Heart failure resident survival guide

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mahmoud Sakr, M.D. [2]; Ayokunle Olubaniyi, M.B,B.S [3]

Acute decompensated heart failure Resident Survival Guide Microchapters
Overview
Classification
Causes
Diagnosis
Treatment
Diuretic Therapy
Medications
Do's
Don'ts

Overview

Heart failure is a complex syndrome whereby there is inadequate output of the heart to meet the metabolic demands of the body. Acute heart failure can occur in the setting of a new onset heart failure or worsening of an existing chronic heart failure (also known as acute decompensated heart failure, flash pulmonary edema, ADHF). The clinical presentation include: dyspnea, swelling of the legsfatigue, and rales on physical examination. The diagnosis is mainly clinical, coupled with investigations such as chest x ray, EKG, echocardiography, BNP. The management therapies aim at achieving symptomatic relief (oxygen, diuresis, morphine) and reducing morbidity and mortality (ACE inhibitors or (ARBs), beta blockers, aldosterone antagonists, and hydralazine/nitrate medications).

Classification

Based on the Stage of Congestive Heart Failure

ACCF/AHA Stages Description
A At high risk for HF but without structural heart disease or symptoms of HF.
B Structural heart disease but without signs or symptoms of HF.
C Structural heart disease with prior or current symptoms of HF.
D Refractory HF requiring specialized interventions.

ACCF - American College of Cardiology Foundation; AHA - American Heart Association.

Based on the Severity of Congestive Heart Failure

NYHA classification Description
I No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF.
II Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of HF.
III Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of HF.
IV Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest.

NYHA - New York Heart Association

Based on Left Ventricular Ejection Fraction (LVEF)

  • Heart failure with preserved ejection fraction (HFpEF) - This is otherwise called diastolic HF. It is characterized with an ejection fraction ≥ 50%.
  • Heart failure with reduced ejection fraction (HFrEF) - This is also called systolic HF. It is characterized with an ejection fraction of ≤ 40%.

Causes

Life Threatening Causes

Acute decompensated heart failure is life threatening and should be treated as such irrespective of the underlying cause.

Common Causes

Diagnosis

 
 
 
 
 
 
 
Characterize the symptoms:

Cardiac

Chest pain
Cough
Dyspnea at rest
Exertional dyspnea
Orthopnea
Palpitation
Paroxysmal nocturnal dyspnea
Peripheral edema

Extracardiac

Anorexia
Bloating
Fatigue
Nausea
Oliguria
Weight loss

Obtain a detailed history:
Medications:

Alcohol
Beta blockers
Calcium channel blockers
Chemotherapy drugs - anthracyclines
NSAIDs
Thiazolidinedione

Past medical history

Arrhythmias
Cardiomyopathy
Diabetes mellitus
Hypertension
Obesity
❑ Previous myocardial infarction
Sleep disorders
Thyroid disease
Valvular heart disease

Family history

❑ History of dilated cardiomyopathy
Radiation to the chest
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Examine the patient:

❑ General examination:

Pulse rate - ↑
Blood pressure - ↑ or ↓
Respiratory rate - ↑
Weight

❑ Head/neck examination:

❑ ↑ JVP

❑ Cardiovascular examination:

Wheeze (cardiac asthma)
❑ S3 or S4 or both
❑ New or changed murmur

❑ Respiratory examination

Crackles/crepitations/rales

❑ Abdominal examination:

Hepatomegaly
Ascites

❑ Neurological examination:

Altered mental status

❑ Extremity examination:

Pedal edema

❑ Assess the severity and functional limitation using ACCF/AHA or NYHA


Consider close differential diagnoses:
❑ Acute asthma
Acute respiratory distress syndrome
Cardiac tamponade
Pneumonia

Pulmonary embolism
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Order laboratory tests:

CBC
Troponin
Electrolytes - ↓Na
serum calcium
serum magnesium
BUN, creatinine - ↑
Arterial blood gas
❑ Fasting blood sugar
Liver function tests
BNP or NT-pro BNP (if diagnosis is uncertain)


