GUIAS PARA EL MANEJO DEL FALLO CARDIACO RAFAEL E. CALDERON,MD.

CARDIOLOGIA DE TRANSPLANTE Y FALLO CARDIACO OCTUBRE DEL 2002

Cost* of Heart Failure to Society

$22.5 billion

15.5

2.2

2.2

1.5

Hospital/Nursing home Home health/ Other medical durables Indirect costs Healthcare providers Drugs 1.1

*Direct and indirect costs in billions of $; estimated for year 2000 AHA.

2000 Heart and Stroke Statistical Update

Predisposing Factors

Toxins/drugs (EtOH)

HTN

Environmental

HTN

Genetic Valvular disease Unknown Infections Age Metabolic (Diabetes)

MI

HFSA. Pharmacotherapy 2000;20:495

HF Cardiomyopathy

Risk Factors, Ischemia, and Heart Failure in the Cardiovascular Continuum

Coronary thrombosis MI Arrhythmia Loss of muscle Myocardial ischemia Neurohormonal activation Sudden death CAD Remodeling Atherosclerosis LVH Risk factors •Hyperlipidemia •HTN •Diabetes •Insulin resistance Ventricular dilation HF Death Adapted with permission from Dzau V, Braunwald E. Am Heart J 1991;121:1244

Pathophysiologic Effects of Angiotensin II

 PAI-1/ thrombosis Abnormal vasoconstriction Ang II Platelet aggregation  Contractility Superoxide production Activate SNS  Aldosterone Myocyte growth Vascular smooth muscle growth  Collagen  Vasopressin  Endothelin Remodeling

Guide for Heart Failure Therapy

Goal:

Prolong life and improve its quality

Objectives: • • Slow progression of underlying disease(s) Improve hemodynamics • • • • • Improve neurohormonal profile Prevent sudden death Decrease symptomatic arrhythmias Relieve symptoms and improve exercise tolerance Decrease ER visits, hospitalizations, and costs HFSA. Pharmacotherapy 2000;20:495

Why Symptom Relief is Not Enough

Heart failure is more than a symptomatic disease

Produces symptoms, limits functional capacity, and impairs quality of life

Heart failure is a progressive disease

Worsening symptoms and clinical deterioration, repeated hospitalization, and death Death occurs frequently even in the presence of minimal symptoms or the absence of progressive symptoms Symptoms do not always correspond with ejection fraction

Evolution of Drug Therapies for CHF

18th Century 19th Century 1960s 1970s-1980s 1980s 1990s •Digitalis •Weak diuretics •Thiazides and furosemide •Vasodilators •IV inotropics •ACE inhibitors •Beta-blockers –Potential role for Angiotensin II antagonists –Aldosterone antagonists

Systemic Effects of RAS Activation in CHF

Schematic Representation of Mortality in Heart Failure Patients

60

CONSENSUS I

n=253

(Class IV) 1

27%  mortality P =0.003

V-HeFT II (Class II–III) 2

n=804 trend toward  death 40

Mortality rate (%)

20 28%  mortality P =0.016

SOLVD-Treatment (Class II–III) 3

n=2569 16%  mortality P =0.0036

SOLVD-Prevention

n=4228 trend toward 

(Class I–II) 4

death 0 0 6 12 18 24 30 36 42 48 54 60

Months

1CONSENSUS Trial Study Group. N Engl J Med 1987;316:1429; 2Cohn JN et al. N Engl J Med 1991;325:303; 3SOLVD Investigators. N Engl J Med 1991;325:293; 4SOLVD Investigators. N Engl J Med 1992;327:685

ACE Inhibitors in CHF: Summary of Key Points

• • • Consistent evidence that neurohormonal blockade alters natural history of CHF ACE inhibitors improve survival across entire heart failure spectrum - mild, moderate, severe Ace inhibitors delay progression of asymptomatic LV dysfunction to overt CHF

The Case for ß-Blockade in Heart Failure

Neurohormonal activation underlies disease progression and provides basis for treatment selection Weight of data for ß-blockade equals or exceeds that of ACE inhibitors ß-Blockade is added to ACE inhibitors for more complete neurohormonal blockade Carvedilol blocks ß 1 -, ß 2 -, and  1 -receptors and is the only agent with ß-blocking properties approved and formulated for use in heart failure

TRIAL

ß-Blockers in Heart Failure: Key Clinical Trials

DRUG TARGET DAILY DOSE RISK REDUCTION / TOTAL MORTALITY

50-100 mg US Carvedilol (n = 1094) Carvedilol MERIT-HF (N = 3718) Metropolol CIBIS II (n = 2647) Copernicus (n = 2289) Bisoprolol Carvedilol 200 mg 10 mg 50 mg 65% (P <0.001) 34% (P = 0.0062) 33% (P <0.0001) 35% (P = 0.0014)

20

MERIT-HF Cardiovascular Mortality

Risk reduction: 38% P =0.00003

15 Placebo 10 TOPROL-XL Risk reduction: 38% P = .00003

5 0 0 3 6 9 12 15 18 21 Months of follow-up

MERIT-HF Study Group. Lancet . 1999;353:2001-2007.

