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

2. The Problem HF is common HF is expensive 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)

3. HF is deadly 20% mortality in 1 year 50% mortality in 5 years n=216
Senni M et al. Circ 1998;98:

4. Clinical diagnosis Based on signs and symptoms of volume overload
DOE, orthopnea, PND
Weight gain
Edema, ascites

5. Jugular venous pressure
Clear lungs and/or CXR do not exclude heart failure!

6. Supportive testing CXR Diagnostic workup 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

7. Etiologies Hypertension Valvular disease Viral myocarditis
Coronary disease
Hypertension
Valvular disease
Viral myocarditis
Diabetes, Obesity
Toxic (alcohol, cocaine, chemotherapy)
Peripartum, Familial, Idiopathic
Sarcoid, Amyloid, Hypertrophic

8. Biomarkers BNP Troponin 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

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

10. Stage A Stage B Stage C At risk:
HTN, CAD, DM, metabolic syndrome, obesity, cardiotoxins, family h/o CM
Heart disease
no HF symptoms
MI, LVH, low EF, valvular disease
Heart disease,
prior or current HF
SOB, reduced exercise tolerance
Treat HTN, lipids
Quit smoking
Regular exercise
Avoid alcohol, drugs
ACEI/ARB for vascular disease or DM
ACEI/ARB
Beta blockers
Diuretics
Salt restriction
ACEI/ARB
Beta blockers
Aldosterone antag
Digoxin
Nitrates/hydraazine
ICD
CRT

11. 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

12. Pathophysiology
Adapted from Maron & Rocco, 2011.

13. Neurohormonal Imbalance in HF
ANP
BNP
Nitric Oxide Bradykinin Prostaglandins
Norepinephrine Angiotensin II Endothelin Aldosterone Vasopressin
Vasodilation
Natriuresis/diuresis
SNS suppression
RAAS suppression
Vasoconstriction Fluid Retention Fibrosis / remodelling
Tachycardia
Adapted from Rev Cardiovasc Med. 2001;2(suppl 2):S2-S6.

14. Management of HFrEF

15. 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

16. 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):

17. Drugs in our medicine bag
Diuretics
ACE inhibitors / ARBs
Beta blockers
Hydralazine/nitrates
Digoxin
Aldosterone antagonists

18. Loop Diuretics Furosemide Torsemide & bumetanide Ethacrynic Acid
6 hr half-life
Variable oral bioavailability
Torsemide & bumetanide
Almost 100% bioavailability
Ethacrynic Acid
For sulfa-allergic
EQUIVALENT DOSES
Furosemide 40 mg po
Furosemide 20 mg IV
Torsemide 20 mg po/IV
Bumetanide 1 mg po/IV
Ethacrynic 50 mg qd would be equivalent
Fear progressive volume overload over hypotension and renal insufficiency

19. 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
Sequential nephron blockade. Class effect. Metolazone peak effect after several hrs (slow, variable absorption)
Metolazone (or 5-10 mg qd x 3 days only)
HCTZ needs glomerular filtration to gain access to the kidney tubules
Jentzer JC et al., JACC 2010;56:

20. 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
Hypotension or renal impairment only in 5% in CONSENSUS and SOLVD
Avoid if Cr>3.0 or K>5.0
Check chem7 after each dose increase
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

21. 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
Long-term studies have shown similar hemodynamic and neurohormonal effects as ACEI, but inconsistent effects on symptoms or exercise tolerance
No difference in ALL CAUSE mortality
Val-HEFT 13% lower risk of combined endpt
For addition Val-HEFT in 2001 subgroup analysis suggested harm, CHARM-added suggested additional benefit
CHARM: EF<40% with and w/o ACEI, and EF>40%
LEVY: losartan qd, valsartan 160 bid, candesartan qd, telmisartan qd
ELITE study compared losartan with captopril in 722 pts >65yo with mild-severe CHF
designed as tolerability study (survival not primary endpt), reported reduction in all-cause mortality
(4.8 vs 8.7% in pts treated with losartan); no difference in renal fxn, hospitalization, combined m/m risk
LIMITATIONS: study size and relatively short f/u
ELITE II mortality study failed to show losartan superior to captopril, but confirmed improved losartan tolerability
RAAS: evaluate safety and tolerability of combo (losartan and enalapril) vs standard or high-dose enalapril
RESOLVD: class II-IV, candesartan vs enalapril or both; no significant difference in exercise tolerance or cardiac events
OPTIMAAL: losartan 50 vs captopril 50 bid, 2002, trend for captopril to be better for all-cause mortality, and SCD, but losartan better tolerated – post-MI patients
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
Konstam MA et al., HEALL Investigators, Lancet 2009;374(9704):

22. Nitrate / Hydralazine Venous 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<0.03
V-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: and 1991;325:303-10

23. 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) 15 10
n=32
10.2%
6.2%
Mortality
P=0.02
n=54 5
n=1050
Placebo
Fixed-dose BiDil
Taylor, AL et al., NEJM 2004;351:

24. 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

25. COMET 40% vs 34% p=.0017 metoprolol tartrate carvedilol
Poole-Wilson PA et al. Lancet 2003;362:7-13.

26. (and a little is much better than none)
More is better
(and a little is much better than none) 6.

27. 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
Do not use atenolol or metoprolol tartrate
Goal to be at target dose in 8-12 wks

28. Clinical Case
60 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 )
ECG shows NSR 90 bpm, LBBB, and old anterior infarct.

29. Which medication(s) would you change?
Carvedilol
Lisinopril
Digoxin
Simvastatin
Torsemide

30. Digoxin
Cardiac glycoside: inhibits Na/K pump , increases intracellular calcium (inotrope)
For patients with symptomatic HFrEF
p=0.8
p<0.001
NEJM 1997;336:525-33

31. Digoxin dose and Mortality
Rathore SS et al., JAMA 2003;289:871-8.

32. 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)

33. Clinical Case
60 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 )
ECG shows NSR 90 bpm, LBBB, and old anterior infarct.

34. Anything other changes to his treatment regimen?

35. 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: and NEJM 2003;348:
Zannad F et al, NEJM 2011;364:11-21.

36. 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

37. Clinical Case
60 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 )
ECG shows NSR 90 bpm, LBBB, and old anterior infarct.
Aldo after Cr back to baseline

38. Devices ICD (primary prevention) CRT (BiV) 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

39. Supplements Omega-3 PUFA Coenzyme Q10
“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: CoQ 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.

40. LCZ696 Inclusion: EF ≤40%, NYHA II-IV, BNP >140 (NT-pro >600)
Exclusion: SBP <100, GFR <30, K >5.2, h/o angioedema

41. LCZ696 = sacubitril + valsartan moiety
Inhibitor of neprilysin = endopeptidase that degrades vasoactive peptides (NPs, adrenomedullin, bradykinin) p=
Valsartan component =160 mg in 200 mg pill
Counters vasoconstriction, sodium retention, maladaptive remodelling
Combined nepro + RAAS inhibition superior than each alone but with ACE  angioedema

42. Progress + LCZ696? Levy WC et al., Circ 2006; 113: 1424-1433.
Only 15% in LCZ trial had ICD
17% vs 20% mortality in LCZ696 study at median f/u 27 months
Levy WC et al., Circ 2006; 113:

43. 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

44. 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
Consortium of 17 health care delivery systems & Dartmouth Institute for Health Policy and Clinical Practice
mission of the HVHC is to improve healthcare value – defined as quality and outcomes over costs, across time
Serve as model for national healthcare reform

45. Thank you