The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 57 ISSUE ISSUE No 1433 1460 Volume 56 January 19, 2015 IN THIS ISSUE Drugs for Chronic Heart Failure p Metreleptin (Myalept) – A Leptin Analog for Generalized Lipodystrophy p 13 In Brief: Concerns About Oseltamivir (Tamiflu) p 14 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) ISSUE ISSUE No 1433 1460 Volume 56 ▶ January 19, 2015 Take CME Exams ALSO IN THIS ISSUE Metreleptin (Myalept) – A Leptin Analog for Generalized Lipodystrophy p 13 In Brief: Concerns About Oseltamivir (Tamiflu) p 14 Drugs for Chronic Heart Failure Related article(s) since publication 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 on page 11 Cautions – ACE inhibitors should be used cautiously in patients with systolic blood pressure 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 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) CW Yancy et al Circulation 2013; 118:e240 J Lindenfeld et al J Card Fail 2010; 16:e1 II (hypotension and renal insufficiency), and reduction of aldosterone production (hyperkalemia) Cough and angioedema can usually be relieved by replacing the ACE inhibitor with an angiotensin receptor blocker (ARB); ARBs 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 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter ® 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 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 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 Vol 57 (1460) January 19, 2015 Adverse Effects – Fatigue, hypotension, bradycardia, 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 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 allcause 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 noninvasive 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 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 – 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 85kg) 80 mg once/d 12.5-25 mg once/d 200 mg once/d 50.20 85.50 25 mg once/d6 50 mg once/d6 12.5-25 mg once/d6 25 mg once/d or bid6 104.10 201.70 5.804 44.70 20 mg/37.5 mg tid 40 mg/75 mg tid 228.60 0.5-1 mg once/d or bid 10 mg once/d or in divided doses 600 mg once/d or in divided doses 200 mg once/d or in divided doses 117.804 20, 40, 80 mg tabs 20-40 mg once/d or bid 5, 10, 20, 100 mg tabs 10-20 mg once/d 0.125, 0.25 mg tabs 0.125 mg once/d 0.0625, 0.125, 0.1875, 0.25 mg tabs 0.125-0.25 mg once/d or once every other day Cost3 $130.004 12.004 663.60 10.40 1.80 43.20 42.30 20.20 98.10 24.10 171.00 9.70 129.30 17.20 55.20 135.60 103.10 119.40 6.00 91.00 264.40 277.80 24.50 149.80 5.404 172.80 173.60 192.004 288.00 73.60 487.20 36.104 67.80 ER = extended-release * Not approved by the FDA for treatment of heart failure For treatment of heart failure with reduced ejection fraction (HFrEF) Dosage adjustment may be needed for hepatic or renal impairment 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 A 30-day supply costs $4.00 at some large discount pharmacies Available as scored tablets 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 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 FDA-approved as adjunctive therapy for treatment of heart failure in black patients 11 The Medical Letter ® Vol 57 (1460) January 19, 2015 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 addition of an aldosterone antagonist can sometimes overcome diuretic resistance 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 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 VASODILATORS — Use of hydralazine plus isosorbide dinitrate may be beneficial for some patients The addition of a fixed-dose combination of hydralazine 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 nonAfrican-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 DIGOXIN — Digoxin can decrease the symptoms of heart failure, increase exercise tolerance, and decrease the rate of hospitalization, but it does not prolong survival Adverse Effects – Hydralazine/isosorbide dinitrate frequently causes headache and dizziness Hydralazine 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 diuretics (1 loop, thiazide-like), or 12 Adverse Effects – The most common adverse effect of diuretic therapy is hypokalemia Diuretics can also cause worsening of renal function 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 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 months or 12 months after discharge.18 Sacubitril plus Valsartan – A recent trial (PARADIGMHF) 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 ® 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 J Lindenfeld et al HFSA 2010 comprehensive heart failure practice guideline J Card Fail 2010; 16:e1 H Svanström et al Association of treatment with losartan vs candesartan and mortality among patients with heart failure JAMA 2012; 307:1506 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 RE Shaddy et al Carvedilol for children and adolescents with heart failure: a randomized controlled trial JAMA 2007; 298:1171 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 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 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 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 Vol 57 (1460) ▶ January 19, 2015 Metreleptin (Myalept) – A Leptin Analog for Generalized Lipodystrophy Metreleptin (Myalept – Amylin), a recombinant leptin analog produced in E coli, has been approved by the FDA to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy It has not been approved to date for the treatment of partial lipodystrophies, including those associated with the use of protease inhibitors in patients with HIV Metreleptin is approved in Japan for the treatment of any lipodystrophy disorder Pronunciation Key Metreleptin: met' re lep' tin Myalept: mye' a lept' THE DISORDER — Generalized lipodystrophy is a rare disorder with fewer than 500 known cases in the world.1 Congenital and acquired generalized lipodystrophy are characterized by a near total lack of adipose tissue Fat is deposited ectopically in muscle and liver tissue and can cause metabolic complications including insulin resistance, hyperinsulinemia, diabetes mellitus, and non-alcoholic fatty liver disease Severe hypertriglyceridemia is common in patients with generalized lipodystrophy and can lead to acute pancreatitis The metabolic abnormalities associated with generalized lipodystrophy are often aggravated by overconsumption of food, which has been attributed to leptin deficiency.2 HIV-associated lipodystrophy, the most common form of lipodystrophy, is also associated with