Prevention, Diagnosis, and Treatment Guideline

Heart Failure

Prevention Diagnosis Treatment Lifestyle Modifications/Non-Pharmacologic Options Pharmacologic Options Device Therapies Follow-up/Monitoring Medication Monitoring Comorbidity Screening Referral Other Organizations Recommendations Evidence Summary References Clinician Lead and Guideline Development Appendix 1. Recommendation Grade Labels

2 2 5 5 9 10 10 12 12 13 15 19 21 22

Most recent comprehensive literature review: April 2011

Guidelines are systematically developed statements to assist patients and providers in choosing appropriate health care for specific clinical conditions. While guidelines are useful aids to assist providers in determining appropriate practices for many patients with specific clinical problems or prevention issues, guidelines are not meant to replace the clinical judgment of the individual provider or establish a standard of care. The recommendations contained in the guidelines may not be appropriate for use in all circumstances. The inclusion of a recommendation in a guideline does not imply coverage. A decision to adopt any particular recommendation must be made by the provider in light of the circumstances presented by the individual patient.

Heart Failure Diagnosis, Screening, and Treatment Guideline Copyright 19982011 Group Health Cooperative. All rights reserved.

Prevention
Group Healths standard preventive care for heart failure is to address modifiable cardiac risk factors, including tobacco cessation, blood pressure control, weight management, and glycemic and cholesterol control.

Diagnosis
For information about clinical lab testing, consult the Group Health Clinical Laboratory Test Directory, the Healthwise Knowledgebase, or other resources.

Table 1. Clinical findings for diagnosing heart failure in patients with suggestive history and/or physical findings Test Possible findings History and clinical findings Volume overload and/or reduced ejection fraction (Probability is > 90% if 3 or more of the findings in bold below are present.) Jugular venous distension Dyspnea Orthopnea Tachycardia Third heart sound Rales Abnormal abdominojugular reflex Edema Pulse > 90 BPM Systolic blood pressure < 90 mm Hg Abnormal apical impulse Prior infarction Lab testing Testing to rule out treatable causes of heart failure: EKG Chest X-ray Echocardiogram or Consider radionuclide angiography if patient is obese (BMI > 35) or has severe COPD. Electrolytes Albumin AST BUN Calcium Consider BNP/proBNP in select patients (see Table 2 regarding BNP) CBC Creatinine Iron TIBC TSH

Arrhythmias or prior Q-wave MI Left bundle branch block Radiographic cardiomegaly or redistribution Pulmonary congestion Evaluation for structural heart disease etiologies that can lead to heart failure

Heart Failure Prevention, Diagnosis, and Treatment Guideline

Table 2. Additional tests to consider for diagnosing heart failure (BNP/proBNP) in select patients Test Brain natriuretic peptide (BNP/proBNP) 1,2 Results < 50 years: NT-proBNP > 450 pg/mL Interpretation Heart failure is likely, but test results should be interpreted in conjunction 5075 years: NT-proBNP > 900 pg/mL with the clinical setting. > 75 years: NT-proBNP > 1,800 pg/mL Any age: NT-proBNP > 10,000 pg/mL Heart failure is very likely. Very high proBNP levels may also be seen in renal failure. Test results should be interpreted in conjunction with the clinical setting.

BNP testing may be helpful in emergency settings, to distinguish between cardiac and pulmonary dyspnea. However, BNP testing is not required for the evaluation of heart failure since a BNP or proBNP does not give a definitive heart failure diagnosis, nor does it risk-stratify patients. BNP has a 1020% false negative rate, especially in patients who are obese or have pulmonary disease. Higher levels are associated with heart failure, but will also be elevated in other clinical situations such as myocardial infarction, pulmonary hypertension, pulmonary embolism, and renal failure. BNP and proBNP assays manufactured by different companies have different reference ranges. Group Health labs use an NT-proBNP (N-terminal prohormone brain natriuretic peptide); hospitals where our patients are admitted may use the BNP instead. See the Evidence Summary for more information on BNP and proBNP.

Table 3. Additional evaluations to consider for identifying treatable causes of heart failure Etiologies Alcohol or cocaine abuse CAD, chronic ischemia/hibernating myocardium 1 Collagen vascular disease Evaluations to perform if suspected AUDIT, DAST-10, urine toxicology Myocardial perfusion study, stress echocardiography, coronary arteriography ANA (anti-nuclear antibody) and RF (rheumatoid factor screen)

Endocrine disorder HbA1c or fasting plasma glucose, TSH Diabetes Hyper- or hypothyroidism HIV Medication-induced Obstructive sleep apnea HIV Ag/Ab combo test Review medications: NSAIDs, beta-blockers, diltiazem/verapamil, thiazelididones, doxorubicin. Review history for key diagnostic factors: chronic snoring, maxillomandibular anomalies, excessive daytime sleepiness, episodes of apnea, episodic gasping, restless sleep, macroglossia. Consider sleep study.

If chronic ischemia/hibernating myocardium is present, consider revascularization. When the patient returns to primary care, continue treatment for heart failure.

Heart Failure Prevention, Diagnosis, and Treatment Guideline

Table 4. New York Heart Association (NYHA) functional classification of heart failure 1 Class I II III IV Symptoms Patients with cardiac disease but without limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. Patients with cardiac disease with a slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. Patients with cardiac disease with marked limitation of physical activity. They are comfortable at rest. Less-than-ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. Patients with cardiac disease with inability to carry on any physical activity without discomfort. Symptoms of heart failure or anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased.
Heart failure classification is used to determine follow-up recommendations and referrals to case management or palliative care, and for coding.

Heart Failure Prevention, Diagnosis, and Treatment Guideline

Treatment
Lifestyle Modifications/Non-Pharmacologic Options
Key self-management strategies for patients: Check weight daily and report gains of more than 2 lbs in a 2- to 3-day period. Limit sodium to < 1500 mg daily. Limit alcohol consumption completely (preferred) or to less than one drink per day. For stable heart failure patients, exercise training may improve survival and quality of life. Recognize and record symptoms.

