Heart disease is expected to be the leading cause of mortality by 2020.1 Currently, 5 million Americans are affected by heart failure (HF), with the number expected to rise to more than 8 million by 2030.2–5 The number of patients with HF is growing, as more individuals are rescued from fatalities related to acute myocardial infarction and then go on to develop HF.1 , 5–7 Although only 2% of the general population has HF, 10% of the population 75 years and older is affected.1 , 6 Hospitalization in patients 65 years and older is most often due to HF.4 Rehospitalization is also a significant issue with this population, as half of the patients with HF will be readmitted to a hospital within 6 months of their initial diagnosis and 67% will be readmitted within 1 year.7–9
Physical therapists need to be well informed about this disease, as we are involved in the rehabilitation, education, and prevention of rehospitalization of these patients. Due to frequent rehospitalizations, HF is an expensive disease with great financial burden placed on patients and the health care system.6 , 10 Physical therapists need to be actively involved in educating patients and family members about the signs and symptoms of worsening HF to facilitate appropriate health care utilization and prevent rehospitalization.11
Mortality is also an issue with this population, as half of the individuals diagnosed with HF will die within 5 years of their initial diagnosis.6 , 10 , 11 Despite extensive evidence-based treatment approaches, there has not been a significant reduction in mortality in these individuals.6
HF is characterized by the inability of the heart muscle to pump blood and adequately maintain cardiac output.12 , 13 HF can involve the left side of the heart, the right side of the heart, or both, but most commonly affects the left side. HF due to weakness in the contraction of the ventricle is termed systolic failure. It is characterized by a reduction in stroke volume, cardiac output, and ejection fraction. HF is termed as diastolic failure when the ventricle is stiff and unable to relax.12 It is characterized by a reduction in stroke volume and cardiac output with normal ejection fraction.12 Patients with left-sided HF present with dyspnea, as the fluid backs up into the lungs.12 , 13 Patients with right-sided HF present with jugular venous distention and edema, as the fluid backs up into the abdomen, legs, and feet.12 , 14
Any form of injury to the heart muscle forms the foundation for the development of HF. The damage to the heart muscle could be due to myocardial infarction, an ischemic episode, valvular disease, or left ventricular hypertrophy leading to decreased myocardial contractility and reduction of the cardiac output.13 The weakened heart muscle can no longer pump adequate blood to meet the body's needs for oxygen and blood, resulting in the backing up of blood in the venous and pulmonary circulation.12 The buildup of blood into body tissues and lungs results in congestive HF, and the high pressure in the pulmonary capillaries results in pulmonary hypertension.12
Due to the reduction in cardiac output, the sympathetic system is stimulated, thereby increasing the rate of myocardial contractility and the tone of the blood vessels thus increasing the venous return. The reduction in cardiac output also causes decreased blood flow to the renal arteriole, triggering the renin-angiotensin-aldosterone system (RAAS). The kidneys increase renin production, which acts on angiotensinogen converting it to angiotensin I. Angiotensin-converting enzyme (ACE) then converts angiotensin I to angiotensin II. Increased production of angiotensin II facilitates sodium and water retention in the renal tubules and stimulates the adrenals to release the hormone aldosterone, which further increases sodium and water reabsorption.
Moderate fluid retention will cause an increase in blood volume. If the injury to the cardiac muscle is severe, the fluid retention is increased significantly, thus raising the blood volume and consequently overstretching the cardiac muscles.6 , 13 The volume overload impairs the alveolar blood gas barrier, impairing diffusion across the alveolar membranes. The cardiac tissue undergoes remodeling to adapt to the fluid overload resulting in hypertrophy.
HF ultimately causes damage to the heart, pancreas, liver, lungs, kidneys, blood, and muscles due to decreased perfusion of cardiac tissues and peripheral organs. This triggers an increase in sympathetic stimulation and activation of the RAAS, setting up a vicious cycle of fluid retention, vasoconstriction, and ventricular hypertrophy.15
HF with reduced ejection fraction
HF with reduced ejection fraction (HFrEF) is associated with HF with reduced cardiac output at rest and during activity. These patients have a decreased ejection fraction.15 Normal ejection fraction is 55% to 70%.15 Survival rates of patients with HFrEF have improved in the past decade while there has been no significant change in survival of patients with HF with preserved ejection fraction.6 , 16
HF with preserved ejection fraction
HF patients who present with normal to near-normal ejection fraction have HF with preserved ejection fraction.16 More than 50% of the patients with HF present with preserved ejection fraction.9 The heart muscle, due to stiffness and thickness, can only hold a small volume of blood. The ejection fraction appears normal although the volume of blood pumped out is inadequate to meet the body's requirements.
HF with preserved ejection fraction is also called diastolic HF. Diastolic dysfunction could be due to abnormal left ventricular relaxation, filling, or distensibility.17 This is typically measured during cardiac catheterization.17 The patients who present with HF with preserved ejection fraction (HFpEF) are typically older women, with cardiovascular risk factors and noncardiovascular comorbidities (renal failure, chronic lung disease, obesity, hepatic disease, hypothyroidism, sarcopenia, and anemia).1 , 6 , 11 , 13 These conditions lead to inflammatory states, resulting in coronary microvascular endothelial dysfunction, cardiac cell hypertrophy, and fibrosis with stiffness leading to diastolic dysfunction. Patients with HFpEF mainly present with fatigue, breathlessness, and fluid retention.
