• August 16, 2007, Coumadin (Warfarin): Updates to the labeling for Coumadin to include pharmacogenomics information to explain that people's genetic makeup may influence how they respond to the drug.
• June 8, 2007, Troponin-I Immunoassay: Class I Recall of all lots of the Architect Stat Troponin-I Immunoassay. The assay may report falsely elevated or falsely decreased results at and near a low level, which may impact patient treatment.

Note from the National Guideline Clearinghouse (NGC) and the Institute for Clinical Systems Improvement (ICSI): For a description of what has changed since the previous version of this guidance, refer to "Summary of Changes Report -- August 2007."

The recommendations for the management of heart failure (HF) in adults are presented in the form of 3 algorithms: Heart Failure in Adults, Emergent Management, and Acute Pulmonary Edema with a total of 58 components, accompanied by detailed annotations. Clinical highlights and selected annotations (numbered to correspond with the algorithm) follow.

Class of evidence (A-D, M, R, X) and conclusion grade (I-III, Not Assignable) definitions are repeated at the end of the "Major Recommendations" field.

Clinical Highlights

• Evaluate patients presenting with heart failure (HF) for exacerbating and underlying causes including coronary artery disease, hypertension, valvular disease, and other cardiac and non-cardiac causes. (Annotation #2)
• Studies show that the distinction between systolic dysfunction and preserved systolic function is important because the choice of therapy may be quite different and some therapies for systolic dysfunction may be detrimental if used to treat preserved systolic function. (Annotation #2)
• After evaluation, diagnosis, and initiation of pharmacologic and non-pharmacologic management of heart failure, follow-up in the ambulatory setting should focus on optimizing pharmacologic and non-pharmacologic therapy and preventing heart failure exacerbations. Patient education is central in this effort. (Annotations #13, 14)
• Daily weights are critical for managing heart failure and early detection of increases in fluid retention. Patients should call their provider about a two-pound or greater weight gain overnight or a five-pound or greater weight gain in a week. (Annotation #14)
• Unless specific contraindications exist, treat all patients, including Class IV patients, with beta-blockers starting with a low dose and titrate upward. Do not unnecessarily reduce or discontinue beta-blockers in severe or decompensated heart failure. After fluid overload and hypotension are corrected and when only one drug can be initiated, beta-blockers are preferred. (Annotation #13)
• Treat all patients with left-ventricular systolic dysfunction with angiotensin-converting enzyme (ACE) inhibitors (or angiotensin receptor blockers [ARBs] if intolerant) unless specific contraindications exist such as intolerance or adverse reactions to ACE inhibitors, serum potassium greater than 5.5 mEq/L, symptomatic hypotension, severe renal artery stenosis, or pregnancy. Gradually titrate dose up over a two- to three-month period. (Annotations #13)
• Consider treatment with aldosterone antagonists for Class III and IV heart failure patients with appropriate follow-up. (Annotation #13)
• Consider early specialty referral for patients with ischemia or those who are refractory despite optimal medical therapy. (Annotation #11)
• Brain natriuretic peptide (BNP) and proBNP is useful in the diagnosis and prognosis of heart failure in patients with dyspnea of unknown etiology. (Annotation #2)

Heart Failure Algorithm Annotations

1. Signs and Symptoms of Heart Failure (Excluding Acute Coronary Syndrome)

   Signs and Symptoms of Congestion:

   • Dyspnea
   • Orthopnea
   • Paroxysmal nocturnal dyspnea
   • Cough (recumbent or exertional)
   • Abdominal or epigastric discomfort
   • Abdominal bloating (ascites)
   • Early satiety
   • Hemoptysis, frothy or pink-tinged sputum
   • Pedal/leg swelling
   • Weight gain (rapid)
   • Sleep disturbances (anxiety or air hunger)
   • Chest tightness or discomfort
   • Unexplained confusion, altered mental status, or fatigue
   • Nausea or anorexia
   • Dependent edema

   Signs and Symptoms of Poor Perfusion/Low Cardiac Output:

   • Easy fatigability
   • Poor energy level or endurance
   • Decreased exercise tolerance
   • Cachexia
   • Muscle wasting or weakness
   • Nausea or anorexia
   • Early satiety
   • Weight loss, unexplained
   • Malaise
   • Impaired concentration or memory
   • Sleep disturbance
   • Altered mentation (somnolence, confusion)
   • Resting tachycardia
   • Daytime oliguria with recumbent nocturia
   • Cool or vasoconstricted extremities
   • Cheyne-Stokes respiration (with or without apnea)

   See Appendix B in the original guideline document for the New York Heart Association (NYHA) Classification and American College of Cardiology/American Heart Association (ACC/AHA) Staging System.

2. Initial Evaluation

   Key Points:

   • The diagnosis of heart failure should not be a single diagnosis. It is important to identify the etiology or precipitating factors as a cause of heart failure.
   • It is important to determine whether ventricular dysfunction is systolic or diastolic because therapies are quite different. Some therapies for systolic dysfunction may even be harmful if used to treat preserved systolic function.
   • Ischemia is responsible for the majority of cases of heart failure. Two-thirds of systolic heart failure is due to ischemic heart disease. Identifying ischemia as a cause of heart failure is important, because a majority of these patients would benefit from revascularization.

   The purpose of the initial evaluation, whether in the inpatient or outpatient setting should be to confirm a diagnosis of heart failure and identify an etiology/precipitating factor(s).

   Early triage should be performed to determine whether emergent or inpatient care is needed. Early identification of acute ischemia as the cause of heart failure is important because prompt reversal of ischemia may impact outcome.

   Consider consultation with cardiology during the initial evaluation and any time that it is felt appropriate in the ongoing management of HF patients.

   Questions to Determine Severity:

   1. History

      Presenting Symptoms:

      • Dyspnea/paroxysmal nocturnal dyspnea (PND)/orthopnea
      • Recent weight gain
      • Chest pain
      • Palpitations
      • Blood loss/causes of anemia
      • Recent fevers/viral infection
      • Cough/sputum production
      • Claudication
      • Exercise tolerance
      • Fatigue
      • Edema/ascites
      • Color changes

      Past Medical History:

      • History of congestive heart failure (CHF)
      • History of myocardial infarction (MI)
      • Cardiac risk factors
      • Hypertension/smoking/diabetes/hyperlipidemia
      • History/risk factors for thromboembolic disease
      • History of thyroid dysfunction
      • Recently postpartum
      • History of snoring/sleep apnea
      • Blunt chest injury
      • Rheumatic fever
      • Human immunodeficiency virus (HIV)
      • Bacterial endocarditis
      • Claudication
      • Screen for depression
      • Foreign travel

      Family History:

      • Screen for family history of ischemic heart disease, CHF, congenital heart disease, risk factors for arteriosclerotic cardiovascular disease (ASCVD) and CHF

      Social History:

      • Smoking
      • Alcohol use/abuse screen
      • Drug abuse

      Dietary History:

      • Salt and daily fluid intake
      • Balanced diet
   2. Physical Exam:
      • Vital signs, including weight and height
      • Diaphoresis
      • Diminished peripheral pulse or bruit
      • Skin color: cyanosis, pallor, jaundice
      • Lower extremity edema in the absence of venous insufficiency
      • Elevated jugular venous pressure, positive hepato-jugular reflux
      • Heart rate: tachycardia, bradycardia/arrhythmias
      • Left lateral displacement of the point of maximal impulse (PMI)
      • Heart sounds - S3, S4, murmur
      • Lungs: labored breathing, rales above the lower 25% of the lung that do not clear with cough
      • Abdomen - large, pulsatile, tender liver or ascites

