  Offending medications should be discontinued. Patients with mild cases of EM generally fare well with symptomatic treatment alone; however, more severe cases may require hospitalization for hydration, analgesia, and antiviral therapy. The use of systemic corticosteroids for EM is controversial and is generally reserved for severe cases with mucosal involvement.   Prophylactic antiviral therapy is indicated for those with recurrent erythema multiforme of viral origin who suffer from six or more episodes per year. Very rarely, erythema multiforme may include ocular involvement leading to serious long-term sequelae, so patients with ocular symptoms should be immediately referred to an ophthalmologist for evaluation.

The patient's biopsy revealed necrotic keratinocytes and exocytosis of lymphocytes and was consistent with EM.  She improved with oral antiviral therapy and topical steroid cream. 

Erythema multiforme

Erythema multiforme (EM) is a hypersensitivity reaction.  Cutaneous lesions generally occur symmetrically on the extensor surfaces of the acral extremities and spread centripetally.  Lesions are polymorphous and may be macular, papular, or bullous, with or without mucosal involvement.  Classic targetoid lesions have a dusky central area, a paler edematous ring, and an erythematous outermost ring. EM can be triggered by multiple causes.  90% of cases are infectious, with herpes simplex virus infection most common and mycoplasma pneumoniae second.  Medications (sulfonamides, anticonvulsants, etc), malignancy, autoimmune disease, immunizations, radiation, and sarcoidosis may also cause EM. 

The differential diagnosis for EM includes urticaria, Stevens-Johnson syndrome, fixed drug eruption, bullous pemphigoid, paraneoplastic pemphigus, acute febrile neutophilic dermatosis (Sweet's syndrome), polymorphous light eruption (PMLE), and cutaneous small vessel vasculitis. The lesions of EM are fixed and all arise within 72 hours of onset, which can help distinguish between urticaria. The distribution of the lesions can help rule out Stevens-Johnson syndrome, which classically begins centrally and spreads distally and often will involve mucosal surfaces. Fixed drug eruption generally presents with fewer lesions and a preceding medication history. Bullous pemphigoid and paraneoplastic pemphigus are both chronic in their course and have distinguishing histopathologic characteristics that will not be present in erythema multiforme.  Sweet's syndrome is also associated with infection; however, histology reveals a dense neutrophilic infiltrate with dermal edema on biopsy.  History can be useful in distinguishing EM from PMLE: preceding infection strongly suggests EM, while ultraviolet radiation exposure is more likely to result in PMLE. Lastly, EM differs from cutaneous small vessel vasculitis through both histopathologic examination and direct immunofluorescence.

EM is usually a self-limited condition of about two weeks without significant sequelae, however, it may vary in both the length and severity of its course. A small subset of patients may experience episodic eruptions over a period of years, in what is known as recurrent EM. An even smaller subset of patients may continuously suffer from the lesions for months or even years, which is termed persistent EM.  Treatment is aimed at the underlying condition or cause.  Offending medications should be discontinued. Patients with mild cases of EM generally fare well with symptomatic treatment alone; however, more severe cases may require hospitalization for hydration, analgesia, and antiviral therapy. The use of systemic corticosteroids for EM is controversial and is generally reserved for severe cases with mucosal involvement.   Prophylactic antiviral therapy is indicated for those with recurrent erythema multiforme of viral origin who suffer from six or more episodes per year. Very rarely, erythema multiforme may include ocular involvement leading to serious long-term sequelae, so patients with ocular symptoms should be immediately referred to an ophthalmologist for evaluation.

The patient's biopsy revealed necrotic keratinocytes and exocytosis of lymphocytes and was consistent with EM.  She improved with oral antiviral therapy and topical steroid cream. 

The National Institutes of Health (NIH) has published a new policy to assure that results of clinical trials are widely shared. NIH Director Francis Collins, MD, said the final rule and NIH policy that have been issued “will help maximize the value of clinical trials, whether publicly or privately supported, and help us honor our commitments to trial participants, who do so much to help society advance knowledge and improve health.”

The National Institutes of Health (NIH) has published a new policy to assure that results of clinical trials are widely shared. NIH Director Francis Collins, MD, said the final rule and NIH policy that have been issued “will help maximize the value of clinical trials, whether publicly or privately supported, and help us honor our commitments to trial participants, who do so much to help society advance knowledge and improve health.”

The National Institutes of Health (NIH) has published a new policy to assure that results of clinical trials are widely shared. NIH Director Francis Collins, MD, said the final rule and NIH policy that have been issued “will help maximize the value of clinical trials, whether publicly or privately supported, and help us honor our commitments to trial participants, who do so much to help society advance knowledge and improve health.”

Clinical Question: How common are neurologic findings in acute HIV infection?

Background: The incidence of neurologic findings with acute HIV is unknown.

Study Design: Cohort study.

Setting: Bangkok, Thailand.