HFpEF is difficult to diagnose, as the patients present with various combinations of cardiac and vascular problems. The patients may present with a combination of the following: ventricular dysfunction, atrial dysfunction, autonomic dysfunction, vascular stiffening, ventriculoarterial coupling dysfunction, improper blood pressure responses to exercise, valvular issues such as mitral regurgitation, lung diseases, iron-deficiency anemia, renal dysfunction from overload, aging and deconditioning, obesity and sarcopenia, psychiatric disorders, and diabetes.14
The American College of Cardiology (ACC) and the European Society of Cardiology (ESC) have different recommendations to diagnose HFpEF. The ACC recommends that the presence of typical signs and symptoms of HF, normal or near-normal left ventricular ejection fraction, and the absence of obvious factors contributing to HF are good guidelines to be used in the diagnosis of HFpEF.17 The ESC recommends the presence of normal or mildly abnormal left ventricular function, increased BNP with signs and symptoms of HF, and the presence of left ventricular dysfunction as guidelines in diagnosing HFpEF.17
Common risk factors for HF are hypertension, coronary artery disease (CAD), cardiomyopathy, sleep apnea, valvular heart disease, diabetes, aging, obesity, dyslipidemia, and hyperthyroidism.2 , 7 A few strong predictors of death in patients with HF included age, renal function, blood pressure, blood sodium levels, left ventricular ejection fraction below 40%, male gender, elevated brain natriuretic peptide (BNP) levels, diabetes, elevated weight or body mass index, exercise capacity, and New York Heart Association (NYHA) class.18
SIGNS AND SYMPTOMS OF HF
Patients with HF commonly present with shortness of breath, which is worse when lying down or with increased activity. The dyspnea may start off only with activity and progress to dyspnea at rest. The dyspnea may be worse at night, causing the patient to wake up or place pillows to raise the level of the upper body and facilitate breathing. It is important to distinguish if the dyspnea is from pulmonary causes or cardiac in origin. Patients with left-sided failure present with dyspnea, as the fluid backs up into the lungs.12 , 13
The heart muscle cannot adequately pump blood and oxygen to the various parts of the body resulting in fatigue. Patients with HF may complain of weakness with activity.
There is backup of fluid into the lungs, which can result in dyspnea, cough, or wheezing. The cough can produce blood-tinged sputum or foamy mucus.
Due to the activation of the RAAS, there is an increase in volume overload. This volume overload can present as peripheral edema in the lower extremities, ascites, weight gain, or pulmonary edema.12 , 14 Patients with right-sided HF present with jugular venous distention and edema, as the fluid backs up into the abdomen, legs, and feet.12 , 14
HF results in decreased cardiac output, stimulating the sympathetic activity, which causes an increase in heart rate.12 , 14
Ejection fraction is the amount of blood ejected or pumped out by the ventricles with each contraction. It represents a percentage of the volume of the blood ejected out of the ventricles to the volume of blood received by the ventricles with each systole.15 The normal ejection fraction is 55% to 70%. Patients with HF typically present with decreased ejection fraction; however, patients with HFpEF may not present with reduced ejection fraction.15
The NYHA functional classification system stages HF as follows:
Class I patients have cardiac disease without limitations of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea.7
Class II patients have cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity can trigger symptoms of fatigue, palpitation, or dyspnea.
Class III patients have cardiac disease with marked limitation of physical activity. Patients are comfortable at rest. Less-than-ordinary activities cause fatigue, palpitation, or dyspnea.
Class IV patients have cardiac disease affecting the patient's ability to carry out any physical activity without discomfort. Symptoms of HF are evident at rest. If any physical activity is undertaken the patient's discomfort increases.16
Another classification system, described by Parker et al,6 groups the disease into several stages:
Stage A describes patients who have risk factors but are asymptomatic and have no structural changes.
Stage B patients are asymptomatic but have structural changes in cardiac tissue (valvular disease, myocardial infarction, left ventricular hypertrophy). Despite medication, these patients will not revert to stage A. However, treatment during stage B can reduce the progression to stage C.
Stage C patients present with signs and symptoms of HF.
Stage D represents patients whose HF has not responded to treatment.6
The main comorbidities associated with HF are hypertension and diabetes mellitus.7 The presence of diabetes as a comorbidity is a strong predictor of poor prognosis for HF. Diabetes causes an increase in BNP levels. Patients with HF who have diabetes are often obese compared with those with HF who are nondiabetic. While obesity without the comorbidity of diabetes is associated with longer survival rates in patients with HF,19 obesity with diabetes is not an independent predictor of survival.19 In fact, diabetes with hypertension, hypercholesterolemia, or both had increased cardiovascular mortality when obese versus normal weight.19
Physical examination should include recording the heart rate and rhythm, supine and standing blood pressure measurements, and jugular venous pressure. Chest auscultation is a simple tool for checking lung congestion and heart sounds to rule out valvular disease. Observe to see whether there are signs of fluid overload by noting whether there is hepatomegaly or ascites. Physical therapists can palpate extremities to note whether they feel cool. Cool extremities indicate a decreased cardiac output.16 Pay close attention to the patient's body mass index and weight, as rapid weight gain is indicative of fluid overload. Patients with HF may have excess retention of fluid, thus causing dilution of the sodium levels. Abnormal sodium levels in the blood can result in reduced flow of blood to the brain, causing confusion or memory problems.16
Electrocardiogram (ECG) can be performed to detect any abnormal rhythm or previous ischemic disease.6 , 16 Patients with HF and reduced ejection fraction often present with an abnormal ECG.
Chest x-rays will reveal cardiomegaly, blunting of the costophrenic angle, and/or lung opacities from pulmonary edema depending on the stage of the disease.6 , 16 Chest x-rays are useful in eliminating other respiratory diseases causing dyspnea.6
Clinical signs and symptoms alone make it difficult to distinguish whether the HF is HFpEF or HFrEF.6 Echocardiography is useful in diagnosing the cause of HF and determining whether the HF is HFrEF or HFpEF.6 , 16 Echocardiograms provide useful information on the wall motion, wall thickness, valvular status, chamber size, and left ventricular function.17
BNP is a hormone released from the cardiac cells in response to ventricular wall stretching, cardiac dilatation, and high arterial pressure.13 , 15 , 19 It is called BNP, as it was first identified in the brain tissue and later found to be present in atrial tissue and secreted by endothelial cells. The BNP value if found to be normal is not indicative of HF. BNP is a strong predictor of poor prognosis for HF.20 , 21 Normal levels are less than 100 pg/mL, values of 100 to 400 pg/mL are of concern, and values above 400 pg/mL are indicative of HF.22 BNP levels alone are unreliable for certain patients, as these levels decrease in individuals who are obese. Patients with HFpEF have lower BNP values than those with HFrEF.6 , 16
In patients with obesity where BNP levels are unreliable, other biomarkers such as troponin, galectin-3, and suppression of tumorigenicity are used to assess the severity of HF.2 , 5 Serum urea and potassium levels need to be closely monitored too.6 A study by Vasudevan et al5 showed that the use of biomarker values is a good tool to measure the severity of HF.
PHARMACOLOGICAL MANAGEMENT OF HEART FAILURE
When considering pharmacological management of HF, one must first consider the type of HF: HFrEF or HFpEF.