Pharmacologic Options
For more information on side effects, contraindications, and other pharmacy-related issues, consult the Group Health Formulary, the Healthwise Knowledgebase, or other resources. Goals Pharmacologic treatment aims both to improve symptomsinitially through diuresis (see Table 5)and to improve cardiac function once euvolemic through the use of ACE inhibitors, beta-blockers, hydralazine, nitrates, and aldosterone antagonists (see Tables 6 and 7ad). Table 5. Diuretic therapy for clinical volume overload (Diuretic therapy improves symptoms and exercise capacity in patients with heart failure.) Clinical presentation Clinical volume overload 1, 2 Line 1st Medication Furosemide 1,2 Initial dose 2040 mg oral or IV once daily 12.5 mg once daily Maximum dose 240480 mg in once- or twice-daily dosing 100 mg once daily 10 mg once daily or as needed

Add if still dyspneic with objective signs of volume overload

1

HCTZ 3

or Metolazone 3 2.5 mg once daily or as needed

Furosemide dosing notes: Administer higher doses of furosemide in patients with renal failure and lower doses in elderly/frail patients with mild volume excess. If patient is already on oral furosemide, use IV dose 12 times the regular oral dose and adjust as needed to achieve desired clinical response. If volume excess remains and patient does not have pre-renal azotemia (increased BUN, extreme alkalosis), titrate to a maximum dose of 240480 mg daily. Consider using twice-daily dosing for higher doses. Patients with heart failure often have diuretic resistance. Strategies to counteract this include: increasing loop diuretic dose or frequency of administration and adding HCTZ or metolazone. For patients who are intolerant of furosemide, other loop diuretics are: Bumetanide (oral: 0.51 mg once daily or b.i.d.; maximum dose: 10 mg daily) Torsemide (initial dose 1020 mg once daily or b.i.d., titrate up until diuretic response is apparent or maximum of 200 mg daily) Metolazone and HCTZ may cause exaggerated diuresis and serum potassium loss when used in combination with furosemide. Starting with a very low initial dose and adjusting based on clinical response is recommended. Closely monitor serum potassium and renal function.

Heart Failure Prevention, Diagnosis, and Treatment Guideline

Table 6. Treatment for left ventricular systolic dysfunction: overview Clinical presentation Euvolemic Patient description Step 1 All patients with ejection fraction < 3540% 1 Medication Initiate ACE inhibitor (see Table 7a for treatment details) and titrate at 1- to 2-week intervals to clinical target dose or maximum tolerated dose. If ACE intolerant, initiate ARB. If ACE and ARB are contraindicated or not tolerated, initiate combination vasodilator therapy (isosorbide dinitrate plus hydralazine) (see Table 7d for treatment details). Add beta-blocker 2 and titrate at 2- to 4-week intervals to clinical target dose or maximum tolerated dose (see Table 7b for treatment details).

If stable patient with systolic dysfunction, SBP > 100 and pulse > 60

Add aldosterone antagonist (spironolactone) Step 2 If persistent symptoms on (see Table 7c for treatment details). ACE inhibitors and betablockers (potassium < 5.0 MEQ/L and creatinine < 2.5 mg/dL) Step 3 If persistent symptoms on ACE, beta-blocker, and adolesterone antagonist Add digoxin 3 (see Table 7d for treatment details). Add ARB if not already on an ARB (see Table 7d for treatment details). 4 For black patients, consider adding combination vasodilator therapy to standard heart failure therapy (including ACE inhibitors and beta-blockers). Add combination vasodilator therapy (isosorbide dinitrate plus hydralazine) (see Table 7d for treatment details).
1

Once patients are stable, most will be on both ACE inhibitor and beta-blocker. There is no need to be at the maximum dose of one before adding the other. Depending on a patient's symptoms, it may be appropriate to begin with beta-blockers. For example, patients with paroxysmal arrhythmia or angina would require preferential initiation of a beta-blocker. Similarly, patients with sinus tachycardia that seems inappropriate for their clinical condition may require beta-blockers first. Beta-blockers may be added for those on ACE inhibitor/ARB with SBP > 100 and pulse > 60. Beta-blockers have been shown to be effective even in the absence of ACE inhibitors or in conjunction with ACE inhibitors without full titration. Giving beta-blockers prior to ACE inhibitors is not inferior to initiating therapy with ACE inhibitors (Willenheimer et al 2005). If the patient is intolerant of ACE inhibitors and ARBs, a beta-blocker may still be beneficial. Has not been shown to decrease mortality. Adding ARBs to maximum doses of ACE inhibitors in addition to the standard heart failure therapy may decrease hospitalization rates, but does not improve mortality. It is recommended that before ARBs are added, a patient should be on the maximum tolerated doses of the medication classes that have been proven to be effective (ACE inhibitors, beta-blockers, and aldosterone antagonists). Adding ARBs to patients already on ACE inhibitors has been shown to increase the risk of hyperkalemia and serum creatinine elevation.

3 4

Heart Failure Prevention, Diagnosis, and Treatment Guideline

Table 7a. Treatment for left ventricular systolic dysfunction: ACE or ARB initiation (or combination vasodilator) Clinical Medication presentation
Titrate at 1- to 2-week intervals to clinical target dose or maximum tolerated dose

Initial dose

Target or maximum dose

Euvolemic

ACE inhibitor 1

Lisinopril 2 (Preferred) or enalapril 3 or captopril 4

2.55 mg once daily 2.5 mg once daily or b.i.d. 6.2512.5 mg t.i.d. 12.525 mg once daily 10 mg t.i.d. or q.i.d. 1025 mg t.i.d. or q.i.d. 1 tablet t.i.d.

2040 mg daily 1020 mg b.i.d. 50 mg t.i.d. 50100 mg once daily 40 mg t.i.d. or q.i.d. 100 mg t.i.d. or 75 mg q.i.d 2 tablets t.i.d.

or if intolerant of ACE, use an ARB

Losartan

or if unable to use Isosorbide ACE or ARB dinitrite and hydralazine (Preferred) or combination isosorbidehydralazine (2037.5 mg)
1

Treatment with ACE inhibitors is recommended for all patients with heart failure and ejection fraction < 35%, unless contraindicated or not tolerated. The benefit is greatest in those with low ejection fractions. Contraindications to ACE inhibitors and ARBs: Absolute contraindications Known hypersensitivity Pregnancy Angioedema irrespective of whether patient was taking an ACE inhibitor at the time (contraindication for ACE inhibitors only) Relative contraindications Renal insufficiency (creatinine > 2 mg/dL) Renal artery stenosis Severe volume depletion Breastfeeding Severe hepatic dysfunction or development of jaundice or elevated liver enzymes during therapy Hyperkalemia (initiate treatment slowly if serum potassium concentration is near 5.0 mmol/L) Neutropenia, autoimmune disease, or immunosuppressant drug therapy may increase risk of blood dyscrasias (ACE inhibitor only) Surgery/anesthesia may increase risk of perioperative hypotension or postoperative acute kidney injury with major cardiac surgery Lipid apheresis with dextran sulfate membranes may increase hypersensitivity reaction (ACE inhibitor only)

Initial dose 2.5 mg for elderly patients or those with systolic blood pressure < 100 mm Hg; 510 mg for other patients. Ideally enalapril is dosed b.i.d in heart failure. Consider starting elderly patients or those with systolic blood pressure < 100 mm Hg on 2.5 mg daily, but switch to b.i.d. dosing as soon as possible. The shorter duration of captopril may be beneficial in patients with hypotension or early in hospitalization, but it may be a disadvantage for long-term adherence. The preferred ARB is losartan for those who do not tolerate ACE inhibitors. The initial dose is 12.5 mg for elderly patients or those with systolic blood pressure < 100, and 25 mg for other patients.

