Systolic CHF Therapy

Rogers Kyle, MD10/2/12

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

• 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)

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

Physical Examination

• Physical diagnostic accuracy (Escape Trial)

CHF - Staging

CHF - Staging

CHF - Staging

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

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

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

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

‘Order of Drugs’

• Loop diuretic• ACE/ARB– ACE vs. ARB; ACE + ARB?

• β – Blocker– CIBIS-III – bisoprolol vs. enalapril first ( no

difference)• After that…

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)

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

Diuretics

• Other options?– Add thiazide– ? Ultrafiltration– Inotropes (milrinone - inc mortality)– Other – nesiritide (no mort/morbid benefit), VR2A

(hypoNa+)

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)

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

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

• 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)

• 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

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

Beta Blockers

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

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

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+

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

Digoxin

• DIG trial– Reduced hospitalization, not mortality

• 2005/09– HYHA II, III, IV– EF < 40%– Sx’s despite diuretic/ACE/BB/aldo antag

Summary

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.

• 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.

• 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.