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Objetivo Drug Reviews desde 1959

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1460 Los fármacos para la insuficiencia cardiaca crónica ............................................. ................................. p 9
volumen 56

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The Medical Letter ®

en medicamentos y terapéutica

Objetivo Drug Reviews desde 1959

Volumen 57 (Edición 1460) 19 de de enero de, el año 2015


Toma los exámenes de CME

▶ Drugs for Chronic Heart Failure Recommendations for Treatment of


Chronic Heart Failure 1,2

La insuficiencia cardíaca se asocia generalmente con disfunción ventricular ▶ Unless there is a specifi c contraindication, all patients with heart failure with
reduced ejection fraction (LVEF ≤ 40%) should take both an ACE inhibitor
izquierda. De acuerdo con las directrices recientes, los pacientes con una fracción
and a beta blocker, and if volume overloaded, a diuretic as well.
de eyección ventricular izquierda (FEVI) ≤ 40% se considera que tienen
insuficiencia cardíaca con fracción de eyección reducida (ICFER) o insuficiencia ▶ An angiotensin receptor blocker (ARB) is recommended for patients who
cannot tolerate an ACE inhibitor.
cardíaca sistólica. Los pacientes con una FEVI ≥ 50% y síntomas de insuficiencia
▶ Addition of an aldosterone antagonist can reduce mortality and
cardíaca se considera que tienen insuficiencia cardíaca con fracción de eyección
hospitalization in patients with symptomatic heart failure or with left
conservada (ICFEP) o insuficiencia cardíaca diastólica; hay poca evidencia de que ventricular dysfunction after a myocardial infarction.
el tratamiento farmacológico mejora los resultados clínicos en estos pacientes. 1,2 El
tratamiento de la insuficiencia cardíaca aguda no se incluye aquí. ▶ Addition of a combination of hydralazine and isosorbide dinitrate to standard
therapy has been shown to reduce mortality and symptoms in black patients
with NYHA class III-IV heart failure with reduced ejection fraction.

▶ Digoxin can decrease symptoms and lower the rate of hospitalization for
Inhibidores de la ECA - Todos los pacientes con insuficiencia cardíaca con
heart failure, but it does not reduce mortality.
fracción de eyección reducida deben recibir un inhibidor de la enzima convertidora
de angiotensina (ACE). Estos fármacos mejoran los síntomas (generalmente más ▶ There is little evidence that drug treatment improves clinical outcomes in
de 4-12 semanas), disminuir la incidencia de hospitalización, y prolongar la patients with heart failure with preserved ejection fraction (HFpEF).

supervivencia en pacientes con insuficiencia cardíaca.


1. CW Yancy et al. Circulation 2013; 118:e240.
2. J Lindenfeld et al. J Card Fail 2010; 16:e1.

Dosis - inhibidores de la ECA deben iniciarse a dosis baja y se ajusta a la


dosis máxima tolerada, la orientación de las dosis máximas diarias inhibidor de ACE con un bloqueador del receptor de angiotensina (ARB);
enumerados en la Tabla 1 en la página 11. ARA II no aumentan las concentraciones de cininas en el mismo grado.
Erupción cutánea, alteraciones del gusto, y neutropenia pueden ocurrir con
precauciones - ACE inhibitors should be used cautiously in patients with
captopril, pero parecen ser poco frecuentes en la dosis recomendada
systolic blood pressure <80 mm Hg, serum creatinine >3 mg/dL, serum
actualmente.
potassium >5.0 mEq/L, or bilateral renal artery stenosis. They should not
be used in patients with a history of angioedema. Blood pressure, renal Elección de un inhibidor de la ECA - están disponibles mostrando que cualquier
function, and serum potassium levels should be monitored in patients inhibidor de ACE es más eficaz que cualquier otra para el tratamiento de la
taking an ACE inhibitor. ACE inhibitors can increase fetal mortality and insuficiencia cardíaca no los datos. Algunos inhibidores de la ECA (perindopril y
should not be used during pregnancy. benazepril) no han sido aprobados por la FDA para el tratamiento de la insuficiencia

cardíaca.