12 9 % of patients 6 3

MERIT-HF Sudden Death

Placebo TOPROL-XL Risk reduction: 41% P = .0002

3 6 9 12 15 18 Months of follow-up MERIT-HF Study Group. 1999;353:2001-2007.

Lancet . 21

DIG Study: Effect of Digoxin vs Placebo on Mortality in Patients With CHF and LVEF



45%

50 40 30 20 10 0 Placebo Digoxin P=0.80

0 4 8 12 16 20 24 28 32 36 40 44 48 52 The Digitalis Investigation Group. N Engl J Med 1997;336:525-533.

RADIANCE: Effect of Digoxin Withdrawal in Patients Optimally Treated With ACEIs

• • • • Risk of deterioration     6-fold Exercise tolerance Ejection fraction Quality of life 0.3

0.25

Probability of worsening heart failure

0.2

0.15

0.1

0.05

0 Packer M, et al. N Engl J Med 1993;329:1-7.

Placebo (n=93) P<0.01

Digoxin (n=85) 0 20 40 60 80

Days after randomization

100

RALES: Aldosterone Receptor Blockade Improves Outcomes in Severe Heart Failure

1 0.9

Spironolactone 0.8

Probability of Survival (%)

0.7

0.6

0.5

Placebo 0.4

0 RALES=Randomized Aldactone Evaluation Study 3 6 9 12 15 18 21 24 27 30 33 36

Months

Pitt B, et al N Engl J Med 1999;341:709-17

Valsartan in Heart Failure Trial (Val-Heft)

• Ace inhibitors are effective treatment for HF, post-MI, diabetic nephropathy, and atherosclerosis, but do not fully suppress RAAS • The RAAS exerts deleterious effects on the development and progression of HF • Addition of ARBs to usual therapy, including ACE inhibitors, is rational therapeutic approach • ARBs inhibit biologic effects of Ang II more completely than ACE inhibitors • ARBs potentially increase AT 2 receptor stimulation resulting in increased bradykinin and NO production

Heart Failure Hospitalizations

0.961

95 90 0.923

85 0.884

80 0.846

75 0.807

70 0.769

65 0 0.730

0 0 3 3 6 6 9 9 12 12 Valsartan 15 18 RR=27.5 %

P

< 0.00001

Placebo 18 21 21 24 27 24 27 Cohn JN. AHA 2000

General Measures for the Management of Heart Failure

Decrease risk of new cardiac injury

Smoking cessation; weight reduction in obese patients; control  BP, lipids, diabetes; discontinue alcohol use

Maintain fluid balance Improve physical conditioning

Moderate salt restriction (to < 3 grams daily); daily weight measurement Moderate exercise to prevent physical deconditioning

Avoid

Antiarrhythmic agents to suppress asymptomatic ventricular arrhythmias, most calcium antagonists, NSAIDs Steering Committee and Membership of the Advisory Council to Improve Outcomes Nationwide in heart Failure Am J Cardiol. 1999;83 (Suppl 2A): 1A-39A

Gottipaty et al: Proportional Mortality Increase

• • • • •

VEST study analysis NYHA Class II-IV patients 3,654 ECGs digitally scanned Age, creatinine, LVEF, heart rate, and QRS duration found to be independent predictors of mortality at 1 year Relative risk of widest QRS group 5x greater than narrowest

QRS Variability in Congestive Heart Failure:

Should QRS Criteria for Cardiac Resynchronization Therapy Be Expanded? (n = 31) Aranda, et al HFSA Sept 2001 50 40 30 20 10 0 43.1

15.8

Pts with QRS 0 0

Multicenter InSync Randomized Clinical Evaluation Results of a Randomized, Double-Blind, Controlled Trial to Assess Cardiac Resynchronization Therapy in Heart Failure Patients

Presented by William T. Abraham, MD For the MIRACLE Investigators at the Late Breaking Clinical Trials II Session, American College of Cardiology Orlando, FL; March 20, 2001

Unanswered Questions

• • • •

Which subset of patients can benefit from biventricular pacing?

