The Medical Letter ®

on Drugs and Therapeutics

Objective Drug Reviews Since 1959
Volume 57 January 19, 2015

ISSUE IN THIS ISSUE

ISSUE No.
1433
1460
Drugs for Chronic Heart Failure .............................................................................. p9

Volume 56

Important Copyright Message

FORWARDING OR COPYING IS A VIOLATION OF U.S. AND INTERNATIONAL COPYRIGHT LAWS

The Medical Letter, Inc. publications are protected by U.S. and international copyright laws.
Forwarding, copying or any distribution of this material is prohibited.

Sharing a password with a non-subscriber or otherwise making the contents of this site
available to third parties is strictly prohibited.

By accessing and reading the attached content I agree to comply with U.S. and international
copyright laws and these terms and conditions of The Medical Letter, Inc.

For further information click: Subscriptions, Site Licenses, Reprints

or call customer service at: 800-211-2769

Published by The Medical Letter, Inc. • A Nonprofit Organization

 The Medical Letter publications are protected by US and international copyright laws.
Forwarding, copying or any other distribution of this material is strictly prohibited.
For further information call: 800-211-2769
The Medical Letter
on Drugs and Therapeutics
Objective Drug Reviews Since 1959
Volume 57 (Issue 1460)
▶ Drugs for Chronic Heart Failure
Heart failure is usually associated with left ventricular
dysfunction. According to recent guidelines, patients
with a left ventricular ejection fraction (LVEF) ≤40% are
considered to have heart failure with reduced ejection
fraction (HFrEF) or systolic heart failure. Patients
with a LVEF ≥50% and symptoms of heart failure
are considered to have heart failure with preserved
ejection fraction (HFpEF) or diastolic heart failure;
there is little evidence that drug treatment improves
clinical outcomes in these patients.1,2 The treatment of
acute heart failure is not included here.
ACE INHIBITORS — All patients with heart failure
with reduced ejection fraction should receive an
angiotensin-converting enzyme (ACE) inhibitor. These
drugs improve symptoms (generally over 4-12 weeks),
decrease the incidence of hospitalization, and prolong
survival in patients with heart failure.
Dosage – ACE inhibitors should be started at low doses
and titrated to the highest tolerated dose, targeting the
maximum daily dosages listed in Table 1 on page 11.
Cautions – ACE inhibitors should be used cautiously
in patients with systolic blood pressure <80 mm Hg,
serum creatinine >3 mg/dL, serum 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 function, and serum potassium
levels should be monitored in patients taking an ACE
inhibitor. ACE inhibitors can increase fetal mortality
and should not be used during pregnancy.
Adverse Effects – The most common adverse
effects of ACE inhibitors are related to inhibiting
breakdown of endogenous kinins (cough and, less
commonly, angioedema), suppression of angiotensin
II (hypotension and renal insufficiency), and reduction
of aldosterone production (hyperkalemia). Cough and
angioedema can usually be relieved by replacing the
Published by The Medical Letter, Inc. • A Nonprofit Organization
®
January 19, 2015
Take CME Exams
Recommendations for Treatment of
Chronic Heart Failure1,2
▶ Unless there is a specific contraindication, all patients with
heart failure with reduced ejection fraction (LVEF ≤40%)
should take both an ACE inhibitor and a beta blocker, and if
volume overloaded, a diuretic as well.
▶ An angiotensin receptor blocker (ARB) is recommended for
patients who cannot tolerate an ACE inhibitor.
▶ Addition of an aldosterone antagonist can reduce mortality
and hospitalization in patients with symptomatic heart
failure or with left ventricular dysfunction after a myocardial
infarction.
▶ 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 heart failure, but it does not reduce
mortality.
▶ There is little evidence that drug treatment improves clinical
outcomes in patients with heart failure with preserved
ejection fraction (HFpEF).
1. CW Yancy et al. Circulation 2013; 118:e240.
2. J Lindenfeld et al. J Card Fail 2010; 16:e1.
ACE inhibitor with an angiotensin receptor blocker
(ARB); ARBs do not increase concentrations of kinins
to the same degree. Rash, taste disturbances, and
neutropenia can occur with captopril, but appear to be
uncommon at the currently recommended dosage.
Choice of an ACE Inhibitor – No data are available
showing that any one ACE inhibitor is more effective
than any other for treatment of heart failure. Some ACE
inhibitors (perindopril and benazepril) have not been
approved by the FDA for treatment of heart failure.
ARBs — Long-term therapy with an angiotensin
receptor blocker (ARB) reduces the risk of death
in patients with heart failure with reduced ejection
fraction; results appear to be similar to those obtained