Synopsis: In this study, 134 patients were identified after presenting for voluntary HIV testing. Five others were enrolled through an ongoing local study. All 139 participants underwent structured neurologic evaluations at enrollment (median of 19 days after presumed exposure), then at four and 12 weeks. Combination antiretroviral therapy (cART) was initiated immediately after initial evaluation.

The cohort was 93% male. Mean age was younger than 30 years. Fifty-three percent of participants experienced some neurologic finding within 12 weeks of diagnosis. One-third (33%) were cognitive symptoms, predominantly problems of concentration (24% of patients) and memory (16% of patients). One-third (34%) were motor findings, and 11% were neuropathy. Forty-nine percent of the neurologic issues were present at diagnosis. Symptoms were mostly mild, although one patient developed fulminant Guillain-Barré syndrome. Patients with neurologic findings had higher viral loads at diagnosis (mean plasma log10 HIV RNA 5.9 versus 5.4; P = 0.006). Participants with and without neurologic findings had similar cerebral spinal fluid viral loads (mean log10 HIV RNA 3.7 versus 3.1, P = 0.14) and serum CD4 counts (339 versus 381 cells/mm3; P = 0.46). Neurologic findings resolved within one month of cART treatment in 90% of patients. Study limitations include lack of a control cohort and potential confounding from illicit drug use among participants.

Bottom Line: Acute HIV infection commonly causes mild neurologic problems, which remit with treatment.

Citation: Hellmuth J, Fletcher JL, Valcour V, et al. Neurologic signs and symptoms frequently manifest in acute HIV infection. Neurology. 2016;87(2):148-154.

Clinical Question: How common are neurologic findings in acute HIV infection?

Background: The incidence of neurologic findings with acute HIV is unknown.

Study Design: Cohort study.

Setting: Bangkok, Thailand.

Synopsis: In this study, 134 patients were identified after presenting for voluntary HIV testing. Five others were enrolled through an ongoing local study. All 139 participants underwent structured neurologic evaluations at enrollment (median of 19 days after presumed exposure), then at four and 12 weeks. Combination antiretroviral therapy (cART) was initiated immediately after initial evaluation.

The cohort was 93% male. Mean age was younger than 30 years. Fifty-three percent of participants experienced some neurologic finding within 12 weeks of diagnosis. One-third (33%) were cognitive symptoms, predominantly problems of concentration (24% of patients) and memory (16% of patients). One-third (34%) were motor findings, and 11% were neuropathy. Forty-nine percent of the neurologic issues were present at diagnosis. Symptoms were mostly mild, although one patient developed fulminant Guillain-Barré syndrome. Patients with neurologic findings had higher viral loads at diagnosis (mean plasma log10 HIV RNA 5.9 versus 5.4; P = 0.006). Participants with and without neurologic findings had similar cerebral spinal fluid viral loads (mean log10 HIV RNA 3.7 versus 3.1, P = 0.14) and serum CD4 counts (339 versus 381 cells/mm3; P = 0.46). Neurologic findings resolved within one month of cART treatment in 90% of patients. Study limitations include lack of a control cohort and potential confounding from illicit drug use among participants.

Bottom Line: Acute HIV infection commonly causes mild neurologic problems, which remit with treatment.

Citation: Hellmuth J, Fletcher JL, Valcour V, et al. Neurologic signs and symptoms frequently manifest in acute HIV infection. Neurology. 2016;87(2):148-154.

Clinical Question: How common are neurologic findings in acute HIV infection?

Background: The incidence of neurologic findings with acute HIV is unknown.

Study Design: Cohort study.

Setting: Bangkok, Thailand.

Synopsis: In this study, 134 patients were identified after presenting for voluntary HIV testing. Five others were enrolled through an ongoing local study. All 139 participants underwent structured neurologic evaluations at enrollment (median of 19 days after presumed exposure), then at four and 12 weeks. Combination antiretroviral therapy (cART) was initiated immediately after initial evaluation.

The cohort was 93% male. Mean age was younger than 30 years. Fifty-three percent of participants experienced some neurologic finding within 12 weeks of diagnosis. One-third (33%) were cognitive symptoms, predominantly problems of concentration (24% of patients) and memory (16% of patients). One-third (34%) were motor findings, and 11% were neuropathy. Forty-nine percent of the neurologic issues were present at diagnosis. Symptoms were mostly mild, although one patient developed fulminant Guillain-Barré syndrome. Patients with neurologic findings had higher viral loads at diagnosis (mean plasma log10 HIV RNA 5.9 versus 5.4; P = 0.006). Participants with and without neurologic findings had similar cerebral spinal fluid viral loads (mean log10 HIV RNA 3.7 versus 3.1, P = 0.14) and serum CD4 counts (339 versus 381 cells/mm3; P = 0.46). Neurologic findings resolved within one month of cART treatment in 90% of patients. Study limitations include lack of a control cohort and potential confounding from illicit drug use among participants.

