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BART COX, M.D., FACC DIRECTOR, ADVANCED HEART FAILURE PROGRAM ASSOCIATE PROFESSOR OF MEDICINE UNIVERSITY OF NEW MEXICO SCHOOL OF MEDICINE. HFrEF : ANSWERS YOU NEVER GET TO QUESTIONS YOU ALWAYS ASK. DISCLOSURES. NONE. WHAT IS THE DEFINITION OF HEART FAILURE?. HEART FAILURE (HF).

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slide1
BART COX, M.D., FACC

DIRECTOR, ADVANCED HEART FAILURE PROGRAM

ASSOCIATE PROFESSOR OF MEDICINE

UNIVERSITY OF NEW MEXICO SCHOOL OF MEDICINE

HFrEF: ANSWERS YOU NEVER GET TO QUESTIONS YOU ALWAYS ASK

heart failure hf
HEART FAILURE (HF)
  • A complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood
heart failure with preserved ejection fraction improved
HEART FAILURE WITH PRESERVED EJECTION FRACTION, IMPROVED
  • HFpEF + LVEF previously < 40% that is now > 40%
new york heart association functional class
NEW YORK HEART ASSOCIATION FUNCTIONAL CLASS
  • NYHA I: Ordinary physical activity does not cause symptoms of HF
  • NYHA II: Ordinary physical activity results in symptoms of HF
  • NYHA III: Less than ordinary physical activity results in symptoms of HF
  • NYHA IV: Unable to carry on any physical activity without HF symptoms, or symptoms of HF at rest
accf aha stages of heart failure
ACCF/AHA STAGES OF HEART FAILURE
  • A: High risk for HF but without structural heart disease or HF symptoms (e.g., DM, metabolic syndrome, CAD, obesity, hypertension, history of familial CM, or use of cardiotoxin)
  • B: Structural heart disease but without history of HF signs or symptoms (e.g., asymptomatic valve disease, LVH, reduced LVEF, MI)
  • C: Structural heart disease + prior / current HF symptoms or signs
  • D: Advanced HF: Refractory HF requiring specialized interventions (e.g., transplant, MCS, etc)
asymptomatic lv dysfunction
ASYMPTOMATIC LV DYSFUNCTION
  • LVEF < 40% with NO history of signs and symptoms of HF
  • If there is ANY history of signs and symptoms of HF, this is NOT asymptomatic LV dysfunction. Must call it HF +NYHA class
    • NYHA I: no symptoms currently with ordinary activity
    • NYHA II: symptoms of HF with ordinary activity
    • NYHA III: symptoms of HF with less than ordinary activity
    • NYHA IV: symptoms of HF with any activity or at rest
acute decompensated heart failure adhf
ACUTE DECOMPENSATED HEART FAILURE (ADHF)
  • Also called “Acute Heart Failure Syndromes”
  • Poor prognosis: mortality 1 year post discharge can be as high as 30%
  • Subgroups include entities such as HF + Acute Coronary Syndromes, shock, acutely worsening right HF, postoperative HF decompensation, and accelerated hypertension with acutely decompensated HF
  • Definition: Rapid or gradual development of HF signs and symptoms requiring urgent therapy
acei the evidence
ACEI: THE EVIDENCE
  • CONSENSUS (Enalapril v. placebo)
  • SOLVD (Enalapril v. placebo)
  • SAVE (Captopril v. placebo)
  • POST MI TRIALS
    • AIRE
    • TRACE
    • ISIS IV
    • GISSI 3
    • CHINESE CAPTOPRIL TRIAL
ace inhibitors acei 2013 accf aha guidelines
ACE INHIBITORS (ACEI): 2013 ACCF/AHA GUIDELINES
  • CLASS I
    • ACE inhibitors are recommended in patients with HFrEF and current or prior symptoms, unless contraindicated, to reduce morbidity and mortality (Level of Evidence A)
acei the answer
ACEI: THE ANSWER
  • Use in all patients with LVEF <40% (both Asymptomatic LV Dysfunction and HFrEF of any NYHA class)