ARA II - La terapia a largo plazo con un bloqueador del receptor de


Adverse Effects – The most common adverse effects of ACE inhibitors angiotensina (ARB) reduce el riesgo de muerte en pacientes con
are related to inhibiting breakdown of endogenous kinins (cough and, insuficiencia cardíaca con fracción de eyección reducida; resultados
less commonly, angioedema), suppression of angiotensin II (hypotension parecen ser similares a los obtenidos con inhibidores de la ECA. ARA II
and renal insuffi ciency), and reduction of aldosterone production pueden utilizarse en pacientes que no pueden tolerar (principalmente
(hyperkalemia). Cough and angioedema can usually be relieved by debido a la tos) un inhibidor de la ECA. Generalmente no se recomienda el
replacing the uso rutinario de un IECA y un ARA juntos.

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The Medical Letter ®
Vol. 57 (1460) January 19, 2015

Dosage – ARBs should be started at low doses and titrated to the highest Choice of a Beta Blocker – Carvedilol, extended-release metoprolol
tolerated dose, which is usually achieved by doubling the dose until the succinate, and bisoprolol have been shown to reduce mortality and
maximum daily dose (listed in Table 1) is reached. hospitalization in patients with heart failure with reduced ejection fraction.
Bisoprolol is not approved by the FDA for treatment of heart failure.
There is no defi nitive clinical trial comparing extended-release
Cautions – As with ACE inhibitors, blood pressure, renal function, and
metoprolol succinate with carvedilol. Carvedilol has been shown to
serum potassium concentrations should be monitored in patients taking
reduce the incidence of diabetes mellitus, 7 hospitalization for heart failure,
an ARB. Angioedema could occur in patients taking an ARB who had
and inappropriate defi brillator therapy. 8 The advantages of
previously developed it while taking an ACE inhibitor. Like ACE inhibitors,
extended-release metoprolol succinate are once-daily dosing, less
ARBs can increase fetal mortality and should not be used during
hypotension, and more selective beta-1 blockade that may reduce the
pregnancy.
risk of bronchospasm.

Adverse Effects – ARBs, like ACE inhibitors, block the effects of


angiotensin II and may cause hypotension, renal insuffi ciency, and
ALDOSTERONE ANTAGONISTS — The addition of an aldosterone
hyperkalemia, but they do not cause cough. Angioedema occurs less
antagonist is recommended for patients with NYHA Class II-IV heart
frequently with ARBs than with ACE inhibitors.
failure with a LVEF
≤ 35%. When added to standard therapy in patients with heart failure,

Choice of an ARB – Candesartan and valsartan are the only ARBs aldosterone antagonists have been shown to reduce the risk of

approved by the FDA for treatment of heart failure; losartan, which is hospitalization and death. 9-11 When used in addition to standard therapy in
available generically, has also been widely used. 3,4 patients with heart failure after myocardial infarction, one study found that
eplerenone signifi cantly reduced the primary endpoints of all- cause
mortality and mortality or hospitalization for cardiovascular reasons. 12 Guidelines
BETA BLOCKERS — Unless there is a specifi c contraindication, all recommend adding an aldosterone antagonist after an acute myocardial
patients with stable heart failure with reduced ejection fraction should infarction in patients with heart failure symptoms and an LVEF ≤ 40%. In
receive a beta blocker in addition to an ACE inhibitor. Use of bisoprolol, a study in patients with heart failure with preserved ejection fraction,
carvedilol, or extended-release metoprolol succinate in addition to an spironolactone improved non- invasive measures of diastolic function, but
ACE inhibitor consistently leads to a 30-40% reduction in hospitalization it did not improve exercise capacity or quality of life. 13 In another trial, use
and mortality in adults with New York Heart Association (NYHA) class
of spironolactone did not signifi cantly reduce the incidence of the
II–IV heart failure. The effi cacy of adding a beta blocker to standard
primary composite endpoint of cardiovascular death, cardiac arrest, or
therapy for heart failure is less certain in children and adolescents and in
heart failure hospitalization compared to placebo. 14
patients with a reduced ejection fraction who are asymptomatic. 5

A recent observational cohort study in patients with


heart failure with preserved ejection fraction found that use of a beta Cautions – Aldosterone antagonists should be avoided in patients with
blocker was associated with a lower rate of all-cause mortality. 6
serum potassium >5.0 mEq/L and in those with reduced renal function
(baseline serum creatinine >2.0 mg/dL for women or >2.5 mg/dL for men,

Dosage – Beta blockers should be started at low doses and increased or an estimated GFR <30 mL/min/1.73 m 2). Renal function and serum

gradually, usually at 2-week intervals, to the highest tolerated dose. Full creatinine concentrations should be monitored during treatment.

clinical benefi ts may not occur for 3-6 months or more.

