REVIEW
Contemporary Strategies in the Diagnosis and Management of Heart Failure Shannon M. Dunlay, MD, MS; Naveen L. Pereira, MD; and Sudhir S. Kushwaha, MD Abstract Heart failure (HF) is an important public health problem, and strategies are needed to improve outcomes and decrease health care resource utilization and costs. Its prevalence has increased as the population ages, and HF continues to be associated with a high mortality rate and frequent need for hospitalization. The total cost of care for patients with HF was $30.7 billion in 2012, and it is estimated to more than double to $69.8 billion by 2030. Given this reality, there has been recent investigation into ways of identifying and preventing HF in patients at risk (stage A HF) and those with cardiac structural and functional abnormalities but no clinical HF symptoms (stage B). For patients who have symptoms of HF (stage C), there has been important research into the most effective ways to decongest patients hospitalized with acute decompensated HF and prevent future hospital readmissions. Successful strategies to treat patients with HF and preserved ejection fraction, which has increased in prevalence, continue to be sought. We are in the midst of a rapid evolution in our ability to care for patients with end-stage HF (stage D) because of the introduction of and improvements in mechanical circulatory support. Left ventricular assist devices used as destination therapy offer an important therapeutic option to patients who do not qualify for heart transplant because of advanced age or excessive comorbidity. This review provides a thorough update on contemporary strategies in the diagnosis and management of HF by stage (A to D) that have emerged during the past several years. ª 2014 Mayo Foundation for Medical Education and Research
From the Division of Cardiovascular Diseases, Department of Internal Medicine (S.M.D., N.L.P., S.S.K.) and Division of Health Care Policy and Research, Department of Health Sciences Research (S.M.D.), Mayo Clinic, Rochester, MN.
662
A
n estimated 5.8 million adults in the United States are currently living with heart failure (HF), and its prevalence is projected to increase to 25% by 2030.1 Heart failure is primarily a disease of the elderly, with prevalence increasing from 0.9% in patients aged 55 to 64 years to 17.4% in those 85 years and older.2 The increasing prevalence of HF is attributed to aging of the population and improved survival from HF and other cardiovascular diseases. Given the increased prevalence and epidemic of hospitalizations in patients with HF, total costs are projected to increase from $30.7 billion in 2012 to $69.8 billion in 2030.1 Although most of the focus in HF is aimed at treatment of affected patients, in 2001, the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) revised the HF classification to also include patients who are at high risk for the disease (stage A; Figure 1) but do not yet have structural cardiac abnormalities or clinical evidence of HF.3 In 2010, Ramani et al4 reviewed the contemporary diagnosis and management of HF in Mayo Clinic Proceedings, including a review of guidelinebased management for patients with HF. Since
n
Mayo Clin Proc. 2014;89(5):662-676
then, there has been an expansion of indications for drug and device therapy, important progress made with mechanical circulatory support (MCS), and new clinical trials aimed toward enhancing the care of patients with HF. This complementary review will provide a thorough update on contemporary strategies in the diagnosis and management of HF by stage (A to D) that have emerged in the past several years, with a focus on new guidelines and research results that may affect clinical practice. STAGE A HF: PATIENTS AT RISK Stage A HF includes patients who do not yet have HF or cardiac structural abnormalities but are at risk because of coronary artery disease, diabetes, hypertension, or other conditions. Because many of these predisposing conditions are highly prevalent, stage A HF is common. In one community study, it was estimated that 56% of the population aged 45 years or older had stage A or B HF.5 Predicting Risk for the Development of HF Although only patients with stage C and D disease would meet criteria for HF, this focus on
Mayo Clin Proc. n May 2014;89(5):662-676 n http://dx.doi.org/10.1016/j.mayocp.2014.01.004 www.mayoclinicproceedings.org n ª 2014 Mayo Foundation for Medical Education and Research