Other additional laboratory tests:
TSH
Urinalysis
ANA, rheumatoid factor
❑ Diagnostic tests for hemochromatosis, pheochromocytoma
Radionuclide ventriculography or MRI
Coronary angiography
Endomyocardial biopsy

Pulmonary artery catheterization - in respiratory distress or shock
 
 
 


Treatment

 
 
 
 
 
 
 
Initial stabilization:

❑ Assess airway, pulse oximetry
❑ Nurse 45 degrees upright
❑ Give oxygen, if Sa02 ↓90%
by non-rebreather face masks
❑ Continuous cardiac monitoring
❑ Intravenous access
❑ Monitor vitals - Pulse, BP
❑ Monitor urine output
Order

Chest x ray
Cardiomegaly
Pulmonary edema
Kerley B lines
EKG
❑ Evidence of ischemia
Infarction
Arrythmia
Left ventricular hypertrophy
❑ 2-D echocardiography with doppler
❑ Ventricular size, function, wall thickness, wall motion, and valve function
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consider admission:[1]

Hypotension and/or cardiogenic shock
❑ Poor end-organ perfusion - worsening renal function, cold clammy extremities, altered mental status
Hypoxemia - Sa02 ↓90%
Atrial fibrillation with a rapid ventricular response resulting in hypotension

❑ Presence of an acute coronary syndrome
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acute treatment
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Persistent respiratory distress

❑ Noninvasive positive pressure ventilation (NPPV)


❑ Mechanical ventilation (PEEP)
 
Cardiogenic shock

❑ Address emergently (ICU or CCU)(e.g. intubate, IV inotropes
❑ IV vasoconstrictor ( e.g. Norepinephrine 0.2–1.0 mcg/kg/min, titrate for best response
❑ Click here for more information regarding cardiogenic shock.

 
Treat precipitating causes/co-morbidities

❑ Acute aortic/mitral regurgitation
❑ Acute coronary syndrome
❑ Anemia
❑ Aortic dissection
❑ Atrial fibrillation
❑ Hypertension
❑ Renal failure

❑ Sepsis
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess hemodynamic and volume status[2]
Congestion & Poor perfusion)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Warm & Dry

❑ Consider outpatient treatment
❑ Dietary sodium restriction (2-3 g daily)
Smoking cessation
❑ Alcohol abstinence (≤2 standard drinks per day for men; ≤1 for women)


ACE inbibitors or (ARBs) if LVEF is ≤ 40%
Beta blockers[3]
❑ Encourage exercise/physical activity
 
Warm & Wet

Diuretic therapy

❑ Treat co-morbidities - HTN, DM, CAD, AF
 
 
 
Cold & Wet

❑ CCU admission
❑ Invasive hemodynamic monitoring (central, arterial line, pulmonary catheter)

❑ Intravenous inotropic drugs (e.g., dobutamine)
Diuretic therapy while monitoring blood pressure
❑ IV vasodilators
 
Cold & Dry

❑ CCU admission
❑ Intravenous inotropic drugs (e.g., dobutamine)
Persistent organ hypoperfusion (e.g., low urine output or persistent low SBP<85)

Norepinephrine 0.2–1.0 mcg/kg/min, titrate for best response
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General measures

Low sodium diet
❑ Monitor BP, volume status, congestion, oxygenation
❑ Daily weights
❑ Intake and output charts
❑ Convert all IV diuretic to oral
Continue or initiate

ACE inhibitors
Beta blockers
Omega-3 fatty acid[4]

❑ Daily serum electrolytes, urea & creatinine
❑ DVT prophylaxis
Influenza & pneumococcal vaccination

❑ Encourage physical activity in stable patients
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge and follow-Up

❑ Patient and family education
❑ Prior to discharge, ensure:

❑ Low salt diet
❑ Oral medication plan is stable for 24 hours
❑ No IV vasodilator or inotropic drugs for 24 hours
❑ Weighing scale is present in patient's home
Smoking cessation counseling
❑ Follow-up clinic visit scheduled within 7 to 10 days
❑ Ambulation prior to discharge to assess functional capacity

