Success with Heart Failure: What’s in our medicine bag? J. Susie Woo MD, FACC Virginia Mason Cardiology February 20, 2015.

Success with Heart Failure: What’s in our medicine bag?

J. Susie Woo MD, FACCVirginia Mason Cardiology

February 20, 2015

The Problem

• HF is common– Increasing in prevalence– Lifetime risk of 20% (1:5) after age 40

• HF is expensive– Most common cause of hospitalization in pts >65 yo– 5% of total healthcare budget ($32 billion/yr)

HF is deadly

20% mortality in 1 year 50% mortality in 5 years

Senni M et al. Circ 1998;98:2282-2289.

n=216

Clinical diagnosis• Based on signs and symptoms of volume overload

– DOE, orthopnea, PND– Weight gain– Edema, ascites

Jugular venous pressure

Clear lungs and/or CXR do not exclude heart failure!

Supportive testing• CXR• BNP• Echocardiogram

– HFrEF vs. HFpEF– Dilated or non-dilated– Ischemic vs. non-ischemic– LVH, diastolic function– Valve disease– RV fxn, pulmonary pressures– Volume status

Diagnostic workup• CMP, CBC, Ca/Mg,

TSH, lipid panel• ECG• Stress testing and/or

coronary angiogram

Etiologies

Ischemic nonischemic

Coronary diseaseHypertension

Valvular diseaseViral myocarditis

Diabetes, ObesityToxic (alcohol, cocaine, chemotherapy)

Peripartum, Familial, Idiopathic Sarcoid, Amyloid, Hypertrophic

Biomarkers

BNP – Much lower in obese pts – Increased with age– Increased in CKD– Higher in women– Lower in HFpEF– Should not be used in

isolation to adjust diuretics

Troponin – Can be elevated in

decompensated HF– Low grade (<2.0)– Increased in CKD– Poor prognostic indicator

Classification

Hunt SA et al. JACC 2001;38:2101-13.Farrell MH et al. JAMA 2002;287:890-7.

Treat HTN, lipidsQuit smokingRegular exerciseAvoid alcohol, drugs

ACEI/ARB for vascular disease or DM

At risk:HTN, CAD, DM, metabolic syndrome, obesity, cardiotoxins, family h/o CM

Heart diseaseno HF symptoms

MI, LVH, low EF, valvular disease

Heart disease, prior or current HF

SOB, reduced exercise tolerance

ACEI/ARBBeta blockers

DiureticsSalt restrictionACEI/ARBBeta blockersAldosterone antagDigoxinNitrates/hydraazineICDCRT

Stage A Stage B Stage C

Key points

• Heart failure has established risk factors

• Heart failure can be prevented

• Evolving, dynamic syndrome with symptomatic and asymptomatic phases

• Morbidity and mortality can be reduced by treatments specific to stage/class

Adapted from Maron & Rocco, 2011.

Pathophysiology

Neurohormonal Imbalance in HF

Norepinephrine Angiotensin II Endothelin Aldosterone Vasopressin

ANPBNP Nitric Oxide Bradykinin Prostaglandins

Vasoconstriction Fluid Retention

Fibrosis / remodellingTachycardia

VasodilationNatriuresis/diuresis

SNS suppressionRAAS suppression

Adapted from Rev Cardiovasc Med. 2001;2(suppl 2):S2-S6.

Management of HFrEF

The patient’s role

• Salt restriction (2000 mg / 24 hrs)• Fluid restriction• Daily weights

Call for weight increase of 3# in 1 day, total of 5#

• Avoidance of NSAIDs and alcohol• CPAP in those with sleep apnea• Regular physical activity• Medication compliance

Cardiac Rehab

• CMS approved in 2014 for stable symptomatic HFrEF• EF 35%, NYHA II-IV • ≥6 weeks since last CV hospitalization or procedure• HF-ACTION: decreased all-cause mortality or

hospitalization (adjusted HR 0.89, p=0.03)

O’Connor CM et al., JAMA 2009;301(14):1439-50.

Drugs in our medicine bag

• Diuretics• ACE inhibitors / ARBs• Beta blockers• Hydralazine/nitrates• Digoxin• Aldosterone antagonists

Loop DiureticsEQUIVALENT DOSESFurosemide 40 mg po

Furosemide 20 mg IV

Torsemide 20 mg po/IV

Bumetanide 1 mg po/IV

• Furosemide– 6 hr half-life– Variable oral bioavailability

• Torsemide & bumetanide– Almost 100% bioavailability

• Ethacrynic Acid– For sulfa-allergic

Fear progressive volume overload over hypotension

and renal insufficiency

Thiazide Synergy

• Useful in refractory volume overload• May be administered simultaneously with loop• Hydrochlorothiazide

– Ineffective if GFR < 30 ml/min

• Metolazone– Avoid daily therapy or long courses of treatment– Start with 2.5 mg, 2-3 days/wk

• BEWARE OF HYPOKALEMIA, hyponatremia, and worsening renal function

Jentzer JC et al., JACC 2010;56:1527-34.