What are the long-term hemodynamic and structural consequences of CRT?

Is there potential to increase ischemic burden in patients with ischemic cardiomyopathy?

Will cardiac resynchronization therapy allow for increased use of beta-blocker therapy in patients with heart failure?

Recommendations

• • •

Class I: There is evidence and/or general agreement that a given procedure/therapy is useful and effective.

Class II: There is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of performing the procedure/therapy

– Class IIa: Weight of evidence/opinion is in favor of usefulness/efficacy.

– Class IIb: Usefulness/efficacy is less well established by evidence/opinion.

Class III: There is evidence and/or general agreement that procedure/therapy is not useful/effective and in some cases may be harmful .

Levels of Evidence

•

Level A: The data was derived from multiple randomized clinical trials

•

Level B: studies Data were derived from single randomized trial or nonrandomized

•

Level C: Consensus of opinion

Clinical Assessment

•

Complete history (Class I Level of evidence C): comorbid conditions, cardiotoxic agents, STD’s, magnitude and duration of symptoms and family history

•

Physical exam (Class I Level of evidence C): Jugular venous pressure as ongoing assessment of volume status and S 3

•

Signs of hypoperfusion narrow pulse pressure, cool extremities, altered mentation, Cheynes-Stokes respiration, resting tachycardia.

Clinical Assessment

•

Laboratory work up

– CBC, U/A, SMA 20, TSH, CXR and 12 lead EKG (Class I Level of evidence C) – Serial monitoring of electrolytes and renal function (Class I Level of evidence C) – Screening evidence C) – HIV status – Routine evidence C) for hemochromatosis, (Class IIb Level of evidence C) measurement of circulating ANA levels, rheumatoid factor, urinary vanillylmandelic acid and metanephrines in selected patients (Class IIa Level of levels electrocardiography (Class III Level of evidence C) of norepinephrine or endothelin (Class III Level of – Routine Holter monitoring or signal averaged

Clinical Assessment

•

Two-dimensional echocardiogram with Doppler flow. Single most useful diagnostic test.

– Evaluation of LV function and other structural heart disease (Class I Level of evidence C) – Asymptomatic evidence C) evidence C) first degree relatives of idiopathic DCMP patients (Class IIa Level of – Repeat measurement of EF in patients with change in clinical status (Class IIa Level of

Clinical Assessment

•

Functional capacity assessment during initial and follow up visits

– Ability to perform routine and desired ADL’s (Class I Level of evidence C) – Maximal exercise testing with measurement of respiratory gas exchange and/or blood oxygen saturation to help determine whether HF is cause of exercise limitation when the contribution of HF is uncertain (Class IIa Level of evidence C) – Maximal exercise testing with measurement of respiratory gas exchange to identify high risk patients who are candidates for cardiac transplantation or other advanced treatments (Class IIa Level of evidence B) – Maximal exercise testing with measurement of respiratory gas exchange to facilitate prescription of exercise program (Class IIb Level of evidence C)

Clinical Assessment

•

Noninvasive testing

– Noninvasive imaging to detect ischemia and viability in patients with known CAD and no angina who are being considered for revascularization (Class IIa Level of evidence C) – Noninvasive imaging to define the likelihood of CAD in patients with LV dysfunction (Class IIb Level of evidence C)

Clinical Assessment

•

Cardiac Catheterization with coronary arteriography

– Patients with angina who are candidates for revascularization (Class I Level of evidence B) – Patients with chest pain who have not had evaluation of their coronary anatomy and who have no contraindications to coronary revascularization (Class IIb Level of evidence C) – Patients with known or suspected CAD but without angina who are candidates for revascularization (Class IIb Level of evidence C) – Repeat study or repeat noninvasive testing for ischemia in patients for whom CAD has been previously excluded as cause of LV dysfunction (Class III Level of evidence C)

Clinical Assessment

•

Endomyocardial Biopsy overall usefulness is unclear

– Patients suspected of having inflammatory or infiltrative disorder of the heart (Class IIb Level of evidence C) – Used to confirm disorders that may disqualify a patient for transplant (amyloidosis) or identify giant-cell myocarditis which due to rapid progression and poor response to therapy mandates immediate transplantation.

– Routine evaluation of patients with HF (Class III Level of evidence C)

Staging of HF

•

A new approach that emphasized both the evolution and progression of HF

•

It reliably and objectively identifies patients in the course of their disease

•

Links treatments that are appropriate at each stage of HF

•

It is intended to complement not substitute NYHA, which subjectively gauges severity of symptoms

Staging of HF

Staging of HF and Therapy

Stage A of HF and Therapy

•

High risk of developing HF.