HFpEF is the most common form of HF and is especially prevalent in women.17 Unfortunately, medication has not been found to be very effective in managing HFpEF.17 The focus of pharmacotherapy is, therefore, more on managing comorbidities and reducing the risk of exacerbation than reducing morbidity or mortality.
In cases of HFrEF, the goal of pharmacological treatment is focused on improving contractility of the heart and decreasing cardiac workload.20 Most of the medications targeting this condition work by affecting neurohormonal responses to decreased cardiac function. By affecting the RAAS and the sympathetic nervous system (SNS), the progression of HF can be reduced.23
In addition to the medications used to manage chronic HF, there are additional medications used, on a short-term basis, to suppress acute exacerbation and/or decrease fluid buildup in cases of advanced congestive HF.
Ultimately, one must realize that pharmacological management of HF is just that, management. Research studies look at the ability of current medications not to cure HF but to reduce morbidity and mortality, minimize episodes of hospitalization, and improve quality of life in patients.
We now discuss specific medications for HFrEF, HFpEF, and acute exacerbations of HF.
PHARMACOLOGICAL MANAGEMENT OF HFrEF
ACE inhibitors (ACE-Is), such as enalapril and captopril, are mainstays in the treatment of HF. These medications target the RAAS by blocking the conversion of angiotensin I to angiotensin II. This results in decreased vasoconstriction, less hypertrophy of the cardiac muscle, and less aldosterone release. These medications also increase bradykinin levels resulting in increased vasodilation.20 All these responses result in decreased load on the heart and improved exercise tolerance in patients with HF.
Many large randomized controlled trials have found ACE-Is to decrease morbidity and mortality in patients with HFrEF.24 This has resulted in the ACC providing a class 1 (strong recommendation) level A (high quality) rating for ACE-Is in the management of HF.25 The ESC guidelines recommend that ACE-Is be used in patients with symptomatic HFrEF to reduce the risk of hospitalization and death. ACE-Is are also recommended for asymptomatic individuals if they have left ventricular systolic dysfunction. ACE-Is can help decrease the risk of these patients developing HF in the future.26
While there is much research to support the use of ACE-Is, there are some risks and potential complications with these medications. Persistent dry cough, due to inhibition of kininase, and skin rash are common side effects with ACE-Is.20 The dry cough is often severe enough to result in patients needing to discontinue these medications.20 There is also the risk of angioedema when taking ACE-Is, especially among the African American population and women. ACE-Is should be given with caution to these populations as well as those with low blood pressure, renal insufficiency, and elevated potassium levels.21
Since ACE-Is can raise blood serum potassium levels, therapists should monitor laboratory values and watch for signs of hyperkalemia such as muscle weakness, slow heart rate, and weak pulse.
Angiotensin receptor blockers
Another class of medication for patients with chronic HFrEF is angiotensin receptor blockers (ARBs). This group includes medications such as losartan and valsartan. ARBs work by preventing angiotensin II from binding to receptors, limiting vasoconstriction and hypertrophy of the heart. ARBs do not inhibit kininase, as ACE-Is do, so persistent, dry cough is less of an issue in patients taking this medication. However, not inhibiting kininase also limits some of the vasodilation that ACE-Is provide.21 ARBs are, therefore, often an alternative medication for patients unable to tolerate the side effects of ACE-Is.20
As with ACE-Is, the ACC also gives ARBs a strong 1A recommendation but again recommends these medications be used cautiously in patients with low blood pressure, renal insufficiency and elevated potassium levels.21
While therapists should monitor these patients for hyperkalemia, these medications do not frequently affect therapeutic interventions.
Angiotensin receptor neprilysin inhibitors
In 2015, the Food and Drug Administration (FDA) approved a new class of medication for HF. These drugs, angiotensin receptor neprilysin inhibitors (ARNIs), combine a neprilysin inhibitor (sacubitril) with an angiotensin II receptor blocker (valsartan).27 This medication works by inhibiting neprilysin, resulting in diuresis and vasodilation, and by blocking angiotensin II, which reduces vasoconstriction and aldosterone release.28
In the PARADIGM-HF trial, the medication was tested against enalapril (an ACE-I).28 The population tested was patients in systolic HF, who tolerated ACE-I and ARBs, with an ejection fraction 40% or less and increased levels of BNP.28 The ARNI group had decreased risk of death by 16% and decreased risk of hospitalization from HF by 21%.28 The medication was so successful in trials that the FDA granted a fast-track review to get it on the market sooner.27
While the ACC gave this medication a strong class 1 (strong) B-R (moderate quality of evidence) recommendation, there are still concerns.28 Hypotension is more common in patients taking ARNIs versus ACE-Is and there is an increased risk of angioedema especially with overlap of ACE-Is with ARNIs.28 Because of this finding, it is recommended that an ACE-I be withheld for at least 36 hours before starting an ARNI.28
Another concern with this medication is the potential risk of Alzheimer disease due to inhibition of neprilysin resulting in a buildup of beta-amyloid peptides. While no signs of cognitive impairment were seen in the trial, long-term safety of the drug has not been assessed, so there is a risk that the medication may impact cognition.28
According to the ACC guidelines, ARNIs are recommended for patients with chronic symptomatic HFrEF if they tolerate ACE-Is and ARBs.25 ARNIs are an alternative to an ACE-I or ARB, but the FDA currently recommends that they be used in place of these medications due to findings of the PARADIGM-HF trial and the side effect profile resulting in less renal dysfunction.29 Similar to ACE-Is and ARBs, ARNIs target the RAAS, so patients on these medications should be monitored for renal dysfunction and abnormal potassium levels.29
Diuretics are used to decrease fluid buildup and reduce congestion in patients with HFrEF. These medications work by inhibiting reabsorption of sodium and water, thereby decreasing cardiac preload.20 Classifications of diuretics include thiazide diuretics, loop diuretics, and potassium-sparing diuretics. Loop diuretics, such as furosemide (Lasix), are commonly used to treat fluid buildup in congestive HF.