Heart Failure Prevention, Diagnosis, and Treatment Guideline

Table 7b. Treatment for left ventricular systolic dysfunction: beta-blocker initiation 1 Clinical presentation Euvolemic If stable patient with systolic dysfunction, SBP > 100 and pulse > 60
1

Medication Add beta-blocker 2 (or consider switching to approved heart failure beta-blocker if on other beta-blocker) Carvedilol 3

Initial dose 3.125 mg b.i.d.

Target or maximum dose 25 mg b.i.d. for weight < 185 lb 50 mg b.i.d. for weight > 185 lb

or metoprolol LA 4

12.525 mg once daily

200 mg once daily

Note: Beta-blockers typically cause a transient increase in symptoms of dyspnea and orthostatic lightheadedness before eventually increasing the ejection fraction and improving symptoms. In the opinion of many cardiologists, carvedilol is preferred over metoprolol. Expert Opinion Beta-blocker cautions/contraindications: Beta-blockers can be used in patients with diabetes, COPD, or PVD. Use with caution in patients with recurrent hypoglycemia, asthma, resting limb ischemia, marked bradycardia. Avoid in asthma patients with active bronchospasm, or patients with sick sinus syndrome, 2 or 3 heart block unless pacemaker present, pheochromotoma unless also on a drug providing alpha blockade (carvedilol is not a problem as it also blocks alpha-adrenergic receptors), prior betablocker intolerance. Carvedilol: take with food. Observe for 1 hour after first dose for signs of dizziness. Double the dose every 2 weeks to maximum tolerated dose or target dose. Metoprolol LA (Toprol XL): initial dose 12.525 mg daily (12.5 mg if NYHA class III or IV). Increase dose every 2 weeks to 200 mg or maximum tolerated dose.

Table 7c. Treatment for left ventricular systolic dysfunction: aldosterone antagonists Clinical presentation Euvolemic If persistent symptoms on ACE and beta-blockers (potassium < 5.0 MEQ/L and creatinine < 2.5 mg/dL in men or < 2 mg/dL in women)
1

Medication Spironolactone 1 If spironolactone causes gynecomastia, consider eplerenone. 1

Initial dose 12.525 mg once daily 25 mg once daily

Target or maximum dose 50 mg once daily or 25 mg b.i.d. After 4 weeks titrate to 50 mg once daily, as tolerated

Reduce potassium supplement dose by at least 50% when initially starting spironolactone/eplerenone, unless serum potassium is < 3.5 mmol/L. Be cautious when prescribing spironolactone or eplerenone for patients with renal insufficiency or with serum potassium concentrations > 4.5 mmol/L. Monitor potassium closely (see Follow-up/Monitoring). Reduce dose if serum potassium 5.55.9 mmol/L.

Heart Failure Prevention, Diagnosis, and Treatment Guideline

Table 7d. Treatment for left ventricular systolic dysfunction: ACE-ARB dual therapy, vasodilators, and digoxin Clinical presentation Euvolemic If persistent symptoms on ACE, beta-blocker, and adolesterone antagonist
1

Medication Digoxin
1

Initial dose 0.125 mg once daily

Maximum dose 0.25 mg once daily 2

Dosing is based on digoxin level and symptoms and adjusted for age and renal function. Consider 0.0625 mg once daily or 0.125 mg every other day initially in patients aged > 70 years or with decreased renal function. The potential for toxicity is likely to be greater in women or thinner patients because the volume of distribution depends on muscle mass. See Follow-up/Monitoring. Doses above 0.25 mg daily (0.375 mg or 0.5 mg daily) are rarely needed in heart failure.

Table 8. Calcium channel blocker for patients with heart failure 1 Recommended Not recommended Amlodipine is approved for use in heart failure patients with hypertension and heart failure (preferred). Felodipine (alternative). Diltiazem and verapamil have been documented to worsen outcomes in post-MI patients with decreased ejection fraction. If possible, they should be avoided in these patients unless angina can't be controlled with beta blockade alone and peak exercise heart rate remains high. Long-acting nifedipine is also negatively inotropic, unlike felodipine, and should be avoided in this patient population.

See the Hypertension Guideline for more information on calcium channel blocker usage.

Device Therapies
Table 9. Device therapy for management of heart failure when patient is on optimal pharmacologic therapy 1 Device Implantable cardioverter defibrillators (ICDs) Eligibility criteria LVEF 35% and not expected to improve NYHA functional class II or III symptoms (or class IV if cardiac resynchronization therapy eligible per CMS criteria) Prognosis > 1 year LVEF 35% NYHA functional class III or IV symptoms Left bundle branch block or QRS > 120 msec in width Consider if NYHA functional class II with left bundle branch block or QRS > 150 msec and in sinus rhythm
1

Cardiac resynchronization therapy (CRT) with or without an ICD

Excluded patients: Cardiogenic shock or symptomatic hypotension while in a stable baseline rhythm Had a CABG or PTCA within the past 3 months Had an acute MI within the past 40 days Clinical symptoms or findings that would make them a candidate for coronary revascularization Irreversible brain damage from preexisting cerebral disease Prognosis of survival < 1 year

Heart Failure Prevention, Diagnosis, and Treatment Guideline

Follow-up/Monitoring
To optimize treatment and prevent complications, the following periodic follow-up and monitoring is advised. Expert Opinion

Follow-up
Table 10. Frequency of patient follow-up Patient condition Frequency Stable, prior history of HF, not active, asymptomatic Annually (cardiac function may be abnormal or improved) Chronic compensated (NYHA III) Acute decompensated (NYHA IIIIV) Every 36 months As clinically indicated

Monitoring
Assess the patients: Ability to perform daily activities Weight and fluid status Diet and sodium intake Repeat echocardiogram when the patient has a change in clinical status or a clinical event or received treatment that might have had a significant effect on cardiac function. Not recommended: Brain natriuretic peptide (BNP/proBNP) testing.

