Treatment of Heart Failure:Medical Therapy

Veronica Franco, MDAssistant Professor – ClinicalDivision of Cardiovascular MedicineVeronica.Franco@osumc.edu

• ~ 4.6 million Americans with HF are alive today

• ~ 550,000 new cases of HF occur each year

• Causes or contributes to ~250,000 deaths/year

• Annual cost ~$22.5 billion

• Mayor contributor to very elevated health costs

and Medicare expenditure

Burden of Heart Failure

Cardiac Remodeling-Mechanism

HF Definition

A complex clinical syndrome that results from any

structural or functional cardiac disorder that impairs

the ability of the ventricle to fill with or eject blood.

Includes HF with systolic and / or diastolic

dysfunction.

Goals of Therapy

A. Reduce heart failure symptoms - “decongest” if ADHF

B. Delay the progression of HF; slow or reverse cardiac remodeling, fibrosis, and enlargement—goal is to make the ‘basketball’ to be a ‘football’

C. Improve survival ( mortality)

Similarities Between Acute MI and Acute Decompensated HF in the US

(Gheorghiade M, et al. Circulation 2005;112:3958-68)

Acute MI ADHF

Incidence 1 million per year 1 million per year

Mortality

    In-hospital 3–4% 3–4%

    After discharge (60–90 d) 2% 10%

Pathophysiological target (s)Clearly defined (coronary

thrombosis)Uncertain

Clinical benefits of interventions in published clinical trials

BeneficialMinimal/no benefit or deleterious

compared with placebo

ACC/AHA recommendationsMany

Level APrimarily expert opinion

Common Factors Precipitating the HF Hospitalization Noncompliance with medical regimen, sodium, or fluid

intake. Myocardial ischemia / infarction Hypertension Atrial fibrillation / arrhythmia Addition of negative inotropic drugs (verapamil, nifedipine,

diltiazem, beta blockers) Pulmonary embolus NSAID’s Excessive ETOH / drugs Endocrine abnormalities Concurrent infections (Pneumonia, viral illness)

Acute Exacerbations Contribute to the Progression of the Disease

Congestion at Rest

LowPerfusion

at Rest

No

No Yes

Yes

Warm & Euvolemic

Warm & Wet

Cold & WetCold & Dry

Signs/symptoms of congestion Orthopnea / PND JVD Ascites Edema Rales (rare in HF)

Evidence of low perfusion Narrow pulse pressure Sleepy/obtunded Low serum sodium

Cool extremities Hypotension with ACE inhibitor Renal dysfunction (one cause)

Stevenson LW. Eur J Heart Fail. 1999;1:251

ADHF – Clinical Presentation

Current Therapy for ADHF

Diuretics Vasodilators Inotropes

Reduce fluid

volume

Reduce preload or afterload

Increase contrac-

tility

Diuretics

“Background” Therapy: not specifically tested but used in all mortality trials

Combination of loop diuretic and thiazide used in severe heart failure (when is difficult to obtain euvolemia)

The use of ACEi and beta-blockers may reduce the need for diuretic therapy

diuretics

Acute HF - Diuretic Therapy

Start with equal or greater dose of loop diuretic (IV) than outpatient regimen (furosemide)

Short half-life; requires multiple doses or continuous infusion

Be cognizant of detrimental effects on renal blood flow, GFR, electrolytes, neurohormones, mortality

Diuretic resistance

Ongoing assessment for congestion Symptoms, exam, weights, I/O, labs, noninvasive impedance,

implanted hemodynamic monitors, invasive hemodynamics

Acute HF – When Initial Diuretics Fail

Is there persistent “congestion” ? Careful exam, labs, BNP May need invasive hemodynamics

Continuous infusion of furosemide 5-20 mg/hr

Add thiazide (distal tubule diuretic)

Ultrafiltration

Additional Vasoactive therapy

Diuretic Resistance: Theoretical Advantage of Continuous Infusion

Avoid post-diuretic sodium rebound

Reduce “braking phenomenon”

Related to less neurohormonal activation

Increased sodium reabsorption in distal tubule

Jaske B. J Card Fail. 2003;9:227-231.

Ultrafiltration for Acute HF

Removal of excess volume mechanically

Predictable amount of fluid removed (up to 500

cc/hr)

Safer than diuretics because remove isotonic salt

and water, therefore the greatest possible amount

of sodium per unit of fluid withdrawn

Ideal for diuretic resistance

Evaluated in multiple observational studies and a

multicenter trial (UNLOAD)

Limitations of Loop Diuretics and Advantages of Ultrafiltration

Limitations of loop diuretics

Hypotonic urine

Diuretic resistance

Electrolyte abnormalities

Direct neurohormonal activation

No clinical trials

Advantages of UF

Isotonic plasma water

Precise control

No effect on electrolytes

No direct neurohormonal activation

Clinical trial evidence

Bart BA. Circ Heart Fail. 2009

This patient has gout due to loop diuretic

Side Effects of Diuretics

Yes

R. Bourge, UAB Cardiology (adapted from L. Stevenson)Stevenson LW. Eur J Heart Failure 1999;1:251-257

No

Warm and EuvolPCW and CI

normal

Warm and WetPCW elevated

CI normal

Cold and WetPCW elevatedCI decreased

Cold and DryPCW low/normal

CI decreased

VasodilatorsNitroprussideNitroglycerine

Nesiritide

Inotropic DrugsDobutamine

Milrinone

High SVR

Congestion at Rest

LowPerfusion

at Rest

No

Yes

Profiles and Therapies for CHF

IV Agents for HF

Therapy CO PCWP BP HR

Ar-rhyth-mia

Shorter Onset

LongerOffset

Diure-sis

Dopamine (mg/kg/min)

Low (<3)

Mod (3–7)

High (7–15)

+++++++++

000

??

