CLINICAL CARDIOLOGY
| HEART FAILURE —Barry H. Greenberg, MD, Professor of Medicine, Director of Heart Failure and Cardiac Transplant
Program, University of California, San Diego, School of Medicine
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| General: >5 million people in United States with heart failure (HF); leading cause of hospitalization for Americans >65 yr
of age; primary cause or major contributor to death of >250,000 Americans annually; only cardiovascular disease rising
in incidence in United States; reasons for increase— aging population; number of people with metabolic abnormalities
that precede HF (eg, type 2 diabetes, obesity) increasing; number of patients who survive with cardiac damage increasing
because of successful treatment of other forms of heart disease; increased survival in patients with HF
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| Causes of HF: 3 basic underlying problems (in both sexes) include hypertension (HTN), myocardial infarction (MI), and
diabetes mellitus (DM); account for 90% of causes; continuum—patients with risk factors identified; patients develop
atherosclerotic disease or left ventricular hypertrophy (LVH); coronary artery disease (CAD); myocardial ischemia;
plaque rupture; coronary thrombosis; MI; coronary muscle loss; remodeling of heart; ventricular dilatation; HF; role of
neurohormonal agents—hemodynamic abnormalities (salt and water retention; peripheral vasoconstriction); neurohormonal
activation implicated in many key events leading to development of HF; pathogenesis of diseases that result in
myocardial injury (eg, HTN, LVH, CAD); myocardial thrombosis and infarction; injury after MI that leads to remodeling
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| Classification: American College of Cardiology and American Heart Association (ACC/AHA) guidelines stage HF early
in course of disease
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 | Stage A: patients at high risk of developing HF because of risk factors (HTN, CAD, and DM); Heart Outcomes Prevention
Evaluation (HOPE) Trial—patients 55 yr of age with atherosclerotic disease or DM and one additional risk factor
randomly assigned to receive angiotensin-converting enzyme (ACE) inhibitor or placebo; 5-yr follow-up; study showed
that intervention with ramipril (ACE inhibitor) had beneficial effect on virtually all cardiovascular end points (HF reduced
by 23%); β-blockers—reduce reinfarction rate, risk for stroke, and progression to overt HF in patients with HTN; meta-
analysis of 18,000 patients randomly assigned to β-blocker or placebo showed >40% risk reduction for HF; early intervention
with neurohormonal blocking agents in people at risk reduces risk of developing HF; metabolic syndrome—defined
as having 3 of following, abdominal obesity, hypertryglyceridemia, low levels of high-density lipoprotein
cholesterol (HDL–C), blood pressure >130/85 mm Hg, or fasting blood glucose >110 mg/dL; ≈25% of adult population
has metabolic syndrome; concern with metabolic consequences of using β-blockers; Glycemic Effects in Diabetes Mellitus:
Carvedilol—Metoprolol Comparison in Hypertensives) (GEMINI) trial—in head-to-head comparison of
carvedilol and metoprolol in patients with HTN and DM, no change in hemoglobin A1c in carvedilol-treated patients
whereas significant changes noted in metoprolol-treated patients; β-blockers not alike in metabolic effect; trial also
showed significant reduction in microalbuminuria (one of key risk factors for development of coronary disease) with
carvedilol and trend toward increase with metoprolol
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| Stage B: patient after MI with left ventricular systolic dysfunction; high risk for subsequent cardiovascular events and HF;
neurohormonal pathways activated with left ventricular dysfunction (LVD); effector molecules (angiotensin II, norepinephrine,
and aldosterone) promote cardiac hypertrophy, programmed cell death of cardiac myocytes, ischemia, predisposition
to arrhythmias, leading to remodeling of heart, development of fibrosis, and worsening of cardiac function; patients
with LVD after MI treated with ACE inhibitors have improved clinical course; Valsartan in Acute Myocardial Infarction
Trial (VALIANT)—patients randomly assigned to receive either angiotensin receptor blocker (ARB; valsartan),
ACE inhibitor (captopril), or both; ARB as effective as ACE inhibitor and had lower side-effect profile; combination therapy
