Outpatient Management of Outpatient Management of Systolic Heart FailureSystolic Heart Failure

J.D. Filippone, M.D, FACCJ.D. Filippone, M.D, FACC

November 5, 2011November 5, 2011

Treatment of Heart FailureTreatment 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, 8Osler: The Principles and Practice of Medicine, 8 thth edition 1913 edition 1913

Hurst’s Textbook 1974Hurst’s Textbook 1974

• Decreased physical activityDecreased physical activity

• DigitalisDigitalis

• Thiazide diureticsThiazide diuretics

• Furosemide if no response to thiazides.Furosemide if no response to thiazides.

Pharmacologic TherapyPharmacologic Therapy

DiureticsDiuretics

• Loop: Inc ULoop: Inc UNaNa, Free H2O clearance, improve symptoms , Free H2O clearance, improve symptoms and cardiac functionand cardiac function

• No proven effect on mortalityNo proven effect on mortality• Most rapid effect on symtoms of any HF drugMost rapid effect on symtoms of any HF drug• Volume status is key in the success of other HF drugsVolume status is key in the success of other HF drugs• Loop vs Thiazide Loop vs Thiazide • Loop diureticsLoop diuretics

– Furosemide, 50% bioavailabilty, inter/intrapatient Furosemide, 50% bioavailabilty, inter/intrapatient variabilityvariability

– Torsemide Bumetadine more predictably absorbedTorsemide Bumetadine more predictably absorbed– Torsemide longer ½ life than bothTorsemide longer ½ life than both– Torsemide vs FurosemideTorsemide vs Furosemide

Murray, MD Am J Med, 2001; 111 (7) 513Murray, MD Am J Med, 2001; 111 (7) 513

Cosin, J Eur J Heart Fail 2002 4(4) 507Cosin, J Eur J Heart Fail 2002 4(4) 507

DiureticsDiuretics

• Reduced response to loop diuretic in CHFReduced response to loop diuretic in CHF– Dec renal blood flowDec renal blood flowdec diuretic delivery dec diuretic delivery – Inc Na reabsorption due to acitvation of RAAS Inc Na reabsorption due to acitvation of RAAS

and SNS.and SNS.– Bowel edemaBowel edema

• Furosemide: 20-40QD max 80-200Furosemide: 20-40QD max 80-200• Torsemide 5-10QD max 100-200Torsemide 5-10QD max 100-200• Bumetadine 0.5-1QD max 5-10Bumetadine 0.5-1QD max 5-10• BID dosingBID dosing• MetolazoneMetolazone• Avoid NSAIDSAvoid NSAIDS• Maintain effective doseMaintain effective dose

ACE-IACE-I

• Reduction in mortality, symptoms and hospitalizationReduction in mortality, symptoms and hospitalization• Which drug?Which drug?

– Most of the survival data is based upon trials with EnalaprilMost of the survival data is based upon trials with Enalapril– Probably a class effectProbably a class effect– captopril, enalapril, lisinopril, perindopril, ramipril, trandolaprilcaptopril, enalapril, lisinopril, perindopril, ramipril, trandolapril

• What dose:What dose:– CONSENSUS, SOLVD, ATLASCONSENSUS, SOLVD, ATLAS– Enalapril 10 BID, Lisinopril 40 QD, Captopril 50 TIDEnalapril 10 BID, Lisinopril 40 QD, Captopril 50 TID– ““start low, go slow”start low, go slow”– Follow BUN, Cr, K after each dose increment.Follow BUN, Cr, K after each dose increment.

• Volume status Volume status – ““wet” Therapeutic effect of ACE-I bluntedwet” Therapeutic effect of ACE-I blunted– ““dry” Adverse renal effects more likelydry” Adverse renal effects more likely

Garg, R, JAMA 1995, /273: 1450Garg, R, JAMA 1995, /273: 1450

CONSENSUS trial investigators, N Engl J Med. 1987;316(23):1429. CONSENSUS trial investigators, N Engl J Med. 1987;316(23):1429.

SOLVD investigators, NEJM 1991, 325 (5):293.SOLVD investigators, NEJM 1991, 325 (5):293.