  • Start with low dose and uptitrate slowly (i.e., every two weeks) after evaluating K, renal function, and orthostasis
  • Uptitrate to the optimally tolerated dose, with the goal dose same as the dose used in trials
arbs the evidence
ARBs: THE EVIDENCE
  • Val-HeFT (Valsartan v. placebo)
  • VALIANT (Valsartan v. Valsartan + Captopril v. Captopril in post MI patients LVEF <35-40%
  • HEAAL (high dose losartan v. low dose losartan)
  • CHARM ADDED (Candesartan v. placebo)
  • CHARM ALTERNATIVE (Candesartan v. placebo)
arbs 2013 accf aha guidelines
ARBs: 2013 ACCF/AHA GUIDELINES
  • CLASS I
    • ARBs are recommended in patients with HFrEF with current or prior symptoms who are ACEI intolerant, unless contraindicated, to reduce morbidity and mortality (Level of Evidence A)
arbs 2013 accf aha guidelines1
ARBs: 2013 ACCF/AHA GUIDELINES
  • CLASS IIa
    • ARBs are reasonable to reduce morbidity and mortality a alternatives to ACEI as first-line therapy for patients with HFrEF, especially for patients already taking ARBs for other indications, unless contraindicated (Level of Evidence A)
arbs 2013 accf aha guidelines2
ARBS: 2013 ACCF/AHA GUIDELINES
  • CLASS IIb
    • Addition of an ARB may be considered in persistently symptomatic patients with HFrEF who are already being treated with an ACEI and a beta blocker in whom an aldosterone antagonist is not indicated or tolerated (Level of Evidence A)
arbs 2013 accf aha guidelines3
ARBs: 2013 ACCF/AHA GUIDELINES
  • CLASS III: HARM
    • Routine combined use of an ACEI, ARB, and aldosterone antagonist is potentially harmful for patients with HFrEF (Level of Evidence C)
arbs the answer
ARBs: THE ANSWER
  • It is recommended to use ARBs in ACEI-intolerant patients (due to cough and PERHAPS angioedema) with NYHA I-IV HFrEF
    • ARBs are reasonable as alternatives to ACEI as first-line therapy in HFrEF
  • Only 3 ARBs have been studied in HFrEF (Valsartan, Losartan, and Candesartan)
  • Uptitrate to the doses used in the trials
  • If ACEI is contraindicated due to hyperkalemia or renal insufficiency, use nitrate-hydralazine combination. DO NOT USE ARB IN THIS SETTING.
beta blockers the evidence
BETA BLOCKERS: THE EVIDENCE
  • U.S. CARVEDILOL HEART FAILURE STUDY
  • CAPRICORN (Carvedilol v. placebo)
  • COPERNICUS (Carvedilol v. placebo)
  • COMET (Carvedilol v. Metoprolol Tartrate)
  • CIBIS II (Bisoprolol v. placebo)
  • MERIT-HF (Metoprolol Succinate CR/XL v. placebo)
  • SENIORS (Nebivolol v. placebo)
beta blockers 2013 accf aha guidelines
BETA BLOCKERS: 2013 ACCF/AHA GUIDELINES
  • CLASS I
    • Use of 1 of the 3 beta blockers proven to reduce mortality (i.e., bisoprolol, carvedilol, and sustained-release metoprolol succinate) is recommended for all patients with current or prior symptoms of HFrEf, unless contraindicated, to reduce morbidity and mortality (Level of Evidence A)
beta blockers the answer
BETA BLOCKERS: THE ANSWER
  • Use in all patients with LVEF <40% (both HFrEF and asymptomatic LV dysfunction all NYHA classes
  • Use only evidence-based beta blockers. Not all beta blockers are alike
  • Start at low dose and uptitrate slowly (i.e., every two weeks) after evaluating for bradycardia, AV block, hypotension, congestion, and fatigue
  • Uptitrate to the doses used in the trials. DO NOT STOP UPTITRATING JUST BECAUSE THEY ARE ASYMPTOMATIC!