offered no additional benefit; Carvedilol Postinfarct Survival Control in LV Dysfunction (CAPRICORN)
study—primary end point, all-cause mortality; showed carvedilol (added to ACE inhibitor patients already on) reduced
mortality risk by 23%; Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study
(EPHESUS)—evaluated use of eplerenone (aldosterone antagonist) in patients after MI with evidence of LVD and taking
ACE inhibitors (87%) or β-blockers (75%); showed further mortality reduction of 15% and significant reduction in sudden
cardiac death; studies led to recommendation to treat with broad-based neurohormonal blockade (renin-angiotensin system
blocker, β-blocker, and aldosterone antagonist)
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| Stage C: patients with symptomatic HF; ACE inhibitors confer beneficial effect on clinical course (reduction in mortality
20%-25%); β-blockers emerged as standard of therapy; meta-analysis shows that overall, β-blockers reduce all-cause
mortality by 35% (in addition to reduction achieved with ACE inhibitor)
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| Stage D: advanced HF; patient dependent on sympathetic stimulation, leading to concern about using β-blockers;
Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS)—very sick patients with HF
(class 3B, early class 4); placebo treatment group had 1-yr mortality of 20%; treatment with carvedilol reduced mortality
by 35%; β-blockers beneficial in advanced HF; Randomized Aldactone Evaluation Study (RALES)—risk reduction
30% when aldosterone antagonist added; evidence unclear whether beneficial in milder HF
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| HF with preserved systolic function (preserved ejection fraction [EF] or diastolic HF): ≈50% of HF population; more common
in older people and women; survival better than in patients with low EF, but mortality still increased; morbidity
nearly identical to patients with low EF; Candesartan in Heart Failure Assessment of Reduction in Mortality and
Morbidity (CHARM)—evaluated use of candesartan (ARB) in >3000 patients with symptomatic HF who had EF >40%;
patients randomized to ARB or placebo and followed for 3 yr; clinical presentation of patients with diastolic dysfunction
similar to those with systolic dysfunction (edema, orthopnea, paroxysmal nocturnal dyspnea (PND), resting dyspnea,
rales, jugular venous distention (JVD; may hear difference in S3 ); study showed no definitive information; evidence that
hospitalizations for HF significantly reduced with ARB
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| Device therapy: cardiac resynchronization therapy (CRT)—used for patients who have evidence of ventricular dyssynchrony
(wide QRS; ≈25% of patients); biventricular pacing (pacing wires put into right atrium, right ventricle, and coronary
sinus) better coordinates contraction between left and right ventricles; CRT shown to improve symptoms and
exercise capacity; meta-analysis—evaluated impact on HF hospitalizations and HF mortality; study suggested both end
points significantly improved; Cardiac Resynchronization in Heart Failure (CARE-HF) trial—showed reduction in
all-cause mortality when CRT added to good medical therapy; when to use CRT—systolic dysfunction (low EF), evidence
of dyssynchrony (wide QRS); highly symptomatic patients on optimal medical therapy; areas of uncertainty—
atrial fibrillation (AF); right bundle branch block; patients with milder HF; rescue therapy
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| Summary: most cases of HF attributed to HTN, CAD, and/or DM; neurohormonal agents play role in pathogenesis of HF;
neurohormonal blockade improves clinical course at all stages; device therapy can improve clinical course and survival
in symptomatic patients
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| Questions: use of glitazones in patients with DM and HF (especially stage B)—effective in DM; use in stage A or B,
not in stage C because of fluid-retention side effect; digitalis use—useful in AF and in symptomatic patients with systolic
dysfunction; evidence digitalis improves exercise capacity and reduces hospitalization; reduced dose (0.125 mg)
used; aim for digitalis level of 0.8 ng/dL in these patients; calcium channel blockers and HF—rarely used; diltiazem
and verapamil associated with worsening cardiac function; amlodipine useful in patients with systolic dysfunction HF
who maintain HTN on maximum doses of ACE inhibitor and β-blocker; hypotension and neurohormonal blocking
