Conventional Treatment of Heart Failure
The Guideline for the Management of Heart Failure issued by the American College of Cardiology Foundation and American Heart Association (ACCF/AHA) was updated in 2017.47,96 The guideline is intended to improve quality of care and meet the needs of the majority of heart failure patients under most, but not all, circumstances.
Recommendations in the guidelines address clinical evaluation and diagnosis, prevention, and treatment and management, and are stratified by disease severity.
Treatment Considerations for Patients at Risk for Heart Failure (ACCF/AHA stage A or B)
Patients with stage A heart failure have no symptoms of heart failure and no structural problems in their heart, but are at high risk due to high blood pressure, unhealthy blood lipid levels, diabetes, or obesity. Stage B heart failure, on the other hand, is defined as structural changes to the heart muscle from a previous history of heart attack or other blood supply blockage, but without signs or symptoms of heart failure.
Patients at stage A who have hypertension and high lipid levels should be treated in accordance with current guidelines to lower heart failure risk. In addition, despite a lack of randomized clinical trial data, diabetes mellitus and obesity should be recognized as risk factors, as treated to prevent heart failure.101 The guideline also acknowledges a role for self-care, patient education, and physical activity for those who are able. Sleep disorders, including sleep apnea, are common in heart failure patients, and should be discussed with a health care provider.47 A restriction of dietary sodium to 1,500 mg per day may also be indicated in most stage A or B heart failure patients.
Medications. Medications that may be used to treat patients with stage A or B heart failure include:
Angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors restrict the activity of angiotensin-converting enzyme (ACE), reducing the synthesis of the hypertensive hormone angiotensin II. Enalapril (Vasotec) and lisinopril (Zestril) are examples of commonly prescribed ACE inhibitors.102 By lowering levels of angiotensin II, these medications promote blood vessel dilation.103 ACE inhibitors are beneficial in all degrees of symptomatic heart failure, regardless of the presence or absence of coronary artery disease. They reduce death and heart failure-related illness in patients whose heart function is compromised.96 ACE inhibitors must be used with caution in patients with very low blood pressure, advanced kidney disease, and elevated blood potassium. This class of drugs can cause a type of severe skin swelling called angioedema, and are contraindicated in patients with this condition. Cough is one of the more common side effects of ACE inhibitors. Not all patients are able to tolerate this class of medication.96,104
Angiotensin receptor blockers (ARBs). ARBs may be prescribed as an alternative to ACE inhibitors, generally in individuals who cannot tolerate the side effects of ACE inhibitors. Randomized, controlled trials have demonstrated that ARBs reduce death and heart failure-related illness, particularly in patients who cannot tolerate ACE inhibitors. Like ACE inhibitors, ARBs must be used with caution in patients with low blood potassium levels, advanced kidney disease, and very low blood pressure. Commonly prescribed ARBs include candesartan (Atacand) and valsartan (Diovan).96,104,105 Intriguingly, the ARB telmisartan (Micardis) has been shown to have additional metabolic benefits, such improvement of insulin sensitivity.106
Beta blockers. Beta blockers lower heart rate and blood pressure by blocking beta-adrenoceptors.107 Beta-adrenoceptors bind adrenaline and norepinephrine (catecholamines), triggering vasoconstriction and increased heart rate and heart contraction force, among other changes in cardiovascular tissues. Examples of beta blockers include carvedilol (Coreg), bisoprolol (Zebeta), and metoprolol (Lopressor). These three medications, including the sustained-release form of metoprolol, reduce risk of death in appropriately selected heart failure patients, and are indicated for patients with current or past history of reduced ejection fraction.47,108
A recent meta-analysis of 11 randomized, double-blind, placebo-controlled studies, including over 14,000 patients, found that beta blockers improve left ventricle ejection fraction and the prognosis for patients in heart failure.109 In stage B patients, beta blockers are recommended in conjunction with either an ACE inhibitor or ARB in patients who have had a heart attack, or another blood supply blockage, and who have reduced ejection fraction.47 Side effects associated with beta blockers include weight gain, fatigue, and cold feet or hands. Less commonly, depression, shortness of breath, or insomnia may occur.
Statins. Statins are drugs typically used to lower cholesterol levels. They prevent endogenous cholesterol production and help reabsorb cholesterol that has built up in artery walls. In patients with a recent or remote history of myocardial infarction or acute coronary syndrome, statins may be useful in preventing symptomatic heart failure and cardiovascular events.101 A recent meta-analysis of 17 trials, including over 130,000 subjects, found statin therapy reduced LDL cholesterol levels, the rate of non-fatal heart failure hospitalization, and composite heart failure outcome, but not heart failure death.110 More research is needed to fully understand the role statins play in treating heart failure.