Adverse Effects – Hyperkalemia occurs frequently with aldosterone


Cautions – Beta blockers should be used cautiously, if at all, in patients
antagonists 15; the risk is higher in patients also taking an ACE inhibitor or
with asthma or severe bradycardia.
an ARB, and in those with renal impairment. Spironolactone has
Adverse Effects – Fatigue, hypotension, brady- cardia, asymptomatic anti-androgenic activity and can cause erectile dysfunction and painful
fluid retention, and worsening heart failure may occur during the fi rst 2-4 gynecomastia in men and menstrual irregularities in women; the
weeks of treatment. Increasing the dose of a concurrent diuretic may be incidence of these effects has been reported to be lower with eplerenone.
helpful for fluid retention.

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The Medical Letter ®
Vol. 57 (1460) January 19, 2015

Table 1. Some Drugs for Chronic Heart Failure with Reduced Ejection Fraction 1

Some Oral Usual Initial Usual Maximum


Drug Formulations Adult Dosage 2 Adult Dosage 2 Cost 3
Angiotensin-Converting Enzyme (ACE) Inhibitors
Captopril 5 – generic 12.5, 25, 50, 100 mg tabs 6.25 mg tid 50 mg tid $130.00 4
Enalapril – generic 2.5, 5, 10, 20 mg tabs 2.5 mg bid 20 mg bid 12.00 4
Vasotec ( Valeant) 663.60
Fosinopril 5 – generic 10, 20, 40 mg tabs 5-10 mg once/d 40 mg once/d 10.40
Lisinopril – generic 2.5, 5, 10, 20, 40 mg tabs 2.5-5 mg once/d 40 mg once/d 1.80
Prinivil ( Merck) 5, 10, 20 mg tabs 43.20
Zestril ( AstraZeneca) 2.5, 5, 10, 20, 30, 40 mg tabs 42.30
Perindopril* – generic 2, 4, 8 mg tabs 2 mg once/d 16 mg once/d 20.20
Aceon ( Symplmed) 98.10
Quinapril – generic 5, 10, 20, 40 mg tabs 5 mg bid 20 mg bid 24.10
Accupril ( Pfi zer) 171.00
Ramipril – generic 1.25, 2.5, 5, 10 mg caps 1.25-2.5 mg once/d 10 mg once/d 9.70
Altace ( Pfi zer) 129.30
Trandolapril – generic 1, 2, 4 mg tabs 1 mg once/d 4 mg once/d 17.20
Mavik ( Abbvie) 55.20
Angiotensin Receptor Blockers (ARBs)
Azilsartan medoxomil* –
Edarbi ( Arbor) 40, 80 mg tabs 40-80 mg once/d 80 mg once/d 135.60
Candesartan cilexetil – generic 4, 8, 16, 32 mg tabs 4-8 mg once/d 32 mg once/d 103.10
Atacand ( AstraZeneca) 119.40
Losartan* – generic 25, 50, 100 mg tabs 25-50 mg once/d 150 mg once/d 6.00
Cozaar ( Merck) 91.00
Valsartan 5 – generic 40, 80, 160, 320 mg tabs 20-40 mg bid 160 mg bid 264.40
Diovan ( Novartis) 277.80
Beta-Adrenergic Blockers
Bisoprolol* – generic 5, 10 mg tabs 5 1.25 mg once/d 10 mg once/d 24.50
Zebeta ( Duramed/Barr) 149.80
Carvedilol – generic 3.125, 6.25, 12.5, 25 mg tabs 3.125 mg bid 25 mg bid 5.40 4
Coreg ( GSK) (50 mg bid for pts >85kg) 172.80
extended-release – Coreg CR 10, 20, 40, 80 mg ER caps 10 mg once/d 80 mg once/d 173.60
Metoprolol succinate ER – generic
25, 50, 100, 200 mg ER tabs 5 12.5-25 mg once/d 200 mg once/d 50.20
Toprol-XL ( AstraZeneca) 85.50
Aldosterone Antagonists
Eplerenone – generic 25, 50 mg tabs 25 mg once/d 6 50 mg once/d 6 104.10
Inspra ( Pfi zer) 201.70
Spironolactone 5 – generic 25, 50, 100 mg tabs 12.5-25 mg once/d 6 25 mg once/d or bid 6 5.80 4
Aldactone ( Pfi zer) 44.70
Vasodilators
Isosorbide dinitrate/hydralazine 7 –
BiDil ( Arbor) 8 20/37.5 mg tabs 20 mg/37.5 mg tid 40 mg/75 mg tid 228.60
Loop Diuretics
Bumetanide – generic 0.5, 1, 2 mg tabs 0.5-1 mg once/d or bid 10 mg once/d or 117.80 4
in divided doses
Furosemide – generic 20, 40, 80 mg tabs 20-40 mg once/d or bid 600 mg once/d or 192.00 4
Lasix ( Sanofi ) in divided doses 288.00
Torsemide – generic 5, 10, 20, 100 mg tabs 10-20 mg once/d 200 mg once/d or 73.60
Demadex ( Meda) in divided doses 487.20
Digitalis Glycoside
Digoxin – generic 0.125, 0.25 mg tabs 0.125 mg once/d 0.125-0.25 mg once/d 36.10 4
Lanoxin ( Covis) 0.0625, 0.125, 0.1875, 0.25 mg tabs or once every other day 67.80
ER = extended-release
* Not approved by the FDA for treatment of heart failure.
1. For treatment of heart failure with reduced ejection fraction (HFrEF).
2. Dosage adjustment may be needed for hepatic or renal impairment.
3. Approximate WAC for 30 days’ treatment at the lowest maximum dosage. WAC = wholesaler acquisition cost or manufacturer’s published price to
wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource® Monthly. January
5, 2015. Reprinted with permission by First Databank, Inc. All rights reserved. ©2015. www.fdbhealth.com/policies/drug-pricing-policy.
4. A 30-day supply costs $4.00 at some large discount pharmacies.
5. Available as scored tablets.
6. For patients with an eGFR ≥ 50 mL/min/1.73 m 2. For patients with an eGFR 30-49 mL/min/1.73 m 2, the initial dose is 25 mg every other day for eplerenone
and 12.5 mg once daily or every other day for spironolactone and the maintenance dose is 25 mg once daily for eplerenone and 12.5-25 mg once daily for spironolactone.