diuretics 2013 accf aha guidelines
DIURETICS: 2013 ACCF/AHA GUIDELINES
  • CLASS I
    • Diuretics are recommended in patients with HFrEf who have evidence of fluid retention, unless contraindicated, to improve symptoms (Level of Evidence C)
diuretics the evidence
DIURETICS: THE EVIDENCE
  • DOSE
    • Low dose infusion v. low dose intermittent bolus v. high dose infusion v. high dose intermittent bolus in patients with Acute Decompensated Heart Failure
diuretics the answer
DIURETICS: THE ANSWER
  • Use for symptomatic relief of systemic or pulmonary congestion
  • Diurese until dry and at the correct rate, then institute maintenance dose
  • Best strategy for maintenance diuretic is to prescribe a weight-based diuretic dose
  • Must combine diuretic with a low Na diet
  • Monitor electrolytes, renal function, and orthostatic symptoms and signs closely
aldosterone antagonists the evidence
ALDOSTERONE ANTAGONISTS: THE EVIDENCE
  • RALES
    • Spironolactone v. placebo
  • EPHESUS
    • Eplerenone v. placebo
  • EMPHASIS-HF
    • Eplerenone v. placebo
aldosterone antagonists 2013 accf aha guidelines
ALDOSTERONE ANTAGONISTS: 2013 ACCF/AHA GUIDELINES
  • CLASS I
    • Aldosterone receptor antagonists (or mineralocorticoid receptor antagonists) are recommended in patients with NYHA class II-IV and who have LVEF of <35%, unless contraindicated, to reduce morbidity and mortality (Level of Evidence A)
      • Patients with NYHA II should have a history of prior cardiovascular hospitalization or elevated plasma natiuretic peptide levels to be considered for aldosteronereceptro antagonists.
aldosterone antagonists 2013 accf aha guidelines1
ALDOSTERONE ANTAGONISTS: 2013 ACCF/AHA GUIDELINES
  • CLASS I
      • Creatinine should be <2.5 mg/dL in men or <2.0 mg/dL in women (or estimated GFR > 30 mL/min/1.73 sq. meters), and potassium should be < 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 hyprekalemia and renal insufficiency
aldosterone antagonists 2013 accf aha guidelines2
ALDOSTERONE ANTAGONISTS: 2013 ACCF/AHA GUIDELINES
  • CLASS I
    • Aldosterone receptor antagonists are recommended to reduce morbidity and mortality following an acute MI in patients who have LVEF of <40% who develop symptoms of HF or who have a history of DM, unless contraindicated (Level of Evidence B)
aldosterone antagonists 2013 accf aha guidelines3
ALDOSTERONE ANTAGONISTS: 2013 ACCF/AHA GUIDELINES
  • CLASS III
    • Inappropriate use of aldosterone receptor antgonists is potentially harmful because of life-threatening hyperkalemia or renal insufficiency when serum creatinine is > 2.5 mg/dL in men or> 2.0 mg/dL in women (or estimated glomerular filtration rate < 30 mL/min/1.73 sq. meters) (Level of Evidence B)
aldosterone antagonists the answer
ALDOSTERONE ANTAGONISTS: THE ANSWER
  • Use to reduce mortality and morbidity in NYHA II-IV HFrEF + LVEF <35% + already on ACEI (or ARB) and evidence beta blocker
    • Start in NYHA II HFrEF only if BNP is elevated or previous CV hospitalization
  • Use post-MI beginning day 3-14 x 1 year (at least) to reduce mortality and morbidity in patients with LVEF<40% + symptoms of HF or presence of DM
  • Remember the contraindications to aldosterone antagonists, and DO NOT COMBINE ACE + ARB+ ALDOSTERONE ANTAGONIST
  • Once initiated, check K and renal function 3 and 7 days later, q 1 month x3, then q 3 months thereafter. Restart the cycle with any change of dose of ACEI (or ARB), diuretic, or aldosteroneantanonist