      Evidence supporting this recommendation is of class: R

   3. Initial Laboratory Evaluation:
      • Initial
        • Complete blood count
        • Electrolytes (Na⁺, K⁺) and Cl^-, Bicarbonate, Ca^++, MG⁺⁺ (if on diuretics)
        • Renal function (blood urea nitrogen [BUN], creatinine [Cr])
        • Liver function (aspartate transaminase [AST], alanine transaminase [ALT], alkaline phosphatase, bilirubin, total protein (T Prot), albumin)
        • Urinalysis
        • Sensitive thyroid-stimulating hormone (sTSH)
        • Prothrombin time/international normalized ratio (PT/INR)
      • Inpatient/Emergency Department
        • Arterial blood gases
        • Tests for myocardial injury: troponin, creatine kinase/creatine kinase muscle band (MB) (CK/CKMB)
        • Brain natriuretic peptide (BNP)
      • Other Causes
        • Ferritin/iron/total iron-binding capacity (TIBC)/macrocytic anemias
        • Lipid profile
        • Blood culture if endocarditis suspected
        • Lyme serology (if suspect bradycardia/heart block)
        • Connective tissue disease work up
        • HIV

      Evidence supporting this recommendation is of class: R

      Refer to the original guideline document for information on ACC/AHA heart failure grading.

      Role of Brain Natriuretic Peptide (BNP) in the Diagnosis and Management of Heart Failure

      Brain natriuretic peptide (BNP) and ProBNP assays have been found useful in the diagnosis of patients with dyspnea of unknown etiology. Since BNP and ProBNP concentrations correlate positively with cardiac filling pressures, measurement of a low concentration make it unlikely that dyspnea is due to cardiac dysfunction.

      Refer to the original guideline document for more details on the role of BNP in the diagnosis and management of heart failure.

      Evidence supporting this recommendation is of classes: A, C, D

   4. Diagnostic Tests:
      • Electrocardiogram
      • Chest radiograph
      • Assessment of ventricular function (echocardiogram, radionuclide ventriculography)
        • It is reasonable to reassess ejection fraction (EF) if patient is clinically decompensated or after patient has been titrated up to target doses of beta-blockers and ACE inhibitors.
      • Ischemia evaluation in patients with coronary artery disease (CAD) risk factors (stress test, angiography). Refer to the National Guideline Clearinghouse (NGC) summary of the Institute for Clinical Systems Improvement (ICSI) guideline Diagnosis and Treatment of Chest Pain and Acute Coronary Syndrome (ACS), and Cardiac Stress Test Supplement.

      An electrocardiogram (ECG) and chest radiograph are fundamental parts of the initial evaluation for heart failure. In addition, the objective evaluation of ventricular performance is also a critical part for patients with suspected or known heart failure. Objective evaluation of left ventricular (LV) function is necessary because Chest x-ray (CXR), ECG, and history and physical examination (H&P) often fail to distinguish normal from low EF in patients with heart failure.

      Evidence supporting this recommendation is of classes D, M, R

      Refer to the original guideline document for additional information on specific etiologies of ventricular dysfunction, interpretation of ventricular function testing, and measurement techniques.

   5. Assess for Causative and Precipitating Factors

      Causes of heart failure can be classified as cardiac and non-cardiac. Refer to tables 2 and 3 in the original guideline document for the salient features of the more common causes.

      In patients with heart failure symptoms, it is important to determine if they have left or right ventricular systolic dysfunction or preserved systolic function. One-third of patients have predominantly preserved systolic function, one-third have both systolic and diastolic dysfunction and one-third have predominantly systolic dysfunction.

      Diastolic dysfunction is difficult to measure. Doppler echocardiography is currently the method of choice to assess diastolic dysfunction. It is, however, technically difficult and requires expert interpretation. Furthermore, loading conditions affect mitral inflow pulsed-wave Doppler parameters, making the differentiation between normal and pseudonormal diastolic dysfunction particularly difficult. Therefore, in addition to mitral inflow parameters, pulmonary venous (PV) flow Doppler and changes in mitral inflow parameters during Valsalva maneuver are commonly used to distinguish pseudonormal from normal diastolic function. BNP and proBNP measurements may help in the diagnosis of heart failure in patients with preserved EF. About two-thirds of patients with heart failure with preserved ejection fraction have moderate to severe diastolic dysfunction.

      The community prevalence of HF with preserved EF is high, and among these patients, most have preserved systolic dysfunction of moderate to severe degree. Heart failure with preserved systolic function has increased in prevalence over time. Patients with preserved ejection fraction are older, are more likely to be women, are less likely to be smokers or have a history of MI, and have a lower New York Heart Association class, but have similar comorbidities.

      Patients with heart failure with preserved systolic function have the same or only slightly better rates of survival than those with systolic heart failure.

      Evidence supporting this recommendation is of classes: B, C, R

3. Unstable Signs and Symptoms Requiring Emergent Management?

   Unstable symptoms may include:

   • Dyspnea: at rest/orthopnea (change from baseline), sudden onset of shortness of breath (SOB), worsening SOB, exertional dyspnea, gasping
   • SaO₂ less than 90%
   • Coughing up pink/frothy sputum
   • Dizziness or syncope
   • Chest pain
   • Systolic blood pressure (BP) less than 80 to 90 mmHg and symptomatic
   • Evidence of hypoperfusion (cyanosis, decreased level of consciousness, etc.)

   Assess Blood Pressure, Perfusion, and Volume Status

   Refer to Figure 1 in the original guideline document for clinical classification of the mode of heart failure.

4. Admit to Hospital if Necessary

   Consider hospitalization in the presence or suspicion of heart failure with any of the following findings:

   • Clinical, laboratory, or electrocardiographic evidence of acute myocardial ischemia or infarction
   • Severe symptoms of heart failure refractory to outpatient therapy
   • Pulmonary edema or severe respiratory distress
   • Thromboembolic complications requiring interventions
   • Severe complicating medical illness (e.g., pneumonia, renal failure)
   • Management of clinically significant arrhythmias (hemodynamic effects)
   • Anasarca (generalized edema)
   • Inadequate social support for safe outpatient management
   • Symptomatic hypotension or syncope
   • Hyperkalemia

   By definition, these patients are Stage C and D, NYHA Class III or IV. (See Appendix B in the original guideline document for the New York Heart Association Classification and ACC/AHA Staging System.) Heart failure should not be the final, stand-alone diagnosis. There should always be an associated etiology and/or contributing factor. The etiology of heart failure and the presence of exacerbating factors or other diseases that may have an important influence on management should be carefully considered in all cases.

6. Initiate Heart Failure Management

   Pharmacologic Management of Heart Failure:

   Medication	Beneficial Subsets
   ACE Inhibitors	NYHA Class I-IV
   ACE inhibitors slow disease progression, improve exercise capacity and decrease hospitalization and mortality. [Conclusion Grade I: See Conclusion Grading Worksheet D - Annotations # 6 and 13 (ACE Inhibitors) in the original guideline document.]
   Angiotensin II Receptor Antagonists	NYHA Class I-IV. Reduce afterload and improve cardiac output. Can be used for patients with ACE inhibitor cough.
   Hydralazine/Isosorbide Dinitrate	Patients intolerant to ACE inhibitors
   Diuretics	Fluid overload (edema, ascites, dyspnea, weight gain)
   Aldosterone Antagonists	NYHA Class III-IV
   Digoxin	NYHA Class II-IV; patients with atrial fibrillation; patients with S3 gallop, left ventricular (LV) dilatation, high filling pressures
   Digitalis improves symptoms, exercise tolerance, and quality of life, but neither increases nor decreases mortality. [Conclusion Grade I: See Conclusion Grading Worksheet E - Annotations #6 and 13 (Digitalis) in the original guideline document.]
   Beta-Blockers	Stable NYHA Class I-IV

   Refer to the original guideline document for information on initial daily doses and optimal (target) daily doses.