7. Both of these drugs are available generically as single agents. Isosorbide dinitrate is available in 5, 10, 20, and 30-mg tablets and hydralazine in 10, 25, 50,
and 100-mg tablets.
8. FDA-approved as adjunctive therapy for treatment of heart failure in black patients.

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The Medical Letter ®
Vol. 57 (1460) January 19, 2015

Choice of an Aldosterone Antagonist – Eplerenone may be similar in Adverse Effects – The most common adverse effect of diuretic therapy is
effectiveness to spironolactone and may have less anti-androgenic hypokalemia. Diuretics can also cause worsening of renal function.
activity, but it costs much more. Comparative studies of their use in heart
failure are lacking.
Choice of a Diuretic – Torsemide is better absorbed than furosemide
and has a longer duration of action, but there is no clinical evidence that

VASODILATORS — Use of hydralazine plus isosorbide dinitrate may be torsemide or bumetanide is more effective than furosemide, which has

benefi cial for some patients. The addition of a fi xed-dose combination of been in use much longer.

hydrala- zine and isosorbide dinitrate ( BiDil) to standard therapy in


African-American patients who remained symptomatic despite standard DIGOXIN — Digoxin can decrease the symptoms of heart failure,
therapy signifi cantly reduced mortality and symptoms. 16 Its benefi t in increase exercise tolerance, and decrease the rate of hospitalization, but
non- African-American patients is less well established, but the it does not prolong survival.
combination can be considered in those intolerant to an ACE inhibitor or
an ARB or in those who need additional blood pressure control despite
Dosage – A low dose of digoxin (0.125 mg/d) is generally recommended
maximal doses of standard therapy.
for patients with heart failure with reduced ejection fraction. Dose
adjustments based on renal function, age, and concomitant medications
may be required. Digoxin levels of 0.5-0.9 ng/mL are recommended.