agents—when treating patients with HF, actual blood pressure not as important as whether patients become symptomatic
as agents uptitrated; use of neurohormonal agents impeded in HF population because of concerns of hypotension
(concerns hypothetical)
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| PHARMOCOINVASIVE THERAPY FOR ST-SEGMENT ELEVATION IN ACUTE MI—Harold L. Dauerman, MD,
Professor of Medicine, University of Vermont College of Medicine, and Director of Cardiac Catheterization Laboratory,
Fletcher Allen Health Care Center, Burlington, Vermont
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| General: mortality rate ≈10% for ST-elevation MI (STEMI; down from 24%); mortality rate decrease attributed to introduction
of reperfusion in 1980s; before 1994, STEMI contraindication to catheterization; today, no one too sick for catheterization;
≈50/50 split in choice of thrombolytics vs primary angioplasty (large group of patients not receiving any
therapy)
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| Primary angioplasty vs lytic drugs: primary angioplasty proven best way to get normal flow in artery; normal flow confers
survival advantage; 15% chance flow will normalize with aspirin and heparin in emergency department (ED); 32%
with half-dose thrombolytics; 55% with full-dose thrombolytics; 90% if taken straight to catheterization laboratory; results
similar when using abciximab (ReoPro) as with half-dose thrombolytics; scar tissue inside stents ameliorated in past
2 yr with use of drug-eluting stents (5% rate of developing clinically recurrent ischemia; 15% with bare metal stents);
better long-term outcomes because of better antiplatelet therapy (clopidogrel [Plavix]); mortality benefit only 0.5% to 1%
better than thrombolytics, even though it restores normal flow nearly twice as often; mortality 1% with angioplasty within
60 min of onset of symptoms; 6.2% if angioplasty done after 90 min; primary angioplasty time-dependent procedure; low-
risk STEMI—30% of patients with STEMI; young; inferior MI; no pulmonary edema; hemodynamically stable; no premature
ventricular contractions (PVCs); nonsustained ventricular tachycardia; no sinus tachycardia; no history of coronary
disease
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| First principle of pharmacoinvasive therapy: time and flow matter; for patients who cannot get angioplasty early, give
thrombolytics; everyone gets catheterization
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| Second principle—initial flow matters; Danish Multicenter Randomized Study on Fibrinolytic Therapy vs Acute Coronary
Angioplasty in Acute MI (DANAMI-2)—780 patients got full-dose tissue plasminogen activator (tPA) and 780
patients got primary angioplasty (majority transferred for procedure); study showed 45% reduction in combined end
point of death, MI, or stroke across all groups; conclusion that primary angioplasty worth wait, time does not matter; time
to open artery 90 min to 114 min (does not hold true in United States); National Registry of MI (NRMI) in United
States—average time to open artery 111 min; among patients requiring transfer, time to open artery 180 min; patients
not candidates for thrombolytics—history of intracranial bleeding; stroke within past 2 mo; recent surgery; appropriate
to transfer these patients; solutions to transfer and time issues—primary angioplasty in every hospital; ACC/AHA
guidelines—patient with STEMI classified as Class I for primary percutaneous coronary intervention (PCI) if referring
to catheterization laboratory that performs >200 PCI per year; operator volume >75 angioplasties per year; laboratory
should do >3 primary PCIs per month; fibrinolysis generally preferred if invasive strategy not option (catheterization not
available; lack of access to skilled PCI), delay of invasive strategy (door to balloon time >90 min), or symptom onset >3
hr before presentation
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| Third principle (prevention of recurrent infarction)—chance of having recurrent ST elevation after first presentation
markedly reduced with primary angioplasty, compared to thrombolytics; patient given thrombolytics can still has 90%
stenosis or thrombus (risk factor for reoccluding); patient with successful primary angioplasty with stenting has low rate
of recurrent thrombosis; antithrombotic therapy—reinfarction rate decreased from 6% to 3.5% when patient given