   Treatment of Systolic Dysfunction

   The cornerstone of treatment is the use of beta-blockers and ACE inhibitors. Certain beta-blocking medications have been shown to improve clinical symptoms and ventricular function in patients with systolic dysfunction.

   Beta-blockers decrease hospitalizations and mortality and have objective beneficial effect on measures of exercise duration. [Conclusion Grade I: See Conclusion Grading Worksheet C – Annotation #6 and 14 (Beta-blockers and Exercise) in the original guideline document]

   ACE inhibitors prolong life in patients with HF symptoms and EF less than 35% and reduce symptom development in asymptomatic patients with EF less than 35%.

   There is also a mortality benefit in the use of ACE inhibitors in patients with recent myocardial infarction and asymptomatic EF less than 40%.

   ACE inhibitors slow disease progression, improve exercise capacity, and decrease hospitalizations and mortality. [Conclusion Grade I: See Conclusion Grading Worksheet D - Annotations #6 and 13 (ACE Inhibitors) in the original guideline document]

   Refer to the original guideline for additional information on treatment of systolic dysfunction.

   Evidence supporting this recommendation is of classes: A, D

   Treatment of Heart failure with Preserved Systolic Function

   For the management of preserved systolic function it is particularly important to address the underlying etiology. Ischemia and hypertension must be optimally controlled. Pericardial disease must be specifically treated if present. Control of atrial tachyarrhythmias may be of particular importance since these patients need adequate time for diastolic filling and they tolerate tachycardias poorly. Beta-blockers may be of value to slow the heart rate and allow a longer time interval for diastolic filling.

   In general, drugs used to treat systolic dysfunction (ACE, ARBs, diuretics, beta-blockers) are generally found to be effective in patients with heart failure with preserved systolic function.

   Diuretics may be helpful to control volume overload and edema. They should be used in the lowest dose needed since excessive diuresis may cause orthostatic hypotension or prerenal azotemia. Arteriolar vasodilators or venodilators should be used with caution as they may cause serious hypotension.

   Patients with hypertrophic cardiomyopathy should be identified and may benefit from genetic counseling. Patients with hypertrophic cardiomyopathy may benefit from beta-blockers to slow heart rate. Some may benefit from verapamil or disopyramide if beta-blockers are not effective. In cases of significant intracavitary pressure gradients, dual chamber pacing or septal myectomy surgery may be indicated.

   Particular attention must be given to the control of atrial tachyarrhythmias. Care should be taken to avoid venodilators and arterial vasodilators.

   See Annotation #13, "Pharmacologic Management" for inpatient medications.

   Evidence supporting this recommendation is of classes: A, C

   For patients with predominant heart failure with preserved systolic function:

   Treat specific contributing causes:

   • Hypertension (goal is blood pressure of 130/85 mm Hg). See also the NGC summary of the ICSI guideline Hypertension Diagnosis and Treatment.
   • Ischemic heart disease
   • Hypertrophic cardiomyopathy - consider referral to subspecialist (for verapamil, disopyramide, surgical myectomy, pacemaker)
   • Constrictive pericarditis

   Pharmacologic Management for Preserved Systolic Function:

   Medication	Beneficial Subsets
   ACE Inhibitors	NYHA Class I-IV. Use with caution as they may cause serious hypotension.
   Angiotensin II Receptor Antagonists	NYHA Class I-IV. Reduce afterload and improve cardiac output. Can be used for patients with ACE inhibitor cough.
   Diuretics	Use with caution to manage fluid retention but not at doses which cause significant orthostatic hypotension or prerenal azotemia.
   Beta Blockers	Patients with atrial fibrillation

   See original guideline document for dosing comments.

   (See also Annotation #13 for further description of pharmacologic management.)

7. Coronary Artery Disease (CAD) Known or Suspected and Potential Revascularization Candidate?

   Refer to the NGC summary of the ICSI guideline Stable Coronary Artery Disease.

11. Consider Specialty Referral/Out of Guideline

    Key Points:

    • Primary care providers should continue to be involved in the decision making process when subspecialty consultation and management are necessary.
    • Communication between the primary care giver and the cardiologist is key and should be encouraged even before the need for a referral in order to integrate seamless diagnostic and therapeutic care.

    Once it has been determined that the patient is a candidate for revascularization, the next step is angiography performed by a cardiologist. Subspecialty consultation will generally involve not only performance of the procedure, but also recommendation for further management. Primary care providers should continue to be involved in the decision-making process. Primary care providers should also be familiar with risks associated with various patterns of disease distribution seen on angiogram. The decision to proceed with revascularization must be determined on an individual basis. Consultation should take place among the patient, primary care provider, cardiologist, and cardiovascular surgeon to determine the most appropriate course of action.

    If the results of the angiogram do not show significant CAD or if the decision is made not to proceed with revascularization, pharmacological management should be continued (see Annotation #13, "Pharmacologic Management").

    Patients with advanced structural heart disease and marked symptoms of heart failure at rest despite maximum medical therapy and who require specialized interventions are outside of this guideline. These are primarily Stage D classed patients.

    • Assumes that all recommendations for Stages A, B, C have been maximized, including utilization of neurohormonal inhibitors.
    • Management of fluid status has been aggressively pursued.
    • Accuracy of Stage D diagnosis is confirmed.
    • Any contributing conditions have been identified and treated.

    Refer to the original guideline document for additional information on surgical procedures; left ventricular assist devices; continuous infusions of positive inotropic agents such as dobutamine, dopamine, or milrinone; hospice; and when to consider referral to subspecialist.

    Evidence supporting this recommendation is of classes: A, R

12. Treat Secondary Causes of HF and Significant Comorbid Conditions and Risk Factors

    Treat as indicated by the particular disease state. Specific treatment modalities for secondary causes of HF are considered outside of the scope of this guideline. See Table 2: Cardiac Related Causes of HF with Reduced Systolic Function and Table 3: Non-Cardiac Related Causes in the original guideline document. See also the NGC summary of the ICSI guideline Hypertension Diagnosis and Treatment.