SAVE investigator, NEJM 1992; 327 (10):669SAVE investigator, NEJM 1992; 327 (10):669

• Renal functionRenal function– In CONSENSUS there was 10-In CONSENSUS there was 10-

15% inc. in Cr in the first 3 wks15% inc. in Cr in the first 3 wks– This increase remained stable at This increase remained stable at

6 months6 months– In practice sig inc (0.3 mg/dl) In practice sig inc (0.3 mg/dl)

occurs in 15-30%occurs in 15-30%

• Some increase in Cr is OK Some increase in Cr is OK • May need to tolerate mild to May need to tolerate mild to

moderate azotemiamoderate azotemia• Significant fall in GFR should Significant fall in GFR should

raise concern for volume raise concern for volume depeletion or bilateral RAS, depeletion or bilateral RAS, NSAID use.NSAID use.

• Baseline CKD not a Baseline CKD not a contraindication.contraindication.– dec intraglomerular pressure, dec dec intraglomerular pressure, dec

proteinuria are renal protectiveproteinuria are renal protective– Use with caution if Cr > 3.0 or Use with caution if Cr > 3.0 or

K >5.5 K >5.5Hasenfuss, G, Basic Res Cardiol. 1989; 84Hasenfuss, G, Basic Res Cardiol. 1989; 84

ARBsARBs

– RationaleRationale• Ang II production persists in the presence of ACE-IAng II production persists in the presence of ACE-I

• Inhibit RAAS without production of excess kininsInhibit RAAS without production of excess kinins

– Considerably less clinical trial experience than with ACE-IConsiderably less clinical trial experience than with ACE-I

– Less cough, angioedema, more expensiveLess cough, angioedema, more expensive

– ACC/AHA: ACE-I first line, ARB reasonable alternative especially in ACC/AHA: ACE-I first line, ARB reasonable alternative especially in patients intolerant of ACE-Ipatients intolerant of ACE-I

– ARB + ACEARB + ACE• Reduced Hospitalizations (CHARM-Added), no change in mortalityReduced Hospitalizations (CHARM-Added), no change in mortality

• ACC/AHA IIbACC/AHA IIb

• ARB + ACE-I + spironolactone = ? contraindicatedARB + ACE-I + spironolactone = ? contraindicated

Granger, CB Lancet 2003Granger, CB Lancet 2003

Cohn, JM NEJM 2001Cohn, JM NEJM 2001

B-BlockersB-Blockers

• reduce myocardial exposure to reduce myocardial exposure to catecholaminescatecholamines

• Reduce circulating levels of Reduce circulating levels of vasoconstrictorsvasoconstrictors

• Reduce ischemia Reduce ischemia

• Upregulate B1 receptorsUpregulate B1 receptors

• Reduce myocardial gene production Reduce myocardial gene production of inflammatory cytokinesof inflammatory cytokines

• Which drug:Which drug:– Bisoprolol, carvedilol, metoprolol (sustained release)Bisoprolol, carvedilol, metoprolol (sustained release)– Probably not a class effect –Bucindolol, short-acting metoprololProbably not a class effect –Bucindolol, short-acting metoprolol

• MERIT- HFMERIT- HF– Metoprolol XL vs placeboMetoprolol XL vs placebo– Target dose 200mg/day (mean 159 mg)Target dose 200mg/day (mean 159 mg)

• Carvedilol HF Program and COMETCarvedilol HF Program and COMET– Carvedilol vs placebo, carvedilol vs metoprolol tartateCarvedilol vs placebo, carvedilol vs metoprolol tartate– Target dose 25mg BIDTarget dose 25mg BID

• CIBIS IICIBIS II– Bisoprolol vs placeboBisoprolol vs placebo– Target dose 10 mg/dayTarget dose 10 mg/day

MERIT-HF investigators Lancet. 1999;353(9169):2001. MERIT-HF investigators Lancet. 1999;353(9169):2001.

Packer, M NEJM 1996; 334 (21): 1349Packer, M NEJM 1996; 334 (21): 1349

CIBIS II, investigators CIBIS II, investigators Lancet 1999, 353 (9146):9Lancet 1999, 353 (9146):9

• Patients who cannot tolerate target doses may derive Patients who cannot tolerate target doses may derive similar benefit if similar a similar degree of B-blockade similar benefit if similar a similar degree of B-blockade is achieved (HR).is achieved (HR).