❑ Telephone follow-up call usually 3 days post discharge

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Diuretic Therapy

 
 
Evidence of volume overload
 
 
 
 
 
 
 
 
 

Low sodium diet (<2 g daily)
❑ Free water restriction to <2 L/day if the Na is < 130 meq/L, and < 1 L/day or more if the Na is < 125 meq/L
❑ Commence IV diuretics

Frusemide 40 mg, or
Torsemide 20 mg, or
Bumetanide 1 mg

Contraindications
Hypotension and cardiogenic shock

Note - Give a higher dose of IV diuretic in patients chronically on diuretic therapy (e.g., 2.5x their maintenance dose)

 
 
 
 
 
 
 
 
 
 
 
Symptomatic improvement?
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes
 
No
 
 
 
 
 
 
 
 
 
 
 
Maintain current IV diuretic dose
 
Double IV diuretic dose
and titrate according to patient's response
or when the maximum dose is reached
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No symptomatic improvement
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Add

❑ Another diuretic e.g., IV chlorothiazide or oral metolazone
or

❑ An aldosterone antagonist e.g., spironolactone or eplerenone, in post MI patients

 
Adjuvants to diuretics

❑ Low dose dopamine to preserve renal function and renal blood flow
❑ IV nitroprusside, nitroglycerin, or nesiritide for hemodynamically stable patients to relieve dyspnea

❑ Vasopressin antagonists (e.g. tolvaptan; start with 15mg orally daily) [5] [6]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No symptomatic improvement
(refractory edema)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ultrafiltration or dialysis
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General measures

❑ Monitor BP, volume status, congestion
❑ Daily weights
❑ Intake and output charts

❑ Convert all IV diuretic to oral
❑ Daily serum electrolytes, urea & creatinine
❑ DVT prophylaxis
 

Medications

Drug Class Drug Daily doses, maximum daily dose
Loop diuretics Furosemide 20 to 40 mg once or twice, 600 mg max daily dose
In HF patients on loop diuretic, the initial IV dose should
be greater or equal to their chronic oral daily dose.[7]
Bumetanide 0.5 to 1.0 mg once or twice, 10 mg
Torsemide 10 to 20 mg once, 200 mg
Thiazide diuretics Chlorothiazide 250 to 500 mg once or twice, 1000 mg
Hydrochlorothiazide 25 mg once or twice, 200 mg
Metolazone 2.5 mg once, 20 mg
K+- sparing diuretic Amiloride 5 mg once, 20 mg
Spironolactone 12.5 to 25.0 mg once, 50 mg
Triamterene 50 to 75 mg twice, 200 mg
ACE inhibitors Enalapril 2.5 mg twice, 10 to 20 mg twice
Lisinopril 2.5 to 5 mg once, 20 to 40 mg once
Ramipril 1.25 to 2.5 mg once, 10 mg once
ARBs Candesartan 4 to 8 mg once, 32 mg once
Losartan 25 to 50 mg once, 50 to 150 mg once
Valsartan 20 to 40 mg twice, 160 mg twice
Beta blockers Bisoprolol 1.25 mg once, 10 mg once
Carvedilol 3.125 mg twice, 50 mg twice
Metoprolol succinate 12.5 to 25.0 mg once, 200 mg once
Aldosterone antagonists Spironolactone 12.5 to 25.0 mg once, 25 mg once or twice
Eplerenone 25 mg once, 50 mg once
Inotropes Dopamine 5 to 10 mcg/kg/min
Dobutamine 2.5 to 5 mcg/kg/min
Milrinone 0.125 to 0.75 mcg/kg/min
Vasodilators Nitroglycerin 5 to 10 mcg/min, increase dose by 5-10mcg/min
every 3-5 mins as tolerated, max is 400mcg/min
Nitroprusside 5 to 10 mcg/min, increase dose by 5-10mcg/min
every 5 mins as tolerated, max is 400mcg/min
Nesiritide 2 mcg/kg bolus; then 0.01 mcg/kg/minute continuous infusion,
maximum of 0.03 mcg/kg/minute
Hydralazine and isosorbide dinitrate Fixed-dose combination 37.5 mg hydralazine/20 mg isosorbide dinitrate 3 times daily,
75 mg hydralazine/40 mg isosorbide dinitrate 3 times daily
Individual doses Hydralazine: 25 to 50 mg 3 or 4 times daily, 300 mg daily in divided doses
Isosorbide dinitrate: 20 to 30 mg 3 or 4 times daily, 120 mg daily in divided doses
Digoxin 0.125 to 0.25 mg daily