13. Pharmacologic Management

    Key Points:

    • Carvedilol, metoprolol succinate (extended release), and bisoprolol have demonstrated reductions in mortality over other generic beta blockers for patients with all classes of heart failure.
    • ACE inhibitors should be prescribed for all patients with left ventricular systolic dysfunction unless specific contraindications exist. An elevated baseline creatinine is not a specific contraindication.
    • ACE inhibitors are more effective in decreasing heart failure mortality than the isosorbide dinitrate/hydralazine combination.
    • Angiotensin receptor blockers should be considered primarily for patients who are intolerant of ACE inhibitors or those receiving standard drug therapy (including ACE inhibitors) who continue to show clinical deterioration.
    • Routine use of angiotensin receptor blockers with ACE inhibitors and aldosterone antagonists cannot be recommended.
    • Diuretics should not be the sole therapy for patients with signs of volume overload, and vasoactive drugs should also be considered.
    • Loop diuretics are more effective in severe heart failure than thiazide diuretics, and combination therapy with thiazide (or thiazide-like medication) and loop diuretic may be used in refractory cases of volume overload.
    • Aldosterone blocking agents (spironolactone, eplerenone) reduce mortality in patients with Class III-IV heart failure for patients on stable doses of digoxin and ACE inhibitors.
    • Currently, the work group recommends that nesiritide be reserved for patients with acutely decompensated heart failure who remain volume overloaded despite aggressive treatment, display tolerance and/or resistance to vasodilators or diuretics, or demonstrate significant side-effects to other vasodilators.
    • ACE inhibitors should be prescribed for all patients with left ventricular systolic dysfunction unless specific contraindications exist. Studies show ACE inhibitors are widely underprescribed.
    • Calcium channel blockers should be used with caution in patients with heart failure.

    Beta-Blockers

    • When only one drug can be initiated, beta blockers are preferred.
    • Studies strongly support use of certain beta-blockers which have demonstrated reductions in mortality (e.g., carvedilol, metoprolol succinate [extended release], bisoprolol) in patients with Class I-IV CHF. Recent data from COMET demonstrated carvedilol to have a 17% risk reduction in mortality over metoprolol tartrate (immediate release).
    • The beta blocker should be started as soon as the patient is stable (without fluid overload or hypotension).
    • After appropriate stabilization, it may be safe to start beta-blockers in the inpatient setting. Beta-blockers decrease hospitalizations and mortality. [Conclusion Grade I: See Conclusion Grading Worksheet F - Annotation #13 (Beta Blockers and Inpatient Setting) in the original guideline document]
    • Beta blockers should be started at low initial doses and titrated up gradually at rates consistent with those from key studies.
    • Do not unnecessarily reduce or discontinue the dose of beta-blocker.
    • If significant bradycardia/atrioventricular (AV) block occurs with use of beta- blockers, the dose may need to be decreased. If hypotension or fluid retention occurs, either the dose of beta-blocker, ACE inhibitor, or diuretics should be adjusted as clinically appropriate.
    • Patients should be informed that positive effects of beta-blockers may not be seen until several months after titration to target dose.
    • Beta-blockers have objective beneficial effect on measures of exercise duration.
    • Beta-blockers have been shown to decrease mortality and reinfarction among patients with compensated HF following acute myocardial infarction.
    • Beta-blockers have been shown to improve hemodynamics in patients with idiopathic dilated cardiomyopathy.
    • For rate control in tachycardia induced heart failure, the work group prefers beta-blockers over other agents.

    Evidence supporting this recommendation is of classes: A, M

    Carvedilol

    • The COMET trial demonstrated carvedilol to have a 17% risk reduction in mortality over metoprolol tartrate.
    • Recommended starting dose for carvedilol is 3.125 mg twice daily for two weeks. Dosage can be doubled every two weeks to highest level tolerated by patient to maximum 25 mg twice daily (less than 85 kg) or 50 mg twice daily (greater than 85 kg). It is suggested that after initiation of each new dose, patients should be observed for signs of dizziness or lightheadedness. Also consider instructing patients to take carvedilol two hours before ACE inhibitors to decrease potentiating effects. Carvedilol should be taken with food to slow the rate of absorption and reduce the risk of postural hypotension.
    • There are now prospective randomized controlled data available for carvedilol that have shown a reduction in hospitalization and death from heart failure.

    Evidence supporting this recommendation is of class: M

    Metoprolol Succinate

    • In the MERIT HF study of metoprolol succinate compared to placebo, a mortality reduction was shown at one year in patients with NYHA Class II-IV heart failure.
    • There are no head-to-head trials comparing carvedilol and metoprolol succinate (extended release).
    • Recommended starting dose of metoprolol succinate is 25 mg/once daily. In patients with more severe heart failure (NYHA Class III or IV) recommended starting dose is 12.5 mg/once daily. The dose may then be doubled every two weeks up to the highest tolerated dose or up to 200 mg/once daily.

    Evidence supporting this recommendation is of classes: A, M

    Vasodilators

    ACE Inhibitors

    • ACE inhibitors are widely underprescribed.
    • ACE inhibitors should be prescribed for all patients with left-ventricular systolic dysfunction unless specific contraindications exist.
    • Contraindications include:
      • History of intolerance or adverse reactions to these agents
      • Serum potassium greater than 5.5 mEq/L
      • Symptomatic hypotension (unless due to excessive diuresis)
      • Severe renal artery stenosis
      • Pregnancy
      • Cough and rash side effects
    • ACE inhibitors should be prescribed or ARBs if contraindications exist.
    • To optimize mortality reductions possible with ACE inhibitors, the dose must be titrated to the moderate to high dose range (e.g., 20 to 40 mg Lisinopril daily). Lower dose therapy has been shown to be less effective in reducing mortality.
    • Approach to initiating ACE inhibitor therapy:
      • Start at a low dose and titrate upward over several weeks to targeted moderate to high doses and maximum tolerated dose.
      • Consider holding one dose of diuretic before giving the first dose of ACE inhibitors, particularly in patients with low baseline blood pressure.
    • Hypotension. Patients should be well hydrated before initiation or increase of ACE inhibitors. If the patient develops hypotension in the absence of hypovolemia, splitting the dose or switching from morning (a.m.) to at-bedtime dosing (in long-acting agents) may be helpful. If this is ineffective, the dose should be reduced to the highest dose tolerated.
    • Periodically monitor for changes in renal function and potassium as well as other electrolytes with these agents, especially when titrating doses and when concomitantly administered with other agents known to affect electrolytes (diuretics, ACE inhibitors, angiotensin blocking agents, aldosterone antagonists).
    • Renal Insufficiency. Creatinine should be monitored regularly in patients on ACE inhibitors, and more frequently during active titration. An increase in serum creatinine of 0.5 mg/dL or more is an indication for reassessment of volume status. There is no absolute level of creatinine to preclude the use of ACE inhibitors.
    • All ACE inhibitors that have been studied to date in treatment of HF have shown benefit. Therefore, simpler dosing regimens may be equally effective and less expensive.
    • For patients with asymptomatic or mildly symptomatic decreases in left ventricular (LV) systolic performance, use of ACE inhibitors has been shown to decrease mortality, progression of HF, and need for hospitalization.
    • In the general population, ACE inhibitors are more effective in decreasing HF mortality than the isosorbide dinitrate/hydralazine combination.
    • In studies demonstrating decreased mortality in HF relatively high doses of ACE inhibitors were used.
    • Enalapril 20 mg daily (twice daily dosing)
    • Captopril 100 to 150 mg daily (three times daily dosing)
    • ACE inhibitors slow disease progression, improve exercise capacity, and decrease hospitalizations and mortality. [Conclusion Grade I: See Conclusion Grading Worksheet E- Annotations #6 and 13 (ACE Inhibitors) in the original guideline document]

    Evidence supporting this recommendation is of class: A

    Angiotensin Receptor Blockers (ARB)

