CARDIOLOGY UPDATE
From Mount Sinai School of Medicine’s 3rd Annual Challenges in Internal Medicine
| ATRIAL FIBRILLATION: PRIORITIES IN CLINICAL MANAGEMENT —Jonathan L. Halperin, MD, Robert
and Harriet Heilbrunn Professor of Medicine, Mount Sinai School of Medicine, and Director, Clinical Cardiology
Services, The Zena and Michael A. Wiener Cardiovascular Institute and The Marie-Josée and Henry R. Kravis Center
for Cardiovascular Health, New York, NY
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| Prevalence and impact: atrial fibrillation (AF) most common cardiac arrhythmia that results in hospitalization;
important cause of morbidity and mortality, in part due to association with ischemic stroke; longer life spans and
improved treatments for cardiac disease contribute to increasing prevalence
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| Patterns: many patients asymptomatic, so duration of AF unknown and effect on patient’s functional capacity difficult
to assess; paroxysmal—intermittent, self-terminating, short (few days) episodes; persistent—episodes generally
last ≥1 wk, but often responsive to antiarrhythmic strategies; permanent—long-standing AF, refractory to
treatment
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| Diagnosis: electrocardiography (ECG) required; physical examination alone cannot distinguish AF from other atrial
tachycardias; symptoms (eg, palpitations, dizziness, shortness of breath) nonspecific and do not reflect severity of
underlying heart disease
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| Management guidelines: joint guidelines by American College of Cardiology/American Heart Association and
European Society of Cardiology state controlling ventricular rate highest priority, followed by prevention of thromboembolic
events (eg, stroke, systemic embolism); rhythm control has lowest priority (guidelines available at
www.americanheart.org)
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| Rate control: achieved primarily with atrioventricular (AV)-nodal blocking agents; digitalis (digoxin)—limited effect
during periods of adrenergic stress or exercise; particularly ineffective for management of paroxysmal AF;
used in combination with other agents; used in patients with AF associated with heart failure (HF); β-blockers—
preferred agents when tolerated; calcium channel blockers—eg, diltiazem, verapamil; alternative for patients unable
to tolerate β-blockers; amiodarone—powerful agent for controlling heart rate (HR) in patients with AF, but
potential for long-term toxicity limits use; contraindications—in acute setting, AV-nodal blocking agents (with exception
of amiodarone) may induce rapid arrhythmias, ventricular fibrillation, and death in patients with ventricular
pre-excitation (eg, Wolff-Parkinson-White syndrome); long-term oral therapy acceptable once patient stabilized;
early cardioversion and ablation appropriate if patient unresponsive to antiarrhythmic agents (types I or III) or amiodarone;
device therapy—AV nodal ablation and permanent pacing provides effective (but irreversible) control of
HR in patients with AF
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| Antithrombotic therapy: all but one clinical trials show significant reduction in risk, but limitations in study design
and patient populations leave unanswered questions (eg, efficacy in women); evidence clearly shows that vitamin K
antagonists (eg, warfarin) better than platelet inhibitors for reducing risk for ischemic stroke, even when used in combination
(eg, aspirin plus clopidogrel); bleeding—warfarin associated with high risk for disabling hemorrhagic stroke
and fatal intracranial hemorrhage, especially in patients >75 yr of age
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| Risk stratification: highest-risk patients—those with rheumatic mitral stenosis, prosthetic heart valve (particularly
in mitral position), or previous thromboembolic event (particularly ischemic stroke or transient ischemic attack
[TIA]), ie, high risk for subsequent stroke; anticoagulation indicated, with or without platelet inhibitors; moderate-risk
factors—include advanced age (>75 yr), hypertension (especially systolic), diabetes, clinical HF or left
ventricular (LV) ejection fraction (EF) <35%; other risk factors— age 65 to 75 yr; female sex; coronary disease;
hyperthyroidism; history of stroke or TIA most important risk factor in patients with AF not associated with valvular
disease
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 | AF and formation of thrombi: anticoagulating patient with thrombus in left atrium or left atrial appendage disperses
thrombus, but prethrombotic state remains; discontinuing anticoagulation increases risk for stroke; AF increases