Do's

  • Order an echocardiogram as soon as possible if no recent one available or if the patient's clinical status is deteriorating.
  • Digitalis decreases hospitalization but not mortality. It can be beneficial in symptomatic patients with low EF.[8][9][10][11][12][13][14]
  • Make sure your patient is on DVT prophylaxis unless contraindicated.[15][16]
  • Make use of aldosterone receptor antagonists (i.e. spironolactone or eplerenone) in patients with NYHA class II-IV and who have LVEF of 35% or less, unless contraindicated, to reduce morbidity and mortality. Patients with NYHA class II should have a history of prior cardiovascular hospitalization or elevated plasma natriuretic peptide levels to be considered for aldosterone receptor antagonists. Creatinine should be 2.5 mg/dL or less in men or 2.0 mg/dL or less in women (or estimated glomerular filtration rate >30 mL/min/1.73 m2), and potassium should be less than 5.0 mEq/L. Careful monitoring of potassium, renal function, and diuretic dosing should be performed at initiation and closely followed thereafter to minimize risk of hyperkalemia and renal insufficiency.[17][18][19]
  • Start hydralazine and isosorbide dinitrate to reduce morbidity or mortality in patients with current or prior symptomatic HFrEF who cannot be given an ACE inhibitor or ARB because of drug intolerance, hypotension, or renal insufficiency, unless contraindicated. This combination has proven beneficial in African American population as well. [20][21][22][23][24]
  • Consider adding another diuretic (e.g. metolazone or thiazides) for worsening congestion despite high doses of loop diuretics.[25][26]
  • Daily serum electrolytes, urea nitrogen, and creatinine concentrations should be measured during the use of IV diuretics or active titration of heart failure medications.
  • Use a combination of hydralazine and isosorbide dinitrate. They have been proven to reduce morbidity or mortality in patients with current or prior symptomatic HFrEF who cannot be given an ACE inhibitor or ARB because of drug intolerance, hypotension, or renal insufficiency, unless contraindicated.[27][28][29][30][31]
  • Schedule an early follow-up visit (within 7 to 14 days) and early telephone follow-up (within 3 days) of hospital discharge .[32][33]

Don'ts

  • If possible, don't order NSAIDs, sympathomimetics, tricyclic antidepressants, class I and III antiarrhythmics (except amiodarone), and nondihydropyridine calcium channel blockers (diltiazem, verapamil as they can cause harm in acute decompensated HF. [34][35][36][37][38][39][40]
  • Don't Use parenteral inotropes in normotensive patients with acute decompensated HF without evidence of decreased organ perfusion. [41]
  • Don't combine an ACEI, ARB, and aldosterone antagonist in patients with HFrEF unless otherwise indicated as this combination carries a risk of renal functions worsening and hyperkalemia.
  • Don't use aldosterone receptor antagonists in patients with hyperkalemia or renal insufficiency when serum creatinine is more than 2.5 mg/dL in men or more than 2.0 mg/dL in women (or estimated glomerular filtration rate <30 mL/min/1.73 m2), and/or potassium more than 5.0 mEq/L.[42][43]
  • Don't continue nutritional supplements with no proven benefit.
  • Don't use statins routinely without other indications.[44][45]