    • ARBs are to be used if ACE inhibitors are not tolerated.
    • Based on the findings of the series of Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) studies, recommendations to consider adding an angiotensin receptor blocker to standard optimized drug therapy for those with systolic dysfunction may be supported. An ARB is the preferred alternative to hydralazine/isosorbide dinitrate in most patients because of ease of use except in renal dysfunction, hyperkalemia, and possibly in African-Americans.
    • Specifically, according to the CHARM-Added trial, there is a benefit in terms of composite cardiovascular endpoints when adding ARB to a regimen of an ACE inhibitor and beta-blockers (triple therapy). This observation is consistent overall, with the results of the Val-HeFT study. In spite of subgroup analysis from Val-HeFT suggesting that the addition of an ARB to the ACE inhibitor and beta-blocker may have resulted in a negative effect on both mortality and morbidity, the group feels that, based on the findings from the CHARM-Added study, the combination of ARBs to an ACE inhibitor and beta-blocker regimen is more favored than disfavored at this time.
    • Only valsartan and candesartan are approved for use in patients with heart failure.
    • Direct comparison with regards to mortality in patients with HF showed no difference between the ARB losartan and captopril.
    • According to the Valsartan In Acute Myocardial Infarction (VALIANT) trial, 2003, there is no benefit when adding ARB to ACE inhibitors in early post MI patients.
    • Contraindications to ARBs include history of intolerance or adverse reactions to serum potassium greater than 5.5 mEq/L, symptomatic hypotension (unless due to excessive diuresis), severe renal artery stenosis, and pregnancy.

    Evidence supporting these recommendations is of class: A

    Diuretics

    • Patients with signs of volume overload should be started on a diuretic; however, this should not be sole therapy.
    • Severe volume overload, severe renal insufficiency (creatinine clearance less than 30 mL/min), or persistent edema despite thiazide diuretics are all indications to use a loop diuretic.
    • Combination therapy that combines a thiazide or a thiazide-like medication such as metolazone with a loop diuretic may be used in refractory cases of volume overload.
    • Periodically monitor for changes in renal function and potassium as well as other electrolytes with these agents, especially when titrating doses and when concomitantly administered electrolytes (diuretics, ACE inhibitors, angiotensin blocking agents, and aldosterone antagonists).
    • Excessive diuresis may result in:
      • Prerenal azotemia
      • Orthostatic hypotension
      • Hypokalemia and hypomagnesemia
      • Inability to achieve optimal dose of ACE inhibitor
      • Activation of the renin-angiotensin-aldosterone (RAAS) system
    • Fluctuating volume status may necessitate ongoing diuretic adjustment that requires frequent monitoring for electrolyte imbalances and hypotension.
    • In patients refractory to furosemide, a combination of oral or intravenous (IV) thiazide diuretics to block the distal tubules followed one hour later by a loop diuretic may be beneficial in achieving diuresis.
    • Diuretic effectiveness may be increased by 1 to 2 hours of bed rest (supine position) after taking diuretics.
    • Hyponatremia is an indication for fluid restriction in a volume-overloaded patient and a decrease in diuretic in a volume-depleted patient.
    • Hyperkalemia may be the result of too much potassium supplementation, potassium-sparing diuretics, digoxin toxicity, ACE inhibitor or ARB use, or renal insufficiency.
    • Hypomagnesemia often accompanies hypokalemia. If high doses of diuretic are used, serum magnesium levels should be checked regularly and oral supplementation given as indicated. Hypomagnesemia may prevent correction of hypokalemia.
    • Orthostatic hypotension may indicate overdiuresis in the absence of congestive symptoms and may be accompanied by an increased blood urea nitrogen (BUN) to creatinine ratio. If volume depletion is not present, intolerance of the ACE inhibitor is likely (see "ACE Inhibitors" earlier in this annotation).

    Evidence supporting these recommendations is of classes: A, C, D

    Aldosterone Blocking Agents

    Spironolactone

    • A multi-center, randomized clinical trial showed a reduction in mortality among patients with Class III-IV HF who were treated with spironolactone 25 to 50 mg per day. These patients were already on stable doses of digoxin and ACE inhibitors. In the Randomized Aldactone Evaluation Study (RALES), 25 mg per day of spironolactone was found to decrease morbidity and mortality. The mechanism is felt to be due to inhibition of aldosterone effects on myocardial cell death. Hyperkalemia is a side effect of spironolactone and potassium levels should be checked three to seven days after starting the drug.

    Eplerenone

    • Eplerenone, a selective aldosterone antagonist with fewer endocrine side effects than spironolactone, was evaluated in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trial. It was used in study subjects who had a myocardial infarction 3 to 14 days prior and had a left ventricular ejection fraction (LVEF) less than 40% with evidence of HF (in 90%) and/or diabetes mellitus. Patients with a plasma creatinine greater than 2.5 mg/dL or potassium over 5 mEq/L were excluded. The starting dose was 25 mg/day, increased to 50 mg/day after four weeks. There was a significant lower rate of all-cause mortality (14.4%) due to reduction in cardiovascular mortality, reduction in sudden cardiac death, decreased mortality and hospitalizations for HF. Most patients in this trial (unlike RALES) were on an ACE Inhibitor, A2 blocker and a beta-blocker
    • The mean left ventricular ejection fraction (LVEF) in EPHESUS was 33% (compared to 25% in RALES), suggesting that patients with less severe heart failure than seen in the RALES trial, might benefit from aldosterone antagonism. The NYHA class in the EPHESUS trial could not be established as most patients had an MI two weeks prior to enrollment.
    • The current recommendation would be to use spironolactone for patients who fulfill the RALES criteria (current or recent NYHA class IV HF, class III HF with patient being in class IV HF in the past 6 months, preserved renal function, or reduced potassium concentration). Eplerenone could be used for patients who have had a recent MI, LVEF less than 40%, and symptomatic HF and/or diabetes as a pharmacologic alternative to spironolactone with less risk of gynecomastia. However, the cost and lack of outcome studies in the heart failure area would be a limiting factor.

    Evidence supporting these recommendations is of class: A

    Inotropes

    The inotropes – dobutamine, dopamine, and milrinone – have failed to demonstrate the ability to improve mortality in the treatment of severe decompensated heart failure. A review of the literature has in fact shown an increase in mortality with the use of these agents. [Conclusion Grade I: See Conclusion Grading Worksheet G - Annotation #13 (Inotropes) in the original guideline document]. The use of these inotropes should therefore be restricted to those patients needing symptomatic relief who are no longer responding to other therapies. [Conclusion Grade III: See Conclusion Grading Worksheet G - Annotation #13 (Inotropes) in the original guideline document] As palliative treatment in select patients, the available data supports continuous infusion over repetitive intermittent infusion.

    Digoxin

    • Digoxin is a useful drug in heart failure patients with atrial fibrillation with a rapid ventricular response.
    • Digoxin in combination with ACE inhibitors has been shown to be of benefit in regard to hospitalization heart failure patients.
    • The initiation of digoxin in asymptomatic heart failure patients still remains unsupported by clinical trials.
    • Loading doses are generally not needed and steady state generally takes one week to reach (longer in patients with renal impairment).
    • Serum levels of 0.7 to 1.5 ng/mL are considered therapeutic. Serum levels do not always correlate to symptoms of digoxin toxicity.
    • Monitor for symptoms of toxicity (nausea, confusion, visual disturbance, anorexia), reduction of renal function, or conduction abnormality.
    • To avoid digitalis toxicity, care should be used to use lower doses in the elderly and those with renal impairment, check digitalis level in one to two weeks after start of therapy in elderly or renal-impaired patients, and beware of drug interactions with new medications.
    • In subjects in normal sinus rhythm with preserved systolic function (PSF) and mild to moderate heart failure symptoms on optimal therapy, digoxin had no effect on the endpoints of all-cause or cardiovascular mortality or hospitalization.
    • Post hoc retrospective analysis of mortality statistics regarding the use of digoxin in heart failure indicate that the drug may actually increase mortality in women when compared to placebo. There are no randomized, prospective studies to confirm gender-based differences, but practitioners may want to consider this information when prescribing digoxin to women. If digoxin therapy is to be continued in women, it may be reasonable to recommend that lower dosing (0.125 mg per day) should be used and lower serum levels (1.0 or less) should be maintained.