CONTEMPORARY STRATEGIES IN HEART FAILURE
identifying patients at risk for HF (stage A) has prompted the development of several incident HF risk scores. The Health ABC (Health, Aging, and Body Composition) study included 3075 community-dwelling elderly patients (aged 7079 years) who were followed up for 7 years for clinical events, including the onset of HF, which developed in 258 participants.6 A simple point score based on independent predictors of HF was developed (Figure 2). Although the risk score is easy to calculate, the ability to discriminate is only acceptable (C statistic, 0.72). Similarly, a model to predict incident HF validated in the ARIC (Atherosclerosis Risk in Communities) cohort7 included many of the same variables (age, coronary artery disease, blood pressure, smoking, heart rate), as well as race, sex, diabetes, and body mass index. The investigators reported predictive ability similar to that of the Health ABC score and found that both models performed better with the addition of N-terminal pro-B-type natriuretic peptide. Either risk model would be acceptable to use in clinical practice to help identify patients who may be at higher risk for the development of HF. Genetic Testing in Patients With Suspected Familial Cardiomyopathy A high proportion (20%-35%) of patients with dilated cardiomyopathy (DCM) may have familial cardiomyopathy (defined as 2 or more closely related family members with DCM).8 A thorough family history should be obtained in patients with newly diagnosed DCM. If familial cardiomyopathy is suggested on the basis of history, genetic testing and referral to a genetic counselor should be considered. However, because pathogenic mutations are identified in only 30% to 35% of familial cases,9 negative results on a genetic screen do not eliminate the possibility of an inherited DCM. Unaffected first-degree relatives of patients with familial DCM should undergo screening with echocardiography at least every 3 to 5 years.8 Hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia can also be inherited, and genetic screening, counseling, and testing in these conditions are thoroughly covered in a recent review.10 Treatment Aimed at Controlling Modifiable Risk Factors Treatment of patients identified to be at high risk for the development of HF should be aimed Mayo Clin Proc. n May 2014;89(5):662-676 www.mayoclinicproceedings.org
n
ARTICLE HIGHLIGHTS n
n
n
n
Heart failure (HF) is becoming more common and is associated with increasing costs of care. Treatment of patients at risk for HF (stage A) should be aimed at controlling modifiable risk factors. Stage B HF (structural heart abnormalities but no clinical symptoms of HF) is 3 to 4 times more common than stages C and D (clinical diagnosis of HF). Referral to an HF specialist should be considered whenever questions arise in the diagnosis and management of patients with HF but particularly when symptom management is difficult, when a patient is unable to tolerate HF-related medications such as b-blockers, when complicated or recurrent HF hospitalizations occur, or when mechanical circulatory support and cardiac transplant may be an option.
at reducing their risk by treatment of modifiable risk factors, including aggressive treatment of hypertension, diabetes, hyperlipidemia, and obesity. In particular, long-term hypertension control may reduce the risk of incident HF by more than 50%.11,12 The choice of antihypertensive therapy should be based on published guidelines,8,13 although a metaanalysis suggested that diuretics, angiotensinconverting enzyme inhibitors (ACE-Is), and angiotensin receptor blockers are the most effective classes of drugs for reducing HF risk.12 STAGE B HF: STRUCTURAL HEART ABNORMALITIES BUT NO CLINICAL HF SYMPTOMS Stage B HF includes patients with prior myocardial infarction, left ventricular remodeling including left ventricular hypertrophy and reduced ejection fraction (EF), and asymptomatic valvular heart disease who have never had active HF symptoms. The number of patients who have stage B HF is estimated to be 3 to 4 times the number of patients with stage C and D combined.4,14 The prevalence of asymptomatic reduced EF is estimated at 3% to 6%15 and increases with age. Asymptomatic diastolic dysfunction is more common, with an estimated prevalence as high as 27%.16 Patients with stage B HF are at high