A Cochrane meta-analysis found that loop and thiazide diuretics decrease the risk of death and progression of HF when compared with a placebo.26 Diuretics have also been shown to improve exercise capacity in patients with HF.26
Potential adverse effects of diuretics include electrolyte imbalance and dehydration. These conditions are more common in the elderly, as they often have comorbidities affecting renal function and a decreased thirst mechanism response.9 Electrolyte imbalance can be monitored by checking sodium and potassium levels. Patients with hyponatremia (sodium levels <135 mEq/L) due to diuretic use may present with weakness, fatigue, headache, nausea, vomiting, muscle cramps, and confusion.15 Diuretic use may also result in hypokalemia (potassium <3.5 mEq/L), which may present as cardiac arrhythmias.15
Dehydration is a common problem with diuretic use and can be assessed by a skin turgor test or an elevated blood urea nitrogen/creatinine ratio; however, one must keep in mind that skin aging and poor renal function may affect these findings. Patients on diuretics should be educated to stay hydrated, as many patients on diuretics avoid drinking water to minimize bathroom trips. Therapists need to closely monitor vitals on these patients, as these patients may present with orthostatic hypotension or arrhythmias.
Mineralocorticoid receptor antagonists
Mineralocorticoid receptor antagonists (MRAs) are another class of drugs targeting HF by altering aldosterone levels. These medications, including spironolactone and eplerenone, are diuretics but by blocking aldosterone receptors in the kidneys they have the additional benefit of also preventing cardiovascular damage caused by aldosterone.20 Eplerenone shows less preference to progesterone or androgen receptors resulting in less impotence and gynecomastia than nonselective spironolactone.30
Current ACC guidelines recommend MRAs for patients with HFrEF and NYHA class II to IV symptoms or for patients after an acute myocardial infarction with an ejection fraction 35% or less.30 ESC guidelines also recommend MRAs, but they recommend caution in using MRAs in those with kidney dysfunction and serum potassium levels of more than 5.0 mmol/L.26
In 15 trials evaluating MRAs, they were found to reduce death and cardiac hospitalizations significantly in patients with HFrEF.30 Current guidelines recommend that they not be used in isolation but in addition to ACE-Is and beta-blockers.26
As with other diuretics, therapists will need to monitor patients on MRAs for dehydration, electrolyte imbalance, orthostatic hypotension, and cardiac arrhythmias.
While many of the medications we have discussed so far target the RAAS, we now discuss a medication class that targets the SNS instead. Beta-blockers, such as carvedilol and bisoprolol, work by binding to beta-1 receptors on the heart decreasing sympathetic activity.20 This is important as elevated resting heart rates have been found to be a predictor of mortality in patients with HF.31 Decreasing the heart rate by even 10 bpm can decrease the risk of HF mortality by 39% and HF hospitalization risk by 30%.31
Beta-blockers were not initially recommended for the treatment of HF, as they decrease the force of the heart's contractions. However, the medication's effect on the SNS and lowering heart rate was found to be beneficial and beta-blockers were found to improve survival in patients with HF.32
The ACC gives beta-blockers a class 1 A recommendation. It recommends that beta-blockers be used along with ACE-Is as first-line treatment in patients with symptomatic HFrEF.24 , 33 The ESC guidelines also recommend beta-blockers be used preventatively for patients with no current symptoms of HF but a history of MI.26 Similar to diuretics, these medications should not be used in isolation with patients in HF but alongside ACE-Is.26
As these medications target the SNS, side effects are often cardiovascular in nature. Therapists need to closely monitor vitals on patients taking beta-blockers, as they may exhibit bradycardia and orthostatic hypotension. Hypotension can be such a significant problem that it may result in patients having to alter their dosage of beta-blockers. In the SHIFT trial almost half of the subjects in the study had to decrease their dosage of beta-blocker due to hypotension.34
Due to the risk of orthostatic hypotension, patients should be monitored closely for fall risk. Therapists must also remember to use RPE (rate of perceived exertion) in place of heart rate when assessing response to exercise in this population, as the medication will blunt normal heart rate changes.
Ivabradine is a newer medication in the battle against HF. This medication was approved by the FDA, in 2015, for patients with symptomatic HFrEF (left ventricular ejection fraction ≤ 35%) in sinus rhythm with a heart rate of 70 bpm or more while on ACE-Is, beta-blockers, and MRAs.26
Like beta-blockers, ivabradine targets the SNS but this medication works not by targeting the beta receptors on the heart but by inhibiting the pacemaker current of the SA (sinoatrial) node. Due to its different mechanism of action, ivabradine reduces heart rate without affecting the force of contraction of the heart or further lowering blood pressure as a beta-blocker does.31 This is beneficial as we mentioned earlier how many patients on high doses of beta-blockers struggle with low blood pressure.34
The research on ivabradine is mixed. The SHIFT (systolic HF treatment with the ivabradine trial) trial had patients with stable, chronic, symptomatic HF with an ejection fraction 35% or less and a sinus rhythm 70 bpm or more taking either ivabradine or a placebo.31 The SHIFT trial found that ivabradine decreased both death and rate of hospital admission, but these findings were not supported by the BEAUTIFUL trial.31
Side effects of ivabradine include blurred vision, bradycardia, and headaches.31 The ACC and the ESC recommend the use of ivabradine if heart rate continues to remain elevated after treatment with a beta-blocker.25
Therapists need to monitor vitals in these patients for signs of bradycardia.
Cardiac glycosides, such as digoxin, are often described by the term digitalis.20 Digoxin is the oldest cardiac drug still in use today but is now used at a much lower frequency due to its narrow therapeutic index and high rate of toxicity compared with newer medications.20
While many of the medications we have discussed work by decreasing load on the heart by affecting fluid levels, digoxin is an inotropic agent, meaning it helps increase the force of contraction of the heart muscle. It does this by inhibiting the sodium pump, thereby affecting calcium influx.35 However, in addition to its effect on the heart muscle, digoxin decreases activation of the SNS impacting heart rate.36
In the DIG (Digitalis Investigation Group) trial, digoxin was found to decrease the risk of hospitalization but not mortality in patients with HF.36 Use of digoxin declined after this trial due to these findings and the risk of toxicity with its use. In 2016, Thomsen et al33 evaluated 5 studies assessing HF hospitalization and 5 studies assessing mortality and found only a reduced risk of hospitalization with patients taking digoxin.