• Start low and go slow (2-3 week intervals)Start low and go slow (2-3 week intervals)

• ““You may feel worse before you feel better”You may feel worse before you feel better”

• Caution if significant volume overload or recent inotrope Caution if significant volume overload or recent inotrope useuse

• Hypotension rarely limits metoprolol titration but may Hypotension rarely limits metoprolol titration but may limit use of carvedilol (alpha blockade, vasodilation).limit use of carvedilol (alpha blockade, vasodilation).

Wikstrand J, et al. MERIT-HF Study Group JACC 2002;40(3):491.Wikstrand J, et al. MERIT-HF Study Group JACC 2002;40(3):491.

ACE-I, B-blocker which one first?ACE-I, B-blocker which one first?

– Clinical Trials with ACE-I performed firstClinical Trials with ACE-I performed first– CIBIS III : outcomes similar if BB started firstCIBIS III : outcomes similar if BB started first– ACE-I provide more rapid hemodynamic benefit ACE-I provide more rapid hemodynamic benefit

and will not exacerbate HF in short-runand will not exacerbate HF in short-run– Hemodynamic benefits of BB are delayed and they Hemodynamic benefits of BB are delayed and they

may cause transient worsening of cardiac function may cause transient worsening of cardiac function short-term.short-term.

– Practical ApproachPractical Approach• Initiate ACE-I, titrate to intermediate doseInitiate ACE-I, titrate to intermediate doseadd BBadd BB

Aldosterone AntagonistsAldosterone Antagonists

• Spironolactone, EplerenoneSpironolactone, Eplerenone• Compete with Aldosterone for the mineralocorticoid receptorCompete with Aldosterone for the mineralocorticoid receptor• Reduce hypokalemia, cardiac hypertrophy and fibrosisReduce hypokalemia, cardiac hypertrophy and fibrosis

– RALES-EF<35%, Class III or IV HF, 25-50 mg Sprionolactone:RALES-EF<35%, Class III or IV HF, 25-50 mg Sprionolactone:– EPHESUS: Recent MI, EF< 40%, clinical HF or DM, 25-50 mg EPHESUS: Recent MI, EF< 40%, clinical HF or DM, 25-50 mg

Eplerenone:Eplerenone:– EMPHASIS-HF: EF < 30%, Class II HF, recent HF hospitalization or EMPHASIS-HF: EF < 30%, Class II HF, recent HF hospitalization or

elevated BNP, Eplerenone 25-50 mg: elevated BNP, Eplerenone 25-50 mg:

HyperkalemiaHyperkalemia

• RALES, dose related increase in K > 5.5, ranging from 5-24%RALES, dose related increase in K > 5.5, ranging from 5-24%

• EPHESUS: K>6.0, 5.5% Eplerenone, 3.9% PlaceboEPHESUS: K>6.0, 5.5% Eplerenone, 3.9% Placebo

• EMPHASIS-HF: K > 5.5, 11.8% Eplerenone vs 7.2% placeboEMPHASIS-HF: K > 5.5, 11.8% Eplerenone vs 7.2% placebo

• Ontario CanadaOntario Canada– After RALES, Sprinolactone prescriptions tripled among HF pt.sAfter RALES, Sprinolactone prescriptions tripled among HF pt.s

– Hospitalizaton for hyperkalemia inc from 2.4 to 11 per 1000Hospitalizaton for hyperkalemia inc from 2.4 to 11 per 1000

• Hypokalemia reduced in all trialsHypokalemia reduced in all trials

• Avoid if Cr. > 2.5 in men, 2.0 in women, careful monitoring of Avoid if Cr. > 2.5 in men, 2.0 in women, careful monitoring of K/Cr.K/Cr.

• If GFR > 50, start 25If GFR > 50, start 2550, GFR 30-50,start 12.550, GFR 30-50,start 12.5 25 25

• BMP, 1wk, 4wks, every 3months. BMP, 1wk, 4wks, every 3months.