ACE-Inhibitors• Indicated in all patients

with HFrEF (EF ≤40%)• RAAS suppression• 30% decrease in

mortality• 25% decrease in

hospitalization

PEARLS• More is better• Dose twice daily for

neurohormonal blockade• Can uptitrate quickly in pts

with normal renal function• Caution in pts with Cr>3.0

or K>5.0

Trial Population Target dose (mg)

CONSENSUS, 1987 NYHA IV Enalapril 20 bid

SOLVD, 1991 EF ≤35%, NYHA II-III Enalapril 10 bid

SAVE, 1992 Post-MI, EF ≤40% Captopril 50 tid

ARBs• Second line (for the ACEI intolerant)• May be as effective as ACEI, not superior

– ELITE, ELITE II, VALIANT, RESOLVD, OPTIMAAL

• Decreases CHF hospitalization and CV death– Val-HEFT, CHARM

• Losartan 150 mg qd more effective than 50 mg qd

Konstam MA et al., HEALL Investigators, Lancet 2009;374(9704):1840-8.

Drug Initial dose (mg) Target dose (mg)

Candesartan 4 – 8 qd 32 qd

Losartan 25 – 50 qd 100 – 150 qd

Valsartan 20 – 40 bid 160 - bid

Nitrate / HydralazineVenous and arterial vasodilators

ISDN 10 tid or Imdur 30 qd (goal 120 qd) Hydralazine 25 tid – qid (goal 100 tid or 75 qid)

V-HeFT I: ISDN-H vs. placebo• Lower mortality and improved EF in ISDN-H vs. placebo

(26% vs. 34%) at 2 yrs, p<0.03V-HEFT II: ISDN-H vs. enalapril • Lower mortality in enalapril vs. ISDN-H (18% vs 25%),

p=0.016

Cohn JN et al. NEJM 1986;314:1547-52 and 1991;325:303-10

Nitrate / hydralazine

• Must be used in combination • TID dosing is difficult• Should be used in all African-

Americans with symptomatic HFrEF despite ACEI and BB (BiDil and the A-HeFT trial)

0

15

10

n=32

10.2%

6.2%

Mortality

P=0.02

n=54

5

Taylor, AL et al., NEJM 2004;351:2049-57.

n=1050

Placebo

Fixed-dose BiDil

Beta-blockers• SNS inhibition• Slows HF progression, reduces hospitalization; • Improves EF, symptoms and survival in NYHA II-IV CHF• 34% decrease in mortality

– U.S. Carvedilol (1996), MERIT-HF (1999), CIBIS II (1999)• NOT a class effect

Drug Initial dose (mg) Target dose (mg)

Carvedilol 3.125 bid 50 bid

Carvedilol CR 10 qd 80 qd

Metoprolol succinate 12.5 – 25 qd 200 qd

Bisoprolol 1.25 qd 10 qd

COMETmetoprolol tartratecarvedilol

Poole-Wilson PA et al. Lancet 2003;362:7-13.

40% vs 34%p=.0017

More is better(and a little is much better than none)

6.

Beta blocker Pearls• Start only when euvolemic • Double dose every 2 wks until target• Do not hold during a decompensation• Use metoprolol succinate or bisoprolol (β1-selective)

for pts with asthma/RAD or lower BP• Fear not the asymptomatic bradycardia

Clinical Case60 yo M with ischemic CM, EF 25-30% on last Echo, presents to clinic with 1 week of increasing dyspnea, orthopnea and LE edema.

Exam: BP 91/65, HR 92, JVP at 19 cm H20, fine bibasilar crackles, distant heart sounds with +S3, palpable liver edge, warm extremities with 1+ pitting LE edema.

Meds: ASA 81 qd, carvedilol 12.5 bid, lisinopril 20 bid, digoxin 0.25 qd, simvastatin 40 qhs, torsemide 50 bid, KCl 40 bid Labs: Na 132, K 4.4, BUN 38, Cr 2.2 (from baseline 1.5), AST 69, ALT 91, AlkP 105, Tbili 2.4, Dig level 1.2 (reference range 0.5-1.9)

ECG shows NSR 90 bpm, LBBB, and old anterior infarct.

Which medication(s) would you change?

• Carvedilol• Lisinopril• Digoxin • Simvastatin• Torsemide

Digoxin

• Cardiac glycoside: inhibits Na/K pump , increases intracellular calcium (inotrope)

• For patients with symptomatic HFrEF

NEJM 1997;336:525-33

Mortality HF Hospitalization05

10152025303540

34.8

26.8

35.1 34.7

Digoxin Placebo

p=0.8 p<0.001

Digoxin dose and Mortality

Rathore SS et al., JAMA 2003;289:871-8.