http://dx.doi.org/10.1016/j.mayocp.2014.01.004
663
MAYO CLINIC PROCEEDINGS
Stage of HF
Stage A At risk for HF
1. Treat risk factors (hypertension, hyperlipidemia, diabetes, CAD Goals and therapies
2. Promote a healthy lifestyle (exercise, quit smoking, lose weight)
Stage C Structural abnormalities and clinical HF symptoms
Stage B Structural abnormalities but no HF symptoms
Stage D Refractory, end-stage HF
1. All stage A guidelines
1. All stage A guidelines
2. ACE-I/ARB and β-blockers if reduced EF
2. Salt restriction
3. Consider ICD if EF 2.3
6
Smoking
LV hypertrophy Status
Points
No
0
Yes
2
Creatinine
Albumin g/dL
Points
≥4.8
–3
Systolic blood pressure
4.5-4.7
–2
mm Hg
Points
4.2-4.4
–1
≤90
–4
3.9-4.1
0
95-100
–3
3.6-3.8
1
3.3-3.5
2
≤3.2
3
105-115
–2
120-125
–1
130-140
0
145-150
1
155-165
2
170-175
3
180-190
4
195-200
5
>200
6
Health ABC HF risk score
Key: Systolic BP to nearest 5 mm Hg Heart rate to nearest 5 bpm Albumin to nearest 0.1 g/dL Creatinine to nearest 0.1 mg/dL
HF risk group
5-y HF risk
≤2 points
Low
3-5 points
Average
5%-10%
6-9 points
High
10%-20%
≥10 points
Very high
20%
FIGURE 2. The Health, Aging, and Body Composition (Health ABC) study risk score for predicting risk of heart failure (HF). BP ¼ blood pressure; bpm ¼ beats/min; LV ¼ left ventricular. From Circ Heart Fail,6 with permission.
STAGE C HF: STRUCTURAL HEART ABNORMALITIES AND SYMPTOMS OF HF Once a patient has clinical signs and symptoms of HF, they are categorized as having stage C disease, even if they later become asymptomatic. Important clinical pearls in the general Mayo Clin Proc. n May 2014;89(5):662-676 www.mayoclinicproceedings.org
n
management of patients with stage C HF were included in the review by Ramani et al,4 and comprehensive guidelines for the management of patients with HF have been published by the ACCF/AHA.8 This section will focus on important areas of recent research in stage C HF.
http://dx.doi.org/10.1016/j.mayocp.2014.01.004
665
MAYO CLINIC PROCEEDINGS
Biomarkers for Estimating Prognosis in Patients with HF Although biomarkers are most widely used to diagnose HF, they can also help to provide an estimate of prognosis in patients with stage C and D HF. The natriuretic peptides, namely Btype natriuretic peptide or its amino-terminal fragment (N-terminal pro-B-type natriuretic peptide), which are released in response to myocardial stretch, and troponins, released in response to myocyte injury, are the most widely reported and used biomarkers for prognosis in HF. Higher natriuretic peptide levels have consistently been shown to predict mortality but have been less useful in predicting hospital readmissions. One emerging biomarker, ST2, a member of the interleukin 1 receptor family, is predictive of mortality in HF,24 may help in identifying patients with HF who would benefit from b-blocker titration,25 and may become more widely used in the coming years. Cystatin C is a marker of acute kidney injury during an HF hospitalization, and an increase of more than 0.3 mg/L in the first 48 hours of HF hospitalization is associated with longer duration of stay and a 4-fold higher in-hospital mortality.26 The clinical value of serial biomarker-guided management of HF remains controversial. Although individual trials have often failed to find any reduction in mortality or HF hospitalizations with a natriuretic peptideeguided strategy,27,28 meta-analyses have suggested there may be some mortality benefit to this approach.29,30 The ongoing GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment) trial may shed some light on this topic as it investigates the efficacy of a strategy of biomarker-guided therapy compared with usual care in high-risk patients with left ventricular systolic dysfunction. Updates on the Long-term Management of Patients With Stage C HF HF With Preserved EF. Half of patients with HF have preserved EF (HFpEF), which is variably defined across studies but usually refers to an EF of more than 40% to 50%. Studies have suggested that the prevalence of HFpEF is increasing over time,31 and it is most common in older women. Additional comorbidities including anemia, hypertension, and atrial fibrillation are more common in patients with HFpEF than in those who have HF with reduced EF (HFrEF).32 Similar to 666
Mayo Clin Proc.