risk for stroke by causing stasis in atrium and atrial appendage; presence of atherosclerotic plaque in aorta (even
in descending branch) marker for vascular disease and increased risk for stroke; transesophageal echocardiography
may help identify patients at high risk; anticoagulation—significantly reduces risk for stroke in patients
with left atrial thrombi or insufficiency and/or aortic plaque; does not appear to have benefit in patients without
these risk factors, regardless of clinical picture
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| CHADS2 index: risk score for patients with AF; congestive HF, hypertension, age >75 yr, and diabetes each receive
1 point; previous stroke or TIA receives 2 points; risk for stroke (based on total points) classified as high
(≥3 points), moderate (1-2 points), or low (0-1 point); number needed to treat—anticoagulating 12 high-risk patients
for 1 yr (vs hundreds of low-risk patients) prevents one stroke
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| Recommendations for antithrombotic therapy: high-risk factors—valvular disease or prosthetic heart valve;
mitral stenosis; history of stroke, TIA, or systemic embolism; moderate-risk factors—HF; low EF; hypertension;
age ≥75 yr; diabetes; treatment—aspirin (81-325 mg/day) sufficient for patients with no risk factors; warfarin indicated
for patients with one high-risk factor or >1 moderate-risk factor; discussion about treatment options appropriate
for patients with one moderate-risk factor
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| Intracranial hemorrhage: risk increases with international normalized ratio (INR) >3, age >75 yr, poorly controlled
hypertension (especially systolic), and history of cerebrovascular events; other factors that may contribute
to risk include concomitant platelet-inhibition therapy, use of tobacco or alcohol, amyloid angiopathy, and leukoaraiosis;
additional considerations—risk for bleeding; history of anticoagulation; availability of anticoagulation
management programs; patient preferences
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| Antiarrhythmic therapy: does not reduce risk for stroke or mortality; recommended in symptomatic patients only
after anticoagulation and rate control have failed to achieve sinus rhythm
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| Medical therapy: flecainide, propafenone, or sotalol—appropriate for patients with minimal or no heart disease and
those with hypertension but no evidence of LV hypertrophy; sotalol or dofetilide (restricted access)—for patients
with coronary disease; amiodarone or dofetilide—for patients with HF; amiodarone also used as second-line therapy
when other drugs fail, but associated with toxicity (avoid dosing >200 mg/day in patients with AF)
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| Catheter ablation: risk for major complications ≤5%; complications include esophageal erosions and perforations
and pericardial tamponade; success rate—≈50% with single procedure; rate increases with second procedure;
indications—symptomatic AF; patient refractory or intolerant to ≥1 class I or class III antiarrhythmic medications;
first-line therapy—in young patients with optimum anatomy; contraindications—thrombus in left atrium
or atrial appendage; follow-up—bridging therapy with low molecular weight heparin or unfractionated heparin if
ablation interrupts oral anticoagulation therapy; continue warfarin ≈3 mo after ablation (procedure possibly
thrombogenic); base decision about long-term anticoagulation on CHADS2 score (continue if score >2)
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| Alternatives to anticoagulation: current approaches include restoration of sinus rhythm through drug therapy or
pulmonary vein AF ablation; investigational approaches include obliteration of left atrial appendage using occluding
devices or plication (preventing thrombi from emerging)
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| Unanswered questions: relationship between AF and stroke (causal or correlational); optimal antithrombotic therapy
for high-risk patients with drug-eluting coronary stents (patients with AF should receive bare metal stents because
of lower risk for acute stent thrombosis); impact of successful rhythm control on need for anticoagulation
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| CONGESTIVE HEART FAILURE —Jill Kalman, MD, Associate Professor of Medicine, and Director, Cardiomyopathy
Program, Mount Sinai Medical Center, New York, NY
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| Definition: complex syndrome, resulting from structural or functional cardiac disorder that impairs ventricular
function
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| Prevalence: >5 million cases in United States; incidence increasing and mortality rates high; prevalence increasing