References

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  2. Nohria A, Tsang SW, Fang JC, Lewis EF, Jarcho JA, Mudge GH; et al. (2003). "Clinical assessment identifies hemodynamic profiles that predict outcomes in patients admitted with heart failure". J Am Coll Cardiol. 41 (10): 1797–804. PMID 12767667.
  3. Metra M, Torp-Pedersen C, Cleland JG, Di Lenarda A, Komajda M, Remme WJ, Dei Cas L, Spark P, Swedberg K, Poole-Wilson PA (2007). "Should beta-blocker therapy be reduced or withdrawn after an episode of decompensated heart failure? Results from COMET". European Journal of Heart Failure. 9 (9): 901–9. doi:10.1016/j.ejheart.2007.05.011. PMID 17581778. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  4. Gissi-HF Investigators. Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG; et al. (2008). "Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial". Lancet. 372 (9645): 1223–30. doi:10.1016/S0140-6736(08)61239-8. PMID 18757090. Review in: Ann Intern Med. 2009 Jan 20;150(2):JC1-11
  5. Gheorghiade M, Gattis WA, O'Connor CM, Adams KF, Elkayam U, Barbagelata A; et al. (2004). "Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial". JAMA. 291 (16): 1963–71. doi:10.1001/jama.291.16.1963. PMID 15113814.
  6. Udelson JE, Smith WB, Hendrix GH, Painchaud CA, Ghazzi M, Thomas I; et al. (2001). "Acute hemodynamic effects of conivaptan, a dual V(1A) and V(2) vasopressin receptor antagonist, in patients with advanced heart failure". Circulation. 104 (20): 2417–23. PMID 11705818.
  7. Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, Goldsmith SR, LeWinter MM, Deswal A, Rouleau JL, Ofili EO, Anstrom KJ, Hernandez AF, McNulty SE, Velazquez EJ, Kfoury AG, Chen HH, Givertz MM, Semigran MJ, Bart BA, Mascette AM, Braunwald E, O'Connor CM (2011). "Diuretic strategies in patients with acute decompensated heart failure". The New England Journal of Medicine. 364 (9): 797–805. doi:10.1056/NEJMoa1005419. PMC 3412356. PMID 21366472. Retrieved 2013-04-30. Unknown parameter |month= ignored (help)
  8. The Captopril-Digoxin Multicenter Research Group. Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. JAMA. 1988;259:539–44.
  9. Dobbs SM, Kenyon WI, Dobbs RJ. Maintenance digoxin after an episode of heart failure: placebo-controlled trial in outpatients. Br Med J. 1977;1:749–52
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  11. Guyatt GH, Sullivan MJ, Fallen EL, et al. A controlled trial of digoxin in congestive heart failure. Am J Cardiol. 1988;61:371–5.
  12. . DiBianco R, Shabetai R, Kostuk W, et al. A comparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure. N Engl J Med. 1989;320:677–83.
  13. Uretsky BF, Young JB, Shahidi FE, et al., for the PROVED Investigative Group. 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;22:955–62.
  14. Packer M, Gheorghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-convertingenzyme inhibitors. RADIANCE Study. N Engl J Med. 1993;329:1–7.
  15. Alikhan R, Cohen AT, Combe S, Samama MM, Desjardins L, Eldor A; et al. (2003). "Prevention of venous thromboembolism in medical patients with enoxaparin: a subgroup analysis of the MEDENOX study". Blood Coagul Fibrinolysis. 14 (4): 341–6. PMID 12945875.
  16. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ, American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel (2012). "Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines". Chest. 141 (2 Suppl): 7S–47S. doi:10.1378/chest.1412S3. PMC 3278060. PMID 22315257.
  17. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A; et al. (1999). "The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators". N Engl J Med. 341 (10): 709–17. doi:10.1056/NEJM199909023411001. PMID 10471456.
  18. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H; et al. (2011). "Eplerenone in patients with systolic heart failure and mild symptoms". N Engl J Med. 364 (1): 11–21. doi:10.1056/NEJMoa1009492. PMID 21073363. Review in: Evid Based Med. 2011 Aug;16(4):121-2 Review in: J Fam Pract. 2011 Aug;60(8):482-4