n
patients with HFrEF, patients with HFpEF are at increased risk for death, with 5-year mortality estimated at 50% in both groups.33 Compared with patients who have HFrEF, patients with HFpEF are more likely to experience a noncardiovascular cause of death.34 Despite its increasing prevalence, there are still no known efficacious pharmacological therapies for HFpEF. Whether renin-angiotensin system antagonists improve outcomes in HFpEF has been highly debated, and a recent analysis of patients enrolled in the Swedish HF registry suggested that there may be mortality reduction associated with renin-angiotensin system inhibition in HFpEF.35 However, randomized controlled trials have consistently failed to document any improvement in mortality in patients with HFpEF treated with ACE-Is36 or angiotensin receptor blockers37,38 compared with placebo. There has been recent interest in using phosphodiesterase 5 inhibitors, a therapy for patients with pulmonary hypertension, to treat patients with HFpEF. However, the RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) multicenter randomized controlled trial found no change in exercise capacity or clinical status after 24 weeks of sildenafil therapy compared with placebo.39 Although aldosterone antagonism with eplerenone did not improve exercise capacity in the recent RAAM-PEF (Randomized Aldosterone Antagonism in Heart Failure with Preserved Ejection Fraction) trial, it had favorable effects on diastolic function.40 The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial results, which were presented at the AHA Scientific Sessions in November 2013, found no reduction in the combined risk of cardiovascular mortality, aborted cardiac arrest, or HF hospitalization in patients with HFpEF treated with spironolactone compared with placebo, although a reduction in the secondary end point of HF hospitalizations was observed. Currently, there is insufficient evidence to recommend routine treatment with aldosterone antagonists in patients with HFpEF, although they could be a reasonable choice for patients with another indication for these therapies such as hypertension.41 Increasing evidence suggests that activation of the sympathetic nervous system plays
May 2014;89(5):662-676
n
http://dx.doi.org/10.1016/j.mayocp.2014.01.004 www.mayoclinicproceedings.org
CONTEMPORARY STRATEGIES IN HEART FAILURE
a prominent role in the pathophysiology of HFpEF.42 Renal denervation is a transcutaneous catheter-based procedure used to disrupt renal sympathetic nerves. Early studies in hypertensive patients have found it to be safe and effective.43,44 There is interest in determining whether renal denervation would be an efficacious therapeutic option in patients with HFpEF, which will be tested in the upcoming DIASTOLE (Denervation of the Renal Sympathetic Nerves in Heart Failure With Normal LV Ejection Fraction) trial.42 Therapy in patients with HFpEF should continue to focus on aggressive management of hypertension, optimizing fluid status with diuretics, and treatment of concomitant comorbidities such as sleep-disordered breathing. Although patients with HFpEF often have dyspnea with exertion, exercise training is safe and improves exercise capacity.45 Monitoring for Hyperkalemia. Close monitoring for hyperkalemia is necessary for patients treated with aldosterone antagonists. In randomized controlled trials, eplerenone46 and spironolactone47 markedly reduced death and readmissions in patients with HFrEF. As a result, aldosterone antagonists have received a class I recommendation in the ACCF/AHA guidelines.8 However, they have not been adopted as readily as other guideline-based therapies, in part due to concern about the risk of hyperkalemia, particularly in high-risk patients such as those treated with renin-angiotensin system antagonists or those with chronic kidney disease. To address the efficacy and safety of these agents in realworld populations, Hernandez et al48 conducted an analysis of 5887 patients enrolled in the Get With the Guidelines-Heart Failure registry, reporting no difference in mortality or allcause rehospitalization in the 18.2% of patients treated with these medications. Although patients treated with aldosterone antagonists did have a lower risk of HF-related rehospitalization, they also had a 2.5-fold increased risk of hospitalization for hyperkalemia within 30 days of initiation of therapy. The implications of these data taken in conjunction with those from randomized trials are that aldosterone antagonists can be efficacious therapies but should be used with caution in patients with a history of hyperkalemia or renal insufficiency (estimated glomerular filtration rate