    Evidence supporting this recommendation is of class: A

    Other Vasodilators

    • Alpha-adrenergic blockers (prazosin, terazosin) have not demonstrated survival or functional benefit in the treatment of HF

    Evidence supporting this recommendation is of class: A

    Nitroglycerin (Intravenous)

    • Food and Drug Administration (FDA) Indication: Intravenous nitroglycerin is indicated for the treatment of heart failure in patients with concomitant acute myocardial infarction.
    • Non-FDA indication: Nitroglycerin can be used to treat pulmonary edema.
    • Following acute MI, early parenteral nitrate therapy has been documented to result in a lower incidence of new heart failure. Intravenous nitroglycerin is the only dosage form approved in the U.S. for use in heart failure associated with acute myocardial infarction, although sublingual, transmucosal, and transdermal dosage forms have been used for both acute and chronic symptomatic control.
    • Nitroglycerin is normally reserved for patients whose cardiac index is adequate but pulmonary wedge pressure is elevated (greater than 18 mm Hg). A combination of diuretics and nitroglycerin or nitrates is effective in lowering pulmonary capillary wedge pressure.
    • In one study versus nitroprusside, results supported a preference for nitroglycerin over nitroprusside for the treatment of heart failure and/or acute hypertension complicating acute myocardial infarction.
    • Severe hypotension, particularly with upright posture, may occur even with small doses of nitroglycerin. The drug, therefore, should be used with caution in subjects who may have volume depletion from diuretic therapy or in patients who have low systolic blood pressure (e.g., below 90 mm Hg).
    • Paradoxical bradycardia and increased angina pectoris may accompany nitroglycerin-induced hypotension. Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.
    • Tolerance to this drug and cross-tolerance to continuous use of other nitrates may occur within days.

    Evidence supporting this recommendation is of classes: A, M, R

    Nitroprusside (Intravenous)

    • Nitroprusside is FDA indicated for the treatment of acute congestive heart failure.
    • Nitroprusside has been shown to cause significant and sustained symptomatic improvement in severe, refractory heart failure due to a variety of causes. However, in acute MI patients with subsequent left ventricular failure, the use of nitroprusside has been associated with an increase in mortality. Due to this study and the well-known propensity for nitroprusside to induce a "coronary steal syndrome," it is recommended to avoid use of nitroprusside in patients experiencing ischemia.

    Evidence supporting this recommendation is of classes: A, D, R

    Nesiritide

    • Nesiritide is FDA approved for the intravenous treatment of patients with acutely decompensated heart failure who have dyspnea at rest or with minimal activity.
    • In patients hospitalized with decompensated heart failure, nesiritide was shown to improve hemodynamic function and clinical status. When added to standard care in patients hospitalized with acutely decompensated heart failure, one study confirmed that nesiritide significantly reduced pulmonary capillary wedge pressure more than nitroglycerin or placebo. These effects were sustained for at least 24 hours.
    • In comparison with dobutamine, nesiritide causes significantly fewer heart rate variances, tachycardia, premature ventricular beats, repetitive beats, and neurohormonal activation. In comparison to dobutamine, nesiritide is associated with a shorter treatment course, the use of fewer additional parenteral agents, a lower hospitalization rate, and a significantly lower mortality rate at six months.
    • Compared with noninotrope-based control therapy, nesiritide may be associated with an increased risk of death after treatment for acutely decompensated heart failure. Until further studies can be done, it is the opinion of this group that other vasodilators and/or diuretics be attempted prior to a trial of nesiritide.
    • If nesiritide is to be used, the best candidates for therapy are patients with decompensated heart failure who have clinical evidence of fluid overload and/or raised central venous pressure.
    • There is little experience with infusions of nesiritide for more than 48 hours.
    • In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with nesiritide may be associated with azotemia.

    Evidence supporting this recommendation is of classes: A, R

    Hydralazine/Isosorbide Dinitrate

    • Hydralazine/isosorbide dinitrate may be considered as a therapeutic option in those patients experiencing hyperkalemia or renal insufficiency secondary to ACE inhibitor, and possibly ARB usage.
    • There is favorable evidence for the use of a fixed dose of hydralazine + isosorbide dinitrate in African-Americans with Class III and IV heart failure.
    • If higher doses of ACE inhibitors or ARBs are not tolerated despite euvolemia, a lower dose should be continued and/or a trial of hydralazine/isosorbide dinitrate instituted.
    • Hydralazine combined with isosorbide dinitrate has been shown to reduce mortality and increase exercise tolerance in patients with symptomatic HF.

    Evidence supporting this recommendation is of class: A

    Calcium Channel Blockers

    • Diltiazem, nifedipine, and verapamil have been associated with adverse outcomes in patients with diminished LV function and should be avoided.
    • Among the calcium antagonists, amlodipine seems less likely to worsen non-ischemic heart failure. The Prospective Randomized Amlodipine Survival Evaluation (PRAISE) study demonstrated no adverse effects on survival or cardiac morbidity when amlodipine was added to patients with Class II or III heart failure with EF less than 30% and in whom an ACE inhibitor, digoxin and diuretics were already being used.

    Evidence supporting these recommendations is of class: A

    Antiarrhythmics

    • The role of prophylactic antiarrhythmic drug therapy to prevent sudden cardiac death in patients with cardiomyopathy, HF, and asymptomatic ventricular ectopic activity (ventricular premature beats [VPBs] or non-sustained ventricular tachycardia [NSVT]) is probably not recommended. These drugs are less likely to suppress ventricular arrhythmias in patients with HF and may be associated with life-threatening complications such as proarrhythmia, which is more likely in HF, and worsening of left ventricular function.
    • Nearly all antiarrhythmic agents can exert clinically significant negative inotropic effects, which may limit the utility and safety of these drugs in patients with left ventricular dysfunction.
    • Only amiodarone and dofetilide have been shown to be mortality neutral when treating arrhythmias in patients with heart failure.
    • The recent publication of the results of the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), demonstrated that in patients with NYHA Class II or Class III CHF and LVEF of 35 percent or less, amiodarone had no favorable effect on survival, despite the use of appropriate dosage and reasonable compliance rates over longer periods than in other placebo controlled trials. Whereas single-lead, shock-only instantaneous cardiac death (ICD) therapy reduces overall mortality and the relative risk of death by 23 percent, resulting in an absolute reduction of 7.2 percentage points at five years among patients with CHF who received state-of-the-art background medical therapy, and the benefit did not vary according to the cause of CHF.
    • In the Multicenter Automatic Defibrillator Implantation Trial 2 (MADIT 2), a study of patients who had had a myocardial infarction, and in the Antiarrhythmics Versus Implantable Defibrillators (AVID) study, a secondary prevention trial, the worse the ejection fraction, the greater the benefit of ICD therapy. In the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial, patients in NYHA Class III derived the largest survival benefit from ICD therapy.