Digoxin Pearls

• Narrow therapeutic window!• Target level: 0.5-0.9• Watch for hypokalemia, hypomagnesemia

– Toxicity may occur at lower digoxin levels

• Watch for drug interactions – Amiodarone, clarithromycin, quinidine

• Typical dose no higher than 0.25 qd– 0.125 qod – qd if >70 yrs, reduced renal function or

low lean body mass (women)

Clinical Case60 yo M with ischemic CM, EF 25-30% on last Echo, presents to clinic with 1 week of increasing dyspnea, orthopnea and LE edema.

Exam: BP 91/65, HR 92, JVP at 19 cm H20, fine bibasilar crackles, distant heart sounds with +S3, palpable liver edge, warm extremities with 1+ pitting LE edema.

Meds: ASA 81 qd, carvedilol 12.5 bid, lisinopril 20 bid, digoxin 0.25 qd, simvastatin 40 qhs, torsemide 50 bid, KCl 40 bid Labs: Na 132, K 4.4, BUN 38, Cr 2.2 (from baseline 1.5), AST 69, ALT 91, AlkP 105, Tbili 2.4, Dig level 1.2 (reference range 0.5-1.9)

ECG shows NSR 90 bpm, LBBB, and old anterior infarct.

Anything other changes to his treatment regimen?

Aldosterone Antagonists

• Decrease sxs, mortality & HF hospitalization

• RALES (spironolactone)– EF <35%, NYHA 3-4

• EPHESUS (eplerenone)– EF <40% after acute MI

• EMPHASIS-HF (eplerenone)– EF <35%, NYHA 2

Pitt et al, NEJM 1999;341:709-17 and NEJM 2003;348:1309-21.Zannad F et al, NEJM 2011;364:11-21.

Aldosterone Antagonist Pearls• Weak diuretics• No gynecomastia with eplerenone

AVOIDING HYPERKALEMIA• Contraindications:

– baseline K >5.0– baseline Cr >2.5 in men, >2.0 in women (GFR <30)

• Start with 12.5 mg qd (or qod if GFR 30-49)• Discontinue or decrease potassium supplement• Chem7 at 1 wk, 1 month, 3 months, q3-6 months

– avoid in the unreliable patient• Hold for dehydration, diarrhea, or K >5.5

Clinical Case60 yo M with ischemic CM, EF 25-30% on last Echo, presents to clinic with 1 week of increasing dyspnea, orthopnea and LE edema.

Exam: BP 91/65, HR 92, JVP at 19 cm H20, fine bibasilar crackles, distant heart sounds with +S3, palpable liver edge, warm extremities with 1+ pitting LE edema.

Meds: ASA 81 qd, carvedilol 12.5 bid, lisinopril 20 bid, digoxin 0.25 qd, simvastatin 40 qhs, torsemide 50 bid, KCl 40 bid Labs: Na 132, K 4.4, BUN 38, Cr 2.2 (from baseline 1.5), AST 69, ALT 91, AlkP 105, Tbili 2.4, Dig level 1.2 (reference range 0.5-1.9)

ECG shows NSR 90 bpm, LBBB, and old anterior infarct.

Devices

• ICD (primary prevention)– EF ≤35%, NYHA 2-3– At least 40 days post-MI– GDMT x 3 months

• CRT (BiV)– EF ≤35%, NSR, QRS ≥150, NYHA 3-4 on GDMT– EF ≤35%, NSR, LBBB, QRS ≥120, NYHA 2-4 on GDMT– EF ≤35%, Afib, if expect 100% pacing

Supplements• Omega-3 PUFA

– “reasonable in NYHA 2-4 pts with HFrEF or HFpEF to reduce mortality and CV hospitalization”

– GISSI-HF, n=6975: fish oil 1 g qd vs. placebo– All-cause mortality 27% vs 29% (p=0.04)

• Coenzyme Q10– Q-SYMBIO, n=420, NYHA 3-4: CoQ10 100 mg tid vs. placebo– MACE endpt 15% vs 26% (HR 0.5; p=0.003)– Low event #s: 18 vs 34 CV deaths (p=0.039)

Yancy CW et al., Circ 2013;128:e240-e327.GISSI-HF Investigators, Lancet 2008; 372: 1223–30.

Mortensen, SA et al., JACC HF 2014;2:641-9.

LCZ696

LCZ696• = sacubitril + valsartan moiety • Inhibitor of neprilysin = endopeptidase that degrades

vasoactive peptides (NPs, adrenomedullin, bradykinin)

p=0.0000004

Progress

Levy WC et al., Circ 2006; 113: 1424-1433.

+ LCZ696?

Final points

• HF is preventable• Always assess volume and symptomatic status• Our medicine bag floweth for HFrEF patients• Remember diet and exercise• Counselling and communication are integral to

preventing morbidity/mortality

HF program at VM• Multidisciplinary clinic

– 2 physicians– 2 ARNPs– 3 nurses– Pharmacists (ACC)– On-site laboratory– Social worker– Dietician– Palliative care team– EP & cath lab support [email protected]

Thank you