Treatment Considerations for Patients with Heart Failure (ACCF/AHA stage C)
For patients with structural changes to the heart muscle, and past or current heart failure symptoms (stage C), the current guideline recognizes the importance of self-care, patient education, and social support. CPAP treatment for patients with sleep apnea can increase ejection fraction and improve overall status in stage C patients. Exercise training, physical activity, or cardiac rehabilitation also improve overall status. Pharmacological treatment for stage C heart failure relies on the same medications as stages A and B, with treatment beginning at very low doses which are gradually increased.47 Additional medications for treating stage C heart failure are:
Angiotensin receptor-neprilysin inhibitors (ARNIs). Although treatment with an ACE inhibitor or ARB has long been a mainstay of medical therapy for symptomatic heart failure, new guidelines recommend an ARNI in most patients with mild-to-moderate symptomatic heart failure with reduced ejection fraction.96 The first of these drugs to gain FDA approval for use in heart failure, Entresto, combines sacubitril and the ARB valsartan.111 By inhibiting the activity of the enzyme neprilysin, sacubitril prevents the breakdown of natriuretic peptides, thus improving fluid balance and renal and cardiovascular function.112,113
Research shows that, in carefully selected patients, sacubitril-valsartan reduced the risks of cardiovascular death and heart failure-related hospitalizations more than standard therapy with an ACE inhibitor.111 In a randomized trial of 881 patients with reduced ejection fraction who were hospitalized for acute decompensated heart failure, subjects received either 97 mg sacubitril and 103 mg valsartan twice daily or 10 mg enalapril twice daily. The sacubitril-valsartan group had a significantly greater reduction in NT-proBNP concentrations, which was evident as early as week one of the trial.114 The side effect profile of sacubitril-valsartan is roughly comparable to the ACE inhibitor enalapril, although it is far more expensive.115-117 Treatment with ARNIs may cause low blood pressure, so dose adjustment may be necessary.
Diuretics. Diuretics are used in stage C heart failure patients with reduced ejection fraction to address fluid retention. They work by altering the way the kidneys handle sodium or chloride, thus increasing urination.118 Furosemide (Lasix) is the most commonly used diuretic to treat heart failure, but many others are available, including thiazide diuretics and spironolactone.47 Spironolactone reduces testosterone production and activity.119 Diuretics can improve symptoms related to fluid retention, and most patients with advanced heart failure take diuretics; however, they have not been shown to consistently improve clinical outcomes or mortality. Diuretics may cause adverse effects as well, such as electrolyte imbalances. Ongoing research is needed to determine the role of diuretic treatment in heart failure.
Aldosterone antagonists. Stage C patients with mild-to-complete activity limitations and markedly compromised ejection fraction may be prescribed aldosterone receptor antagonists.47 Aldosterone is a hormone produced by the adrenal glands that increases the kidneys’ retention of sodium and water. Spironolactone and other aldosterone antagonists inhibit aldosterone, decreasing fluid retention and diminishing blood volume.120 Spironolactone was shown to reduce heart-failure-related hospitalizations in patients with HFpEF.121
Note that when using aldosterone antagonists, potassium, renal function, and diuretic dosing should be carefully monitored to reduce risk of hyperkalemia and renal problems. Spironolactone is also associated with gynecomastia, the swelling of breast tissue in males. Eplerenone (Inspra) is an aldosterone antagonist with weaker effects but also with less effect on sexual hormones, and can be used as an alternative to spironolactone.122 Inappropriate use of these medications may be potentially harmful or life threatening.101
Cardiac glycosides. Cardiac glycosides are anti-cancer compounds present in many plants. They are historically derived from the Digitalis (foxglove) genus of plants, and have been used to treat cardiac problems for over 200 years.123 Cardiac glycosides function as positive inotropes, meaning they increase the contractile force of the heart muscle. Digoxin (Lanoxin), a particular blend of cardiac glycosides, is the most commonly used variation. It is sometimes used in stage C patients with reduced ejection fraction, as it reduces heart failure hospitalizations.47 Digoxin toxicity can cause potentially serious heart rhythm irregularities, as well as vomiting, headache, and confusion.124 Other agents mentioned previously are generally preferred over digoxin as first-line therapies, and while clinical trials have shown that digoxin may alleviate some symptoms, it does not improve survival.