nitrate hydralazine combination the evidence
NITRATE-HYDRALAZINE COMBINATION: THE EVIDENCE
  • V-HeFT
    • ISDN/hydralazine v. prazosin v. placebo
  • A-HeFT
    • ISDN/Hydralazine v. placebo
nitrate hydralazine 2013 accf aha guidelines
NITRATE-HYDRALAZINE: 2013 ACCF/AHA GUIDELINES
  • CLASS I
    • The combination of hydralazine and isosorbide dinatrate is recommended to reduce morbidity and mortality for patients self-described as African Americans with NYHA class III-IV HFrEF receiving optimal therapy with ACEI and beta blockers, unless contraindicated (Level of Evidence A)
nitrate hydralazine 2013 accf aha guidelines1
NITRATE-HYDRALAZINE: 2013 ACCF/AHA GUIDELINES
  • CLASS IIa
    • A combination of hydralazine and isosorbide dinatrate can be useful to reduce morbidity or mortality in patients with current or prior symptomatic HFrEF who cannot be given an ACEI or ARB because of drug intolerance, hypotension, or renal insufficiency, unless contraindicated (Level of Evidence B)
nitrate hydralazine combination the answer
NITRATE-HYDRALAZINE COMBINATION: THE ANSWER
  • Use the combination to reduce mortality and morbidity in African Americans + HFrEF +NYHA III-IV +already on optimum therapy with evidence-based beta blockers, ACEI (or ARB), and aldosterone antagonist
  • Use the combination to reduce mortality and morbidity in HFrEF + contraindication to ACEI or ARB (due to hypotension, renal insufficiency, or drug intolerance)
digoxin the evidence
DIGOXIN: THE EVIDENCE
  • DIGITALIS INVESTIGATION GROUP (DIG) TRIAL
  • DIGOXIN WITHDRAWAL TRIALS
    • RADIANCE
    • PROVED
digoxin 2013 accf aha guidelines
DIGOXIN: 2013 ACCF/AHA GUIDELINES
  • CLASS IIa
    • Digoxin can be beneficial in patients with HFrEF, unless contraindicated, to decrease hospitalizations for HF (IIa, Level of Evidence B)
digoxin answer
DIGOXIN: ANSWER
  • Digoxin is indicated for HFrEF patients already treated with ACEI (or ARB), evidence based beta blockers, aldosterone antagonist, diuretic, and persistent NYHA II-IV symptoms to reduce rehospitalization
  • If the patient with HFrEF is stable on digoxin with an appropriate level, do not discontinue
  • Keep the digoxin level between 0.5-0.9
anticoagulation the evidence
ANTICOAGULATION: THE EVIDENCE
  • WATCH
    • Warfarin v. aspirin v. clopidogrel
  • WARCEF
    • Warfarin v. asppirin
anticoagulation 2013 accf aha guidelines
ANTICOAGULATION: 2013 ACCF/AHA GUIDELINES
  • CLASS I
    • Patients with chronic HF with permanent/ persistent/ paroxysmal AF and an additional risk factor for cardioembolic stroke (history of hypertension, DM, previous stroke or TIA, or > 75 years of age) should receive chronic anticoagulant therapy (Level of Evidence A)
anticoagulation 2013 accf aha guidelines1
ANTICOAGULATION: 2013 ACCF/AHA GUIDELINES
  • CLASS I
    • The selection of an anticoagulant agent (warfarin, dabigatran, apixaban, or rivaroxaban) for permanent/ persistent/ paroxysmal AF should be individualized on the basis of risk factors, cost, tolerability, patient preference, potential for drug interactions, and other clinical characteristics, including time in the INR therapeutic range if the patient has been taking warfarin (Level of Evidence C)
anticoagulation 2013 accf aha guidelines2
ANTICOAGULATION: 2013 ACCF/AHA GUIDELINES
  • CLASS IIa
    • Chronic anticoagulation is reasonable for patients with chronic HF who have permanent/ persistent/ paroxysmal AF but are without an additional risk factor for cardioembolic stroke (Level of Evidence B)