Bottom Line: Acute HIV infection commonly causes mild neurologic problems, which remit with treatment.

Citation: Hellmuth J, Fletcher JL, Valcour V, et al. Neurologic signs and symptoms frequently manifest in acute HIV infection. Neurology. 2016;87(2):148-154.

Clinical Question: Is the 10-point cognitive screener (10-CS) effective in screening for delirium in older adults with hip fracture?

Background: Delirium in elderly hip fracture patients has been established as a significant comorbidity. There is, however, no agreement on the most appropriate and practical screening tool. Commonly used screening methods, which focus on the detection of cognitive impairment as a surrogate, are time-consuming, insensitive for mild impairment, and limited in their application to patients with impaired dexterity and poor education.

Study Design: Prospective cohort study.

Setting: Tertiary referral hospital in São Paulo, Brazil.

Synopsis: In the study, 147 consecutive hip fracture patients over age 60 were screened using the 10-CS. This test stratifies patients into three categories: normal, possible, and probable cognitive impairment. Development of in-hospital delirium was evaluated by daily Confusion Assessment Method testing administered by a geriatrician. Patients categorized as probable cognitive impairment were more likely to develop delirium (hazard ratio, 7.48; 95% CI, 2.2–25.4).

Hospitalists involved in perioperative care should consider using this simple screening tool. With an area under ROC curve of 0.83 (95% CI, 0.76–0.89), it effectively detects delirium in this high-risk population. Independently, patients who developed delirium had a longer length of stay (median 11.0 versus 7.0; P < 0.001). This serves as a reminder of the importance of screening and preventing delirium in this population.

Bottom Line: The 10-CS tool is practical in its application and effective in identifying elderly hip fracture patients at risk for delirium.

Citation: Fortes-Filho SQ, Apolinario D, Melo JA, Suzuki I, Sitta MD, Garcez-Leme LE. Predicting delirium after hip fracture with a 2-min cognitive screen: prospective cohort study [published online ahead of print May 17, 2016]. Age Ageing. pii:afw084.

Clinical Question: Is the 10-point cognitive screener (10-CS) effective in screening for delirium in older adults with hip fracture?

Background: Delirium in elderly hip fracture patients has been established as a significant comorbidity. There is, however, no agreement on the most appropriate and practical screening tool. Commonly used screening methods, which focus on the detection of cognitive impairment as a surrogate, are time-consuming, insensitive for mild impairment, and limited in their application to patients with impaired dexterity and poor education.

Study Design: Prospective cohort study.

Setting: Tertiary referral hospital in São Paulo, Brazil.

Synopsis: In the study, 147 consecutive hip fracture patients over age 60 were screened using the 10-CS. This test stratifies patients into three categories: normal, possible, and probable cognitive impairment. Development of in-hospital delirium was evaluated by daily Confusion Assessment Method testing administered by a geriatrician. Patients categorized as probable cognitive impairment were more likely to develop delirium (hazard ratio, 7.48; 95% CI, 2.2–25.4).

Hospitalists involved in perioperative care should consider using this simple screening tool. With an area under ROC curve of 0.83 (95% CI, 0.76–0.89), it effectively detects delirium in this high-risk population. Independently, patients who developed delirium had a longer length of stay (median 11.0 versus 7.0; P < 0.001). This serves as a reminder of the importance of screening and preventing delirium in this population.

Bottom Line: The 10-CS tool is practical in its application and effective in identifying elderly hip fracture patients at risk for delirium.

Citation: Fortes-Filho SQ, Apolinario D, Melo JA, Suzuki I, Sitta MD, Garcez-Leme LE. Predicting delirium after hip fracture with a 2-min cognitive screen: prospective cohort study [published online ahead of print May 17, 2016]. Age Ageing. pii:afw084.

Clinical Question: Is the 10-point cognitive screener (10-CS) effective in screening for delirium in older adults with hip fracture?

Background: Delirium in elderly hip fracture patients has been established as a significant comorbidity. There is, however, no agreement on the most appropriate and practical screening tool. Commonly used screening methods, which focus on the detection of cognitive impairment as a surrogate, are time-consuming, insensitive for mild impairment, and limited in their application to patients with impaired dexterity and poor education.

Study Design: Prospective cohort study.

Setting: Tertiary referral hospital in São Paulo, Brazil.

Synopsis: In the study, 147 consecutive hip fracture patients over age 60 were screened using the 10-CS. This test stratifies patients into three categories: normal, possible, and probable cognitive impairment. Development of in-hospital delirium was evaluated by daily Confusion Assessment Method testing administered by a geriatrician. Patients categorized as probable cognitive impairment were more likely to develop delirium (hazard ratio, 7.48; 95% CI, 2.2–25.4).

Hospitalists involved in perioperative care should consider using this simple screening tool. With an area under ROC curve of 0.83 (95% CI, 0.76–0.89), it effectively detects delirium in this high-risk population. Independently, patients who developed delirium had a longer length of stay (median 11.0 versus 7.0; P < 0.001). This serves as a reminder of the importance of screening and preventing delirium in this population.