with ACE inhibitors. ARBs can be used in patients
who cannot tolerate (primarily due to cough) an ACE
inhibitor. Routine use of an ACE inhibitor and an ARB
together is generally not recommended.
9
 The Medical Letter ®
Dosage – ARBs should be started at low doses and
titrated to the highest tolerated dose, which is usually
achieved by doubling the dose until the maximum
daily dose (listed in Table 1) is reached.
Cautions – As with ACE inhibitors, blood pressure,
renal function, and serum potassium concentrations
should be monitored in patients taking an ARB.
Angioedema could occur in patients taking an ARB
who had previously developed it while taking an ACE
inhibitor. Like ACE inhibitors, ARBs can increase fetal
mortality and should not be used during pregnancy.
Adverse Effects – ARBs, like ACE inhibitors, block the
effects of angiotensin II and may cause hypotension,
renal insufficiency, and hyperkalemia, but they do not
cause cough. Angioedema occurs less frequently with
ARBs than with ACE inhibitors.
Choice of an ARB – Candesartan and valsartan are the
only ARBs approved by the FDA for treatment of heart
failure; losartan, which is available generically, has
also been widely used.3,4
BETA BLOCKERS — Unless there is a specific
contraindication, all patients with stable heart failure
with reduced ejection fraction should receive a
beta blocker in addition to an ACE inhibitor. Use of
bisoprolol, carvedilol, or extended-release metoprolol
succinate in addition to an ACE inhibitor consistently
leads to a 30-40% reduction in hospitalization and
mortality in adults with New York Heart Association
(NYHA) class II–IV heart failure. The efficacy of
adding a beta blocker to standard therapy for heart
failure is less certain in children and adolescents and
in 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 blocker was associated with a lower
rate of all-cause mortality.6
Dosage – Beta blockers should be started at low
doses and increased gradually, usually at 2-week
intervals, to the highest tolerated dose. Full clinical
benefits may not occur for 3-6 months or more.
Cautions – Beta blockers should be used cautiously, if at
all, in patients with asthma or severe bradycardia.
Adverse Effects – Fatigue, hypotension, brady-
cardia, asymptomatic fluid retention, and worsening
heart failure may occur during the first 2-4 weeks of
treatment. Increasing the dose of a concurrent diuretic
may be helpful for fluid retention.
10
Vol. 57 (1460) January 19, 2015
Choice of a Beta Blocker – Carvedilol, extended-release
metoprolol succinate, and bisoprolol have been shown
to reduce mortality and 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 definitive clinical trial comparing
extended-release metoprolol succinate with carvedilol.
Carvedilol has been shown to reduce the incidence of
diabetes mellitus,7 hospitalization for heart failure, and
inappropriate defibrillator therapy.8 The advantages of
extended-release metoprolol succinate are once-daily
dosing, less hypotension, and more selective beta-1
blockade that may reduce the risk of bronchospasm.
ALDOSTERONE ANTAGONISTS — The addition of an
aldosterone antagonist is recommended for patients
with NYHA Class II-IV heart failure with a LVEF
≤35%. When added to standard therapy in patients
with heart failure, aldosterone antagonists have
been shown to reduce the risk of hospitalization and
death.9-11 When used in addition to standard therapy
in patients with heart failure after myocardial
infarction, one study found that eplerenone
significantly reduced the primary endpoints of all-
cause mortality and mortality or hospitalization for
cardiovascular reasons.12 Guidelines recommend
adding an aldosterone antagonist after an acute
myocardial infarction in patients with heart failure
symptoms and an LVEF ≤40%.
In a study in patients with heart failure with preserved
ejection fraction, spironolactone improved non-
invasive measures of diastolic function, but it did not
improve exercise capacity or quality of life.13 In another
trial, use of spironolactone did not significantly reduce
the incidence of the primary composite endpoint of
cardiovascular death, cardiac arrest, or heart failure
hospitalization compared to placebo.14
Cautions – Aldosterone antagonists should be avoided
in patients with 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, or an estimated GFR <30 mL/min/1.73 m2). Renal
function and serum creatinine concentrations should
be monitored during treatment.
Adverse Effects – Hyperkalemia occurs frequently with
aldosterone antagonists15; the risk is higher in patients
also taking an ACE inhibitor or an ARB, and in those with
renal impairment. Spironolactone has anti-androgenic
activity and can cause erectile dysfunction and painful
gynecomastia in men and menstrual irregularities
in women; the incidence of these effects has been
reported to be lower with eplerenone.
The Medical Letter ®
Vol. 57 (1460) January 19, 2015