Contemporary Strategies in the Diagnosis and Management of Heart Failure Shannon M. Dunlay, MD, MS; Naveen L. Pereira, MD; and Sudhir S. Kushwaha, MD Abstract Heart failure (HF) is an important public health problem, and strategies are needed to improve outcomes and decrease health care resource utilization and costs. Its prevalence has increased as the population ages, and HF continues to be associated with a high mortality rate and frequent need for hospitalization. The total cost of care for patients with HF was $30.7 billion in 2012, and it is estimated to more than double to $69.8 billion by 2030. Given this reality, there has been recent investigation into ways of identifying and preventing HF in patients at risk (stage A HF) and those with cardiac structural and functional abnormalities but no clinical HF symptoms (stage B). For patients who have symptoms of HF (stage C), there has been important research into the most effective ways to decongest patients hospitalized with acute decompensated HF and prevent future hospital readmissions. Successful strategies to treat patients with HF and preserved ejection fraction, which has increased in prevalence, continue to be sought. We are in the midst of a rapid evolution in our ability to care for patients with end-stage HF (stage D) because of the introduction of and improvements in mechanical circulatory support. Left ventricular assist devices used as destination therapy offer an important therapeutic option to patients who do not qualify for heart transplant because of advanced age or excessive comorbidity. This review provides a thorough update on contemporary strategies in the diagnosis and management of HF by stage (A to D) that have emerged during the past several years. ª 2014 Mayo Foundation for Medical Education and Research
From the Division of Cardiovascular Diseases, Department of Internal Medicine (S.M.D., N.L.P., S.S.K.) and Division of Health Care Policy and Research, Department of Health Sciences Research (S.M.D.), Mayo Clinic, Rochester, MN.
662
A
n estimated 5.8 million adults in the United States are currently living with heart failure (HF), and its prevalence is projected to increase to 25% by 2030.1 Heart failure is primarily a disease of the elderly, with prevalence increasing from 0.9% in patients aged 55 to 64 years to 17.4% in those 85 years and older.2 The increasing prevalence of HF is attributed to aging of the population and improved survival from HF and other cardiovascular diseases. Given the increased prevalence and epidemic of hospitalizations in patients with HF, total costs are projected to increase from $30.7 billion in 2012 to $69.8 billion in 2030.1 Although most of the focus in HF is aimed at treatment of affected patients, in 2001, the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) revised the HF classification to also include patients who are at high risk for the disease (stage A; Figure 1) but do not yet have structural cardiac abnormalities or clinical evidence of HF.3 In 2010, Ramani et al4 reviewed the contemporary diagnosis and management of HF in Mayo Clinic Proceedings, including a review of guidelinebased management for patients with HF. Since
n
Mayo Clin Proc. 2014;89(5):662-676
then, there has been an expansion of indications for drug and device therapy, important progress made with mechanical circulatory support (MCS), and new clinical trials aimed toward enhancing the care of patients with HF. This complementary review will provide a thorough update on contemporary strategies in the diagnosis and management of HF by stage (A to D) that have emerged in the past several years, with a focus on new guidelines and research results that may affect clinical practice. STAGE A HF: PATIENTS AT RISK Stage A HF includes patients who do not yet have HF or cardiac structural abnormalities but are at risk because of coronary artery disease, diabetes, hypertension, or other conditions. Because many of these predisposing conditions are highly prevalent, stage A HF is common. In one community study, it was estimated that 56% of the population aged 45 years or older had stage A or B HF.5 Predicting Risk for the Development of HF Although only patients with stage C and D disease would meet criteria for HF, this focus on
