Treatment of Heart Failure: Medical Therapy Veronica Franco, MD Assistant Professor – Clinical Division of Cardiovascular Medicine

~ 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: )

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 Low Perfusion at Rest No 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: 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: No Warm and Euvol PCW and CI normal Warm and Wet PCW elevated CI normal Cold and Wet PCW elevated CI decreased Cold and Dry PCW low/normal CI decreased Vasodilators Nitroprusside Nitroglycerine Nesiritide Inotropic Drugs Dobutamine Milrinone High SVR Congestion at Rest Low Perfusion at Rest No Yes Profiles and Therapies for CHF

IV Agents for HF TherapyCOPCWPBPHR Ar- rhyth- mia Shorter Onset Longer Offset Diure- sis Dopamine (mg/kg/min) Low (<3) Mod (3–7) High (7–15)         ???? Dobutamine  +++0  Milrinone  +++  Nitroglycerin   +++0  Nesiritide  ++  Nitroprusside    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: Stages and Treatment Options for Chronic systolic HF

Moderate CHF Severe CHF Mild CHF Post-MI LV 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

Effects of ACEi

Beta-blockers

European Journal of Heart Failure : 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

 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 Aldosterone antagonist β-Blocker *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 Dinitrate A-HeFT for African-Americans  Study terminated because primary end point reached early  ISDN/hydralazin e 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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