1. Systolic CHF Therapy Rogers Kyle, MD 10/2/12

2. Learning Objectives Review the staging and evaluation of patients with systolic heart failure Review the current guidelines for therapy of systolic heart failure Identify the classes and dosing of medications used in the therapy of systolic heart failure

3. 5 million people in US – 500,000 new cases annually – 1 million hospitalizations/yr as primary dx – 50,000+ CHF as primary dx deaths annually – 10 yr mortality almost 90% Most frequent cause of hospitalization in the elderly $38 billion, (over 5% of total healthcare cost)

4. Staging Stage A - high risk, no structural disease – HTN, DM, CAD, Obesity, met syn, cardiotoxins Treat underlying med probs…ACE/ARB Stage B - structural disease but no s/s CHF – LVH, ↓EF, MI, asymptomatic valvular disease ACE/ARB, β-blocker Stage C - structural disease with current or prior sx’s (NYHA I-IV) – Sx’c ↓EF or asymptomatic on Rx Diuretics, ACE, β-blocker, also aldo antag, ARB, dig, hydral/nitrates ICD, CRT Stage D – refractory HF – Recurrent hosp despite Rx, need for transplant/VAD

5. Physical Examination Physical diagnostic accuracy (Escape Trial)

6. CHF - Staging

8. Stage A – control risk – HTN – DM – Met Syn – Lifestyle mod (tob, etoh, drug abuse, etc.)

9. CHF - Staging Stage B – All of A – Recent MI – ACE, β-blocker – Reduced EF (no CAD) – ACE, β-blocker. ARB if ACE intol – Valvular disease – LVH – ACE/ARB – ICM - > 40 days p-MI, EF ≤ 30% → ICD – NO dig, CCB with (-) inotropy

10. CHF - Staging Stages C, D (refractory sx’s) – A, B – Diuretics, Na restrict if vol overloaded – ACE/ARB if ACE intol. ACE+ARB with ↓EF if still with sx’s on max rx (IIB) – β – Blocker – bisoprolol, carvedilol, metoprolol sustained release (succinate) – Aldosterone antagonist – preserved Cr (< 2.5), nl K+ – Hydralazine/nitrate – AA with continued CHF sx’s on optimal ACE, β-blocker, diuretics (level I) – all non-AA (level II) – Digoxin – reduced EF – ICD’s, CRT – NO ACE/ARB/Aldo antag combo, CCB

11. CHF - Staging Stages C, D (refractory sx’s) – A, B – Diuretics, Na restrict if vol overloaded – ACE/ARB if ACE intol. ACE+ARB with ↓EF if still with sx’s on max rx (IIB) – β – Blocker – bisoprolol, carvedilol, metoprolol sustained release (succinate) – Aldosterone antagonist – preserved Cr (< 2.5), nl K+…DM? – Hydralazine/nitrate – AA with continued CHF sx’s on optimal ACE, β-blocker, diuretics (level I) – all non-AA (level II) – Digoxin – reduced EF – ICD’s, CRT – NO ACE/ARB/Aldo antag combo, CCB

12. ‘Order of Drugs’ Loop diuretic ACE/ARB – ACE vs. ARB; ACE + ARB? β – Blocker – CIBIS-III – bisoprolol vs. enalapril first ( no difference) After that…

13. Diuretics Studies date back to the 60’s (!) Lasix most studied – Bumetanide, torsemide both better absorbed, torsemide lasts longer Torsemide may have less readmissions (vs. lasix) for CHF (AJM 2001; 111(7):513) - ? Cost effective; now generic. Also, one observational study suggesting lower mortality (Eur J Heart Fail 2002; 4(4): 507)

14. Diuretics Dosing strategy (NEJM 2011; 364(9): 797) – Comparison of dose and route of administration of lasix in acute decompensated CHF Low dose (equivalent to outpatient dose) or high dose (2.5 x outpatient dose) Given as bolus Q12 or continuous infusion

16. Diuretics Other options? – Add thiazide – ? Ultrafiltration – Inotropes (milrinone - inc mortality) – Other – nesiritide (no mort/morbid benefit), VR2A (hypoNa+)

17. ACE/ARB Multiple trials have established benefit (sx’s and mortality) of ACE in all stages of CHF. – LVEF < 40% – Elderly, women, maybe less beneficial in AA but recommended Less evidence for ARB’s but considered interchangeable (Cochrane Rev 2012)

18. ACE/ARB Choice of agent – Class effect – Enalapril most studied Dosing – Usually started first – Less azotemia, hypotension if started at low doses Enalapril 2.5 BID; captopril 6.25 TID; lisinopril 5 QD