    Evidence supporting this recommendation is of class: A

    Anticoagulants

    • Anticoagulation with warfarin is indicated in heart failure (HF) patients with atrial fibrillation mechanical heart valves, or in patients with impaired systolic function (i.e., ejection fraction [EF] less than 20%) and prior thromboemboli and left ventricular mural thrombi. No studies to date have shown a significant difference in major outcomes with patients taking warfarin.
    • Emboli due to ventricular thrombi in patients with chronic congestive failure are uncommon and occur most frequently in patients with very low ejection fractions (less than 20%).
    • Patients with atrial fibrillation and heart failure are at high risk for thromboemboli.

    Refer to the NGC summary of the ICSI guideline Antithrombotic Therapy Supplement.

    Evidence supporting these recommendations is of classes: A, B

14. Non-Pharmacologic Management

    Key Points:

    • Dietary indiscretion is the most common cause of exacerbation of heart failure.
    • Sodium restriction alone may provide substantial benefits for heart failure patients. Dietary counseling is important for patients to learn the need for fluid balance management, avoiding excess sodium and/or water intake. Referral to a dietitian should be considered for patients with comorbid conditions or repeat episodes of edema.
    • Daily weights are important for managing heart failure and early detection of increases in fluid retention. Patients should call their provider for a two-pound or greater weight gain over night or a five-pound or greater weight gain in a week.
    • Simplifying medication regimes as much as possible should be explored. All medications, including over the counter (OTC) medications should be reviewed at each visit.
    • Major depression is common in patients hospitalized with heart failure and is independently associated with a poor prognosis. Additionally, depression is independently associated with a substantial increased risk of heart failure in older patients with isolated systolic hypertension.
    • Consider utilizing a heart failure clinic or case management for patients with medical problems or at high risk for re-hospitalization.

    Patient education for early symptom recognition and counseling about their disease process should be initiated at this time. See the Other Resources Available section in the original guideline document for Web sites and tools to assist the provider and patient with non-pharmacologic management of heart failure.

    Refer to the original guideline documents for additional information on dietary recommendations, daily weights, medication regimens, exercise and activity guidelines, smoking cessation, coping with chronic diseases, advanced directives, and end-of-life considerations.

15. Symptom Control Satisfactory?
    • Consider reassessment of ventricular function (echocardiography or radionuclide ventriculography) if the symptoms persist despite changes in pharmacologic management or if symptoms markedly change.

16. Ongoing Assessment of Response to Treatment and Evaluation for Symptom Exacerbation
    • After initial evaluation and diagnosis, follow-up of HF patients in the ambulatory setting should focus on optimizing pharmacologic therapy and prevention of HF exacerbations.
    • Patient education should be ongoing and consistently reinforced, and family members should be a part of this process whenever possible. Symptoms of worsening heart failure should be explained, and patients should be advised to contact their provider or nurse if these symptoms develop.
    • Patients should be advised to call their provider for a greater or equal two pounds/day weight gain or five or more pounds/week.
    • Also refer to Appendix A in the original guideline document, "Strategies to Address Adherence to Treatment Plan."

    Accessibility

    Intimidation by or frustration with large health care systems and social isolation are factors that distance patients from their health care providers. A patient's failure to maintain this contact, as well as inadequate patient education, contribute to poor patient compliance and high hospital admission and readmission rates in this population.

    • To prevent HF exacerbation, efforts and resources should be directed toward early intervention in the form of increased accessibility to care and education aimed at symptom recognition and treatment plan adherence.
    • Frequently, patients wait until they are in crisis before seeking medical assistance, bypassing the provider's office and going straight to the emergency department (ED). Limited hours and limited/untrained staff at providers' offices have been cited as reasons patients seek acute care with worsening symptoms of heart failure.
    • Case managers and HF clinics may be effective strategies to avert ED visits and hospitalizations by providing patients with a contact person who is familiar with their care to expedite treatment alternatives. This contact person, usually a nurse, is available to answer questions and clarify instructions, potentially increasing treatment plan compliance. The nurse should have adequate ancillary support services available (e.g., social workers, dietary, etc.)
    • Time between visits is important for the patient to formulate questions and assimilate the previously presented information. Family members and care givers should also be involved in education to support the patient's efforts.

    Evidence supporting these recommendations is of classes: A, R

Emergent Management Algorithm Annotations

18. Initial Patient Assessment
    • History
    • Physical

    Notes:

    • Patients with decompensated aortic stenosis should not receive vasodilator agents (vs. mitral regurgitation patients that benefit greatly).
    • Patients with jugular venous distension from right ventricular infarct may require a fluid challenge.
    • Patients with low cardiac output and peripheral vasoconstriction have unreliable noninvasive blood pressure measures.
    • Digoxin, as an inotrope, is not useful in the acute management of decompensated heart failure (may be used to control atrial fibrillation).

    Differential Diagnosis:

    • Chronic obstructive lung disease
    • Asthma exacerbation
    • Volume overload (iatrogenic)
    • Chordae rupture
    • Acute coronary syndrome
    • Pulmonary embolism
    • Sepsis
    • Severe pneumonia
    • Anaphylaxis
    • Takotsubo cardiomyopathy

21. Initiate O₂ Therapy, Start IV, Order Labs, Chest X-Ray and Electrocardiogram (ECG). Consider Echocardiogram (ECHO)
    1. Initial Laboratory Assessment:
       • Complete blood count (CBC)
       • Electrolytes (Na⁺, K⁺)
       • Renal function (blood urea nitrogen [BUN], creatinine)
       • Magnesium (if on diuretics)
       • Calcium
       • Urinalysis
       • Digoxin level (if on digoxin)
       • Prothrombin time/international normalized ratio (PT/INR) if on coumadin
       • Cardiac markers (creatine kinase muscle band [CKMB], troponin)
       • Glucose
       • BNP (if the diagnosis is uncertain)
       • Blood gases (may be indicated if the patient is hypoxic, has underlying lung disease, or has persistent respiratory distress)
    2. ECG and continuous rhythm monitoring: Recommended in all cases.
    3. Imaging: A chest x-ray is recommended in all cases.
       • An emergent echocardiogram is indicated for the patient who is not improving with initial interventions.

23. Adjust O₂ Delivery/Consider Continuous Positive Airway Pressure (CPAP)/Bilevel PAP (BiPAP)/Intubation

    Non-invasive ventilatory support has been proven effective and may reduce the need for intubation. Continuous positive airway pressures (CPAP) and bilevel positive airway pressure are both effective airway supports. Bilevel use is controversial in patients with acute MI.

    Evidence supporting these recommendations is of class: R

Acute Pulmonary Edema Algorithm

41. Volume Overload?

    Patients with persistent volume overload may be candidates for continuous IV diuretics, ultrafiltration, or hemodialysis (all out of guideline).

43. Loop Diuretic: IV Bolus, Consider IV Infusion
    • Furosemide is the most commonly used loop diuretic, with the dose adjusted upward if the patient is currently on oral doses. Diuretic effect occurs in 30 minutes with peak effect in one to two hours.
    • Torsemide or Bumetanide IV is an alternative loop diuretic.

    The pharmacologic characteristics of all loop diuretics are similar. Therefore, a lack of response to adequate doses of one loop diuretic mitigates against the administration of another loop diuretic; instead, combinations of diuretics with different mechanisms of action should be given.