Mayo Clin Proc. n May 2014;89(5):662-676 n http://dx.doi.org/10.1016/j.mayocp.2014.01.004 www.mayoclinicproceedings.org n ª 2014 Mayo Foundation for Medical Education and Research
CONTEMPORARY STRATEGIES IN HEART FAILURE
identifying patients at risk for HF (stage A) has prompted the development of several incident HF risk scores. The Health ABC (Health, Aging, and Body Composition) study included 3075 community-dwelling elderly patients (aged 7079 years) who were followed up for 7 years for clinical events, including the onset of HF, which developed in 258 participants.6 A simple point score based on independent predictors of HF was developed (Figure 2). Although the risk score is easy to calculate, the ability to discriminate is only acceptable (C statistic, 0.72). Similarly, a model to predict incident HF validated in the ARIC (Atherosclerosis Risk in Communities) cohort7 included many of the same variables (age, coronary artery disease, blood pressure, smoking, heart rate), as well as race, sex, diabetes, and body mass index. The investigators reported predictive ability similar to that of the Health ABC score and found that both models performed better with the addition of N-terminal pro-B-type natriuretic peptide. Either risk model would be acceptable to use in clinical practice to help identify patients who may be at higher risk for the development of HF. Genetic Testing in Patients With Suspected Familial Cardiomyopathy A high proportion (20%-35%) of patients with dilated cardiomyopathy (DCM) may have familial cardiomyopathy (defined as 2 or more closely related family members with DCM).8 A thorough family history should be obtained in patients with newly diagnosed DCM. If familial cardiomyopathy is suggested on the basis of history, genetic testing and referral to a genetic counselor should be considered. However, because pathogenic mutations are identified in only 30% to 35% of familial cases,9 negative results on a genetic screen do not eliminate the possibility of an inherited DCM. Unaffected first-degree relatives of patients with familial DCM should undergo screening with echocardiography at least every 3 to 5 years.8 Hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia can also be inherited, and genetic screening, counseling, and testing in these conditions are thoroughly covered in a recent review.10 Treatment Aimed at Controlling Modifiable Risk Factors Treatment of patients identified to be at high risk for the development of HF should be aimed Mayo Clin Proc. n May 2014;89(5):662-676 www.mayoclinicproceedings.org
n
ARTICLE HIGHLIGHTS n
n
n
n
Heart failure (HF) is becoming more common and is associated with increasing costs of care. Treatment of patients at risk for HF (stage A) should be aimed at controlling modifiable risk factors. Stage B HF (structural heart abnormalities but no clinical symptoms of HF) is 3 to 4 times more common than stages C and D (clinical diagnosis of HF). Referral to an HF specialist should be considered whenever questions arise in the diagnosis and management of patients with HF but particularly when symptom management is difficult, when a patient is unable to tolerate HF-related medications such as b-blockers, when complicated or recurrent HF hospitalizations occur, or when mechanical circulatory support and cardiac transplant may be an option.
at reducing their risk by treatment of modifiable risk factors, including aggressive treatment of hypertension, diabetes, hyperlipidemia, and obesity. In particular, long-term hypertension control may reduce the risk of incident HF by more than 50%.11,12 The choice of antihypertensive therapy should be based on published guidelines,8,13 although a metaanalysis suggested that diuretics, angiotensinconverting enzyme inhibitors (ACE-Is), and angiotensin receptor blockers are the most effective classes of drugs for reducing HF risk.12 STAGE B HF: STRUCTURAL HEART ABNORMALITIES BUT NO CLINICAL HF SYMPTOMS Stage B HF includes patients with prior myocardial infarction, left ventricular remodeling including left ventricular hypertrophy and reduced ejection fraction (EF), and asymptomatic valvular heart disease who have never had active HF symptoms. The number of patients who have stage B HF is estimated to be 3 to 4 times the number of patients with stage C and D combined.4,14 The prevalence of asymptomatic reduced EF is estimated at 3% to 6%15 and increases with age. Asymptomatic diastolic dysfunction is more common, with an estimated prevalence as high as 27%.16 Patients with stage B HF are at high