While digoxin is no longer a first-line medication in the treatment of HF, there is a still a place for it in the management of HF. Many of the medications mentioned earlier, such as MRAs and ACE-Is, can affect renal function, and poor renal function may limit medication options. Patients receiving digoxin were actually found to have improved renal function.36
In addition, digoxin does not decrease blood pressure.36 As mentioned earlier, hypotension is a common side effect of HF medication and the additive effect on blood pressure from multiple medications can be especially problematic, so it can be beneficial to have a medication that works by a different mechanism. So while digoxin is no longer the drug of choice in the treatment of HF, current guidelines recommend digoxin be used in patients who are symptomatic for HF, despite treatment with diuretics, ACE-Is, and beta-blockers.26
Therapists treating patients taking digoxin need to monitor patients for signs and symptoms of toxicity including bradycardia, hallucinations, and fatigue.20 This is especially important in high-risk patients such as the elderly and those with kidney problems.26 If caught early, the condition can be treated with administration of digoxin immune Fab to counter the toxicity.20 A thorough history with a medication screen and proper differential screening will allow the therapist to determine if an arrhythmia may be a sign of digitalis toxicity or a separate medical condition (Table 1).
SUMMARY OF GUIDELINES FOR PHARMACOLOGICAL MANAGEMENT of HFrEF
In summary, ESC guidelines recommend pharmacological management of symptomatic HFrEF start with ACE-Is (or ARBs) in addition to a beta-blocker.26 If a patient is still symptomatic with these medications and left ventricular ejection fraction is 35% or less, the ESC recommends adding an MRA to the regimen. If the patient is able to tolerate ACE-Is or ARBs and is still symptomatic on the above medications, the ESC recommends replacing the ACE-I or ARB with an ARNI.26 If the patient is in sinus rhythm but still has a heart rate over 70 bpm with the above medications, then ivabradine should be added to the patient's regimen. If the patient still remains symptomatic with all of these medications, then digoxin or cardiac procedures should be considered.26
The ACC guidelines are similar, with recommendations to initiate treatment of HF with ACE-Is and ARBs alongside beta-blockers.25 If the patient is still symptomatic on these medications, further medications are recommended based on ethnicity, resting heart rate, laboratory values, and NYHA class. If the patient is NYHA class II to IV with normal creatinine clearance and potassium levels, an MRA is recommended. For symptomatic patients with NYHA classes II to III, it is recommended that the patient discontinue ACE-Is or ARBs in place of an ARNI. ACC guidelines do not recommend that ARNIs be given to patients with a history of angioedema. For patients with NYHA classes II to III with a heart rate of 70 bpm or more, already on a maximum dose of beta-blocker, ivabradine is recommended.25
Research supports these drug combinations. Burnett et al37 performed a meta-analysis comparing efficacy, over the last 30 years, of the standard medications for HF. They found that ARNI + beta-blocker + MRA and ACE-I + beta-blocker + MRA are the best combinations for reducing all-cause mortality. The combination of an ARNI + beta-blocker + MRA was found to reduce death by 63% compared with a placebo while ARNIs in isolation reduced mortality by 29%.37 ACE-Is are currently recommended over ARNIs, as there are more long-term studies supporting their use, but this may change with further research into ARNIs.
While a combination of medications is most effective in managing HF, therapists must remember that polypharmacy often results in more drug/drug interactions and side effects in patients.
MEDICATIONS NOT RECOMMENDED FOR HFrEF
Statins, commonly used for hyperlipidemia, have not been found to be beneficial for patients with chronic HFrEF. If patients are already taking statins for CAD or high cholesterol, continuing with the medication may be advised by the doctor.26
Oral anticoagulants and antiplatelet medications have also not been found to influence morbidity and mortality in patients with HFrEF unless they also were experiencing atrial fibrillation or CAD.26 As with statins, these medications should be continued if started for other conditions but not taken solely for a diagnosis of HF.
Aliskiren, a direct renin inhibitor, has not shown benefit in patients with HF and is not currently recommended by ESC guidelines.26
Calcium-channel blockers have not proven beneficial in helping those with HF, and some are believed to cause more harm than good. For example, diltiazem and verapamil are unsafe in patients with HFrEF.26
PHARMACOLOGICAL MANAGEMENT of HFpEF
There have been great strides in the medical management of HFrEF, but much less progress in the treatment of HFpEF.
ACE-Is and ARBs have shown minimal effect on HF hospitalization rates in patients with HFpEF while beta-blockers, such as carvedilol (J-DHF study) and nebivolol (ELANDD study), were found to have no impact on mortality or hospitalization rates.17 In the Digitalis Interaction Group (DIG), digoxin was compared to a placebo, with no significant findings regarding either hospitalization rates or mortality but a possible effect on improving exercise capacity.17 Hospitalization and mortality have not been assessed with ivabradine, but studies have found that it does seem to improve exercise tolerance.31 MRAs improved ECG and biochemical markers of diastolic function but did not show a significant change in cardiovascular outcomes.30 However, they are not recommended for use in HFpEF due to the high risk of side effects with these medications.30
The outcome measures in many of these studies were death and hospitalization rates. While these measures were not found to be affected significantly in studies, the medications did have some impact on exercise tolerance. Exercise intolerance and poor quality of life are common complaints of patients with HF; improving these factors may be better goals until the pathophysiology of this condition is better understood.
Another consideration is, since HFpEF is strongly influenced by aging and the impact of comorbidities, medications may need to be directed more toward targeting these co-morbid conditions than the cardiovascular system in general.14 , 17 In other words, a one-size-fits-all approach may not work for patients with HFpEF as it does for HFrEF.