enoxaparin (Lovenox) but at price (intracranial bleeding among elderly increases from <1% to >6%; death increased);
ACC/AHA guidelines state Class III contraindication in elderly; unfractionated heparin (UFH) preferred to Lovenox for
patients receiving full-dose thrombolytics; glycoprotein IIb/IIIa inhibitors, when combined with lytics, double intracranial
bleeding rates in elderly (combination contraindicated); catheterization and stent placement only safe method to prevent
reinfarction after thrombolytics; study showed 0% incidence of stroke or groin bleeding in patients having urgent
PCI after thrombolytics; timing of catheterization after lytics—study (Assessment of the Safety and Efficacy of a New
Treatment Strategy for AMI [ASSENT-4 PCI]) of 4000 patients in Europe randomized to full-dose thrombolytics (then
catheterization within 4 hr) vs primary angioplasty showed no increased bleeding in facilitated PCI arm, but more adverse
cardiac events; catheterization not indicated immediately in patients who received thrombolytics, but transfer immediately
to facility for stent to prevent reinfarction (almost all recurrent MIs happen in first 12-48 hr, not first 2 hr);
>85% of recurrent MIs prevented if patient catheterized in 12 to 24 hr after thrombolytics; mortality rate after catheterization
lower if done during day with rested staff to do procedure (immediate catheterization not more beneficial); Plavix—
data show beneficial to patients with STEMI; intravenous metoprolol (Lopressor)—increases risk for cardiogenic
shock in patients with STEMI
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| Algorithm: STEMI in ED, give aspirin and Plavix 300 mg po; PCI-capable hospital, give patient β-blocker only if hypertensive
and tachycardic, may give IIb/IIIa inhibitor and go straight to catheterization; if no PCI capability, give UFH 60
U/kg, β-blockers only if hypertensive, full-dose lytics if no contraindication, and transfer to PCI-capable facility; at PCI-
capable facility, emergent PCI with stent if reperfusion fails or continued chest pain or ST elevation, otherwise go to
catheterization in 12 to 24 hr
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Educational Objectives
| The goal of this program is to provide the listener with information on heart failure (HF) and pharmacoinvasive therapy for
ST-segment elevation myocardial infarction (STEMI). After hearing and assimilating the clinician will be better able to:
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| 1. Describe the role of neurohormonal agents in the development of HF.
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| 2. Review the data showing the role of neurohormonal blockade in the treatment of different stages of HF.
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| 3. Discuss the role of cardiac resynchronization and the treatment of HF.
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| 4. Discuss the role of thrombolytics and primary percutaneous coronary intervention (PCI) in the treatment of a patient
with STEMI.
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| 5. Provide initial treatment for a patient with STEMI.
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Discussed on This Program
Abciximab [ReoPro]
Amlodipine [AmVaz, Norvasc]
Aspirin (acetylsalicylic acid; ASA) [several trade names]
Candesartan cilexetil [Atacand]
Captopril [Capoten]
Carvedilol [Coreg]
Clopidogrel bisulfate [Plavix]
Digitalis [Digifortis, Digiglusin]
Diltiazem HCl [several trade names]
Eplerenone [Inspra]
Heparin sodium injection
Enoxaparin sodium [Lovenox]
Metoprolol succinate [Lopressor, Metoprolol Tartrate, Toprol XL]
Ramipril [Altace]
Spironolactone [Aldactone]
Tirofiban HCl [Aggrastat]
Tissue plasminogen activator, recombinant (tPA)
Valsartan [Diovan]
Verapamil HCl [several trade names]
| Suggested Reading
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Cohen M, et al: The role of gender and other factors as predictors of not receiving reperfusion therapy and of outcome in ST-
segment elevation myocardial infarction. J Thromb Thrombolysis 19:155, 2005; Davies JI, et al: Autonomic effects of
spironolactone and MR blockers in heart failure. Heart Fail Rev 10:63, 2005; Fauchier L, et al: Different criteria of cardiac
resynchronization therapy and their prognostic value for worsening heart failure or major arrhythmic events in patients with idiopathic
dilated cardiomyopathy. Am J Cardiol 97:393, 2006; Fonarow GC: An approach to heart failure and diabetes mellitus.