Bottom Line: The 10-CS tool is practical in its application and effective in identifying elderly hip fracture patients at risk for delirium.

Citation: Fortes-Filho SQ, Apolinario D, Melo JA, Suzuki I, Sitta MD, Garcez-Leme LE. Predicting delirium after hip fracture with a 2-min cognitive screen: prospective cohort study [published online ahead of print May 17, 2016]. Age Ageing. pii:afw084.

Regular physical exercise significantly improved measures of nonalcoholic fatty liver disease independently of dietary changes, according to a meta-analysis of randomized controlled* trials published in the October issue of Clinical Gastroenterology and Hepatology.

“On the basis of the current findings, physical activity should be recommended not only in combination with dietary changes but also independently as an effective approach to manage NAFLD,” wrote Lorenzo Orci, MD, and his associates at the University of Geneva. “We propose that the level of evidence surrounding the specific role of physical activity in the management of NAFLD is now sufficient to be awarded a grade of Ia.”

Nonalcoholic fatty liver disease, “the hepatic manifestation of metabolic syndrome,” affects at least one in four U.S. adults and 15%-35% of individuals in Europe, the Middle East, China, and Japan, the researchers noted. Dietary changes are the cornerstone of NAFLD management, and there is less evidence for how physical exercise affects liver fat content. Therefore, the researchers searched MEDLINE, Embase, and the Cochrane databases from inception through October 2015 to find randomized trials of the impact of physical activity on markers of liver steatosis and liver inflammation in patients diagnosed with NAFLD, obesity, type 2 diabetes, or metabolic syndrome. This approach yielded 28 trials with data from more than 1,600 patients. Only two trials were multicenter, 13 required participants to have an NAFLD diagnosis, four focused on type 2 diabetes, and most of the rest included sedentary obese patients without requiring a diagnosis of NAFLD, the researchers said (Clin Gastroenterol Hepatol. 2016 May 4. doi: 10.1016/j.cgh.2016.04.036).

After researchers accounted for dietary changes, physical activity led to a significant drop in intrahepatic lipid content with a standardized mean difference of –0.69 compared with controls (95% confidence interval, –0.90 to –0.48; P less than .0001). “Because effect sizes such as standard mean difference [SMD] are difficult to interpret, the translation of such a statistical measure into a clinically relevant notion has been the focus of research for more than a decade,” the investigators added. “A commonly used interpretation was proposed by Cohen, who suggested that SMDs of 0.2, 0.5, and 0.8 correspond to small, moderate, and large effect sizes, respectively. By using this rule of thumb, our results indicate that physical activity exerts a moderate-to-large impact on the reduction of intrahepatic lipid content.”

Exercise reduced liver fat content even more in pediatric patients (SMD, –0.75; 95% CI, –0.1 to –0.5; P less than .0001) and in patients who had been specifically diagnosed with NAFLD (SMD, –0.86; 95% CI, –1.26 to –0.46; P less than .0001). Patients with the highest baseline body mass index also seemed to benefit more than patients with lower baseline BMI (P = .04). Indeed, exercise reduced BMI itself by a weighted mean difference of 0.8 (95% CI, –1.22 to 0.38; P less than .001), the researchers noted. Exercise intensity did not seem to affect the likelihood of benefit. There was a trend toward a greater effect of aerobic over resistance training (P = .06), and few studies examined the effects of combining both types of exercise.

The multivariable analysis also linked physical activity to an average 3.30 IU/L drop in alanine aminotransferase levels (95% CI, –5.57 to –1.04) and to a 4.9 IU/L decrease in aspartate aminotransferase levels (95% CI, –8.68 to –1.02). The investigators were unable to assess the long-term effects of physical exercise, nor its effects on hepatic fibrosis or inflammation, they noted. Nonetheless, the moderate to large effect size “provides strong evidence for the recommendation of physical activity as an effective intervention in the treatment of NAFLD,” they concluded. “Physical activity is also associated with an improvement in blood levels of aminotransferases and is particularly beneficial in patients presenting with severe obesity at baseline.”

The work was funded by the Ligue Genevoise contre le Cancer and the Dr Henri Dubois-Ferrière/Dinu Lipatti Foundation and by the Swiss National Science Foundation. The investigators had no disclosures.

*Content was updated on 10/25/2016 

Regular physical exercise significantly improved measures of nonalcoholic fatty liver disease independently of dietary changes, according to a meta-analysis of randomized controlled* trials published in the October issue of Clinical Gastroenterology and Hepatology.

“On the basis of the current findings, physical activity should be recommended not only in combination with dietary changes but also independently as an effective approach to manage NAFLD,” wrote Lorenzo Orci, MD, and his associates at the University of Geneva. “We propose that the level of evidence surrounding the specific role of physical activity in the management of NAFLD is now sufficient to be awarded a grade of Ia.”