MEDICATIONS FOR ACUTE EXACERBATION OF HEART FAILURE
Diuretics are a cornerstone of management for acute HF and congestion, but other medications can also help with exacerbations of HF.26
Phosphodiesterase inhibitors, such as inamrinone and milrinone, are used for short-term treatment of acute, severe HF.20 These medications, administered by intravenous infusion, work by inhibiting the phosphodiesterase enzyme resulting in increased calcium levels and improved force of contraction of the heart.20 Side effects include arrhythmias, hypotension, thrombocytopenia, gastrointestinal issues, and hypokalemia.38
Another medication used for exacerbation of HF is dopamine or dobutamine. While beta-blockers decrease stimulation to the beta-1 receptors to decrease heart rate in cases of chronic HF, these medications work by stimulating the beta-1 receptors to increase contractility of the heart in cases of acute HF.20 Vital signs will need to be monitored in these patients, as side effects of these medications include hypertension, increased heart rate, and premature ventricular contractions.38
Despite much research and advancement in the medical management of HF, the prognosis is still poor. One-year mortality rates range from 15% to 20%, with a median survival of 4 to 5 years postdiagnosis.33 One of the reasons for this may be poor compliance with medication regimens. Poor adherence to medication is believed to play a role in 20% to 64% of rehospitalizations.32 One study found self-reported medication nonadherence to be as high as 66%.32 This can be a significant problem, as another study found to really impact mortality and hospitalization rates among patients with HF, medication adherence rates need to be 88% or greater.39
In assessing the reason for such a poor prognosis in treating HF, one of the most powerful factors found to be predictive of mortality was not having a prescription for a beta-blocker.32 However, having a prescription for a beta-blocker is only helpful in that the patient is actually taking the medication as prescribed and one analysis found that out of 17 000 patients prescribed beta blockers after an MI, only 45% were still taking them by 1-year postdischarge.32 Poor adherence has also been found to be an issue with other medications such as ACE-Is (39%-51%) and statins (40%-44%).32 Compliance is especially an issue as the number of medications a patient is taking increases. Percentages of medication compliance drop to 21% to 39% when a patient is prescribed 3 or more medications.32
There are many factors that may play a role in medication adherence. Patients may stop medications due to unpleasant side effects, cost, or they may just be forgetting to take them. A lot of research is going into figuring out how to improve compliance with medication regimens. Changes that might improve adherence were found to be an in-hospital initiation of the medication, fewer daily doses, and better timing of medication dosing to minimize side effects such as dizziness.32 Common in Europe, polypills, multiple drugs combined into 1 pill, may also be a good solution to improving medication adherence in patients.32 The first several weeks after initiation of a medication seem to be the most important in developing adherence, as this is when most patients will discontinue medications.32 This period is also when medication side effects are often most severe.
Direct/intensified patient education on the importance of adherence was one technique found to improve medication adherence.32 Other studies found improved adherence with telephone and telemonitoring of the patient after discharge.40 Motivational interviewing might also be helping in improving adherence and one study found a small effect size supporting its use.41
While educating patients, following-up with them, and decreasing the number of pills to keep track of may improve adherence, decreasing cost may be one of the most effective ways to impact medication adherence rates.32 Many patients skip doses or avoid refilling a prescription due to cost. High copayments and increases in copayments have been found to deter patients from refilling prescriptions.42
NONPHARMACOLOGICAL MANAGEMENT Of HF
Many patients with HF may benefit from surgical procedures for placement of an implantable cardioverter defibrillator (ICD), pacemaker, heart pump, or ventricular assist device (VAD).6 , 13 A VAD is a surgically implanted mechanical pump that is attached to the heart to help pump more blood with less effort. The VAD continuously draws blood from the ventricle, delivering it to the aorta without relying on the force of the ventricle muscle to pump the blood.12
Patients who have CAD with severe blockage may benefit from coronary artery bypass surgery, while patients with faulty heart valves may benefit from surgery to correct the valvular defect so long as the damage to the cardiac muscle has not progressed to affect the size of the cardiac chambers. Patients with severe HF who do not respond to these surgical procedures or pharmacological treatment may be good candidates for heart transplants.
Many patients with HF have irregular heart rhythms that cause progression of the HF. These patients can benefit from cardiac resynchronization therapy, implantable ICD, and pacemakers.13 Patients undergoing cardiac resynchronization therapy have a dollar-sized pacemaker placed below the collar bone with wires to detect heart rate irregularities and emit impulses to correct these abnormal rates. ICD and implantable biventricular pacemakers have shown to reduce mortality in patients with arrhythmia.6 Patients who have an ICD and have received an ICD shock from the device have anxiety about receiving more shocks and avoid endurance training. This inactivity leads to further worsening of the HF.43 Our role as physical therapists is to teach patients with ICDs how to exercise within limits that avoid triggering an ICD shock.
Patients with tachycardia due to left ventricular hypertrophy benefit from oxygen to help relieve the tachycardia. Oxygen levels need to be maintained above 90%. Precautions must be taken with patients with chronic obstructive pulmonary disease to maintain oxygen amounts by careful monitoring.3 Therapists should monitor patients while exercising to ensure that oxygen saturation stays above 90%.
Patients with chronic sleep deprivation experience progression of cardiovascular disease, changes in immune and inflammatory response, and a tendency toward unhealthy behaviors such as overeating.44 This lack of sleep at night may result in decreased activity levels during the day. Ninety-six percent of patients with HF have impaired sleep.44 A study by Suk Lee et al showed that sleep disturbances in patients with HF were a significant independent predictor of survival even without a cardiac event.4 , 20 We, as physical therapists, can educate patients on the importance of increasing activity levels during the day and decreasing daytime sleeping to encourage better nighttime sleeping.4 , 25
A study by Michael Evans11 showed that patients are more in tune with symptoms of dyspnea than symptoms such as fatigue, difficulty sleeping, decreased functional ability, edema, cough, increased tightness to clothes, increased urination, and nausea. Detection of symptoms other than dyspnea can be a good tool to assess whether the HF is worsening. It is important for health care personnel to educate patients and family members about the signs and symptoms of worsening HF to facilitate appropriate health care utilization.11
Avoiding fluid overload
Education on controlling sodium intake by following a low-sodium diet by avoiding processed foods helps deter rehospitalization.3 Patients should also be educated on the importance of compliance with diuretic medication and the importance of restricting fluid intake to 1500 mL.
Patients are encouraged to weigh themselves daily and report any weight gain of more than 2 lb.3 To avoid an acute exacerbation of HF and prevent any procrastination in seeking medical help, patients are encouraged to use a diary to monitor daily signs and symptoms.19
In response to the financial burden placed on hospitals for patients with HF readmitted within 30 days, Waring et al8 conducted a prospective, single-center study of adult patients who were discharged after hospitalization for HF. The study showed that patients with HF with decreased physical activity in the first week after discharge from the hospital had a higher rate of hospital readmission8 (Table 2).
THERAPIST'S ROLE IN MANAGEMENT OF HEART FAILURE
As physical therapists, we may not play a role in prescribing medication or determining medical management of a patient's condition, but we can still play a key role in the patient's medical care. According to the APTA House of Delegates: “Physical Therapist patient/client management integrates an understanding of a patient's/client's prescription and nonprescription medication regimen with consideration of its impact upon health, impairments, functional limitations, and disabilities”.46
The APTA goes on to report that gathering medications from the patient/client history is included in the Guide to Physical Therapist Practice. Therefore, a patient screen in which medications are assessed is within a physical therapist's scope of practice.46
Based on the findings of our medication screen, we should encourage and monitor compliance with the patient's medication regimens. As direct patient education has been shown to improve compliance, we can get medication lists from patients and ensure that they understand the importance of taking their medications consistently as prescribed. We can also introduce them to resources to encourage compliance such as pill boxes or timers for a more complex regimen or a patient with cognitive issues.