http://dx.doi.org/10.1016/j.mayocp.2014.01.004
663
MAYO CLINIC PROCEEDINGS
Stage of HF
Stage A At risk for HF
1. Treat risk factors (hypertension, hyperlipidemia, diabetes, CAD Goals and therapies
2. Promote a healthy lifestyle (exercise, quit smoking, lose weight)
Stage C Structural abnormalities and clinical HF symptoms
Stage B Structural abnormalities but no HF symptoms
Stage D Refractory, end-stage HF
1. All stage A guidelines
1. All stage A guidelines
2. ACE-I/ARB and β-blockers if reduced EF
2. Salt restriction
3. Consider ICD if EF 2.3
6
Smoking
LV hypertrophy Status
Points
No
0
Yes
2
Creatinine
Albumin g/dL
Points
≥4.8
–3
Systolic blood pressure
4.5-4.7
–2
mm Hg
Points
4.2-4.4
–1
≤90
–4
3.9-4.1
0
95-100
–3
3.6-3.8
1
3.3-3.5
2
≤3.2
3
105-115
–2
120-125
–1
130-140
0
145-150
1
155-165
2
170-175
3
180-190
4
195-200
5
>200
6
Health ABC HF risk score
Key: Systolic BP to nearest 5 mm Hg Heart rate to nearest 5 bpm Albumin to nearest 0.1 g/dL Creatinine to nearest 0.1 mg/dL
HF risk group
5-y HF risk
≤2 points
Low
3-5 points
Average
5%-10%
6-9 points
High
10%-20%
≥10 points
Very high
20%
FIGURE 2. The Health, Aging, and Body Composition (Health ABC) study risk score for predicting risk of heart failure (HF). BP ¼ blood pressure; bpm ¼ beats/min; LV ¼ left ventricular. From Circ Heart Fail,6 with permission.
STAGE C HF: STRUCTURAL HEART ABNORMALITIES AND SYMPTOMS OF HF Once a patient has clinical signs and symptoms of HF, they are categorized as having stage C disease, even if they later become asymptomatic. Important clinical pearls in the general Mayo Clin Proc. n May 2014;89(5):662-676 www.mayoclinicproceedings.org
n
management of patients with stage C HF were included in the review by Ramani et al,4 and comprehensive guidelines for the management of patients with HF have been published by the ACCF/AHA.8 This section will focus on important areas of recent research in stage C HF.
http://dx.doi.org/10.1016/j.mayocp.2014.01.004
665
MAYO CLINIC PROCEEDINGS
Biomarkers for Estimating Prognosis in Patients with HF Although biomarkers are most widely used to diagnose HF, they can also help to provide an estimate of prognosis in patients with stage C and D HF. The natriuretic peptides, namely Btype natriuretic peptide or its amino-terminal fragment (N-terminal pro-B-type natriuretic peptide), which are released in response to myocardial stretch, and troponins, released in response to myocyte injury, are the most widely reported and used biomarkers for prognosis in HF. Higher natriuretic peptide levels have consistently been shown to predict mortality but have been less useful in predicting hospital readmissions. One emerging biomarker, ST2, a member of the interleukin 1 receptor family, is predictive of mortality in HF,24 may help in identifying patients with HF who would benefit from b-blocker titration,25 and may become more widely used in the coming years. Cystatin C is a marker of acute kidney injury during an HF hospitalization, and an increase of more than 0.3 mg/L in the first 48 hours of HF hospitalization is associated with longer duration of stay and a 4-fold higher in-hospital mortality.26 The clinical value of serial biomarker-guided management of HF remains controversial. Although individual trials have often failed to find any reduction in mortality or HF hospitalizations with a natriuretic peptideeguided strategy,27,28 meta-analyses have suggested there may be some mortality benefit to this approach.29,30 The ongoing GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment) trial may shed some light on this topic as it investigates the efficacy of a strategy of biomarker-guided therapy compared with usual care in high-risk patients with left ventricular systolic dysfunction. Updates on the Long-term Management of Patients With Stage C HF HF With Preserved EF. Half of patients with HF have preserved EF (HFpEF), which is variably defined across studies but usually refers to an EF of more than 40% to 50%. Studies have suggested that the prevalence of HFpEF is increasing over time,31 and it is most common in older women. Additional comorbidities including anemia, hypertension, and atrial fibrillation are more common in patients with HFpEF than in those who have HF with reduced EF (HFrEF).32 Similar to 666
Mayo Clin Proc.