anticoagulation the answer
ANTICOAGULATION: THE ANSWER
  • Chronic HFrEF + Atrial Fibrillation (paroxysmal, persistent, or permanent) + one additional risk factor for cardioembolic stroke should receive chronic anticoagulant therapy (hypertension, age>75,DM, prior stroke or TIA)
  • The selection of an anticoagulant agent (Dabigatran, Rivaroxaban, Apixiaban, or Warfarin) should be individualized
anticoagulation the answer1
ANTICOAGULATION: THE ANSWER
  • HFrEF + Atrial Fibrillation (paroxysmal, persistent, or permanent) with NO additional risk factors for cardioembolic stroke is reasonable
  • Anticoagulation is NOT recommended in patients with chronic HFrEF without AF, a prior thromboembolic event, or a cardioembolic source
omega 3 pufa the evidence
OMEGA-3 PUFA: THE EVIDENCE
  • GISSI-HF
    • Fish oil v. placebo
omega 3 fatty acids 2013 accf aha guidelines
OMEGA-3 FATTY ACIDS: 2013 ACCF/AHA GUIDELINES
  • CLASS IIa
    • Omega-3 polyunsaturated fatty acid (PUFA) supplementation is reasonable to use as adjunctive therapy in patients with NYHA class II-IV symptoms and HFrEF or HFpEF, unless contraindicated to reduce mortality and cardiovascular hospitalizations (Level of Evidence B)
omega 3 pufa the answer
OMEGA-3 PUFA: THE ANSWER
  • Omega-3 PUFA supplementation is reasonable to use as adjunctive therapy in HFrEF or HFpEF patients with NYHA II-IV to reduce mortality and cardiovascular hospitalizations
  • The appropriate dose of Omega-3 PUFA is 1 gram daily containing 850 mg eicosapentaenoic acid and 882 mg docosahexaenoic acid both as ethyl esters
icd 2013 accf aha guidelines
ICD: 2013 ACCF/AHA GUIDELINES
  • CLASS I
    • ICD therapy is recommended for primary prevention of sudden cardiac death to reduce total mortality in selected patients with nonischemic DCM or ischemic heat disease at least 40 days post-MI with LVEF< 35% and NYHA class II or III symptoms on chronic GDMT, who have reasonable expectation of meaningful survival for more than 1year (Level of Evidence A)
icd 2013 accf aha guidelines1
ICD: 2013 ACCF/AHA GUIDELINES
  • CLASS I
    • ICD therapy is recommended for primary prevention of sudden cardiac death to reduce total mortality in selected patients at least 40 days post-MI with LVEF < 30% and NYHA class I symptoms while receiving GDMT, who have reasonable expectation of menaingful survival for more than 1 year (Level of Evidence B)
icd 2013 accf aha guidelines2
ICD: 2013 ACCF/AHA GUIDELINES
  • CLASS IIb
    • The usefulness of implantation of an ICD is of uncertain benefit to prolong meaningful survival in patients with a high risk of non-sudden death as predicted by frequent hospitalizations, advanced frailty, or comorbidities such as systemic malignancy or severe renal dysfunction (Level of Evidence B)
icd 2013 accf aha guidelines pearls
ICD: 2013 ACCF/AHA GUIDELINES PEARLS
  • CLASS I
    • LVEF < 35% + GDMT +NYHA II and III
    • LVEF < 30% + GDMT + NYHA I + Ischemic CM
crt trials demonstrating improved survival in hfref ef 35
CRT TRIALS DEMONSTRATING IMPROVED SURVIVAL IN HFrEF (EF<35%)
  • MUSTIC
  • MIRACLE
  • MIRACLE-ICD
  • COMPANION
  • CARE-HF
  • MADIT-CRT
  • RAFT
  • BLOCK HF
crt 2013 accf aha guidelines
CRT: 2013 ACCF/AHA GUIDELINES
  • CLASS I
    • CRT is indicated for patients who have LVEF<35%, sinus rhythm, left bundle-branch block (LBBB) with a QRS duration of > 150 msec, and NYHA class II, III, or ambulatory IV symptoms on GDMT (Level of Evidence B)
crt 2013 accf aha guidelines1