Therapists should also monitor for adverse effects of the patient's medications. Some of these reactions may be common side effects, such as hypotension, but if they are interfering with a patient's function or creating a risk of falls, we need to be in contact with the prescribing physician to relay these findings.
Therapists will be establishing exercise programs for many of these patients and need to monitor the patient's vital signs closely to differentiate a progressing condition, intolerance to exercise, and medication side effects. Changes in respiration may suggest an acute exacerbation of HF while a decrease in heart rate could be an indication of digitalis toxicity. A blunted heart rate response to exercise should be expected in patients taking beta-blockers requiring the use of a perceived exertion scale in place of heart rate monitoring during exercise.
The therapist may also play a role in educating the patient on preventing an exacerbation of HF. A study by Federal et al47 found a strong association between poor patient self-care and increased rate of hospital admissions.47 Self-care included daily weigh-ins, self-checking for swelling around the ankles, daily physical activity, regular follow-ups with medical providers, and decreasing salt intake in the diet. The therapist can play an ancillary role in encouraging proper self-care.
Physical therapists are important members of the medical team working to minimize exacerbations, rehospitalization, and progression of HF through proper medication compliance, appropriate activity, and adherence to a healthy diet and lifestyle. We can also play a key role in monitoring for side effects and adverse reactions to the complicated drug regimen required to manage this disease.
By 2030, it is expected that the number of HF cases in America will reach more than 8 million.2 Due to its high incidence and prevalence, HF is a growing health problem, which has a major impact on health care cost.
Poor patient self-care and lack of adherence to medications result in frequent exacerbations and hospital readmissions of patients with HF. Prompt recognition of symptoms and implementation of treatment strategies by patients and health care professionals can minimize rehospitalization and further progression of HF. Physical therapists working in various settings such as acute care, skilled nursing, outpatient, and home health frequently treat patients with HF and need to be aware of the indications and side effects of medications used to treat this condition. Therapists play an important role in facilitating mobility and educating patients on symptom recognition and self-care, but we also play an important role in screening medication regimens, monitoring for side effects and encouraging adherence.
1. Beni FH, Ehsani SR, Tabatabaee A, Mohammadnejad E. The effect of peer education on quality of life in heart failure
patients: a randomized clinical trial. J Nurs Midwifery Sci. 2017;4(1):3–7.
2. Kanwar M, Walter C, Clarke M, Patarroyo-Aponte M. Targeting heart failure
with preserved ejection fraction: current status and future prospects. Vasc Health Risk Manag. 2016;12:129–142.
3. Harrison G, Evans MM, Shaffer A, Romero L. Treating a patient experiencing an acute exacerbation of chronic heart failure
. Acad Med Surg Nurses. 2016;25(4):8–11.
4. Liebzeit D, Phelan C, Moon C, Brown R, Bratzke L. Rest-activity patterns in older adults with heart failure
and healthy older adults. J Aging Phys Act. 2017;25(1):116–122. doi:10.1123/japa.2016-0058.
5. Vasudevan A, Jazi HH, Won JI, et al Personalized treatment of heart failure
with biomarker guidance using a novel disease severity score. Proc (Bayl Univ Med Cent). 2017;30(2):139–142.
6. Parker RB, Nappi JM, Cavallari LH. Chronic Heart Failure
. In: DiPiro JT, Talbert RL, Yee GC, et al eds. Pharmacotherapy: A Pathophysiologic Approach. 10th ed. New York, NY: McGraw-Hill; 2017.
7. De Sousa M, Oliveira J, Soares M, De Araujo A, Oliveira S. Quality of life of patients with heart failure
: Integrative review. J Nurs UFPE Line. 2017;11(3):1289–1298. doi:10.5205/reuol.10544-93905-1-RV.1103201720.
8. Waring T, Gross K, Soucier R, ZuWallack R. Measured physical activity and 30-day rehospitalization in heart failure
patients. J Cardiopulm Rehabil Prev. 2017;37(2):124–129. doi:10.1097/HCR.0000000000000204.
9. Iacoviello M, Antoncecchi V. Heart failure
in elderly: progress in clinical evaluation and therapeutic approach. J Geriatr Cardiol. 2013;10:165–177. doi:10.3969/j.issn.1671-5411.2013.02.010.
10. Cook JC, Tran RH, Patterson JH, Rodgers JE. Evolving therapies for the management of chronic and acute decompensated heart failure
. Am J Heal Syst Pharm. 2016;73(21):1745–1754. doi:10.2146/ajhp150635.
11. Evans MM. Symptom recognition and healthcare utilization in adult patients with heart failure
: an integrative review of the literature. Medsurg Nurs. 2016;25(5):319–368.
12. Goodman CC, Fuller KS. Pathology. Implications for the Physical Therapist. 4th ed. St Louis, MO: Elsevier Saunders; 2015.
13. Frownfelter D, Dean E. Cardiovascular and Pulmonary Physical Therapy
: Evidence to Practice. 5th ed. St Louis, MO: Elsevier Mosby; 2012.
14. Senni M, Paulus WJ, Gavazzi A, et al New strategies for heart failure
with preserved ejection fraction: the importance of targeted therapies for heart failure
phenotypes. Eur Heart J. 2014;35(40):2797–2811. doi:10.1093/eurheartj/ehu204.
15. Hillegass E. Essentials of Cardiopulmonary Physical Therapy
. 4th ed. St Louis, MO: Elsevier; 2017.
16. Webb J, Jackson T, Claridge S, Sammut E, Behar J, Carr-White G. Management of heart failure
with preserved ejection fraction. Practitioner. 2015;259(1786):21–24, 2–3.
17. Upadhya B, Taffet GE, Cheng CP, Kitzman DW. Heart failure
with preserved ejection fraction in the elderly: scope of the problem. J Mol Cell Cardiol. 2015;83:73–87. doi:10.1016/j.yjmcc.2015.02.025.
18. Rahimi K, Bennett D, Conrad N, et al Risk prediction in patients with heart failure
: a systematic review and analysis. JACC Heart Fail. 2014;2(5):440–446. doi:10.1016/j.jchf.2014.04.008.