Table 1. Some Drugs for Chronic Heart Failure with Reduced Ejection Fraction1
Some Oral Usual Initial Usual Maximum
Drug Formulations Adult Dosage2 Adult Dosage2 Cost3
Angiotensin-Converting Enzyme (ACE) Inhibitors
Captopril5 – generic 12.5, 25, 50, 100 mg tabs 6.25 mg tid 50 mg tid $130.004
Enalapril – generic 2.5, 5, 10, 20 mg tabs 2.5 mg bid 20 mg bid 12.004
Vasotec (Valeant) 663.60
Fosinopril5 – 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 (Pfizer) 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 (Pfizer) 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
Valsartan5 – 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 tabs5 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 5.404
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 tabs5 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/d6 50 mg once/d6 104.10
Inspra (Pfizer) 201.70
Spironolactone5 – generic 25, 50, 100 mg tabs 12.5-25 mg once/d6 25 mg once/d or bid6 5.804
Aldactone (Pfizer) 44.70
Vasodilators
Isosorbide dinitrate/hydralazine7 –
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 117.804
in divided doses
Furosemide – generic 20, 40, 80 mg tabs 20-40 mg once/d or bid 600 mg once/d or 192.004
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 36.104
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 m2. For patients with an eGFR 30-49 mL/min/1.73 m2, 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.