Medication Monitoring
For more information on side effects, contraindications, and other pharmacy-related issues, consult the Group Health Formulary, the Healthwise Knowledgebase, or other resources.

Heart Failure Prevention, Diagnosis, and Treatment Guideline

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Table 11. Recommended monitoring for medication side effects Medication ACE inhibitors or ARBs
1

Test(s) or conditions Potassium and Creatinine or BUN Potassium and Creatinine or BUN Sodium as indicated 3

Frequency Before initiating therapy and 2 weeks after initiating therapy and with each increase in dose and every 612 months when stable At 24 hours and 35 days after initiating therapy, and then 1, 2, and 3 months after initiating therapy and within 1 week of any dose change and every 36 months If reported or noted

Diuretics 2

Aldosterone antagonists 2 Potassium (spironolactone or eplerenone) and Creatinine 4

Gynecomastia 5 Digoxin Digoxin level

6

1014 days after initiating therapy and Note: Digoxin serum levels within 1014 days of any dose should be drawn at least 6 hours change or change in renal function after an oral dose (optimally 1224 hours after a dose). Not applicable

Beta-blockers and/or calcium channel blockers

1

No routine monitoring is required.

For patients on ACE inhibitors and/or ARBs, renal function (BUN and creatinine) should be checked because treatment may be associated with deterioration of renal function and/or increases in serum creatinine, particularly in patients dependent on renin-angiotensin-aldosterone system; potassium should be checked because 25% of patients develop hyperkalemia. For patients on diuretics or aldosterone antagonists, potassium should be checked at least once a year, and perhaps twice a year and with any change of dose because excessive dosages can lead to profound diuresis with fluid and electrolyte loss; renal function (creatinine) should be checked because use of diuretics may cause oliguria, azotemia, and reversible increases in BUN and creatinine. For patients who are elderly, on multiple medications, or who have heart failure, consider checking sodium levels to monitor for electrolyte disturbances: hypokalemia, hypochloremic alkalosis, and hyponatremia. Hold, stop, or reduce spironolactone or eplerenone if the patient develops renal insufficiency or significant hyperkalemia. About 2% of the men taking spironolactone experience problematic gynecomastia (Pitt et al 1999). In these rare cases, eplerenone can be prescribed. Mean blood levels in clinical trials were 0.70.8 ng/mL. Levels over 1.0 ng/mL are probably undesirable due to the risk of toxicity during heart failure exacerbations, which may be accompanied by decreased hepatic and renal blood flow. The target range for digoxin is 0.61.0 ng/mL. Following absorption of digoxin into the blood stream, levels are transiently high for 8 hours prior to redistribution of digoxin into the tissues. To avoid confusion generated by measuring digoxin levels too soon after a morning dose, instruct the patient to take digoxin in the evening. The potential harms of withdrawing digoxin should be considered before discontinuation in patients who tolerate it well.

Heart Failure Prevention, Diagnosis, and Treatment Guideline

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Comorbidity Screening
Table 12. Recommended comorbidity screening for patients with heart failure Comorbid condition Depression Alcohol misuse Anemia Hypertension Renal function
1

Test(s) Consider screening with Patient Health Questionnaire (PHQ-9). 1, 2 Consider screening with Alcohol Use Disorders Identification Test (AUDIT). Hematocrit Blood pressure Creatinine clearance

See the Depression Guideline for additional guidance. Patients with major depression can be treated in primary care or offered a referral to Behavioral Health Services for counseling and/or drug therapy. Evidence suggests that patients with depression are less likely to be adherent to recommended management plans and less likely to be effective at self-management of chronic conditions.

Referral
Consultative Specialty Service
Prior to referral for consultative specialty service, consider ordering an echocardiogram if not previously done.

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Other Organizations Recommendations

Kaiser national criteria (2007)
Prophylactic ICD to prevent sudden cardiac death in left ventricular systolic dysfunction (LVSD) Ischemic (prior myocardial infarction [MI]) or non-ischemic cardiomyopathy, NYHA class II to III, and left ventricular ejection fraction (LVEF) < 35% after completion of titration of ACE/ARB and beta-blocker therapy to maximally tolerated doses per heart failure (HF) guidelines (typically at least 40 days or longer from MI, 3 months from coronary artery bypass graft [CABG] or percutaneous coronary intervention [PCI], and 9 months from initial diagnosis of non-ischemic LVSD) or NYHA class IV and patient meets all current Centers for Medicare and Medicaid Services (CMS) coverage requirements for cardiac resynchronization therapy (CRT)

Kaiser Southern California criteria (2009)

ICD LVEF 35% and is not expected to improve and NYHA class II or III symptoms (class IV if CRT eligible per CMS) and Prognosis > 1 year and Avoidance of sudden death is desired LVEF 35% and NYHA class III or IV symptoms and Left bundle branch block of 120 msec in width

CRT

American College of Cardiology / American Heart Association criteria (2009; focused update)

ICD secondary prevention (Grade A) Current or prior symptoms of HF and Reduced LVEF and a history of cardiac arrest, ventricular fibrillation (VF), or hemodynamically destabilizing ventricular tachycardia (VT)

ICD primary prevention (Grade A) Non-ischemic dilated cardiomyopathy or ischemic heart disease at least 40 days post-MI and LVEF 35% and NYHA class II or III symptoms while receiving chronic optimal medical therapy and Survival prognosis with a good functional status for > 1 year CRT with or without an ICD, unless contraindicated (Grade A) LVEF 35% and Sinus rhythm and NYHA class III or ambulatory class IV symptoms on recommended, optimal medical therapy and QRS 0.12 seconds CRT with or without an ICD is reasonable (Grade B) LVEF 35% and Atrial fibrillation and NYHA class III or ambulatory class IV symptoms on recommended, optimal medical therapy and QRS 0.12 seconds CRT with or without an ICD is reasonable (Grade C) LVEF 35% and NYHA class III or ambulatory class IV symptoms on recommended, optimal medical therapy and Frequent dependence on ventricular pacing

Heart Failure Prevention, Diagnosis, and Treatment Guideline

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European Society of Cardiology criteria (2010)