Dobutamine +++ 0

Milrinone + ++

Nitroglycerin +++ 0

Nesiritide ++ ++

Nitroprusside ++++ 0

Young JB. Rev Cardiovasc Med .2001;2(suppl 2):S19

• Identify cause (e.g. alcohol)• Dietary Na restriction <2g/day (Rule of 2)• Weight loss• Restriction of physical activity• Fluid restriction• Discontinuation of deleterious drugs

-ve inotropes (verapamil, diltiazem, disopyramide, flecainide)NSAIDs, aspirin

• Administration of oxygen, stop smoking• Management of sleep apnea• Dialysis or ultrafiltration• CHF Telemanagement by nurses

Non-pharmacological Therapy

Jessup et al. N Engl J Med 2003;348:2007-2018

Stages and Treatment Options for Chronic systolic HF

ModerateCHF

SevereCHF

MildCHF

Post-MILV dysfunction

SOLVD Treatment(enalapril)

CONSENSUS(enalapril)

AIRE/SAVE(ramipril/captopril)

US Carvedilol/MERIT(carvedilol/metoprolol)

COPERNICUS(carvedilol)

CAPRICORN(carvedilol)

RALES(spironolactone)

EPHESUS(eplerenone)

CHARM/Val-HeFT(candesartan/valsartan)

Neurohormonal Interventions Across the Continuum

www.nntonline.net

Effects of ACEi

Beta-blockers

European Journal of Heart Failure 2001 3: 351-357

Number to Treat

• Patients with fluid retention or overload

• Patients not in CCU/ICU

• Patients on positive inotropic drugs

• Beta-blockade is not a rescue operation

• Always start with a very low dose (“start low, go slow”)

Beta-blockers--when to avoid in HF

Aldosterone receptor blockade

Spironolactone:

hyperkalemia (avoid when Cr>2 mg/dl)

anti-androgenic (gynecomastia, impotence)

anti-progestesterone (oligomenorrhea) Eplerenone: derivative without the latter 2 side effects

Spironolactone

Spironolactone

Benefits are NOT solely due to diuresis Benefits due to reduction of myocardial fibrosis by

autocrine/paracrine effects Spironolactone reduces cardiac NE release Spironolactone is a vasodilator Even a small rise of K+ may be anti-arrhythmics

Aldosterone Antagonists

EPHESUS

Number need to treat (NNT) = ~44.

The number needed to harm (NNH) for serious hyperkalaemia = ~63

EMPHASIS-HF

• Number of patients who would need to be treated to prevent one primary outcome from occurring, per year of follow-up, was 19

• Number needed to treat to postpone one death, per year of follow-up, was 51

Cumulative benefits of HF therapies

THERAPY* RELATIVE RISK REDUCTION, %

2-YEAR MORTALITY, %

None 35

ACE inhibitor 23 27

Aldosterone antagonist 30 19

β-Blocker 35 12

*Cumulative risk reduction if all three therapies are used: 63% Absolute risk reduction: 22%;

Number needed to treat = 5

Hydralazine+Isosorbide Dinitrate

“Older” agents Used in patients intolerant to ACEi or ARBS Particularly useful in chronic renal failure Improves survival (VeHeFT Trial) but not as good as

ACEi

Hydralazine+Isosorbide DinitrateA-HeFT for African-Americans

Study terminated because primary end point reached early

ISDN/hydralazine group: 43% reduction in the rate of death, 53% in first hospitalization, plus "significant" improvement in QoL

6800 patients with LVEF ≤45% were randomized to digoxin or placebo in addition to diuretics and angiotensin-converting-enzyme inhibitors average follow-up, 37 months• No reduction in overall

mortality• Reduction in the rate of

hospitalization both overall (by 6%) and for worsening heart failure.

DIG Trial

NEJM 1997

Digoxin and Mortality

• No life conserving properties• May be reserved for more severe heart

failure especially in atrial fibrillation, rest dyspnea or symptoms despite diuretics, ACE and beta-blockers

Digoxin – Clinical Pearls

Summary

Reduce mortality; Must use: ACEi, beta-blockers and

spironolactone, Consider AICD/CRT

Improve symptoms; use clinical judgment: diuretics,

low dose digoxin, nitrates, ultrafiltration

May be harmful: use with caution: inotropes, inotropic

dilators, calcium channel blockers, high-dose digoxin,

anti-arrhythmics (except amiodarone and beta-

blockers)

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