Nonalcoholic fatty liver disease, “the hepatic manifestation of metabolic syndrome,” affects at least one in four U.S. adults and 15%-35% of individuals in Europe, the Middle East, China, and Japan, the researchers noted. Dietary changes are the cornerstone of NAFLD management, and there is less evidence for how physical exercise affects liver fat content. Therefore, the researchers searched MEDLINE, Embase, and the Cochrane databases from inception through October 2015 to find randomized trials of the impact of physical activity on markers of liver steatosis and liver inflammation in patients diagnosed with NAFLD, obesity, type 2 diabetes, or metabolic syndrome. This approach yielded 28 trials with data from more than 1,600 patients. Only two trials were multicenter, 13 required participants to have an NAFLD diagnosis, four focused on type 2 diabetes, and most of the rest included sedentary obese patients without requiring a diagnosis of NAFLD, the researchers said (Clin Gastroenterol Hepatol. 2016 May 4. doi: 10.1016/j.cgh.2016.04.036).

After researchers accounted for dietary changes, physical activity led to a significant drop in intrahepatic lipid content with a standardized mean difference of –0.69 compared with controls (95% confidence interval, –0.90 to –0.48; P less than .0001). “Because effect sizes such as standard mean difference [SMD] are difficult to interpret, the translation of such a statistical measure into a clinically relevant notion has been the focus of research for more than a decade,” the investigators added. “A commonly used interpretation was proposed by Cohen, who suggested that SMDs of 0.2, 0.5, and 0.8 correspond to small, moderate, and large effect sizes, respectively. By using this rule of thumb, our results indicate that physical activity exerts a moderate-to-large impact on the reduction of intrahepatic lipid content.”

Exercise reduced liver fat content even more in pediatric patients (SMD, –0.75; 95% CI, –0.1 to –0.5; P less than .0001) and in patients who had been specifically diagnosed with NAFLD (SMD, –0.86; 95% CI, –1.26 to –0.46; P less than .0001). Patients with the highest baseline body mass index also seemed to benefit more than patients with lower baseline BMI (P = .04). Indeed, exercise reduced BMI itself by a weighted mean difference of 0.8 (95% CI, –1.22 to 0.38; P less than .001), the researchers noted. Exercise intensity did not seem to affect the likelihood of benefit. There was a trend toward a greater effect of aerobic over resistance training (P = .06), and few studies examined the effects of combining both types of exercise.

The multivariable analysis also linked physical activity to an average 3.30 IU/L drop in alanine aminotransferase levels (95% CI, –5.57 to –1.04) and to a 4.9 IU/L decrease in aspartate aminotransferase levels (95% CI, –8.68 to –1.02). The investigators were unable to assess the long-term effects of physical exercise, nor its effects on hepatic fibrosis or inflammation, they noted. Nonetheless, the moderate to large effect size “provides strong evidence for the recommendation of physical activity as an effective intervention in the treatment of NAFLD,” they concluded. “Physical activity is also associated with an improvement in blood levels of aminotransferases and is particularly beneficial in patients presenting with severe obesity at baseline.”

The work was funded by the Ligue Genevoise contre le Cancer and the Dr Henri Dubois-Ferrière/Dinu Lipatti Foundation and by the Swiss National Science Foundation. The investigators had no disclosures.

*Content was updated on 10/25/2016 

Regular physical exercise significantly improved measures of nonalcoholic fatty liver disease independently of dietary changes, according to a meta-analysis of randomized controlled* trials published in the October issue of Clinical Gastroenterology and Hepatology.

“On the basis of the current findings, physical activity should be recommended not only in combination with dietary changes but also independently as an effective approach to manage NAFLD,” wrote Lorenzo Orci, MD, and his associates at the University of Geneva. “We propose that the level of evidence surrounding the specific role of physical activity in the management of NAFLD is now sufficient to be awarded a grade of Ia.”

Nonalcoholic fatty liver disease, “the hepatic manifestation of metabolic syndrome,” affects at least one in four U.S. adults and 15%-35% of individuals in Europe, the Middle East, China, and Japan, the researchers noted. Dietary changes are the cornerstone of NAFLD management, and there is less evidence for how physical exercise affects liver fat content. Therefore, the researchers searched MEDLINE, Embase, and the Cochrane databases from inception through October 2015 to find randomized trials of the impact of physical activity on markers of liver steatosis and liver inflammation in patients diagnosed with NAFLD, obesity, type 2 diabetes, or metabolic syndrome. This approach yielded 28 trials with data from more than 1,600 patients. Only two trials were multicenter, 13 required participants to have an NAFLD diagnosis, four focused on type 2 diabetes, and most of the rest included sedentary obese patients without requiring a diagnosis of NAFLD, the researchers said (Clin Gastroenterol Hepatol. 2016 May 4. doi: 10.1016/j.cgh.2016.04.036).

