Outpatient Management of
Systolic Heart Failure
J.D. Filippone, M.D, FACC
November 5, 2011
Treatment of Heart Failure
– “Special care should be taken of the
bowels”
– “A cold tub in the morning, if
unsuccessful a lukewarm tub at
night”
– “Young people should be allowed
plenty of sleep including an hour’s
rest in the middle of the day”
– “The question of marriage is always a
distressing one”
– “During the winter months a change
in climate is most helpful”
– “Moderation in all things should be
the motto of the patient”
– “Golf is a particularly suitable game
for young men”
Osler: The Principles and Practice of Medicine, 8th edition 1913
Hurst’s Textbook 1974
• Decreased physical activity
• Digitalis
• Thiazide diuretics
• Furosemide if no response to thiazides.
Pharmacologic Therapy
Diuretics
• Loop: Inc UNa, Free H2O clearance, improve symptoms
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and cardiac function
No proven effect on mortality
Most rapid effect on symtoms of any HF drug
Volume status is key in the success of other HF drugs
Loop vs Thiazide
Loop diuretics
– Furosemide, 50% bioavailabilty, inter/intrapatient
variability
– Torsemide Bumetadine more predictably absorbed
– Torsemide longer ½ life than both
– Torsemide vs Furosemide
Murray, MD Am J Med, 2001; 111 (7) 513
Cosin, J Eur J Heart Fail 2002 4(4) 507
Diuretics
• Reduced response to loop diuretic in CHF
– Dec renal blood flowdec diuretic delivery
– Inc Na reabsorption due to acitvation of RAAS
and SNS.
– Bowel edema
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Furosemide: 20-40QD max 80-200
Torsemide 5-10QD max 100-200
Bumetadine 0.5-1QD max 5-10
BID dosing
Metolazone
Avoid NSAIDS
Maintain effective dose
ACE-I
• Reduction in mortality, symptoms and hospitalization
• Which drug?
– Most of the survival data is based upon trials with Enalapril
– Probably a class effect
– captopril, enalapril, lisinopril, perindopril, ramipril, trandolapril
• What dose:
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CONSENSUS, SOLVD, ATLAS
Enalapril 10 BID, Lisinopril 40 QD, Captopril 50 TID
“start low, go slow”
Follow BUN, Cr, K after each dose increment.
• Volume status
– “wet” Therapeutic effect of ACE-I blunted
– “dry” Adverse renal effects more likely
Garg, R, JAMA 1995, /273: 1450
CONSENSUS trial investigators, N Engl J Med. 1987;316(23):1429.
SOLVD investigators, NEJM 1991, 325 (5):293.
SAVE investigator, NEJM 1992; 327 (10):669
• Renal function
– In CONSENSUS there was 1015% inc. in Cr in the first 3 wks
– This increase remained stable at 6
months
– In practice sig inc (0.3 mg/dl)
occurs in 15-30%
• Some increase in Cr is OK
• May need to tolerate mild to
moderate azotemia
• Significant fall in GFR should
raise concern for volume
depeletion or bilateral RAS,
NSAID use.
• Baseline CKD not a
contraindication.
– dec intraglomerular pressure, dec
proteinuria are renal protective
– Use with caution if Cr > 3.0 or
K >5.5
Hasenfuss, G, Basic Res Cardiol. 1989; 84
ARBs
– Rationale
• Ang II production persists in the presence of ACE-I
• Inhibit RAAS without production of excess kinins
– Considerably less clinical trial experience than with ACE-I
– Less cough, angioedema, more expensive
– ACC/AHA: ACE-I first line, ARB reasonable alternative especially in
patients intolerant of ACE-I
– ARB + ACE
• Reduced Hospitalizations (CHARM-Added), no change in mortality
• ACC/AHA IIb
• ARB + ACE-I + spironolactone = ? contraindicated
Granger, CB Lancet 2003
B-Blockers
• reduce myocardial exposure to
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catecholamines
Reduce circulating levels of
vasoconstrictors
Reduce ischemia
Upregulate B1 receptors
Reduce myocardial gene production
of inflammatory cytokines
• Which drug:
– Bisoprolol, carvedilol, metoprolol (sustained release)
– Probably not a class effect –Bucindolol, short-acting metoprolol
• MERIT- HF
– Metoprolol XL vs placebo
– Target dose 200mg/day (mean 159 mg)
• Carvedilol HF Program and COMET
– Carvedilol vs placebo, carvedilol vs metoprolol tartate
– Target dose 25mg BID
• CIBIS II
– Bisoprolol vs placebo
– Target dose 10 mg/day
MERIT-HF investigators Lancet. 1999;353(9169):2001.