CRT with pacemaker or defibrillator to reduce morbidity and mortality (Grade A) LVEF 35% and Sinus rhythm and NYHA class III on optimal medical therapy or ambulatory class IV symptoms (no hospital admissions in last 6 months and reasonable expectation of survival > 6 months) on recommended, optimal medical therapy and QRS 0.12 seconds CRT with pacemaker or defibrillator to reduce morbidity and prevent disease progression (Grade LVEF 35% and Sinus rhythm and NYHA class II on optimal medical therapy and QRS 0.150 seconds CRT with pacemaker or defibrillator to reduce morbidity (Grade B) LVEF 35% and Permanent atrial fibrillation (pacemaker dependency induced by AV nodal ablation) and Reasonable survival with good functional status for > 1 year and NYHA class III or class IV and QRS 0.130 seconds CRT with pace maker or defibrillator to reduce morbidity (Grade C) LVEF 35% and Slow ventricular rate and frequent pacing ( 95% pacemaker dependence) and Reasonable survival with good functional status for > 1 year and NYHA class III or class IV and QRS 0.130 seconds
A)

Noridian CMS criteria for Medicare recipients (2005)

Indications and limitations of coverage Covered indications (heart failure-related): CAD with a history of MI (< 40 days past), LVEF < 0.35, and inducible, sustained VT or VF at electrophysiology (EP) study or History of MI, LVEF < 0.30 or Ischemic dilated cardiomyopathy (IDCM), history of MI, NYHA class II or III, and measured LVEF < 35% or Non-ischemic dilated cardiomyopathy (NIDCM) > 9 months, NYHA class II or III, and measured LVEF < 35% or Patients who meet all current CMS coverage requirements for a CRT device and have NYHA class IV or Patients with NIDCM > 3 months, NYHA class II or III, and measured LVEF < 35% Excluded patients (any): Cardiogenic shock or symptomatic hypotension while in a stable baseline rhythm Had a CABG or percutaneous transluminal coronary angioplasty (PTCA) within the past 3 months Had an acute MI within the past 40 days Clinical symptoms or findings that would make them a candidate for coronary revascularization Irreversible brain damage from preexisting cerebral disease Prognosis of survival < 1 year

Heart Failure Prevention, Diagnosis, and Treatment Guideline

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Evidence Summary Diagnostic testing with BNP and proBNP

BNP The published literature provides evidence that brain natriuretic peptide (BNP) testing may help differentiate dyspnea due to congestive heart failure from that due to other causes among patients presenting to emergency departments with shortness of breath as the prominent symptom. BNP levels of < 80100 pg/mL suggest a diagnosis other than heart failure, while very high levels (> 500600 pg/mL) suggest heart failure. There is no precise diagnostic cutoff for the tests. The sensitivity and specificity varied between studies depending on the test assay used as well as the study setting and population characteristics. The evidence indicates that the tests have a high negative predictive valuethey may be useful to rule out a cardiac cause of the dyspnea when used in conjunction with clinical findings and other diagnostic tests. There is insufficient evidence on the value of BNP serial measurement in guiding the therapy for patients with heart failure. The sensitivity, specificity, and predictive values of BNP from the largest available study (1,586 patients) are shown below (Maisel 2002). The study was performed in an emergency room setting. BNP (pg/mL) Sensitivity Specificity Accuracy Positive predictive value 71% 77% 79% 80% 83% Negative predictive value 96% 92% 89% 87% 85%

50 80 100 125 150

97% 93% 90% 87% 85%

62% 74% 76% 79% 83%

79% 83% 83% 83% 84%

N-terminal (NT)-proBNP ProBNP is more stable than BNP and is the ideal analyte to measure when the sample needs to be transported to another lab for testing. BNP, on the other hand, is unstable and must be performed within 1 hour after blood draw and so must performed at a site close to the patient. As for assessing for congestive heart failure, both analytes have the same sensitivity, specificity, and limitations. Below are the sensitivity, specificity, and predictive values of NT-proBNP in the diagnosis of acute cardiac dyspnea among patients > 70 years of age in an emergency room setting (Berdague 2006).

NT-proBNP (pg/mL) 1000 1630 2000 3000 4500 5500

Sensitivity

Specificity

Accuracy

Positive predictive value 71% 77% 80% 83% 86% 85%

Negative predictive value 93% 86% 81% 72% 65% 62%

97% 92% 87% 75% 64% 58%

49% 65% 72% 80% 86% 87%

76% 80% 80% 78% 74% 71%

Heart Failure Prevention, Diagnosis, and Treatment Guideline

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Note: Mean BNP levels are higher in older patients, and are 510 pg/mL higher in women. Levels found in healthy older women may overlap with those found in patients with heart failure. Additional factors that can account for high BNP when heart failure is absent include renal failure, myocardial infarction, or acute coronary syndrome. Factors that can account for low BNP when heart failure is present include flash pulmonary edema (in which BNP levels take 1 to 2 hours to rise) or a cause of heart failure occurring upstream from the left ventricle (e.g., mitral stenosis). The following conditions also may cause an increase in BNP: hyperthyroidism, Cushing's disease, exogenous glucosteroids, primary aldosteronism, Addison's disease, hepatic cirrhosis with ascites, or subarachnoid hemorrhage. Source: Anthony E. Steimle, MD, FACC, director, Kaiser Northern California Heart Failure Program, personal communication. Factors that can account for low BNP when heart failure is present include flash pulmonary edema (in which BNP levels take 1 to 2 hours to rise) or a cause of heart failure occurring upstream.

Medications
Diuretics Several large randomized controlled trials showed that diuretic therapy of hypertensive patients reduces their risk of developing heart failure. There is supporting evidence from the ALLHAT trial with 33,357 participants55 years of age or older with stages 1 and 2 hypertensionthat the use of diuretics is associated with a lower incidence of heart failure (Davis 2006). There is also evidence from a metaanalysis of 14 trials, involving 525 participants, that using diuretics in the management of chronic heart failure patients may improve survival and exercise capacity (Faris 2006). ACE inhibitors In patients with heart failure, ACE inhibitors were found to reduce the absolute risk of death by 2.8% within 90 days, equivalent to a number needed to treat (NNT) to avoid one death of 36. Benefit continues to accrue after 90 days, but at a lower rate. Similar risk reductions were observed for all of the ACE inhibitors, indicating a class effect. The greatest benefits were observed in patients with the lowest ejection fractions, and the impact of treatment on patients with ejection fractions > 30% is unclear (Garg 1995). In the largest long-term study of patients with symptomatic heart failure (with ejection fractions 35%), treatment with enalapril for 4 years reduced the absolute risk of death from 40% to 35%. This is an absolute risk reduction of 5%, equivalent to an NNT to avoid one death of 20. The degree of benefit was greatest in those with low ejection fractions (SOLVD Investigators 1991). A meta-analysis of 20 trials involving more than 12,000 patients showed that ACE inhibitor therapy is associated with an improvement in symptoms and survival compared to placebo (Abdulla 2006). The improvement in NYHA class was significant for patients with chronic heart failure, but not for those with LVSD after an acute MI. It is unclear whether patients with asymptomatic left ventricular dysfunction benefit from treatment with ACE inhibitors (SOLVD Investigators 1992). Over 5 years of treatment there were non-significant trends toward reduced mortality, and significant reduction in heart failurerelated hospitalizations. Expert opinion strongly endorses the use of ACE inhibitors or ARBs for patients with asymptomatic left ventricular dysfunction, although in the presence of significant side effects, the threshold to discontinue treatment can be somewhat lower. One clinical trial compared the benefits of large doses of ACE inhibitors (lisinopril 33 mg) with smaller doses (4 mg) (Packer 1999). There was a non-significant trend toward reduced mortality with the higher dose, and a significant reduction in hospitalization due to heart failure. Angiotensin II receptor blockers (ARBs) There is good evidence that losartan is not more effective than captopril in improving survival among patients with heart failure. However, it was better tolerated and had significantly fewer side effects, particularly cough (Dickstein 2002, Pitt 2000).