After researchers accounted for dietary changes, physical activity led to a significant drop in intrahepatic lipid content with a standardized mean difference of –0.69 compared with controls (95% confidence interval, –0.90 to –0.48; P less than .0001). “Because effect sizes such as standard mean difference [SMD] are difficult to interpret, the translation of such a statistical measure into a clinically relevant notion has been the focus of research for more than a decade,” the investigators added. “A commonly used interpretation was proposed by Cohen, who suggested that SMDs of 0.2, 0.5, and 0.8 correspond to small, moderate, and large effect sizes, respectively. By using this rule of thumb, our results indicate that physical activity exerts a moderate-to-large impact on the reduction of intrahepatic lipid content.”

Exercise reduced liver fat content even more in pediatric patients (SMD, –0.75; 95% CI, –0.1 to –0.5; P less than .0001) and in patients who had been specifically diagnosed with NAFLD (SMD, –0.86; 95% CI, –1.26 to –0.46; P less than .0001). Patients with the highest baseline body mass index also seemed to benefit more than patients with lower baseline BMI (P = .04). Indeed, exercise reduced BMI itself by a weighted mean difference of 0.8 (95% CI, –1.22 to 0.38; P less than .001), the researchers noted. Exercise intensity did not seem to affect the likelihood of benefit. There was a trend toward a greater effect of aerobic over resistance training (P = .06), and few studies examined the effects of combining both types of exercise.

The multivariable analysis also linked physical activity to an average 3.30 IU/L drop in alanine aminotransferase levels (95% CI, –5.57 to –1.04) and to a 4.9 IU/L decrease in aspartate aminotransferase levels (95% CI, –8.68 to –1.02). The investigators were unable to assess the long-term effects of physical exercise, nor its effects on hepatic fibrosis or inflammation, they noted. Nonetheless, the moderate to large effect size “provides strong evidence for the recommendation of physical activity as an effective intervention in the treatment of NAFLD,” they concluded. “Physical activity is also associated with an improvement in blood levels of aminotransferases and is particularly beneficial in patients presenting with severe obesity at baseline.”

The work was funded by the Ligue Genevoise contre le Cancer and the Dr Henri Dubois-Ferrière/Dinu Lipatti Foundation and by the Swiss National Science Foundation. The investigators had no disclosures.

*Content was updated on 10/25/2016 

A once-daily regimen of two investigational, direct-acting anti-HCV agents, ABT-493 and ABT-530, was well tolerated and achieved sustained viral response at 12 weeks (SVR12) for nearly all patients with compensated cirrhosis and chronic genotype (GT) 1 or 3 hepatitis C virus infection, according to open-label phase II studies.

“The unique potency of these agents against all genotypes, even in the presence of common NS3 and/or NS5A baseline substitutions that confer resistance to most contemporary NS3/4A protease inhibitors and NS5A inhibitors, offers the potential for pangenotypic [HCV] therapy without ribavirin,” Edward J. Gane, MD, of the University of Auckland, New Zealand, and his associates wrote in the October issue of Gastroenterology. Phase III trials are now testing this hypothesis by focusing on cohorts of treatment-experienced, genotype 3–infected patients, on patients with renal impairment, and on patients who failed earlier-generation direct-acting antiviral regimens, they said.

The prevalence of HCV-related cirrhosis has yet to peak, and gold standard therapies for GT3 and GT1a infections can take weeks of treatment and the use of ribavirin, which causes undesirable side effects, the investigators noted. Attempts to surmount these residual barriers led to the development of ABT-493, an HCV nonstructural (NS) protein 3/4A protease inhibitor, and ABT-530, an HCV NS5A inhibitor. During in vitro studies, both agents showed “potent” activity against all major HCV genotypes, including variants with mutations that confer resistance to earlier, direct-acting antivirals, the researchers said (Gastroenterology. 2016 Jul 22. doi: 10.1053/j.gastro.2016.07.020). Their two open-label phase II studies enrolled adults with compensated cirrhosis and chronic GT3 (55 patients) or GT1 (27 patients) infection. Among GT1 patients, 41% had baseline NS3 substitutions conferring resistance to earlier-generation drugs, 19% had NS5A substitutions, and 11% had both mutations. The GT1-infected patients received 200 mg ABT-493 and 120 mg of ABT-530. The GT3-infected patients received 300 mg ABT-493 and 120 mg ABT-530, and half (27 patients) also received ribavirin. Most patients were treatment-naive, male, and white, with Child-Pugh scores of 5 and HCV RNA levels averaging about 6.2-6.6 log10 IU/mL.