Anticoagulants. Anticoagulants are used for patients with chronic heart failure, atrial fibrillation, or stroke risk factors.47 Atrial fibrillation is prevalent in patients with heart failure and is a risk factor for blood clotting events. A recent meta-analysis studied the safety and efficacy of non-vitamin K oral anticoagulants (NOACs, formerly referred to as “novel oral anticoagulants”) as compared with warfarin in patients with atrial fibrillation and heart failure. The analysis covered four studies and over 55,000 patients. Researchers concluded that NOACs had a similar efficacy and safety profile as warfarin, and they significantly reduced the risk of bleeding events.125
Another study found that NOAC use in heart failure patients significantly reduced the risk of stroke and systemic embolism and major, intracranial, and total bleeding compared with warfarin.126 Another review found that there was reasonable evidence for benefits of NOACs compared with warfarin in patients with heart failure.127
A summary comparing NOACs to warfarin noted that NOACs have fewer food and drug interactions, are associated with a lower bleeding risk, and may have more predictable pharmacokinetics (ie, may move and function through the body more predictably). However, safety and efficacy data for the use of NOACs in those with renal insufficiency, the elderly, and those who struggle with treatment adherence is lacking. NOACs may have a lower risk of intracranial bleeding and stroke than warfarin and do not require routine lab monitoring. However, they tend to have a higher drug cost and may increase the risk of GI bleeding.128
Aspirin, which interferes with blood clotting, may lower the risk of certain cardiovascular events in select patient groups. Aspirin use in heart failure remains controversial, however, as some research suggests its use in this population increases risk of hospitalization. A recent retrospective cohort study found that low-dose aspirin (75 mg/day) was associated with a reduced morbidity and mortality risk.129 In heart failure patients with reduced ejection fraction in sinus rhythm, randomized clinical trials have shown that warfarin had increased bleeding risk compared with aspirin. However, stroke is a potential complication for people with significantly reduced ejection fraction—even in those whose heart rhythm is normal. In these situations, clinical trial data suggest warfarin is likely favorable over aspirin for risk reduction.130,131
A multi-center, double-blind trial followed 2,305 patients with heart failure in sinus rhythm for six years. The primary outcome was ischemic stroke, intracerebral hemorrhage, or death. There was no difference in primary outcome for the aspirin or warfarin groups for the first three years; after four years, warfarin demonstrated a reduced risk of ischemic stroke, but also an increased risk of hemorrhage. The authors concluded that treatment choices must be individualized to the patient.132
Sinoatrial current inhibitor. Increased resting heart rate is a risk factor for heart failure-related hospitalization and death.133 Ivabradine (Corlanor), classified as a sinoatrial current inhibitor, has reduced cardiac hospitalization risk.96 Ivabradine is indicated for those being managed according to treatment guidelines, including the maximum tolerated dose of a beta blocker, and who have a resting heart rate of 70 beats per minute or higher.96,134 Side effects, such as an excessively low heart rate and abnormal heart rhythm, and a high cost, limit its use.135
Digoxin is a medication used to treat heart conditions, including atrial fibrillation and heart failure. Digoxin has fallen out of favor in recent years due to concerns over potential toxicity as well as several newer treatment options being developed. However, studies suggest there may be some compelling reasons to continue using digoxin in cases of heart failure.136
One randomized crossover study compared ivabradine to digoxin in 42 patients with diastolic heart failure with preserved left ventricle function (HFpEF). Both medications had positive effects on dyspnea (shortness of breath), heart rate, and signs of diastolic function, but digoxin was more effective.137
Medical devices. In select cases of relatively advanced stage C heart failure with reduced ejection fraction, implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy (CRT) may lower the risk of cardiac-related death.47 ICDs are similar to pacemakers, and they monitor the heart’s rhythm to ensure it beats at an optimal rate. CRT is a pacemaker that sends timed electrical impulses to the heart’s left and right ventricles so they pump more efficiently. In addition, a ventricular assist device (VAD), an implantable pump that moves blood from the ventricles to the rest of the body, can be an alternative to heart transplantation in properly selected patients.138 A trial of catheter ablation for patients with both atrial fibrillation and HFrEF found that the procedure significantly reduced the risk of dying from any cause, and reduced the risk of being hospitalized for worsening of heart failure.139 Other devices, including biventricular assist devices and a total artificial heart, are sometime used as bridge therapies while a patient is awaiting a transplant.140
An implantable device called CardioMEMS was approved in 2014 for use in NYHA stage III patients. The device is placed inside the pulmonary artery where it communicates with an external monitor to report pulmonary artery pressure to the patient’s physician. Regularly monitoring pulmonary artery pressure can help doctors adjust treatment regimens appropriately. The CardioMEMS device was shown in a rigorous clinical trial to reduce hospitalization rates by about 28% compared with controls. A suggestive reduction in mortality was also evident, but this was not statistically significant.141
Advanced Heart Failure (ACCF/AHA stage D)
Stage D heart failure, called advanced heart failure or refractory end-stage heart failure, accounts for 5‒10% of heart failure cases. Stage D indicates that the condition is not responding to available evidence-based treatment.96 This stage is characterized by severe symptoms, including unintentional weight loss, fatigue, and shortness of breath while performing daily tasks (eg, getting dressed or bathing) or at rest.
Although certain aggressive measures, such as mechanical circulatory support or heart transplant, may be considered, end-of-life hospice care and palliative treatments should be discussed as well. Before stage D is diagnosed, all other possible causes and treatable disorders, such as thyroid disorders and pulmonary conditions, must be considered and ruled out.47,142,143