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Combined use of ACE inhibitors and ARBs There is evidence from a large meta-analysis of 24 trials involving 38,000 patients that a combination therapy of ACE inhibitors and ARBs significantly reduces hospitalization rates compared to ACE inhibitors alone (Lee 2004). The CHARM-Added trial also provided evidence that adding ARBs to ACE inhibitors given at their maximum dose, together with standard heart failure therapy, reduced the heart failure hospitalization rate (McMurray 2006). The combination therapy, however, was not associated with a significant reduction in all-cause mortality among heart failure patients (Lee 2004, Dimopoulos 2004, Pfeffer 2003). Vasodilators There is strong evidence that adding hydralazine and isosorbide to digoxin and diuretics reduces mortality after 2 years by 9% (Cohn et al 1986). One study comparing hydralazine and isosorbide with enalapril (Cohn et al 1991) showed: In patients with mild to moderate heart failure (symptoms slightly limited with normal physical activity, NYHA class I or II), enalapril was more effective than hydralazine. The absolute annual reduction in mortality was 47%. In patients with more severe heart failure (symptoms occurring upon minimal exertion, NYHA class III or IV), enalapril and vasodilators were equally effective. Beta-blockersmetoprolol LA (Toprol XL)/carvedilol There is evidence from three meta-analyses that adding a beta-blocker to the standard therapy of chronic heart failure significantly increases survival and reduces morbidity among patients with left ventricular dysfunction and in NYHA class IIIV (Bouzamondo 2003, Brophy 2001, Lee and Spencer 2001). None of the included trials evaluated the use of beta-blockers for patients in NYHA class I. These meta-analyses also provide evidence that all three beta-blockers (carvedilol, metoprolol LA [Toprol XL], and bisoprolol) significantly reduced death and hospitalization of patients with heart failure when compared to placebo. There is insufficient evidence to determine the relative efficacy of these agents, and positive findings with all three agents do not indicate a class effect of beta-blockers. The COPERNICUS trial provided evidence that euvolemic patients with severe chronic heart failure benefit from adding carvedilol to their optimum treatment (Krum 2003). The addition of carvedilol to the conventional therapy also reduced the risk of death in postmyocardial infarction patients with left ventricular dysfunction, with or without heart failure (Dargie 2001). The literature also indicates that giving beta-blockers as a first-line therapy is not inferior to initiating the therapy with ACE inhibitors in the management of patients with compensated systolic heart failure (Krum 2005, Willenheimer 2005). Packer et al found that benefits accrue early when carvedilol is started in the hospital once the patient is euvolemic and stable (Packer 2001). There was apparent benefit even in the first month of treatment, despite initiation of carvedilol at the lowest dose. A valid randomized controlled trial showed carvedilol (target dose 50 mg daily) to be superior to immediaterelease metoprolol (target dose 100 mg daily) in heart failure (Poole-Wilson 2003). A head-tohead comparison of sustained-release metoprolol and carvedilol has not been conducted. Aldosterone antagonists There is strong evidence that patients with an ejection fraction < 35% and with NYHA class III or IV have improved outcomes if treated with spironolactone in addition to their loop diuretic and ACE inhibitor (Pitt 1999). RALES, a large longterm trial, showed that low doses of spironolactone (starting at 12.5 mg/day) added to the standard treatment of heart failure patients in class III or IV with an ejection fraction 35% reduced the risk of death from 46 to 35% (NNT of 9 in 2 years) (Pitt 1999). EPHESUS, a more recent trial (Pitt 2003), investigated the use of the newer aldosterone antagonist, eplerenone, in addition to standard treatment for patients with left ventricular systolic dysfunction (LVSD), left ventricular ejection fraction (LVEF) < 40%, recent myocardial infarction (MI), and clinical evidence of congestive heart failure. The study showed a decrease in mortality from 13.6 to 11.8% in 1 year (NNT of 50 for 1 year). Spironolactone was associated with gynecomastia but not with serious hyperkalemia in RALES trial; the reverse was true in EPHESUS.

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There is no head-to-head comparison between spironolactone and eplerenone, and it is difficult to compare the two trials as they were conducted among different patient populations. The RALES trial was conducted among sicker patients with a lower ejection fraction (mean of 25% vs. 33% in EPHESUS). Patients in RALES had chronic heart failure versus LVSD after an acute MI in EPEHESUS. Moreover, only 11% of the patients in RALES used beta-blockers compared to 75% in EPHESUS. EMPHASIS-HF (Zannad 2010) examined the effect of eplerenone in patients with NYHA class II and LVEF < 35% and showed a significant reduction in the risk of death and hospitalization for any cause or for heart failure compared to placebo. Eplerenone, however, was associated with a significantly higher risk of hyperkalemia compared to placebo. The trial included patients with mild symptoms (NYHA class II), however, they were at a higher risk as their mean LVEF was 26.2%, 26% had a mean QRS duration > 130 ms, 53% were previously hospitalized for heart failure, half had a history of myocardial infarction, two thirds had hypertension, one third had diabetes, 26.5% had left bundle branch block (LBBB), and 30% had atrial fibrillation. These limit generalization of the results to similar populations. Digoxin Studies showed that digoxin does not reduce overall mortality in patients with heart failure receiving diuretics and ACE inhibitor therapy; however, digoxin therapy reduces the absolute risk of hospitalization by 2.8% over 3 years. The NNT for 3 years to avoid one hospitalization is 36, and to prevent one hospitalization due to worsening heart failure is 13 (Digitalis Investigation Group 1997, Hood 2004). There is strong evidence that withdrawing digoxin from patients who are tolerating the drug well leads to an increased risk of adverse outcomes within 3 months. In the RADIANCE study (subjects well controlled on digoxin and an ACE inhibitor), digoxin withdrawal increased the absolute risk of an emergency room visit or hospitalization by 12% (Packer 1993). In the PROVED study (subjects with heart failure not on ACE inhibitors), there was a 20% increase in the absolute risk of worsening heart failure, including the need for increased diuretic therapy, emergency room treatment, or hospital admission, when digoxin was withdrawn (Utretsky 1993). Nesiritide (a recombinant form of human B-type natriuretic peptide) There is some evidence from a meta-analysis by Sackner-Bernstein and colleagues that the use of nesiritide in the management of acutely decompensated heart failure may be associated with an increased risk of mortality (Sackner-Bernstein 2005a). A larger meta-analysis by the same principal author indicates that the use of nesiritide therapy also leads to worsening of renal function (SacknerBernstein 2005b).