n
patients with HFrEF, patients with HFpEF are at increased risk for death, with 5-year mortality estimated at 50% in both groups.33 Compared with patients who have HFrEF, patients with HFpEF are more likely to experience a noncardiovascular cause of death.34 Despite its increasing prevalence, there are still no known efficacious pharmacological therapies for HFpEF. Whether renin-angiotensin system antagonists improve outcomes in HFpEF has been highly debated, and a recent analysis of patients enrolled in the Swedish HF registry suggested that there may be mortality reduction associated with renin-angiotensin system inhibition in HFpEF.35 However, randomized controlled trials have consistently failed to document any improvement in mortality in patients with HFpEF treated with ACE-Is36 or angiotensin receptor blockers37,38 compared with placebo. There has been recent interest in using phosphodiesterase 5 inhibitors, a therapy for patients with pulmonary hypertension, to treat patients with HFpEF. However, the RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) multicenter randomized controlled trial found no change in exercise capacity or clinical status after 24 weeks of sildenafil therapy compared with placebo.39 Although aldosterone antagonism with eplerenone did not improve exercise capacity in the recent RAAM-PEF (Randomized Aldosterone Antagonism in Heart Failure with Preserved Ejection Fraction) trial, it had favorable effects on diastolic function.40 The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial results, which were presented at the AHA Scientific Sessions in November 2013, found no reduction in the combined risk of cardiovascular mortality, aborted cardiac arrest, or HF hospitalization in patients with HFpEF treated with spironolactone compared with placebo, although a reduction in the secondary end point of HF hospitalizations was observed. Currently, there is insufficient evidence to recommend routine treatment with aldosterone antagonists in patients with HFpEF, although they could be a reasonable choice for patients with another indication for these therapies such as hypertension.41 Increasing evidence suggests that activation of the sympathetic nervous system plays
May 2014;89(5):662-676
n
http://dx.doi.org/10.1016/j.mayocp.2014.01.004 www.mayoclinicproceedings.org
CONTEMPORARY STRATEGIES IN HEART FAILURE
a prominent role in the pathophysiology of HFpEF.42 Renal denervation is a transcutaneous catheter-based procedure used to disrupt renal sympathetic nerves. Early studies in hypertensive patients have found it to be safe and effective.43,44 There is interest in determining whether renal denervation would be an efficacious therapeutic option in patients with HFpEF, which will be tested in the upcoming DIASTOLE (Denervation of the Renal Sympathetic Nerves in Heart Failure With Normal LV Ejection Fraction) trial.42 Therapy in patients with HFpEF should continue to focus on aggressive management of hypertension, optimizing fluid status with diuretics, and treatment of concomitant comorbidities such as sleep-disordered breathing. Although patients with HFpEF often have dyspnea with exertion, exercise training is safe and improves exercise capacity.45 Monitoring for Hyperkalemia. Close monitoring for hyperkalemia is necessary for patients treated with aldosterone antagonists. In randomized controlled trials, eplerenone46 and spironolactone47 markedly reduced death and readmissions in patients with HFrEF. As a result, aldosterone antagonists have received a class I recommendation in the ACCF/AHA guidelines.8 However, they have not been adopted as readily as other guideline-based therapies, in part due to concern about the risk of hyperkalemia, particularly in high-risk patients such as those treated with renin-angiotensin system antagonists or those with chronic kidney disease. To address the efficacy and safety of these agents in realworld populations, Hernandez et al48 conducted an analysis of 5887 patients enrolled in the Get With the Guidelines-Heart Failure registry, reporting no difference in mortality or allcause rehospitalization in the 18.2% of patients treated with these medications. Although patients treated with aldosterone antagonists did have a lower risk of HF-related rehospitalization, they also had a 2.5-fold increased risk of hospitalization for hyperkalemia within 30 days of initiation of therapy. The implications of these data taken in conjunction with those from randomized trials are that aldosterone antagonists can be efficacious therapies but should be used with caution in patients with a history of hyperkalemia or renal insufficiency (estimated glomerular filtration rate