– Control systolic and diastolic BP A) (Class I Level of evidence – Adequate control of DM. (not yet shown to reduce subsequent HF) – Treatment of lipid disorders in accordance with guidelines as patients with atherosclerotic disease are likely to develop HF (Class I Level of evidence B) – Treat Thyroid disease (Class I Level of evidence C) – Periodic evaluation for signs and symptoms of HF I Level of evidence C) (Class

Stage A of HF and Therapy

– Avoidance of cardiotoxic agents and behaviors such as smoking, illicit drug use and alcohol consumption.

(Class I Level of evidence C) – Ionizing chemotherapeutic agents such as anthracyclines, high dose cyclophosphamide and the monoclonal agent trastuzumab.

radiation to mediastinum and – Control ventricular rate of tachyarrhythmias of evidence B) (Class I Level – ACE inhibition in patients with history of atherosclerotic vascular disease, DM, HBP and associated cardiovascular risk factors (Class I Level of evidence B)

Stage B of HF and Therapy

•

LV dysfunction without HF symptoms.

– Patients with AMI should receive thrombolytic or undergo PTCA to decrease risk of developing HF. ACEI regardless of EF and even if ischemic episode is remote (Class I Level of evidence A) and /or beta-blocker regardless of EF (Class I Level of evidence A) improve survival.

– Long term use of ACEI has been shown to delay onset of HF symptoms in patients with low EF independently of MI or not (Class I Level of evidence B) – Beta blockers independent of whether the patient has had MI should be given in low LVEF (Class I Level of evidence B)

Stage B of HF and Therapy

– Valve replacement or repair for patients with hemodynamically significant stenosis or regurgitation (Class I Level of evidence B) – Long term treatment with vasodilators in severe aortic regurgitation has not been shown to reduce risk of HF or death (Class IIb Level of evidence B) – Treatment with digoxin in asymptomatic patient with LV dysfunction who are in sinus rhythm is not recommended (Class III Level of evidence C)

Stage C of HF and Therapy

•

LV dysfunction with current or prior symptoms.

– Sodium restriction.

– Daily weight.

– Influenza and pneumococcal vaccination.

– Physical activity exercise program.

evidence A) – Avoidance of channel NSAIDs (including COX2), calcium blockers antiarrhythmic agents (except amiodarone).

Level of evidence B) ( except amlodipine) and (Class I – Monitor potassium magnesium.

(3.8-5.2mmol

(Class IIa Level of – Patient education and close supervision.

per L) and

Stage C of HF and Therapy

Stage C of HF and Therapy

•

Diuretics. For fluid retention. (Class I Level of evidence A)

– Inhibit reabsorption of sodium or chloride at specific sites in the renal tubule.

– Loop diuretics excrete up to 20-25% Na, enhance free water clearance and remain effective unless severe renal impairment.

– No long term studies effects on morbidity and mortality are not known – Produce symptomatic relief more rapidly than any other drug.

– Risk of use is electrolyte depletion, hypotension and azotemia.

Stage C of HF and Therapy

•

ACE inhibitors. (Class I Level of evidence A)

– Not only interferes with RAS but potentates action of kinins and kinin-mediated prostaglandin.

– Alleviate symptoms, improve clinical status, reduce risk of death and of hospitalization.

– Contraindicated if angioedema or pregnant .

– Fluid retention can blunt effects and fluid depletion can potentate adverse effects (Hypotension, hyperkalemia, renal failure) – Cough. All other causes must be excluded medication withdrawn with improvement after 1-2 weeks and reappearance after rechallenge with another ACEI.

Stage C of HF and Therapy

•

Beta-blockers principally inhibit effects of sympathetic nervous system and should be given to all patients with symptoms (Class I Level of evidence A)

– Alleviate symptoms, improve clinical status, reduce risk of death and of hospitalization.

– Diuretics are needed to maintain sodium balance and prevent fluid retention that can accompany initiation of beta-blocker.

– Should be given only if no or only minimal evidence of fluid retention and no recent use of intravenous positive inotropic agent.

Stage C of HF and Therapy

•

Beta-blockers

– A patient who has been using medication for more than 3 months and has acute decompensation should not be taken off medication and diuretics should be adjusted.

If decompensation is cause due to hypoperfusion then medication should be stopped and positive inotropic agent that doesn’t mediate its effects through beta receptor is preferred.

– Side effects include fatigue, fluid retention,bradychardia, heart block, and hypotension.

– Should not be given to patients with hyperactive airway disease yet should be given to COPD patients.