Cardiac resynchronization therapy (CRT)

There is good evidence from several randomized controlled trials including MIRACLE (Abraham 2002), MIRACLE-ICD (Young 2003), COMPANION (Anand 2009), CARE-HF (Cleland 2006), and others that biventricular pacing together with or without an implantable cardioverter defibrillator (ICD), and in addition to optimal medical treatment, reduces all cause mortality and hospitalization for heart failure in patients with symptomatic (NYHA class III and IV) heart failure. Standard indications for CRT are LVEF < 35%, with QRS > 120 ms, sinus rhythm, and NYHA class III or IV after optimal medical therapy (according to the ACC/American Heart Association/Heart Rhythm Society guidelines). More recent trials (MADIT-CRT [Moss 2009], and RAFT [Tang 2010]) on the use of CRT in less symptomatic patients showed that its use in addition to ICD and optimal medical treatment reduces heart failure hospitalization and mortality due to any cause among selected groups of patients with mild heart failure symptoms, more significantly among those with QRS duration > 150ms, and LBBB; however, the therapy was associated with increased serious device-related complications and hospitalization.

Physical activity
There is evidence from a meta-analysis of nine studies with 800 participants that exercise training improves survival of patients with chronic heart failure due to left ventricular systolic dysfunction, and extends their time to death or hospitalization (Piepoli 2004). Another meta-analysis of 35 studies with a total of 1,486 patients showed that exercise training for patients with mild to moderate heart failure was associated with a significant improvement in their exercise capacity and health-related quality of life (van Tol 2006).
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References
Abdulla J, Pogue J, Abildstrom SZ, et al. Effect of angiotensin-converting enzyme inhibition on functional class in patients with left ventricular systolic dysfunction-a meta-analysis. Eur J Heart Fail. 2006;8:9096. Anand IS, Carson P, Galle E, et al. Cardiac resynchronization therapy reduces the risk of hospitalizations in patients with advanced heart failure: results from the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) trial. Circulation. 2009;119:96977. Badgett RG, Lucey CR, Mulrow CD. Can the clinical examination diagnose left-sided heart failure in adults? JAMA. 1997;277:17121719. Berdague P, Caffin PY, Barazer I, et al. Use of N- terminal prohormone brain natriuretic peptide assay for etiologic diagnosis of acute dyspnea in elderly patients. Am Heart J. 2006;151:690698. Bouzamondo A, Hulot JS, Sanchez P, Lechat P. Beta-blocker benefit according to severity of heart failure. Eur J Heart Fail. 2003;5:281289. Brophy JM, Joseph L, Rouleau JL. Beta-blockers in congestive heart failure. A Bayesian meta-analysis. Ann Intern Med. 2001;134:550560. Charlon V, Dollow S, Fidel J, et al. Reproducibility of angiotensin converting enzyme inhibitor induced cough: a double-blind randomised study. Br J Clin Pharmacol. 1995;39:125129. Cleland JG, Daubert JC, Erdmann E, et al. The effects of cardiac resynchronization therapy on morbidity and mortality in heart failure. N Engl J Med. 2005;352:15391549. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med. 1986;314:1547 1552. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991;325:303310. Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet. 2001;357:13851390. Davis BR, Piller LB, Cutler JA, et al for the ALLHAT Collaborative Research Group. Role of diuretics in the prevention of heart failure. Circulation. 2006;113:22012210. Dickstein K, Kjekshus J, and the OPTIMAAL steering committee of the OPTIMAAL Study Group. Effects of losartan and captopril on mortality in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Lancet. 2002;360:752760. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336:525533. Dimopoulos K, Salukhe TV, Coats AJ, Mayet J, Piepoli M, Francis DP. Meta-analyses of mortality and morbidity effects of an angiotensin receptor blocker in patients with chronic heart failure already receiving an ACE inhibitor (alone or with a beta-blocker). Int J Cardiol. 2004;93:105111. Faris R, Flather MD, Purcell H, Poole-Wilson PA, Coats AJ. Diuretics for heart failure. Cochrane Database Syst Rev. 2006;(1):CD003838.2006. Garg R, Yusaf S, for the Collaborative Group on ACE Inhibitor Trials. Overview of randomized trial of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA. 1995;273:14501456. Hood WB Jr, Dans AL, Guyatt GH, Jaeschke R, McMurray JJ. Digitalis for treatment of congestive heart failure in patients in sinus rhythm. Cochrane Database Syst Rev. 2004;(2):CD002901. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult. Circulation. 2005;112(12):e154235. Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med. 2004;351:543551. Krum H, Haas SJ, Eichhorn E, et al. Prognostic benefit of beta-blockers in patients not receiving ACEInhibitors. Eur Hart J. 2005;26:21542158.
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Krum H, Roecker EB, Mohacsi P, et al, for the Carvedilol Prospective Randomized Cumulative Survival Study Group. Effects of initiating carvedilol in patients with severe chronic heart failure: results from the COPERNICUS study. JAMA. 2003;289:712718. Lee S, Spencer A. Beta-blockers to reduce mortality in patients with systolic dysfunction: a meta-analysis. J Fam Pract. 2001;50:499504. Lee VC, Rhew DC, Dylan M, Badamgarav E, Braunstein GD, Weingarten SR. Meta-analysis: angiotensinreceptor blockers in chronic heart failure and high-risk acute myocardial infarction. Ann Intern Med. 2004;141:693704. Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure [published correction appears in N Engl J Med. 2002;347:1126]. N Engl J Med. 2002;347:161167. McMurray JJ, Young JB, Dunlap ME, et al. Relationship of dose of background angiotensin-converting enzyme inhibitor to the benefits of Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-added trial. Am Heart J. 2006;349:985991. Moss AJ, Jackson W, Cannon DS, et al for the MADIT-CRT investigators. Cardiac resynchronization therapy for the prevention of heart failure events. N Engl J Med. 2009;361:13291338. Packer M, Coats AJS, Fowler MB, et al, for the Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:16511658. Packer M, Gheorghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic heart failure treated with ACE inhibitors. RADIANCE study. N Engl J Med. 1993;329:17. Packer M, O'Connor CM, Ghali JK, et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med. 1996;335:11071114. Packer M, Poole-Wilson PA, Armstrong PW, et al, on behalf of the ATLAS Study Group. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation. 1999;100:23122318. Pfeffer MA, McMurray JJV, Velazquez EJ, et al, for the Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:18931906. Piepoli MF, Davos C, Francis DP, Coats AJ; ExTraMATCH Collaborative. Exercise training meta-analysis of trials in patients with chronic heart failure (ExTraMATCH). BMJ. 2004;328(7433):189. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trialthe Losartan Heart Failure Survival Study ELITE II. Lancet. 2000;355:15821587. Pitt B, Remme W, Zannad F, et al, for the Eplerenone Post-Acute Myocardial infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:13091321. Pitt B, Zannad F, Remme WJ, et al, for the Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709717. Poole-Wilson PA, Swedberg K, Cleland JG, et al, for the COMET investigators. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the carvedilol or metoprolol European trial (COMET): randomized controlled trial. Lancet. 2003;362:713. Ravid D, Lishner M, Lang R, Ravid M. Angiotensin-converting enzyme inhibitors and cough: a prospective evaluation in hypertension and in congestive heart failure. J Clin Pharmacol. 1994;34:11161120. Reisin L, Schneeweiss A. Complete spontaneous remission of cough induced by ACE inhibitors during chronic therapy in hypertensive patients. J Hum Hypertens. 1992;6:333335. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA. 2005a;293:19001905.
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Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation. 2005b;111:14871491. The SOLVD investigators. The effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fraction. N Engl J Med. 1992;327:685691. The SOLVD investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293302. Tang ASL, Wells GA, Talajic M, et al for the RAFT investigators. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med. 2010;363:23852395. Utretsky BF, Young JG, Shahidi FE, Yellen LG, Harrison MC, Jolly MK. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial. J Am Coll Cardiol. 1993;22:955962. van Tol BA, Huijsmans RJ, Kroon DW, Schothorst M, Kwakkel G. Effects of exercise training on cardiac performance, exercise capacity and quality of life in patients with heart failure: A meta-analysis. Eur J Heart Fail. 2006; 8(8):841-50. West JA, Miller NH, Parker KM, et al. A comprehensive management system for heart failure improves clinical outcomes and reduces resource utilization. Am J Cardiol. 1997;79:5863. Willenheimer R, van Veldhuisen DJ, Silke B, et al. Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite sequence: results of the randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III. Circulation. 2005;112:24262435. Young JB, Abraham WT, Smith AL, et al for the MIRACLE-ICD investigators. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD trial. JAMA. 2003;289:26852694. Yusuf S, Sleight P, Pogue J, Bush J, Davis R, Dagenais G. Effects of angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145153. Zannad F, McMurray JJ, Krum H for the EMPHASIS-HF investigators. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364:1121.