  19. Vizzardi E, D'Aloia A, Giubbini R, Bordonali T, Bugatti S, Pezzali N; et al. (2010). "Effect of spironolactone on left ventricular ejection fraction and volumes in patients with class I or II heart failure". Am J Cardiol. 106 (9): 1292–6. doi:10.1016/j.amjcard.2010.06.052. PMID 21029826.
  20. Carson P, Ziesche S, Johnson G, et al., for the Vasodilator-Heart Failure Trial Study Group. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. J Card Fail. 1999;5:178–87.
  21. Cohn JN. The Vasodilator-Heart Failure Trials (V-HeFT). Mechanistic data from the VA Cooperative Studies. Introduction. Circulation. 1993; 87:VI1–4.
  22. Carson P, Ziesche S, Johnson G, et al., for the Vasodilator-Heart Failure Trial Study Group. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. J Card Fail. 1999;5:178–87.
  23. 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;314:1547–52.
  24. Loeb HS, Johnson G, Henrick A, et al., for the V-HeFT VA Cooperative Studies Group. Effect of enalapril, hydralazine plus isosorbide dinitrate, and prazosin on hospitalization in patients with chronic congestive heart failure. Circulation. 1993;87:VI78–87.
  25. Grosskopf I, Rabinovitz M, Rosenfeld JB (1986). "Combination of furosemide and metolazone in the treatment of severe congestive heart failure". Isr J Med Sci. 22 (11): 787–90. PMID 3793436.
  26. Rosenberg J, Gustafsson F, Galatius S, Hildebrandt PR (2005). "Combination therapy with metolazone and loop diuretics in outpatients with refractory heart failure: an observational study and review of the literature". Cardiovasc Drugs Ther. 19 (4): 301–6. doi:10.1007/s10557-005-3350-2. PMID 16189620.
  27. Carson P, Ziesche S, Johnson G, et al., for the Vasodilator-Heart Failure Trial Study Group. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. J Card Fail. 1999;5:178–87.
  28. Cohn JN. The Vasodilator-Heart Failure Trials (V-HeFT). Mechanistic data from the VA Cooperative Studies. Introduction. Circulation. 1993; 87:VI1–4.
  29. Carson P, Ziesche S, Johnson G, et al., for the Vasodilator-Heart Failure Trial Study Group. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. J Card Fail. 1999;5:178–87.
  30. 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;314:1547–52.
  31. Loeb HS, Johnson G, Henrick A, et al., for the V-HeFT VA Cooperative Studies Group. Effect of enalapril, hydralazine plus isosorbide dinitrate, and prazosin on hospitalization in patients with chronic congestive heart failure. Circulation. 1993;87:VI78–87.
  32. Krumholz HM, Chen YT, Wang Y, Vaccarino V, Radford MJ, Horwitz RI (2000). "Predictors of readmission among elderly survivors of admission with heart failure". Am Heart J. 139 (1 Pt 1): 72–7. PMID 10618565.
  33. Hernandez AF, Greiner MA, Fonarow GC, Hammill BG, Heidenreich PA, Yancy CW; et al. (2010). "Relationship between early physician follow-up and 30-day readmission among Medicare beneficiaries hospitalized for heart failure". JAMA. 303 (17): 1716–22. doi:10.1001/jama.2010.533. PMID 20442387.
  34. Heerdink ER, Leufkens HG, Herings RM, et al. NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics. Arch Intern Med. 1998;158:1108–12.
  35. . Herchuelz A, Derenne F, Deger F, et al. Interaction between nonsteroidal anti-inflammatory drugs and loop diuretics: modulation by sodiumbalance. J Pharmacol Exp Ther. 1989;248:1175–81.
  36. Gottlieb SS, Robinson S, Krichten CM, et al. Renal response to indomethacin in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 1992;70:890–3
  37. Bank AJ, Kubo SH, Rector TS, et al. Local forearm vasodilation with intra-arterial administration of enalaprilat in humans. Clin Pharmacol Ther. 1991;50:314–21.
  38. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med. 1989;321:406–12.
  39. The Cardiac Arrhythmia Suppression Trial II Investigators. Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. N Engl J Med. 1992;327:227–33.
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