CRT: 2013 ACCF/AHA GUIDELINES
  • CLASS IIa
    • CRT can be useful for patients who have LVEF <35%, sinus rhythm, a non-LBBB pattern with QRS of > 150 msec, and NYHA class III/ambulatory class IV (Level of Evidence A)
    • CRT can be useful for patients who have LVEF <35%, sinus rhythm, LBBB with a QRS duration of 120-149 msec, and NYHA class II, III, or ambulatory IV symptoms on GDMT (Level of Evidence B)
crt 2013 accf aha guidelines2
CRT: 2013 ACCF/AHA GUIDELINES
  • CLASS IIa
    • CRT can be useful in patients with AF and LVEF <35% on GDMT if:
      • The patient requires ventricular pacing or otherwise meets CRT criteria

AND

      • Atrioventricular nodal ablation or pharmacological rate control will allow near 100% ventricular pacing with CRT (Level of Evidence B)
crt 2013 accf aha guidelines3
CRT: 2013 ACCF/AHA GUIDELINES
  • CLASS IIa
    • CRT can be useful for patients on GDMT who have LVEF <35%, and are undergoing placement of a new or replacement device with anticipated requirement for significant (>40%) ventricular pacing
crt 2013 accf aha guidelines4
CRT: 2013 ACCF/AHA GUIDELINES
  • CLASS IIb
    • CRT may be considered for patients who have LVEF <35%, sinus rhythm, a non-LBBB pattern with QRS duration of 120-149 ms, and NYHA class III/ambulatory class IV on GDMT (Level of Evidence B)
    • CRT may be considered for patients who have LVEF <35%, sinus rhythm, a non-LBBB pattern with a QRS duration of > 150 msec, and NYHA class II symptoms on GDMT (Level of Evidence B)
crt 2013 accf aha guidelines5
CRT: 2013 ACCF/AHA GUIDELINES
  • CLASS IIb
    • CRT may be considered for patients who have LVEF of < 30%, ischemic etiology of HF, sinus rhythm, LBBB with a QRS duration of > 150 msec, and NYHA class I symptoms on GDMT
crt 2013 accf aha guidelines6
CRT: 2013 ACCF/AHA GUIDELINES
  • CLASS III (NO BENEFIT)
    • CRT is not recommended for patients with NYHA class I or II symptoms and non-LBBB pattern with QRS duration < 150 msec (Level of Evidence B)
    • CRT is not indicated for patients whose comorbidities and/ or frailty limit survival with good functional capacity to < 1 year (Level of Evidence C)
crt 2013 accf aha guidelines7
CRT: 2013 ACCF/AHA GUIDELINES
  • REQUIREMENTS:
    • LVEF <35%
    • Must be on GDMT
    • Must have QRS duration > 120 msec
    • Must be NYHA class III or ambulatory IV
      • Indicated for NYHA II only with LBBB and QRS > 150 msec
      • Never indicated for NYHA 1
crt 2013 accf aha guidelines class i and iia pearls
CRT: 2013 ACCF/AHA GUIDELINES CLASS I AND IIa PEARLS
  • LVEF <35% + GDMT +NSR +LBBB WITH QRS >120 + NYHA II, III, AMBULATORY IV
  • LVEF <35% + GDMT + NSR +NON LBBB+ QRS >150 + NYHA III, AMBULATORY IV
  • LVEF <35% + GDMT + AF + OTHERWISE MEETS REQUIREMENTS FOR CRT OR REQUIRES PACEMAKER:
    • After AVN ablation or pharmacologic rate control requireing 100% pacing
    • Already has RV pacemaker pacing > 40% of rhythm
2013 accf aha heart failure guidelines
2013 ACCF/AHA HEART FAILURE GUIDELINES
  • J Am Coll Cardiol 2013;62:1495-1539 (Executive Summary)
  • J Am Coll Cardiol 2013; 62: e147-239 (Full Text)
bibliography ace inhibitors
BIBLIOGRAPHY: ACE INHIBITORS
  • CONSENSUS
    • N Engl J Med. 1987;23: 1429-35.
  • SOLVD
    • N Engl J Med. 1991; 5:293-302.
  • SAVE
    • N Engl J. Med. 1992; 10: 669-77.
  • AIRE
    • Lancet. 1993; 342: 821-828.
bibliography ace inhibitors1
BIBLIOGRAPHY: ACE INHIBITORS
  • TRACE
    • N Engl J Med. 1995; 25: 1670-6.
  • ISIS 4
    • Lancet. 1995; 345 : 669-85.