11
 The Medical Letter ®
Choice of an Aldosterone Antagonist – Eplerenone
may be similar in effectiveness to spironolactone and
may have less anti-androgenic activity, but it costs
much more. Comparative studies of their use in heart
failure are lacking.
VASODILATORS — Use of hydralazine plus isosorbide
dinitrate may be beneficial for some patients. The
addition of a fixed-dose combination of hydrala-
zine and isosorbide dinitrate (BiDil) to standard
therapy in African-American patients who remained
symptomatic despite standard therapy significantly
reduced mortality and symptoms.16 Its benefit in non-
African-American patients is less well established, but
the combination can be considered in those intolerant
to an ACE inhibitor or an ARB or in those who need
additional blood pressure control despite maximal
doses of standard therapy.
Adverse Effects – Hydralazine/isosorbide dinitrate
frequently causes headache and dizziness. Hydrala-
zine alone can cause tachycardia, peripheral neuritis,
and a lupus-like syndrome. Phosphodiesterase
inhibitors, such as sildenafil (Viagra, Revatio, and
generics), should not be taken concurrently with
hydralazine/isosorbide dinitrate because of the risk of
additive hypotension.
DIURETICS — Most patients with heart failure have
fluid retention. In such patients, diuretics relieve
symptoms, but their effect on survival is unknown.
Diuretics provide symptomatic relief of pulmonary and
peripheral edema more rapidly than other drugs used
for the treatment of heart failure. Diuretics that act on
the loop of Henle, such as furosemide, bumetanide,
or torsemide, are more effective for treatment of
heart failure than thiazide-type diuretics, such as
hydrochlorothiazide or chlorthalidone, which act on
the distal tubule.
Dosage – Diuretics should be started at a low dose,
which can be titrated upward until urine output
increases and weight decreases. Patients with renal
dysfunction or prior refractoriness to loop diuretics can
be started at higher doses. Intravenous administration,
concurrent use of 2 diuretics (1 loop, 1 thiazide-like), or
addition of an aldosterone antagonist can sometimes
overcome diuretic resistance.
12
Vol. 57 (1460) January 19, 2015
Adverse Effects – The most common adverse effect
of diuretic therapy is hypokalemia. Diuretics can also
cause worsening of renal function.
Choice of a Diuretic – Torsemide is better absorbed
than furosemide and has a longer duration of action,
but there is no clinical evidence that torsemide or
bumetanide is more effective than furosemide, which
has been in use much longer.
DIGOXIN — Digoxin can decrease the symptoms of
heart failure, increase exercise tolerance, and decrease
the rate of hospitalization, but it does not prolong
survival.
Dosage – A low dose of digoxin (0.125 mg/d) is
generally recommended 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 – The most common adverse effects
of digoxin are conduction disturbances, cardiac
arrhythmias, nausea, vomiting, confusion, and visual
disturbances.
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
1 gram daily to standard therapy for a median of 3.9
years modestly reduced all-cause mortality and
cardiovascular hospitalizations compared to placebo.17
Aliskiren (Tekturna) is a direct renin inhibitor approved
for treatment of hypertension. Although it offers the
theoretical benefit of upstream renin-angiotensin
system inhibition, one study in patients hospitalized
for heart failure found that addition of aliskiren to
standard therapy did not reduce cardiovascular death
or rehospitalization for heart failure at 6 months or 12
months after discharge.18
Sacubitril plus Valsartan – A recent trial (PARADIGM-
HF) found that the combination of the investigational
neprilysin inhibitor sacubitril and the ARB valsartan
was superior to the ACE inhibitor enalapril alone
in reducing the rate of death from cardiovascular
causes or hospitalization for heart failure, the primary
composite endpoint, in patients with heart failure with
reduced ejection fraction.19,20 ■
 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 report of the American College of Cardiology
Foundation/American Heart Association Task Force on practice
guidelines. Circulation 2013; 128:e240.
2. J Lindenfeld et al. HFSA 2010 comprehensive heart failure
practice guideline. J Card Fail 2010; 16:e1.
3. H Svanström et al. Association of treatment with losartan vs
candesartan and mortality among patients with heart failure.
JAMA 2012; 307:1506.
4. MA Konstam et al. Effects of high-dose versus low-dose
losartan on clinical outcomes in patients with heart failure
(HEAAL study): a randomised, double-blind trial. Lancet 2009;
374:1840.
5. RE Shaddy et al. Carvedilol for children and adolescents
with heart failure: a randomized controlled trial. JAMA 2007;
298:1171.
6. LH Lund et al. Association between use of β-blockers and
outcomes in patients with heart failure and preserved ejection
fraction. JAMA 2014; 312:2008.
7. C Torp-Pederson et al. Effects of metoprolol and carvedilol on
pre-existing and new onset diabetes in patients with chronic
heart failure: data from the Carvedilol Or Metoprolol European
Trial (COMET). Heart 2007; 93:968.
8. MH Ruwald. Impact of carvedilol and metoprolol on
inappropriate implantable cardioverter-defibrillator therapy:
the MADIT-CRT trial (Multicenter Automatic Defibrillator
Implantation with Cardiac Resynchronization Therapy). J Am
Coll Cardiol 2013; 62:1343.
9. G Sayer and G Bhat. The renin-angiotensin-aldosterone system
and heart failure. Cardiol Clin 2014; 32:21.
10. F Zannad et al. Eplerenone in patients with systolic heart failure
and mild symptoms. N Engl J Med 2011; 364:11.
11. B Pitt et al. The effect of spironolactone on morbidity and
mortality in patients with severe heart failure. Randomized
Aldactone Evaluation Study Investigators. N Engl J Med 1999;
341:709.
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.
13. F Edelmann et al. Effect of spironolactone on diastolic
function and exercise capacity in patients with heart failure
with preserved ejection fraction: the Aldo-DHF randomized
controlled trial. JAMA 2013; 309: 781.
14. B Pitt et al. Spironolactone for heart failure with preserved
ejection fraction. N Engl J Med 2014; 370:1383.
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.
16. AL Taylor et al. Early and sustained benefit on event-free
survival and heart failure hospitalization from fixed-dose
combination of isosorbide dinitrate/hydralazine: consistency
across subgroups in the African-American Heart Failure Trial.
Circulation 2007; 115:1747.
17. GISSI-HF Investigators et al. Effect of n-3 polyunsaturated fatty
acids in patients with chronic heart failure (the GISSI-HF trial):
a randomised, double-blind, placebo-controlled trial. Lancet
2008; 372:1223.
18. M Gheorghiade et al. Effect of aliskiren on postdischarge
mortality and heart failure readmissions among patients
hospitalized for heart failure: the ASTRONAUT randomized trial.
JAMA 2013; 309:1125.
19. JJ McMurray et al. Angiotensin-neprilysin versus enalapril in
heart failure. N Engl J Med 2014; 371:993.
20. O Vardeny et al. Combined neprilysin and renin-angiotensin
system inhibition for the treatment of heart failure. JACC Heart
Fail 2014; 2:663.

EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.;
ASSISTANT EDITORS, DRUG INFORMATION: Susan M. Daron, Pharm.D., Corinne Z. Morrison, Pharm.D., Michael P. Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M. Shah, Pharm.D.,
F. Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard
CONTRIBUTING EDITORS: Carl W. Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K. Dalton, M.D., M.P.H., University of Michigan Medical
School; Eric J. Epstein, M.D., Albert Einstein College of Medicine; Jane P. Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine; Jules Hirsch, M.D., Rockefeller
University; David N. Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B. Kim, M.D., University of Western Ontario; Hans Meinertz, M.D., University Hospital,
Copenhagen; Sandip K. Mukherjee, M.D., F.A.C.C., Yale School of Medicine; Dan M. Roden, M.D., Vanderbilt University School of Medicine; Esperance A.K. Schaefer, M.D., M.P.H.,
Harvard Medical School; F. Estelle R. Simons, M.D., University of Manitoba; Neal H. Steigbigel, M.D., New York University School of Medicine; Arthur M. F. Yee, M.D., Ph.D., F.A.C.R.,
Weill Medical College of Cornell University
MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown
EXECUTIVE DIRECTOR OF SALES: Gene Carbona; FULFILLMENT & SYSTEMS MANAGER: Cristine Romatowski; DIRECTOR OF MARKETING COMMUNICATIONS: Joanne F. Valentino;
VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy
Founded in 1959 by
Arthur Kallet and Harold Aaron, M.D.
Copyright and Disclaimer: The Medical Letter, Inc. is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations. The editorial
process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants. The Medical Letter,
Inc. is supported solely by subscription fees and accepts no advertising, grants, or donations. No part of the material may be reproduced or transmitted by any process in whole or in part without
prior permission in writing. The editors do not warrant that all the material in this publication is accurate and complete in every respect. The editors shall not be held responsible for any damage
resulting from any error, inaccuracy, or omission.
Subscription Services
Address: Customer Service: Permissions: Subscriptions (US): Site License Inquiries:
The Medical Letter, Inc. Call: 800-211-2769 or 914-235-0500 To reproduce any portion of this issue, 1 year - $98; 2 years - $189; E-mail: info@medicalletter.org
145 Huguenot St. Ste. 312 Fax: 914-632-1733 please e-mail your request to: 3 years - $279. $49 per year Call: 800-211-2769 ext. 315
New Rochelle, NY 10801-7537 E-mail: custserv@medicalletter.org permissions@medicalletter.org for students, interns, residents, and Special rates available for bulk
www.medicalletter.org fellows in the US and Canada. subscriptions.
Reprints - $12 each.

13