Adverse Effects – Hydralazine/isosorbide dinitrate frequently causes


headache and dizziness. Hydrala- zine alone can cause tachycardia,
Adverse Effects – The most common adverse effects of digoxin are
peripheral neuritis, and a lupus-like syndrome. Phosphodiesterase
conduction disturbances, cardiac arrhythmias, nausea, vomiting,
inhibitors, such as sildenafi l ( Viagra, Revatio, and generics), should not
confusion, and visual disturbances.
be taken concurrently with hydralazine/isosorbide dinitrate because of
the risk of additive hypotension.
OTHER DRUGS — A large trial in patients with NYHA class II-IV systolic
heart failure (GISSI-HF) found that the addition of n-3 polyunsaturated
fatty acids
DIURETICS — Most patients with heart failure have fluid retention. In 1 gram daily to standard therapy for a median of 3.9 years modestly
such patients, diuretics relieve symptoms, but their effect on survival is reduced all-cause mortality and cardiovascular hospitalizations compared
unknown. Diuretics provide symptomatic relief of pulmonary and to placebo. 17
peripheral edema more rapidly than other drugs used for the treatment of
Aliskiren ( Tekturna) is a direct renin inhibitor approved for treatment of
heart failure. Diuretics that act on the loop of Henle, such as furosemide,
hypertension. Although it offers the theoretical benefi t of upstream
bumetanide, or torsemide, are more effective for treatment of heart
renin-angiotensin system inhibition, one study in patients hospitalized for
failure than thiazide-type diuretics, such as hydrochlorothiazide or
heart failure found that addition of aliskiren to standard therapy did not
chlorthalidone, which act on the distal tubule.
reduce cardiovascular death or rehospitalization for heart failure at 6
months or 12 months after discharge. 18

Dosage – Diuretics should be started at a low dose, which can be titrated


Sacubitril plus Valsartan – A recent trial (PARADIGM- HF) found that
upward until urine output increases and weight decreases. Patients with
the combination of the investigational neprilysin inhibitor sacubitril and
renal dysfunction or prior refractoriness to loop diuretics can be started at
the ARB valsartan was superior to the ACE inhibitor enalapril alone in
higher doses. Intravenous administration, concurrent use of 2 diuretics (1
reducing the rate of death from cardiovascular causes or hospitalization
loop, 1 thiazide-like), or addition of an aldosterone antagonist can
for heart failure, the primary composite endpoint, in patients with heart
sometimes overcome diuretic resistance.
failure with reduced ejection fraction. 19,20 ■

12
The Medical Letter ®
Vol. 57 (1460) January 19, 2015

1. CW Yancy et al. 2013 ACCF/AHA guideline for the management of heart failure: a Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341:709.
report of the American College of Cardiology Foundation/American Heart Association
Task Force on practice guidelines. Circulation 2013; 128:e240. 12. B Pitt et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular
dysfunction after myocardial infarction. N Engl J Med 2003; 348:1309.
2. J Lindenfeld et al. HFSA 2010 comprehensive heart failure practice guideline. J Card
Fail 2010; 16:e1. 13. F Edelmann et al. Effect of spironolactone on diastolic function and exercise capacity
3. H Svanström et al. Association of treatment with losartan vs candesartan and mortality in patients with heart failure with preserved ejection fraction: the Aldo-DHF
among patients with heart failure. JAMA 2012; 307:1506. randomized controlled trial. JAMA 2013; 309: 781.

4. MA Konstam et al. Effects of high-dose versus low-dose losartan on clinical outcomes in 14. B Pitt et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J
patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet Med 2014; 370:1383.
2009; 374:1840. 15. KB Shah et al. The adequacy of laboratory monitoring in patients treated with
spironolactone for congestive heart failure. J Am Coll Cardiol 2005; 46:845.
5. RE Shaddy et al. Carvedilol for children and adolescents with heart failure: a
randomized controlled trial. JAMA 2007; 298:1171. 16. AL Taylor et al. Early and sustained benefi t on event-free survival and heart failure
hospitalization from fi xed-dose combination of isosorbide dinitrate/hydralazine:
6. LH Lund et al. Association between use of β-blockers and outcomes in patients with consistency across subgroups in the African-American Heart Failure Trial. Circulation
heart failure and preserved ejection fraction. JAMA   2014; 312:2008. 2007; 115:1747.