Am J Cardiol 96:47E, 2005; Gershlick AH, et al: Rescue angioplasty after failed thrombolytic therapy for acute
myocardial infarction. N Engl J Med 353:2758, 2005; Gheorghiade M, et al: Pharmacology of new agents for acute heart
failure syndromes. Am J Cardiol 96:68G, 2005; Harada M, et al: Biventricular Pacing Has an Advantage over Left Ventricular
Epicardial Pacing Alone to Minimize Proarrhythmic Pertubation of Repolarization. J Cardiovasc Electrophysiol
17:151, 2006; Henriques JP, et al: Primary percutaneous coronary intervention versus thrombolytic treatment: long term follow
up according to infarct location. Heart 92:75, 2006; Ibrahim OA, Dunlap ME: combination pharmacologic therapies
for heat failure: what next after angiotensin-converting enzyme inhibitors and beta-blockers? Curr Heart Fail Rep 2:89,
2005; Karha, J Topol EJ: Primary percutaneous coronary intervention vs. fibrinolytic therapy for acute ST-elevation myocardial
infarction in the elderly. Am J Geriatr Cardiol 15:19, 2006; Keeley EC, et al: Comparison of primary and facilitated
coronary interventions for ST-elevation myocardial infarction: quantitative review of randomized trials. Lancet 367:579,
2006; Le May MR, et al: combined angioplasty and pharmacological intervention versus thrombolysis alone in acute myocardial
infarction (Capital AMI study). J AM Coll Cardiol 46:471, 2005; Mancini D, Burkoff D: Mechanical device-based
methods of managing and treating heart failure. Circulation 112:438, 2005; Owen TE, Redfield MM: Epidemiology of diastolic
heart failure. Prog Cardiovasc Dis 47:320, 2005; Parker AB, et al: Clinical prognosis, pre-existing conditions and the
use of reperfusion therapy for patients with ST segment elevation acute myocardial infarction. Can J Cardiol 22:131, 2006;
Rivera DA, Bristow MR: Cardiac resynchronization—a heart failure perspective. Ann Noninvasive Electrocardiol 10:16,
2005; Sawani S, et al: Beta-adrenergic blockers in heart failure: review of mechanisms of action and clinical outcomes. J
Cardiovasc Pharmachol Ther 9:243, 2004; Sauls JL, Rone T: Emerging trends in the management of heart failure: Beta
blocker therapy. Nurs Clin North Am 40:135, 2005; Selmer R, et al: cost-effectiveness of primary percutaneous coronary intervention
versus thrombolytic therapy for acute myocardial infarction. Scand Cardiovasc J 39:279, 2005; Thune JJ, et al:
Danish Multicenter Randomized Study on Fibrinolytic Therapy Versus Acute Coronary Angioplasty in Acute Myocardial Infarction
(DANAMI)-2 Investigators. Circulation 112:2017, 2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following has been disclosed:
Dr. Greenberg is a consultant for CHF Solutions, Pfizer, and Merck. Dr Dauerman is a consultant for Genentech,
Boston Scientific, and Medicine Company.
Dr. Greenberg was recorded at the 49th Annual Postgraduate Symposium Family Medicine Update:2005, held June 24-
26, 2005, in San Diego, California and sponsored by the San Diego Academy of Family Physicians. Dr. Dauerman was recorded
at the 31st Annual Vermont Family Medicine Review Course, held June 8-11, 2005, in Burlington, Vermont and
sponsored by the University of Vermont College of Medicine. The Audio-Digest Foundation thanks the speakers and the
sponsors for their cooperation in the production of this program.
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