19. Suk Lee K, Moser DK, Lennie TA, Pelter MM, Nesbitt T, Jeffrey A. Obesity paradox: comparison of heart failure
patients with and without comorbid diabetes. Am J Crit Care. 2017;26(2):140–148.
20. Ciccone CD. Pharmacology
in Rehabilitation. 5th ed. Philadelphia: F.A. Davis Company; 2016.
21. Yancy CW, Jessup M, Bozkurt B, et al 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure
: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure
: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure
Society of America. J Card Fail. 2016;22(9):659–669. doi:10.1016/j.cardfail.2016.07.001.
22. Doust J, Lehman R, Glasziou P. The role of BNP testing in heart failure
. Am Fam Physician. 2006;74(11):1893–1898.
23. Oni-Orisan A, Lanfear DE. Pharmacogenomics in heart failure
: where are we now and how can we reach clinical application. Cardiol Rev. 2014;22(5):193–198. doi:10.1097/CRD.0000000000000028.
24. Yancy CW, Jessup M, Bozkurt B, et al 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure
: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure
: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure
Society of America. Circulation. 2016;134:e282–e293. doi:10.1161/CIR.0000000000000435.
25. Yancy CW, Jessup M, Bozkurt B, et al 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure
: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure
Society of America. J Am Coll Cardiol. 2017;70(6):776–803. doi:10.1016/j.jacc.2017.04.025.
26. Ponikowski P, Voors AA, Anker SD, et al 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure
: the task force for the diagnosis and treatment of acute and chronic heart failure
of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure
Association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129–2200. doi:10.1093/eurheartj/ehw128.
27. Fala L. Entresto (Sacubitril/valsartan): first-in-class angiotensin receptor neprilysin inhibitor FDA approved for patients with heart failure
. Am Heal Drug Benefits. 2015;8(6):330–334.
28. Kaplinsky E. Sacubitril/valsartan in heart failure
: latest evidence and place in therapy. Ther Adv Chronic Dis. 2016;7(6):278–290. doi:10.1177/2040622316665350.
29. Jhund PS, Mcmurray JJ. The neprilysin pathway in heart failure
: a review and guide on the use of sacubitril/valsartan. Hear J. 2016;102(17):1342–1347. doi:10.1136/heartjnl-2014-306775.
30. Berbenetz NM, Mrkobrada M. Mineralocorticoid receptor antagonists for heart failure
: systematic review and meta-analysis. BMC Cardiovasc Disord. 2016;16(1):246. doi:10.1186/s12872-016-0425-x.
31. Müller-werdan U, Stöckl G, Werdan K. Advances in the management of heart failure
: the role of ivabradine. Vasc Health Risk Manag. 2016;12:453–470.
32. Albert NM. Improving medication adherence in chronic cardiovascular disease. Crit Care Nurse. 2008;28(5):54–64.
33. Thomsen MM, Lewinter C, Køber L. Varying effects of recommended treatments for heart failure
with reduced ejection fraction: meta-analysis of randomized controlled trials in the ESC and ACCF/AHA guidelines. ESC Hear Fail. 2016;3(3):235–244. doi:10.1002/ehf2.12094.
34. Anantha Narayanan M, Reddy YN, Baskaran J, Deshmukh A, Benditt DG, Raveendran G. Ivabradine in the treatment of systolic heart failure
—a systematic review and meta-analysis. World J Cardiol. 2017;9(2):182–190. doi:10.4330/wjc.v9.i2.182.
35. Opie LH. Digitalis, yesterday and today, but not forever. Circ Cardiovasc Qual Outcomes. 2013;6(5):511–513. doi:10.1161/CIRCOUTCOMES.113.000544.
36. Ambrosy AP, Butler J, Ahmed A, et al The use of digoxin in patients with worsening chronic heart failure
: reconsidering an old drug to reduce hospital admissions. J Am Coll Cardiol. 2014;63(18):1823–1832. doi:10.1016/j.jacc.2014.01.051.
37. Burnett H, Earley A, Voors AA, et al Thirty years of evidence on the efficacy of drug treatments for chronic heart failure
with reduced ejection fraction. Circ Heart Fail. 2017;10(1):pii: e003529. doi:10.1161/CIRCHEARTFAILURE.116.003529.
38. Ciccone CD. Davis's Drug Guide. Philadelphia, PA: F.A. Davis Company; 2013.
39. Hale TM, Jethwani K, Kandola MS, Saldana F, Kvedar JC. A remote medication monitoring system for chronic heart failure
patients to reduce readmissions: a two-arm randomized pilot study. J Med Internet Res. 2016;18(4):e91. doi:10.2196/jmir.5256.
40. Molloy GJ, O'Carroll RE, Witham MD, McMurdo MET. Interventions to enhance adherence to medications in patients with heart failure
a systematic review. Circ Hear Fail. 2012;5(1):126–133. doi:10.1161/CIRCHEARTFAILURE.111.964569.
41. Zomahoun HTV, Guénette L, Grégoire JP, et al Effectiveness of motivational interviewing interventions on medication adherence in adults with chronic diseases: a systematic review and meta-analysis. Int J Epidemiol. 2017;46(2):589–602. doi:10.1093/ije/dyw273.
42. Kessler RC, Cantrell CR, Berglund P, Sokol MC. The effects of copayments on medication adherence during the first two years of prescription drug treatment. J Occup Environ Med. 2007;49(6):597–609. doi:10.1097/JOM.0b013e318057772b.
43. Kato M, Masuda T, Ogano M, et al Stretching exercises improve vascular endothelial dysfunction through attenuation of oxidative stress in chronic heart failure
patients with an implantable cardioverter defibrillator. J Cardiopulm Rehabil Prev. 2017;37(2):130–138. doi:10.1097/HCR.0000000000000229.
44. Kyoung B, Lee S, Lennie TA, Heo S, Song EK, Moser DK. Prognostic importance of sleep quality in patients with heart failure
. Am J Crit Care. 2016;25(6):516–525.
45. Writing Committee Members; Yancy CW, Jessup M, Bozkurt B, et al 2013 ACCF/AHA guideline for the management of heart failure
: A report of the American college of cardiology foundation/American heart association task force on practice guidelines. Circulation. 2013;128(16):e240–e327. doi:10.1161/CIR.0b013e31829e8776.
47. Federal U, Ciências D, De Porto S, Porto A, Grande R. Association between self-care and hospital readmissions of patients with heart failure
. Rev Bras Enferm. 2016;69(3):469–475.