Outpatient Management of Systolic Heart Failure

1. Outpatient Management of Systolic Heart Failure J.D. Filippone, M.D, FACC November 5, 2011

2. 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

3. Hurst’s Textbook 1974 • Decreased physical activity • Digitalis • Thiazide diuretics • Furosemide if no response to thiazides.

4. Pharmacologic Therapy

6. Diuretics • Loop: Inc UNa, Free H2O clearance, improve symptoms 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

7. 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 • 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

8. 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: • 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

9. Renal function • In CONSENSUS there was 10-15% 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

10. 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 Cohn, JM NEJM 2001

11. B-Blockers • reduce myocardial exposure to catecholamines • Reduce circulating levels of vasoconstrictors • Reduce ischemia • Upregulate B1 receptors • Reduce myocardial gene production of inflammatory cytokines

12. 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

13. Patients who cannot tolerate target doses may derive 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.

14. 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

15. 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:

16. Hyperkalemia • 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

17. 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 • 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

18. 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

19. 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

20. Summary • 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”