  • GISSI 3
    • Lancet. 1994; 343:1115-22.
bibliography arb
BIBLIOGRAPHY: ARB
  • Val-HeFT
    • N Engl J Med. 2001;345:1667-75.
  • CARM-Added
    • Lancet. 2003; 362:767-71.
  • CHARM-Alternative
    • Lancet. 2003; 362: 772-6.
  • CHARM-Preserved
    • Lancet. 2003; 362: 777-81.
  • VALIANT
    • N Engl J Med. 2003;349: 1893-906.
bibliography arb1
BIBLIOGRAPHY: ARB
  • I-PRESERVE
    • N Engl J Med. 2008; 23: 2456-67.
  • HEAAL
    • Lancet. 2009 374: 1840-8.
bibliography beta blockers
BIBLIOGRAPHY: BETA BLOCKERS
  • U.S. CARVEDILOL HEART FAILURE STUDY GROUP
    • N Engl J Med. 1996; 334: 1349-55
  • CIBIS-II
    • Lancet. 1999; 353: 9-13.
  • MERIT-HF
    • Lancet. 1999; 353: 2001-7.
  • CAPRICORN
    • Lancet. 2001; 357: 1385-90.
bibliography beta blockers1
BIBLIOGRAPHY: BETA BLOCKERS
  • COPERNICUS
    • N Engl J Med. 2001; 344: 1651-8.
  • COMET
    • Lancet. 2003; 362: 7-13.
  • SENIORS
    • Eur. Heart J. 2005; 3:215-25.
bibliography aldosterone antagonists
BIBLIOGRAPHY: ALDOSTERONE ANTAGONISTS
  • RALES
    • N Engl. J Med. 1999; 341: 709-17.
  • EPHESUS
    • N Engl. J Med. 2003; 348: 1309-21.
  • EMPHASIS-HF
    • N Engl J Med. 2011; 364:11-21.
bibliography nitrate hydralazine combination
BIBLIOGRAPHY: NITRATE-HYDRALAZINE COMBINATION
  • V-HeFT
    • N Engl J Med. 1986; 314: 1547-52.
  • A-HeFT
    • N Engl J Med. 2004; 351: 2049-57.
bibliography digoxin
BIBLIOGRAPHY: DIGOXIN
  • DIG
    • N Engl J Med. 1997; 336: 525-33.
  • RADIANCE
    • N Engl J Med. 1993; 329: 1-7.
  • PROVED
    • J Am Coll Cardiol. 1993; 22: 955-62.
bibliography diuretics
BIBLIOGRAPHY: DIURETICS
  • DOSE
    • N Engl. J Med. 2011; 364: 797-805.
bibliography antithrombotics
BIBLIOGRAPHY: ANTITHROMBOTICS
  • WATCH
    • Circulation. 2009; 119: 1616-1624.
  • WARCEF
    • N Engl. J Med. 2012;
bibliography fish oil
BIBLIOGRAPHY: FISH OIL
  • GISSI-HF
    • Lancet. 2008; 372: 1223-30.
bibliography anemia and iron therapy
BIBLIOGRAPHY: ANEMIA AND IRON THERAPY
  • FAIR-HF
    • N Engl J Med. 2009; 361: 2436-48.
  • RED-HF
    • N Engl J Med. 2013: 368: 1210-9.
bibliography icd
BIBLIOGRAPHY: ICD
  • MADIT
    • N Engl J Med. 1996; 335:1933-40.
  • AVID
    • N Engl J Med. 1997; 337: 1576-1583.
  • MADIT-II
    • N Engl J Med. 2002; 346: 877-83.
  • DEFINITE
    • N Engl. J Med. 2004; 350: 2151-8.
  • SCD-HeFT
    • N Engl J Med. 2005; 352: 225-37.
bibliography crt
BIBLIOGRAPHY: CRT
  • MUSTIC
    • N Engl J Med. 2001; 344: 873-80.
  • MIRACLE
    • N Engl J Med. 2002; 346: 1845-53.
  • MIRACLE-ICD
    • JAMA. 2003; 289: 2685-94
  • COMPANION
    • N Engl J Med. 2004; 350: 2140-50.