Stage C of HF and Therapy

•

Digitalis (Class I Level of evidence A)

– Inhibits Na-K ATPase • In cardiac cells causing increased contractility • Vagal afferent fibers sensitize carotid baroreceptor which reduces sympathetic out flow of CNS • Kidney reduces renal tubular reabsorption of Na which leads to suppression of of renin secretion – Improves symptoms, exercise tolerance and quality of life yet little effect on mortality – Dose should be of 0.125-0.25mg QD, without loading and lower if patient is over age 70, has renal impairment or low lean body mass – Serum levels are followed for purpose of toxicity and not to guide therapy

Stage C of HF and Therapy

•

Spironolactone (Class IIa Level of evidence B)

– Low doses reduced risk of mortality in patents with current or recent class IV symptoms – Effects were most marked in those taking digitalis and beta blockers – Role in mild to moderate HF not clear and use cannot be recommended – Risk of hyperkalemia and painful gynecomastia

Stage C of HF and Therapy

•

Angiotensin receptor blocker

– Should not be considered superior or equivalent to ACEI (Class III Level of evidence B) – Added to therapy before a beta-blocker (Class III Level of evidence A) – Should not be added to therapy if taking an ACEI and beta-blocker – Should be given if ACEI intolerant (Class IIa Level of evidence A)

Stage C of HF and Therapy

• •

Hydralazine and nitrate combination should be given only if ACEI intolerant and patient on beta-blocker, diuretic and digitalis (Class IIa Level of evidence B) and should no be added if ACEI in use (Class IIb Level of evidence B) Long term intermittent intravenous positive inotropic therapy has been associated with increased mortality and should not be used (Class III Level of evidence C). Continuous infusion for palliation of stage D symptoms is Class IIb Level of evidence C yet is commonly used in patients awaiting transplant.

Stage D of HF and Therapy

•

Refractory End stage HF

– Must be considered for specialized treatment strategies, such as mechanical circulatory support, continuous inotropic therapy, transplantation (Class I Level of evidence B), referral to a specialized HF program (Class I Level of evidence A) or hospice care.

– Control of fluid retention with increments of dose or adding second diuretic (metolazonel). Increases in BUN and creatinine are tolerated and should not guide therapy. If refractant to diuretics ultrafiltration may be needed.Patients should not be discharged until euvolemia is achieved. (Class I Level of evidence B) – All previous stage class I recommendations (Class I Level of evidence A,B and C)

Stage D of HF and Therapy

Patient Subgroups

•

Women are the majority of patients in general population with HF yet are underrepresented in most studies which doesn’t allow for treatment conclusions to be made. Have diastolic dysfunction most often.

•

HF is more common among black patients and progresses more rapidly and may derive less benefit of ACEI. Almost 50% of Asians can develop cough related to ACEI.

•

HF is a disease of the elderly affecting 6-10% of population over age 65. Diastolic dysfunction is a major cause. Diminished response to diuretics ACEI and inotropic agents.

Diastolic Dysfunction

Therapy of Diastolic Dysfunction

•

Control systolic and diastolic BP (Class I Level of evidence A)

•

Control ventricular rate in atrial fibrillation (Class I Level of evidence C)

•

Diuretics to control pulmonary congestion and peripheral edema (Class I Level of evidence C)

•

Coronary revascularization I patients with CAD in whom ischemia is judged to have effect on diastolic dysfunction (Class IIa Level of evidence C)

Therapy of Diastolic Dysfunction

•

Restoration of sinus rhythm in atrial fibrillation (Class IIb Level of evidence C)

•

Use of beta blockers, ACEI, ARB, CCB in patients with controlled hypertension to minimize symptoms of HF (Class IIb Level of evidence C)

•

Digitalis to minimize symptoms of HF (Class IIb Level of evidence C)

Treatment of CHF in the Year 2001

Inactive ANP BNP

OVERTURE

NEP

NATRE-COR

Inotropes NO EDRF   Na  H 2 O Vasodilation Hypertrophy  CO

DIG TRIAL VEST PROMISE OPTIME-CHF PROVED

Inactive Bradykinin Catecholamines ADH Aldosterone

CIBIS II MERIT-HF BEST COPERNICUS

Positive Effect Neutral Effect Unknown Effect Negative Effect ACE Brain  Angio 1 Angio 2

SOLVD CONSENSUS II ATLAS SAVE Elite I, II Val-HeFT

Kidney BP  Na

RALES

 Hypertrophy  HR Vascular Endothelin

•

EECP

• • The CorCap (Acorn) Resembles a net that is placed around and attached to the heart.

Cardiology Today,October 2002

Cardiology today, october 2002.

The End