Clinician Lead and Guideline Development

Clinician Lead David K. McCulloch, MD Medical Director, Clinical Improvement Phone: 206-326-3938 Most recent comprehensive literature review: April 2011 Process of Development This evidence-based guideline was developed using an explicit evidence-based process, including systematic literature search, critical appraisal with evidence grading, and evidence synthesis. The following specialties were represented on the development and/or update teams: cardiology, family medicine, nursing, epidemiology, laboratory services, and pharmacy.

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Appendix 1. Recommendation Grade Labels

About the Labeling System
This labeling system is adapted from the U.S. Preventive Services Task Force (USPSTF). The label is based on the degree to which the evidence supports the specific clinical recommendation as written by the Group Health guideline team. In this system, certainty refers to the likelihood that the guideline teams assessment of net benefit (i.e., the benefit minus harm of the service as implemented in a general primary care population) is correct, based on the nature of the overall evidence available. While the grades are useful tools in assessing recommendations, they are not meant to replace the clinical judgment of the individual provider or to establish a standard of care.

Recommendation Grade Definitions

Label Grade A Grade B Grade C Definition The service is recommended. There is high certainty that the net benefit (i.e., benefits minus harms) is substantial. The service is recommended. There is high certainty that the net benefit is moderate, or there is moderate certainty that the net benefit is moderate to substantial. The recommendation is against routinely providing the service. There may be considerations that support providing the service to an individual patient. There is at least moderate certainty that the net benefit is small. The recommendation is against providing the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits. The current evidence is insufficient to assess the balance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined. If the service is offered, patients should understand the uncertainty about the balance of benefits and harms. Expert opinion refers to the collective opinion of the Group Health guideline team. The language of the recommendation is at the team's discretion. The evidence is assumed to be insufficient unless otherwise stated. In the rare case there is fair or good evidence, the evidence does not support the expert opinion recommendation put forth by the team.

Grade D I statement

Expert opinion

Levels of Certainty Regarding Net Benefit

Level of certainty High Description The available evidence usually includes consistent results from well-designed, wellconducted studies in representative primary care populations. These studies assess the effects of the preventive service on health outcomes. This conclusion is therefore unlikely to be strongly affected by the results of future studies. The available evidence is sufficient to determine the effects of the preventive service on health outcomes, but confidence in the estimate is constrained by such factors as: The number, size, or quality of individual studies Inconsistency of findings across individual studies Limited generalizability of findings to routine primary care practice Lack of coherence in the chain of evidence As more information becomes available, the magnitude or direction of the observed effect could change, and this change may be large enough to alter the conclusion. The available evidence is insufficient to assess effects on health outcomes. Evidence is insufficient because of: The limited number or size of studies Important flaws in study design or methods Inconsistency of findings across individual studies Gaps in the chain of evidence Findings that are not generalizable to routine primary care practice A lack of information on important health outcomes More information may allow an estimation of effects on health outcomes.

Moderate

Low

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