  • CARE-HF
    • N Engl J Med. 2005; 352: 1539-49.
bibliography crt1
BIBLIOGRAPHY: CRT
  • RethinQ
    • N Engl J Med. 2007; 357: 2461-71
  • MADIT-CRT
    • N Engl J Med. 2009; 361: 1329-38.
  • RAFT
    • N Engl J Med. 2010: 363: 2385-95.
  • BLOCK HF
  • N Engl J Med. 2013; 368: 1585-1593.
bibliography calcium channel blockers
BIBLIOGRAPHY: CALCIUM CHANNEL BLOCKERS
  • PRAISE
    • N Engl J Med. 1996; 335: 1107-14
bibliography sinus node inhibitors
BIBLIOGRAPHY: SINUS NODE INHIBITORS
  • SHIFT
    • Lancet. 2010: 376: 875-85.
bibliography vasopressin receptor blockers
BIBLIOGRAPHY: VASOPRESSIN RECEPTOR BLOCKERS
  • EVEREST
    • JAMA. 2007; 297: 1319-31.
bibliography pde 5 inhibitors
BIBLIOGRAPHY: PDE-5 INHIBITORS
  • RELAX
    • JAMA. 2013: 309: 1268-77.
bibliography antiarrhythmics
BIBLIOGRAPHY: ANTIARRHYTHMICS
  • GESICA
    • Lancet. 1994; 344: 493-98.
  • CHF-STAT
    • N Engl J Med. 1995; 333: 77-82
  • DIAMOND-CHF
    • N Engl J Med. 1999; 341: 857-65.
  • SCD-HeFT
    • N Engl J Med 2005; 352: 225-37.
  • ANDROMEDA
    • N Engl J Med. 2008; 358: 2678-87.
bibliography atrial fibrillation
BIBLIOGRAPHY: ATRIAL FIBRILLATION
  • PABA-CHF
    • N Engl J Med. 2008; 359: 1778-85.
  • AF-CHF
    • N Engl J Med. 2008; 358: 2667-2677
bibliography direct renin inhibitors
BIBLIOGRAPHY: DIRECT RENIN INHIBITORS
  • ASTRONAUT
    • JAMA . 2013; 309: 1125-35.
bibliography lvads
BIBLIOGRAPHY: LVADs
  • REMATCH
    • N Engl J Med. 2001; 345; 1435-43
  • Heartmate II
    • N Engl J Med. 2009; 361: 2241-51.
bibliography cell therappy
BIBLIOGRAPHY: CELL THERAPPY
  • FOCUS-CCTRN
    • JAMA. 2012; 307: 1717-26.
bibliography surgery
BIBLIOGRAPHY: SURGERY
  • STITCH-2
    • N Engl J Med. 2009; 360: 1705-17.
  • STITCH-1
    • N Engl J Med. 2011; 364: 1607-16.
bibliography pulmonary artery catheters
BIBLIOGRAPHY: PULMONARY ARTERY CATHETERS
  • ESCAPE
    • JAMA. 2005; 294: 1625-1633
bibliography telemonitoring
BIBLIOGRAPHY: TELEMONITORING
  • Tele-HF
    • N Engl J Med. 2010; 363: 2301-9.
  • CHAMPION
    • Lancet. 2011; 377: 658-66.
bibliography ultrafiltration
BIBLIOGRAPHY: ULTRAFILTRATION
  • UNLOAD
    • J Am Coll Cardiol. 2007; 49: 675-83.
  • CARRESS-HF
    • N Engl J Med. 2012;
bibliography exercise therapy
BIBLIOGRAPHY: EXERCISE-THERAPY
  • HF-ACTION
    • JAMA. 2009; 301; 1439-50.
bibliography counseling
BIBLIOGRAPHY: COUNSELING
  • HART
    • JAMA. 2010; 304: 1331-38.
bibliography bnp guided therapy
BIBLIOGRAPHY: BNP-GUIDED THERAPY
  • TIME-CHF
    • JAMA. 2009; 301: 383-92.
bibliography statins
BIBLIOGRAPHY: STATINS
  • CORONA
    • N Engl J Med. 2007; 357: 2248-61.
  • GISSI-HF
    • Lancet. 2008; 372: 1231-39.
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