Packer, M NEJM 1996; 334 (21): 1349
CIBIS II, investigators Lancet 1999, 353 (9146):9
• Patients who cannot tolerate target doses may derive
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similar benefit if similar a similar degree of B-blockade
is achieved (HR).
Start low and go slow (2-3 week intervals)
“You may feel worse before you feel better”
Caution if significant volume overload or recent inotrope
use
Hypotension rarely limits metoprolol titration but may
limit use of carvedilol (alpha blockade, vasodilation).
Wikstrand J, et al. MERIT-HF Study Group JACC 2002;40(3):491.
ACE-I, B-blocker which one first?
– Clinical Trials with ACE-I performed first
– CIBIS III : outcomes similar if BB started first
– ACE-I provide more rapid hemodynamic benefit
and will not exacerbate HF in short-run
– Hemodynamic benefits of BB are delayed and they
may cause transient worsening of cardiac function
short-term.
– Practical Approach
• Initiate ACE-I, titrate to intermediate doseadd BB
Aldosterone Antagonists
• Spironolactone, Eplerenone
• Compete with Aldosterone for the mineralocorticoid receptor
• Reduce hypokalemia, cardiac hypertrophy and fibrosis
– RALES-EF<35%, Class III or IV HF, 25-50 mg Sprionolactone:
– EPHESUS: Recent MI, EF< 40%, clinical HF or DM, 25-50 mg
Eplerenone:
– EMPHASIS-HF: EF < 30%, Class II HF, recent HF hospitalization or
elevated BNP, Eplerenone 25-50 mg:
Hyperkalemia
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RALES, dose related increase in K > 5.5, ranging from 5-24%
EPHESUS: K>6.0, 5.5% Eplerenone, 3.9% Placebo
EMPHASIS-HF: K > 5.5, 11.8% Eplerenone vs 7.2% placebo
Ontario Canada
– After RALES, Sprinolactone prescriptions tripled among HF pt.s
– Hospitalizaton for hyperkalemia inc from 2.4 to 11 per 1000
• Hypokalemia reduced in all trials
• Avoid if Cr. > 2.5 in men, 2.0 in women, careful monitoring of
K/Cr.
• If GFR > 50, start 2550, GFR 30-50,start 12.5 25
• BMP, 1wk, 4wks, every 3months.
Juurlink DN, NEJM 2004;351:543
Digitalis
– Inotrope?
• Inhibition of Na/K ATPase in vagal afferents reduces CNS sympathetic
outflow
• Inhibition of Na/K kidneyalters tubular Na handling and reduces renin
secretion.
– RADIANCE
– In stable Class II-III patients taking ACE-I/diuretic, discontinuation of Dig led to a
5-fold increase in the rate of wrosening HF
– Dig trial
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Digoxin vs Placebo in HF patients with background of ACE-I therapy
No difference in mortality. Fewer hospiatlizations
Levels 0.5-0.9 ng/mL associated with dec. mortality
Levels >1 ng/mL associated with increased morbidity and mortality.
Packer, M NEJM 1993; 13: 134
Garg R, NEJM 197;336:525
– Physicians may consider
adding digoxin in
patients with persistent
symptoms of HF during
therapy with diuretics, an
ACEI (or ARB), and a
beta blocker” Class IIa
2009 ACC/AHA Guidleines for the Treatment of CHF
Hydralazine + Nitrates
– Combined Afterload and Preload reduction
– Enhanced Nitric oxide availability
– V-HeFT I
– Hydralazine (300), Isosorbide dinitrate (160) added to Digoxin and diueticsmodest
reduction in mortality
– V-HeFT II
– Enalapril vs Hydralazine/nitrate better survival with Enalapril
– A-HeFT
– Hydralazine/nitrate added to ACE-I/BB/spironolactone in Aferican American
patientsReduced mortality and hospitaliaztions
– “recommended for African Americans who remain symptomatic despite
optimal medical therapy”
– “Despite the lack of data with the vasodilator combination in patients who are
intolerant of ACEIs, the combined use of hydralazine and isosorbide dinitrate
may be considered as a therapeutic option in such patients”
Cohn JN, NEJM 1986; 314(24):1547
Cohn JN, NEJM 1991;325(5):303
2009 ACC/AHA Guidelines in the treatment of CHF
Summary
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Diuretics for symptoms, but not too wet, not too dry
ACE-I/BB at target doses!
Increased Cr. is OK, their nephrons will thank you
Don’t forget about Aldosterone Antagonists, Beware
Hyperkalemia.
Digoxin and Hydralazine/nitrates in selected
populations
“During the winter months a change in climate is
most helpful”