In all, 26 patients with GT1 infection (96%) achieved SVR12 (95% confidence interval, 82% to 99%). The remaining patient relapsed after completing treatment. All treatment-naive GT3 patients achieved SVR12 whether or not they received ribavirin. However, one treatment-experienced GT3 patient who did not receive ribavirin relapsed after 16 weeks of treatment. Thus, rates of SVR12 were 96% (95% confidence interval, 82%-99%) for GT3 patients who did not receive ribavirin and 100% (95% CI, 88%-100%) for those who did. Notably, 94% of patients with baseline substitutions in NS3 and NS5A achieved SVR12, and there was no apparent link between treatment failure and any demographic or clinical characteristics, the investigators wrote.

Adverse events affected about 74% of patients and were usually mild or moderate in severity. Patients who did not receive ribavirin were most likely to report headache (15%), diarrhea (13%), and fatigue (11%). Only 4% of GT1 patients and 7% of the GT3 cohorts developed serious adverse events, and the only serious adverse event considered possibly treatment related involved a delusional disorder in a 57-year-old male who was receiving ribavirin and admitted amphetamine and alcohol use on the day it occurred. Treatment-related laboratory abnormalities were uncommon, no patients stopped treatment because of adverse events, and there were no deaths. “The rates of some adverse events were numerically higher with the higher ABT-493 dose, though the sample sizes are small and this was a cross-study comparison,” the investigators added. “Though not included in this study, patients with severe or end-stage kidney disease are predicted to be able to be treated with ABT-493 and ABT-530 because both agents have negligible renal excretion. These drugs were well tolerated in HCV-uninfected patients with renal impairment and can be administered without dose adjustment.”AbbVie funded the study and makes ABT-493 and ABT-530. Dr. Gane disclosed ties to AbbVie, Achillion Pharmaceuticals, Alnylam, Janssen, Merck, Novartis, and Novira.

A once-daily regimen of two investigational, direct-acting anti-HCV agents, ABT-493 and ABT-530, was well tolerated and achieved sustained viral response at 12 weeks (SVR12) for nearly all patients with compensated cirrhosis and chronic genotype (GT) 1 or 3 hepatitis C virus infection, according to open-label phase II studies.

“The unique potency of these agents against all genotypes, even in the presence of common NS3 and/or NS5A baseline substitutions that confer resistance to most contemporary NS3/4A protease inhibitors and NS5A inhibitors, offers the potential for pangenotypic [HCV] therapy without ribavirin,” Edward J. Gane, MD, of the University of Auckland, New Zealand, and his associates wrote in the October issue of Gastroenterology. Phase III trials are now testing this hypothesis by focusing on cohorts of treatment-experienced, genotype 3–infected patients, on patients with renal impairment, and on patients who failed earlier-generation direct-acting antiviral regimens, they said.

The prevalence of HCV-related cirrhosis has yet to peak, and gold standard therapies for GT3 and GT1a infections can take weeks of treatment and the use of ribavirin, which causes undesirable side effects, the investigators noted. Attempts to surmount these residual barriers led to the development of ABT-493, an HCV nonstructural (NS) protein 3/4A protease inhibitor, and ABT-530, an HCV NS5A inhibitor. During in vitro studies, both agents showed “potent” activity against all major HCV genotypes, including variants with mutations that confer resistance to earlier, direct-acting antivirals, the researchers said (Gastroenterology. 2016 Jul 22. doi: 10.1053/j.gastro.2016.07.020). Their two open-label phase II studies enrolled adults with compensated cirrhosis and chronic GT3 (55 patients) or GT1 (27 patients) infection. Among GT1 patients, 41% had baseline NS3 substitutions conferring resistance to earlier-generation drugs, 19% had NS5A substitutions, and 11% had both mutations. The GT1-infected patients received 200 mg ABT-493 and 120 mg of ABT-530. The GT3-infected patients received 300 mg ABT-493 and 120 mg ABT-530, and half (27 patients) also received ribavirin. Most patients were treatment-naive, male, and white, with Child-Pugh scores of 5 and HCV RNA levels averaging about 6.2-6.6 log10 IU/mL.

In all, 26 patients with GT1 infection (96%) achieved SVR12 (95% confidence interval, 82% to 99%). The remaining patient relapsed after completing treatment. All treatment-naive GT3 patients achieved SVR12 whether or not they received ribavirin. However, one treatment-experienced GT3 patient who did not receive ribavirin relapsed after 16 weeks of treatment. Thus, rates of SVR12 were 96% (95% confidence interval, 82%-99%) for GT3 patients who did not receive ribavirin and 100% (95% CI, 88%-100%) for those who did. Notably, 94% of patients with baseline substitutions in NS3 and NS5A achieved SVR12, and there was no apparent link between treatment failure and any demographic or clinical characteristics, the investigators wrote.