because of improved primary prevention and more aggressive treatment (ie, more patients survive myocardial infarction
[MI]) and live to develop systolic dysfunction HF); aging population leads to growing numbers of patients
with HF
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| Goals of treatment: improve clinical outcomes; improve quality of life
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| Case study: obese woman, 63 yr of age, with long-standing hypertension, diabetes, and lipid disorder, presents with
acute MI; clinical HF developed during MI; stent placed; 3 days later, she has low EF (30%), elevated blood pressure
(BP) and HR, and abnormal levels of glucose and lipids
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| Post-MI remodeling: MI or other cardiac insult results in tissue death within hours; infarct expands over hours to
days with no additional insult; global remodeling results in abnormal architecture and dilation, adding stress to uninjured
cardiac tissue; metabolic and neurohormonal abnormalities contribute to progression to HF over years
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| Continuum of HF: stage A—high risk of developing HF; stage B—cardiac insult occurs, but patient remains asymptomatic;
stage C—symptomatic HF; stage D—refractory advanced HF; treatment—early intervention has
most impact; medical and device therapies reduce mortality rates
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| Neurohormonal activation: decrease in LV performance or cardiac output (as result of myocardial injury) activates
renin-angiotensin-aldosterone system and sympathetic nervous system; initial compensatory response preserves
blood flow to vital organs; associated peripheral vasoconstriction and hemodynamic alterations that increase
afterload and wall stress and further impair LV function, resulting in vicious cycle; vasoconstriction responsible for
HF symptoms; neurohormones also have toxic effects on tissues, causing fibrosis, apoptosis, and other cellular molecular
abnormalities which lead to progression and remodeling and increase morbidity and mortality
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| Angiotensin-converting enzyme (ACE) inhibitors: clinical trials show decreased mortality in post-MI patients
and those with chronic HF; recommendation—indicated in all patients with low EF, unless contraindicated or
patient unable to tolerate; early initiation recommended; outcomes—cardiac remodeling attenuated but not eliminated;
EF improved; comparison with angiotensin receptor blockers (ARBs)—trials consistently show similar effects
on mortality; ARBs used in patients intolerant to ACE inhibitors
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| Combination therapy (ACE inhibitor and ARB): blocking renin-angiotensin system at enzyme and receptor
levels should improve outcomes; ACE inhibitors also augment bradykinin levels; clinical trials—Valsartan Heart
Failure Trial (ValHeFT), Valsartan in Acute Myocardial Infarction Trial (VALIANT), and Candesartan in Heart
Failure Assessment of Reduction in Morbidity and Mortality (CHARM) trial show no added mortality benefit associated
with combination therapy, but hospitalizations decreased
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| Aldosterone antagonists: toxic effects of elevated levels of aldosterone include electrolyte abnormalities, fibrosis,
and changes in LV mass, result in impaired baroreceptor function, arterial compliance, and endothelial function;
agents—spironolactone binds to mineralocorticoid receptors (with partial affinity for glucocorticoid receptors);
eplerenone has greater specificity for mineralocorticoid receptors and fewer adverse effects; add-on therapy—
when added to medical regimen (ACE inhibitors; β-blockers), 25 mg spironolactone reduced mortality by ≈35% in
patients with advanced HF; eplerenone decreased cardiovascular mortality and produced 15% reduction in all-
cause mortality in post-MI patients when added to standard therapy
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| β-blockers: sympathetic outflow resulting from myocardial insult eventually impairs heart, vasculature, and kidneys,
leading to disease progression; blocking adrenergic pathway slows progression of disease; clinical trials—
bisoprolol, long-acting metoprolol, and carvedilol shown to significantly reduce all-cause mortality (and other end
points) in various patient populations; in United States, long-acting metoprolol ( β1 -selective) and carvedilol (nonselective
β-blocker with α-blocking properties) commonly used; safety and efficacy—carvedilol reduces mortality
and hospitalization and improves EF (compared to placebo) even at low dose (6.25 mg bid); although concerns exist