7. C Torp-Pederson et al. Effects of metoprolol and carvedilol on pre-existing and new 17. GISSI-HF investigadores et al. Efecto de n-3 ácidos grasos poliinsaturados en los pacientes
onset diabetes in patients with chronic heart failure: data from the Carvedilol Or con insuficiencia cardíaca crónica (el ensayo GISSI-HF): un estudio doble ciego,
Metoprolol European Trial (COMET). Heart 2007; 93:968. aleatorizado, controlado con placebo. The Lancet 2008; 372: 1223.

8. MH Ruwald. Impacto de carvedilol y metoprolol en 18. M Gheorghiade et al. Efecto de aliskiren en la mortalidad tras el alta y reingresos por
inapropiada implantable terapia desfibrilador cardioversor-fi de: el ensayo insuficiencia cardiaca en pacientes hospitalizados por insuficiencia cardíaca: el
MADIT-CRT (Desfibrilador automático De multicéntrico ensayo aleatorizado ASTRONAUTA. JAMA 2013; 309: 1125.
La implantación con terapia de resincronización cardiaca). J Am Coll Cardiol 2013; 62:
1343. 19. JJ McMurray et al. La angiotensina-neprilisina frente enalapril en la insuficiencia cardíaca. N
9. G Sayer y G Bhat. El sistema renina-angiotensina-aldosterona y la insuficiencia Engl J Med 2014; 371: 993.
cardíaca. Clin Cardiol 2014; 32:21. 20. O Vardeny et al. neprilisina Combinado y la inhibición del sistema renina-angiotensina para el
10. F Zannad et al. Eplerenona en pacientes con insuficiencia cardíaca sistólica y síntomas tratamiento de la insuficiencia cardíaca. JACC del corazón no 2014; 2: 663.
leves. N Engl J Med 2011; 364: 11.
11. B Pitt et al. El efecto de la espironolactona sobre la morbilidad y la mortalidad en
pacientes con insuficiencia cardíaca grave. aleatorizado

EDITOR EN JEFE: Marcos Abramowicz, MD; EDITOR EJECUTIVO: Gianna Zuccotti, MD, MPH, FACP, Escuela Médica de Harvard; EDITOR: Jean-Marie Pflomm, Pharm.D .;
Asistentes de editores, información sobre drogas: Susan M. Daron, Pharm.D., Corinne Z. Morrison, Doctor en Farmacia., Michael P. Viscusi, Pharm.D .; CONSULTAR LOS REDACTORES: Brinda M. Shah, Pharm.D.,
F. Peter Swanson, MD; MAYOR editor asociado: Amy Faucard

Editores colaboradores: Carl W. Bazil, MD, Ph.D., Universidad de Columbia Colegio de Médicos y Cirujanos; Vanessa K. Dalton, MD, MPH, Universidad de Michigan Medical School; Eric J. Epstein, MARYLAND, Albert Einstein College of
Medicine; Jane P. Gagliardi, MD, MHS, FACP, Escuela de Medicina de la Universidad de Duke de; Jules Hirsch, MD, Universidad Rockefeller; David N. Juurlink, BPhm, MD, Ph.D., Centro de Ciencias de la Salud Sunnybrook; Richard B.
Kim, MD, Universidad de Ontario Occidental; Hans Meinertz, MD, Hospital de la Universidad de Copenhague; Sandip K. Mukherjee, MD, FACC, Escuela de Medicina de Yale; Dan M. Roden, MD, Escuela de la Universidad de Vanderbilt de
Medicina; Esperance AK Schaefer, MD, MPH,
Escuela Médica de Harvard; F. Estelle R. Simons, MD, Universidad de Manitoba; Neal H. Steigbigel, MD, Escuela Universitaria de Medicina de Nueva York; Arthur MF Yee, MD, Ph.D., FACR,
Weill Medical College de la Universidad de Cornell

JEFE DE REDACCIÓN: Susie Wong; Subdirector asistente: Liz Donohue; ASISTENTE EDITORIAL: Cheryl Brown

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y Harold Aaron, MD
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