19. BUT…doses were high in the trials – Enalapril 10-20 BID; lisinopril 20-40 QD – Up-titrate doses every 2 weeks

20. ARB – Recommended for same indications as ACE in pts intolerant of ACE Intolerance does NOT include azotemia or hyperkalemia BUT should be considered in angioedema in ACE – Add to ARB? CHARM-Added (+) vs. Val-HeFT (-) vs. VALIANT (p-MI)

21. 2009 Update – Consider adding to ACE in persistently sx’c pts with EF < 40% on conventional therapy – However… EMPAHSIS – HF (eplerenone) Routine use of ACE + ARB + aldo inhib is not recommeded Dosing – Candesartan (most studied) – start at 4-8 mg QD, titrate to 32 mg QD – Valsartan 20-40 mg BID titrate to 160 mg BID – Losartan 25-50 mg QD titrate to 50-100 mg QD

22. Beta Blockers Demonstrated to reduce sx’s and hospitalizations and improve survival – Meta analysis 2001 AIM; > 20 trials, > 10,000 pts – Carvedilol (COPERNICUS); metoprolol ex release (MERIT-HF); bisoprolol (CIBIS) 2005/09 – Current or prior CHF sx’s with reduced EF – ‘09 added – minimal or no evidence fluid retention, already on ACE

23. Beta Blockers Relative contraindications – HR < 60 – Hypotension – More than minimal fluid retention – Peripheral hypoperfusion – PR > 0.24, 2 nd /3 rd degree HB – Asthma – Resting LE ischemia from PVD

24. Beta Blockers Metoprolol - primarily β-1, some β-2 at doses > 100 mg – Start 12.5-25 mg QD, titrate to 200 mg QD Carvedilol - non-selective β + alpha blockade – Start 3.125 mg BID, titrate to 25-50 mg BID Bisoprolol - primarily β-1, some β-2 at doses > 20 mg – Start 1.25 mg QD, titrate to 5-10 mg QD

25. Aldosterone Antagonists Aldosterone levels tend to rise over time in pts on ACE/ARB ?independent effect on structure/function Emphasis- HF (RALES) (NEJM 2011; 364(1): 11) – Eplerenone added to usual rx – EF < 30-35%, NYHA II or more – 20% mortality benefit Risk is  K+ – Careful with NSAIDS, ACE/ARBS, DM, renal dys (Cr > 2.5), volume depletion – Do not use in combination with ACE + ARB Start at 12.5 mg spironolactone, measure K+

26. Hydralazine + Nitrates Pre and afterload reduction Early trials – – V-HeFT (hydralazine + nitrates similar to enalapril) – A-HeFT (+ enalapril beneficial in AA) NYHA III, IV; EF < 40%, AA 2005/09 – AA on diuretic/ACE/BB for NYHA II, III – Pts with sx’s depsite diuretic/ACE/BB – Intol of ACE/ARB Dosing – Start 25/20 mg TID; target 75/40 TID

27. Digoxin DIG trial – Reduced hospitalization, not mortality 2005/09 – HYHA II, III, IV – EF < 40% – Sx’s despite diuretic/ACE/BB/aldo antag

28. Summary

29. References Hunt SA et al. (2009) 2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults. Circulation. 119: e391-e479. Hunt SA et al. (2009) 2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults. Circulation. 119: e391-e479. Heran BS, Musini VM, Bassett K, Taylor RS, Wright JM. Angiotensin receptor blockers for heart failure. Cochrane Database of Systematic Reviews (2012), Issue 4. Art. No.: CD003040. DOI: 10.1002/14651858.CD003040.pub2. Heran BS, Musini VM, Bassett K, Taylor RS, Wright JM. Angiotensin receptor blockers for heart failure. Cochrane Database of Systematic Reviews (2012), Issue 4. Art. No.: CD003040. DOI: 10.1002/14651858.CD003040.pub2 McAlister, FA, et al. 2009. Meta-analysis: -Blocker Dose, Heart Rate Reduction, and Death in Patients With Heart Failure. Ann Intern Med 150:784-794. McAlister, FA, et al. 2009. Meta-analysis: -Blocker Dose, Heart Rate Reduction, and Death in Patients With Heart Failure. Ann Intern Med 150:784-794. Willenheimer, R. et al. (2005) Effect on Survival and Hospitalization of Initiating Treatment for Chronic Heart Failure With Bisoprolol Followed by Enalapril, as Compared With the Opposite Sequence :Results of the Randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III. Circulation 112: 2426-2435. Willenheimer, R. et al. (2005) Effect on Survival and Hospitalization of Initiating Treatment for Chronic Heart Failure With Bisoprolol Followed by Enalapril, as Compared With the Opposite Sequence :Results of the Randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III. Circulation 112: 2426-2435 Zannad, F. et al. (2011) Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms N Engl J Med 364 (1): 11-21. Zannad, F. et al. (2011) Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms N Engl J Med 364 (1): 11-21.