about negative inotropic properties of β-blockers, clinical trials found significant reductions in mortality in patients
with severe HF; dosage—carvedilol begun at 3.125 mg bid and increased to target dose of 6.25 mg to 25 mg
bid; metoprolol begun at 12.5 mg to 25 mg daily and increased to target dose of 200 mg daily; carvedilol vs
metoprolol—Carvedilol Or Metoprolol European Trial (COMET) showed carvedilol superior to short-acting metoprolol
for reducing all-cause mortality
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| Combination therapy: ACE inhibitors, β-blockers, and aldosterone antagonists independently reduce mortality;
combination associated with maximum benefit; adding ARB associated with additional reduction in hospitalizations
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| Resolution of case study: discharge medications include aspirin, clopidogrel, β-blocker (carvedilol, 6.25 mg bid),
ACE inhibitor (lisinopril, 5 mg/day), aldosterone antagonist (eplerenone, 25 mg/day), and treatment for diabetes
and lipid disorder
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Suggested Reading
Albers GW: Warfarin prevails for stroke prevention in atrial fibrillation—even in octogenarians. Lancet Neurol
6:844, 2007; Bohm M: Angiotensin receptor blockers versus angiotensin-converting enzyme inhibitors: where do
we stand now? Am J Cardiol 100:38J, 2007; de Groote P et al: The effects of beta-blockers in patients with stable
chronic heart failure. Predictors of left ventricular ejection fraction improvement and impact on prognosis. Am Heart
J 154:589, 2007; Desilvey DL: Risk of anticoagulation for atrial fibrillation in the elderly. Am J Geriatr Cardiol
16:325, 2007; Ford GA et al: Direct thrombin inhibition and stroke prevention in elderly patients with atrial fibrillation.
Experience from the SPORTIF III and V trials. Stroke Sep 20, 2007 [Epub ahead of print]; Gislason GH et
al: Persistent use of evidence-based pharmacotherapy in heart failure is associated with improved outcomes. Circulation
, 116:737, 2007; Go AS et al: Comparative effectiveness of beta-adrenergic antagonists on the risk of rehospitalization
in adults with heart failure. Am J Cardiol 100:690, 2007; Hughes M et al: Risk factors for
anticoagulation-related bleeding complications in patients with atrial fibrillation: a systematic review. QJM Sep 10,
2007 [Epub ahead of print]; O’Neill MD et al: Catheter ablation for atrial fibrillation. Circulation 116:1515, 2007;
Salehian O et al: Impact of ramipril on the incidence of atrial fibrillation: results of the Heart Outcomes Prevention
Evaluation study. Am Heart J 154:448, 2007; Sepehrdad R et al: Direct inhibition of renin as a cardiovascular
pharmacotherapy: focus on aliskiren. Cardiol Rev 15:242, 2007; Vassallo P, Trohman RG: Prescribing amiodarone:
an evidence-based review of clinical indications. JAMA 298:1312, 2007.
For additional information about upcoming meetings sponsored by the Mount Sinai School of Medicine and the
Department of Medicine, Mount Sinai Hospital, please visit: http://fusion.mssm.edu/cme
Educational Objectives
| The goal of this program is to reduce morbidity and mortality associated with atrial fibrillation (AF) and heart failure
(HF). After hearing and assimilating this program, the clinician will be better able to:
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| 1. Apply clinical guidelines to the management of AF.
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| 2. Discuss the relative importance of rate control and rhythm control in patients with AF.
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| 3. Assess risk for thromboembolic events and determine appropriate prophylactic therapy.
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| 4. Describe the role of neurohormonal activation in the progression of HF.
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| 5. Devise management plans to minimize mortality rates in patients with HF.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose
relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any
identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the following has been disclosed: Dr. Halperin has received
consulting fees from Astellas Pharma, Bayer HealthCare, Boehringer Ingelheim, Daiichi Sankyo,
GlaxoSmithKline, Johnson & Johnson, and Sanofi-Aventis; Dr. Kalman is on the Speakers’ Bureau for GlaxoSmithKline
and the heart failure advisory board for Boston Scientific.
Acknowledgments
Drs. Halperin and Kalman were recorded at 3rd Annual Challenges in Internal Medicine, sponsored by Mount Sinai
School of Medicine and the Department of Medicine, Mount Sinai Hospital, and held June 20-22, 2007, in New York,
NY. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this
program.
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