    In patients who have poor responses to intermittent doses of a loop diuretic, a continuous intravenous infusion can be tried. If an effective amount of the diuretic is maintained at the site of action at all times, a small but clinically important increase in the response may occur. There are other reasons to consider giving a continuous infusion of a loop diuretic. It may be easier for nursing staff to give a continuous infusion than intermittent bolus intravenous doses. In addition, with a continuous infusion, decisions about the timing of doses of an additional diuretic are simplified. Finally, by closely monitoring urinary output, one can unambiguously determine whether the added drug was beneficial.

    Another strategy to enhance the response to a loop diuretic is to add an oral or IV thiazide diuretic. Metolazone is frequently given in the United States, whereas other thiazides are given elsewhere. The pharmacologic characteristics of metolazone are similar to those of other thiazides. Some formulations of the drug are absorbed poorly and slowly, and it has a long elimination half-life (about two days). Thus, metolazone accumulates over a period of about 10 days. Other thiazides have the same synergistic effects when combined with a loop diuretic. Since the absorption of other thiazides, such as hydrochlorothiazide, is more rapid and predictable, they may be preferable to metolazone.

    Evidence supporting this recommendation is of classes: A, D, R

44. Nitroglycerin Sublingual (SL) or Drip

    Concurrent with diuretic therapy is the initiation of vasodilators

    • Nitroglycerin, 0.4 mg sublingual or paste.

    Many patients will improve symptomatically with the "first-line therapy" and may be transferred to an observation unit or inpatient bed.

    Patients who are not improving will need more aggressive treatment:

    • Begin nitroglycerin infusion at 10 to 20 micrograms/minute (min) and increase by 10 to 20 mcg/min every 3 to 5 min to achieve desired effect. The maximum dose is 300 micrograms/min.
    • This work group recommends the upward titration of nitroglycerin before converting to nesiritide.

    Alternative dosing protocols exist which may provide a greater safety margin, such as:

    IV: non-PVC tubing, 5 mcg/min, initial titration should be in 5 mcg/min increments at intervals of 3 to 5 min guided by patient response; if no response is seen at 20 mcg/min, incremental increases of 10 and 20 mcg/min may be used; PVC tubing, initial dose 25 mcg/min IV

    Additional note: some intensive care units (ICUs) and EDs are now titrating in mcg/kg/min.

    A patient who continues to exhibit signs and symptoms of volume overload despite aggressive loop diuretics and IV nitroglycerin may be a candidate for nesiritide.

    Nesiritide reduces pulmonary capillary wedge pressure and improves dyspnea in patients with acute decompensated heart failure. Compared with dobutamine, ventricular arrhythmias and cardiac arrest occurred less frequently with nesiritide. Nesiritide can cause symptomatic hypotension comparable to nitroglycerin; however, the duration of symptomatic hypotension with nesiritide is longer (2.2 hours versus 0.7 hours).

    • Nesiritide 2 mcg IV bolus, then 0.01 mcg/kg/min IV infusion.
    • Nesiritide, a natriuretic peptide, has been tested in combination with diuretics but not with IV nitroglycerin. The safety profile is favorable in comparison with the phosphodiesterase inhibitors (e.g., milrinone) or the adrenergic inotropes (e.g., dobutamine).

    The experience with nesiritide to date has been limited, in comparison with the other two drugs.

    Evidence supporting this recommendation is of classes: A, R

46. Stabilized?

    Patients who stabilize may be admitted to an observation unit or monitored hospital bed.

    Unstable criteria include:

    • Unstable vital signs
    • ECG or serum markers of myocardial ischemia
    • Decompensation (concomitant end-organ hypoperfusion, volume overload, and systemic vasoconstriction)
    • Requiring continuous vasoactive medication (e.g., nitroglycerin, nitroprusside, dobutamine, or milrinone) to stabilize hemodynamics
    • Non-sustained ventricular tachycardia not caused by electrolyte imbalance
    • Acute mental status abnormality
    • Severe electrolyte imbalances

48. Emergency Department (ED) Observation or Short Stay Admission?

    Some heart failure patients may be managed in a short stay or observation unit. A short stay for diagnosis, intensive therapy, and education has demonstrated advantages. Institutions that utilize observation units will need to have selection criteria and observation protocols to achieve optimal results.

    Peacock and Albert provide a framework for the use of observation units in the management of heart failure patients. Observation units provide a cost-effective alternative to hospitalization for select patients.

    Evidence supporting this recommendation is of class: R

Definitions:

Conclusion Grades:

Grade I: The evidence consists of results from studies of strong design for answering the question addressed. The results are both clinically important and consistent with minor exceptions at most. The results are free of any significant doubts about generalizability, bias, and flaws in research design. Studies with negative results have sufficiently large samples to have adequate statistical power.

Grade II: The evidence consists of results from studies of strong design for answering the question addressed, but there is some uncertainty attached to the conclusion because of inconsistencies among the results from the studies or because of minor doubts about generalizability, bias, research design flaws, or adequacy of sample size. Alternatively, the evidence consists solely of results from weaker designs for the question addressed, but the results have been confirmed in separate studies and are consistent with minor exceptions at most.

Grade III: The evidence consists of results from studies of strong design for answering the question addressed, but there is substantial uncertainty attached to the conclusion because of inconsistencies among the results of different studies or because of serious doubts about generalizability, bias, research design flaws, or adequacy of sample size. Alternatively, the evidence consists solely of results from a limited number of studies of weak design for answering the question addressed.

Grade Not Assignable: There is no evidence available that directly supports or refutes the conclusion.

Classes of Research Reports:

1. Primary Reports of New Data Collection:

   Class A: Randomized, controlled trial

   Class B: Cohort study

   Class C:
   Non-randomized trial with concurrent or historical controls
   Case-control study
   Study of sensitivity and specificity of a diagnostic test
   Population-based descriptive study

   Class D:
   Cross-sectional study
   Case series
   Case report

2. Reports that Synthesize or Reflect upon Collections of Primary Reports:

   Class M:
   Meta-analysis
   Systematic review
   Decision analysis
   Cost-effectiveness analysis

   Class R:
   Consensus statement
   Consensus report
   Narrative review

   Class X: Medical opinion

• Heart Failure in Adults
• Emergent Management
• Acute Pulmonary Edema

ICSI, 8009 34th Avenue South, Suite 1200, Bloomington, MN 55425; telephone, (952) 814-7060; fax, (952) 858-9675; e-mail: icsi.info@icsi.org; Web site: www.icsi.org.

ICSI's conflict of interest policy and procedures are available for review on ICSI's website at www.icsi.org.

Electronic copies: Available from the Institute for Clinical Systems Improvement (ICSI) Web site.

Print copies: Available from ICSI, 8009 34th Avenue South, Suite 1200, Bloomington, MN 55425; telephone, (952) 814-7060; fax, (952) 858-9675; Web site: www.icsi.org; e-mail: icsi.info@icsi.org.

• Heart failure in adults. Executive summary. Bloomington (MN): Institute for Clinical Systems Improvement, 2007 Aug. 2 p. Electronic copies: Available from the Institute for Clinical Systems Improvement (ICSI) Web site.
• ICSI pocket guidelines. April 2006 edition. Bloomington (MN): Institute for Clinical Systems Improvement, 2006. 298 p.

A measurement tool worksheet for recording patient's ACE inhibitor use is available in the original guideline document.

Print copies: Available from ICSI, 8009 34th Avenue South, Suite 1200, Bloomington, MN 55425; telephone, (952) 814-7060; fax, (952) 858-9675; Web site: www.icsi.org; e-mail: icsi.info@icsi.org.

Electronic copies: Available from the Institute for Clinical Systems Improvement (ICSI) Web site.

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