Download HFrEF: ANSWERS YOU NEVER GET TO QUESTIONS YOU

BART COX, M.D., FACC
DIRECTOR, ADVANCED HEART FAILURE PROGRAM
ASSOCIATE PROFESSOR OF MEDICINE
UNIVERSITY OF NEW MEXICO SCHOOL OF MEDICINE

NONE

A complex clinical syndrome that results
from any structural or functional
impairment of ventricular filling or ejection
of blood
HF with LVEF < 40%
HF with LVEF > 50%
HF with LVEF 41-49%

HFpEF + LVEF previously < 40% that is now >
40%




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

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)


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




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




CONSENSUS (Enalapril v. placebo)
SOLVD (Enalapril v. placebo)
SAVE (Captopril v. placebo)
POST MI TRIALS





AIRE
TRACE
ISIS IV
GISSI 3
CHINESE CAPTOPRIL TRIAL

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)



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





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)

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)

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)

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)

CLASS III: HARM
 Routine combined use of an ACEI, ARB, and
aldosterone antagonist is potentially harmful for
patients with HFrEF (Level of Evidence C)

It is recommended to use ARBs in ACEIintolerant 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.







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)

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)
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!


CLASS I
 Diuretics are recommended in patients with
HFrEf who have evidence of fluid retention,
unless contraindicated, to improve symptoms
(Level of Evidence C)

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





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

RALES
 Spironolactone v. placebo

EPHESUS
 Eplerenone v. placebo

EMPHASIS-HF
 Eplerenone v. placebo

CLASS I
 Aldosterone receptor antagonists (or
mineralocorticoid receptor antagonists) are
recommended in patients with NYHA class IIIV 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
aldosterone receptro antagonists.

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

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)

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)

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 aldosterone
antanonist


V-HeFT
 ISDN/hydralazine v. prazosin v. placebo

A-HeFT
 ISDN/Hydralazine v. placebo

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)

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)


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)


DIGITALIS INVESTIGATION GROUP (DIG)
TRIAL
DIGOXIN WITHDRAWAL TRIALS
 RADIANCE
 PROVED

CLASS IIa
 Digoxin can be beneficial in patients with
HFrEF, unless contraindicated, to decrease
hospitalizations for HF (IIa, Level of Evidence
B)



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

WATCH
 Warfarin v. aspirin v. clopidogrel

WARCEF
 Warfarin v. asppirin

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)

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)

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)


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


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

GISSI-HF
 Fish oil v. placebo

CLASS IIa
 Omega-3 polyunsaturated fatty acid (PUFA)
supplementation is reasonable to use as
adjunctive therapy in patients with NYHA class IIIV symptoms and HFrEF or HFpEF, unless
contraindicated to reduce mortality and
cardiovascular hospitalizations (Level of Evidence
B)


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





MADIT
AVID
MADIT-II
DEFINITE
SCD-HeFT

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)

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)

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)

CLASS I
 LVEF < 35% + GDMT +NYHA II and III
 LVEF < 30% + GDMT + NYHA I + Ischemic CM








MUSTIC
MIRACLE
MIRACLE-ICD
COMPANION
CARE-HF
MADIT-CRT
RAFT
BLOCK HF

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)

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)

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)

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

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)

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

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)

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



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


J Am Coll Cardiol 2013;62:1495-1539
(Executive Summary)
J Am Coll Cardiol 2013; 62: e147-239 (Full Text)

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.

TRACE
 N Engl J Med. 1995; 25: 1670-6.

ISIS 4
 Lancet. 1995; 345 : 669-85.

GISSI 3
 Lancet. 1994; 343:1115-22.

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.

I-PRESERVE
 N Engl J Med. 2008; 23: 2456-67.

HEAAL
 Lancet. 2009 374: 1840-8.

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.

COPERNICUS
 N Engl J Med. 2001; 344: 1651-8.

COMET
 Lancet. 2003; 362: 7-13.

SENIORS
 Eur. Heart J. 2005; 3:215-25.

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.

V-HeFT
 N Engl J Med. 1986; 314: 1547-52.

A-HeFT
 N Engl J Med. 2004; 351: 2049-57.

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.

DOSE
 N Engl. J Med. 2011; 364: 797-805.

WATCH
 Circulation. 2009; 119: 1616-1624.

WARCEF
 N Engl. J Med. 2012;

GISSI-HF
 Lancet. 2008; 372: 1223-30.

FAIR-HF
 N Engl J Med. 2009; 361: 2436-48.

RED-HF
 N Engl J Med. 2013: 368: 1210-9.

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.

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.

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.

PRAISE
 N Engl J Med. 1996; 335: 1107-14

SHIFT
 Lancet. 2010: 376: 875-85.

EVEREST
 JAMA. 2007; 297: 1319-31.

RELAX
 JAMA. 2013: 309: 1268-77.

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.

PABA-CHF
 N Engl J Med. 2008; 359: 1778-85.

AF-CHF
 N Engl J Med. 2008; 358: 2667-2677

ASTRONAUT
 JAMA . 2013; 309: 1125-35.

REMATCH
 N Engl J Med. 2001; 345; 1435-43

Heartmate II
 N Engl J Med. 2009; 361: 2241-51.

FOCUS-CCTRN
 JAMA. 2012; 307: 1717-26.

STITCH-2
 N Engl J Med. 2009; 360: 1705-17.

STITCH-1
 N Engl J Med. 2011; 364: 1607-16.

ESCAPE
 JAMA. 2005; 294: 1625-1633

Tele-HF
 N Engl J Med. 2010; 363: 2301-9.

CHAMPION
 Lancet. 2011; 377: 658-66.

UNLOAD
 J Am Coll Cardiol. 2007; 49: 675-83.

CARRESS-HF
 N Engl J Med. 2012;

HF-ACTION
 JAMA. 2009; 301; 1439-50.

HART
 JAMA. 2010; 304: 1331-38.

TIME-CHF
 JAMA. 2009; 301: 383-92.

CORONA
 N Engl J Med. 2007; 357: 2248-61.

GISSI-HF
 Lancet. 2008; 372: 1231-39.