Adverse events affected about 74% of patients and were usually mild or moderate in severity. Patients who did not receive ribavirin were most likely to report headache (15%), diarrhea (13%), and fatigue (11%). Only 4% of GT1 patients and 7% of the GT3 cohorts developed serious adverse events, and the only serious adverse event considered possibly treatment related involved a delusional disorder in a 57-year-old male who was receiving ribavirin and admitted amphetamine and alcohol use on the day it occurred. Treatment-related laboratory abnormalities were uncommon, no patients stopped treatment because of adverse events, and there were no deaths. “The rates of some adverse events were numerically higher with the higher ABT-493 dose, though the sample sizes are small and this was a cross-study comparison,” the investigators added. “Though not included in this study, patients with severe or end-stage kidney disease are predicted to be able to be treated with ABT-493 and ABT-530 because both agents have negligible renal excretion. These drugs were well tolerated in HCV-uninfected patients with renal impairment and can be administered without dose adjustment.”AbbVie funded the study and makes ABT-493 and ABT-530. Dr. Gane disclosed ties to AbbVie, Achillion Pharmaceuticals, Alnylam, Janssen, Merck, Novartis, and Novira.

A once-daily regimen of two investigational, direct-acting anti-HCV agents, ABT-493 and ABT-530, was well tolerated and achieved sustained viral response at 12 weeks (SVR12) for nearly all patients with compensated cirrhosis and chronic genotype (GT) 1 or 3 hepatitis C virus infection, according to open-label phase II studies.

“The unique potency of these agents against all genotypes, even in the presence of common NS3 and/or NS5A baseline substitutions that confer resistance to most contemporary NS3/4A protease inhibitors and NS5A inhibitors, offers the potential for pangenotypic [HCV] therapy without ribavirin,” Edward J. Gane, MD, of the University of Auckland, New Zealand, and his associates wrote in the October issue of Gastroenterology. Phase III trials are now testing this hypothesis by focusing on cohorts of treatment-experienced, genotype 3–infected patients, on patients with renal impairment, and on patients who failed earlier-generation direct-acting antiviral regimens, they said.

The prevalence of HCV-related cirrhosis has yet to peak, and gold standard therapies for GT3 and GT1a infections can take weeks of treatment and the use of ribavirin, which causes undesirable side effects, the investigators noted. Attempts to surmount these residual barriers led to the development of ABT-493, an HCV nonstructural (NS) protein 3/4A protease inhibitor, and ABT-530, an HCV NS5A inhibitor. During in vitro studies, both agents showed “potent” activity against all major HCV genotypes, including variants with mutations that confer resistance to earlier, direct-acting antivirals, the researchers said (Gastroenterology. 2016 Jul 22. doi: 10.1053/j.gastro.2016.07.020). Their two open-label phase II studies enrolled adults with compensated cirrhosis and chronic GT3 (55 patients) or GT1 (27 patients) infection. Among GT1 patients, 41% had baseline NS3 substitutions conferring resistance to earlier-generation drugs, 19% had NS5A substitutions, and 11% had both mutations. The GT1-infected patients received 200 mg ABT-493 and 120 mg of ABT-530. The GT3-infected patients received 300 mg ABT-493 and 120 mg ABT-530, and half (27 patients) also received ribavirin. Most patients were treatment-naive, male, and white, with Child-Pugh scores of 5 and HCV RNA levels averaging about 6.2-6.6 log10 IU/mL.

In all, 26 patients with GT1 infection (96%) achieved SVR12 (95% confidence interval, 82% to 99%). The remaining patient relapsed after completing treatment. All treatment-naive GT3 patients achieved SVR12 whether or not they received ribavirin. However, one treatment-experienced GT3 patient who did not receive ribavirin relapsed after 16 weeks of treatment. Thus, rates of SVR12 were 96% (95% confidence interval, 82%-99%) for GT3 patients who did not receive ribavirin and 100% (95% CI, 88%-100%) for those who did. Notably, 94% of patients with baseline substitutions in NS3 and NS5A achieved SVR12, and there was no apparent link between treatment failure and any demographic or clinical characteristics, the investigators wrote.

Adverse events affected about 74% of patients and were usually mild or moderate in severity. Patients who did not receive ribavirin were most likely to report headache (15%), diarrhea (13%), and fatigue (11%). Only 4% of GT1 patients and 7% of the GT3 cohorts developed serious adverse events, and the only serious adverse event considered possibly treatment related involved a delusional disorder in a 57-year-old male who was receiving ribavirin and admitted amphetamine and alcohol use on the day it occurred. Treatment-related laboratory abnormalities were uncommon, no patients stopped treatment because of adverse events, and there were no deaths. “The rates of some adverse events were numerically higher with the higher ABT-493 dose, though the sample sizes are small and this was a cross-study comparison,” the investigators added. “Though not included in this study, patients with severe or end-stage kidney disease are predicted to be able to be treated with ABT-493 and ABT-530 because both agents have negligible renal excretion. These drugs were well tolerated in HCV-uninfected patients with renal impairment and can be administered without dose adjustment.”AbbVie funded the study and makes ABT-493 and ABT-530. Dr. Gane disclosed ties to AbbVie, Achillion Pharmaceuticals, Alnylam, Janssen, Merck, Novartis, and Novira.