Juurlink DN, NEJM 2004;351:543Juurlink DN, NEJM 2004;351:543

DigitalisDigitalis

– Inotrope?Inotrope?• Inhibition of Na/K ATPase in vagal afferentsInhibition of Na/K ATPase in vagal afferents reduces CNS sympathetic reduces CNS sympathetic

outflowoutflow • Inhibition of Na/K kidneyInhibition of Na/K kidneyalters tubular Na handling and reduces renin alters tubular Na handling and reduces renin

secretion.secretion.

– RADIANCERADIANCE– In stable Class II-III patients taking ACE-I/diuretic, discontinuation of Dig led to a In stable Class II-III patients taking ACE-I/diuretic, discontinuation of Dig led to a

5-fold increase in the rate of wrosening HF5-fold increase in the rate of wrosening HF

– Dig trialDig trial– Digoxin vs Placebo in HF patients with background of ACE-I therapyDigoxin vs Placebo in HF patients with background of ACE-I therapy

– No difference in mortality. Fewer hospiatlizationsNo difference in mortality. Fewer hospiatlizations

– Levels 0.5-0.9 ng/mL associated with dec. mortalityLevels 0.5-0.9 ng/mL associated with dec. mortality

– Levels >1 ng/mL associated with increased morbidity and mortality.Levels >1 ng/mL associated with increased morbidity and mortality.

Packer, M NEJM 1993; 13: 134Packer, M NEJM 1993; 13: 134

Garg R, NEJM 197;336:525Garg R, NEJM 197;336:525

– Physicians may consider Physicians may consider adding digoxin in adding digoxin in patients with persistent patients with persistent symptoms of HF during symptoms of HF during therapy with diuretics, an therapy with diuretics, an ACEI (or ARB), and a ACEI (or ARB), and a beta blocker” Class IIabeta blocker” Class IIa

2009 ACC/AHA Guidleines for the Treatment of CHF2009 ACC/AHA Guidleines for the Treatment of CHF

Hydralazine + NitratesHydralazine + Nitrates– Combined Afterload and Preload reductionCombined Afterload and Preload reduction– Enhanced Nitric oxide availabilityEnhanced Nitric oxide availability– V-HeFT IV-HeFT I

– Hydralazine (300), Isosorbide dinitrate (160) added to Digoxin and diueticsHydralazine (300), Isosorbide dinitrate (160) added to Digoxin and diueticsmodest modest reduction in mortalityreduction in mortality

– V-HeFT IIV-HeFT II– Enalapril vs Hydralazine/nitrateEnalapril vs Hydralazine/nitrate better survival with Enalapril better survival with Enalapril

– A-HeFTA-HeFT– Hydralazine/nitrate added to ACE-I/BB/spironolactone in Aferican American Hydralazine/nitrate added to ACE-I/BB/spironolactone in Aferican American

patientspatientsReduced mortality and hospitaliaztionsReduced mortality and hospitaliaztions

– ““recommended for African Americans who remain symptomatic despite recommended for African Americans who remain symptomatic despite optimal medical therapy”optimal medical therapy”

– ““Despite the lack of data with the vasodilator combination in patients who are Despite the lack of data with the vasodilator combination in patients who are intolerant of ACEIs, the combined use of hydralazine and isosorbide dinitrate intolerant of ACEIs, the combined use of hydralazine and isosorbide dinitrate may be considered as a therapeutic option in such patients” may be considered as a therapeutic option in such patients”

Cohn JN, NEJM 1986; 314(24):1547Cohn JN, NEJM 1986; 314(24):1547

Cohn JN, NEJM 1991;325(5):303Cohn JN, NEJM 1991;325(5):303

2009 ACC/AHA Guidelines in the treatment of CHF2009 ACC/AHA Guidelines in the treatment of CHF

SummarySummary

• Diuretics for symptoms, but not too wet, not too dryDiuretics for symptoms, but not too wet, not too dry• ACE-I/BB at ACE-I/BB at target doses!target doses!• Increased Cr. is OK, their nephrons will thank youIncreased Cr. is OK, their nephrons will thank you• Don’t forget about Aldosterone Antagonists, Beware Don’t forget about Aldosterone Antagonists, Beware

Hyperkalemia.Hyperkalemia.• Digoxin and Hydralazine/nitrates in selected Digoxin and Hydralazine/nitrates in selected

populationspopulations• “During the winter months a change in climate is

most helpful”