reduced leptin levels, dyslipidemia, hypertriglyceridemia, and insulin resistance Table Pharmacology Drug class Route Leptin analog Subcutaneous Formulation 11.3 mg lyophilized powder (5 mg/mL after reconstitution) Tmax 4.0-4.3 hours Half-life 3.8-4.7 hours in healthy subjects Elimination Primarily renal LEPTIN — Leptin is a protein hormone secreted by adipose tissue that acts on the hypothalamus to induce satiety In patients with leptin deficiency, exogenous leptin administration results in weight loss and reductions in blood insulin, glucose, and triglyceride levels It has not been effective in treating ordinary obesity CLINICAL STUDIES — FDA approval of metreleptin was based on an unpublished, open-label, single-arm clinical trial (summarized in the package insert) in 48 patients with congenital or acquired generalized lipodystrophy and diabetes mellitus, hypertriglyceridemia, and/or 13 The Medical Letter ® hyperinsulinemia Compared to baseline, mean HbA1c and fasting glucose levels and median fasting triglyceride levels were all significantly reduced after 12 months of therapy with metreleptin Earlier small uncontrolled clinical trials in patients with generalized lipodystrophy produced similar results Some other small studies have found that metreleptin can correct metabolic abnormalities and decrease truncal fat mass in patients with HIV-associated lipodystrophy.2 ADVERSE EFFECTS — The most common adverse effects reported in patients taking metreleptin have been headache, hypoglycemia, weight loss, and abdominal pain A boxed warning states that anti-metreleptin antibodies, serious infections, and worsening metabolic control have been reported in patients taking the drug, and that some patients with acquired generalized lipodystrophy taking metreleptin (as well as some not taking the drug) have developed T-cell lymphoma As part of a Risk Evaluation and Mitigation Strategy (REMS), the FDA has required healthcare providers to be trained in the use of metreleptin before prescribing it and to attest that patients for whom they prescribe metreleptin have a labeled indication for the drug Metreleptin is classified as category C (no adequate studies in women) for use during pregnancy DOSAGE, ADMINISTRATION, AND COST — Metreleptin is administered subcutaneously once daily at starting doses of 0.06 mg/kg, 2.5 mg, and mg for patients ≤40 kg, males >40 kg, and females >40 kg, respectively, and may be titrated to a maximum daily dose of 0.13 mg/kg in patients ≤40 kg or 10 mg in those >40 kg The drug is available in vials containing 11.3 mg of metreleptin as a lyophilized powder, which should be refrigerated during storage Each vial is reconstituted with 2.2 mL of sterile water for injection (WFI) or sterile bacteriostatic water for injection (BWFI) to a final concentration of mg/mL If reconstituted with BWFI, metreleptin solution can be refrigerated and used within days of preparation; solution prepared with WFI must be used immediately or discarded Neonates and infants should not receive metreleptin solution prepared with BWFI because of its benzyl alcohol content A 30-day supply of Myalept at a daily dose of mg costs $20,608.3 CONCLUSION — The results of an unpublished, singlearm, open-label trial indicate that the leptin analog metreleptin (Myalept) can ameliorate the metabolic abnormalities found in patients with generalized lipodystrophy, but controlled trials are lacking and the drug’s long-term safety is unknown Metreleptin may also be effective in treating HIV-associated lipodystrophy, but more data are needed, and it has not been approved by the FDA for that indication ■ 14 Vol 57 (1460) January 19, 2015 A Garg Acquired and inherited lipodystrophies N Engl J Med 2004; 350:1220 MA Tsoukas et al Leptin in congenital and HIV-associated lipodystrophy Metabolism 2015; 64:47 Approximate WAC for 30 days’ treatment WAC = wholesaler acquisition cost, or manufacturer’s published price to wholesalers; WAC represents published catalogue or list prices and may not represent actual transactional prices Source: AnalySource® Monthly January 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy IN BRIEF Concerns about Oseltamivir (Tamiflu) Some readers of our article on Antiviral Drugs for Seasonal Influenza1 have expressed concerns regarding our recommendation for use of the oral neuraminidase inhibitor oseltamivir (Tamiflu) to treat high-risk patients with confirmed or suspected influenza illness, citing the British Medical Journal and The Cochrane Collaboration, which have contended that there is no acceptable evidence that the drug prevents complications or hospitalizations and have questioned the completeness of the results of controlled trials conducted by the manufacturer (Roche).2 Randomized controlled trials, mainly in patients with mild influenza illness, have shown that treatment with oseltamivir or zanamivir (Relenza), an inhaled neuraminidase inhibitor, started within 48 hours of the onset of illness can shorten the duration of symptoms by about one day Most controlled trials of the effectiveness of these drugs in preventing pneumonia or other serious complications of influenza have not been powered adequately to provide convincing evidence of efficacy, but a broad consensus of expert clinicians has interpreted the combined results of controlled trials, observational studies, and meta-analyses as showing that early antiviral treatment of high-risk patients with influenza can reduce the risk of complications such as pneumonia, respiratory failure, and death.3,4 Influenza kills about 50,000 patients annually in the US Oseltamivir and zanamivir are generally well tolerated, and there is no alternative treatment (Since this article was first posted online, peramivir (Rapivab), an IV neuraminidase inhibitor, has been approved by the FDA It will be reviewed in our February 2, 2015 issue.) Antiviral drugs for seasonal influenza 2014-2015 Med Lett Drugs Ther 2014; 56:121 T Jefferson et al Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children Cochrane Database Syst Rev 2014; 4:CD008965 CDC Influenza antiviral medications: summary for clinicians Available at http://www.cdc.gov/flu/professionals/antivirals/ summary-clinicians.htm Accessed December 23, 2014 IDSA Statement by the Infectious Disease Society of America (IDSA) on the recent publication on "Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children." April 2014 Available at: http://www.idsociety.org/Influenza_Statement.aspx Accessed December 23, 2014 The Medical Letter ® Continuing Medical Education Program medicalletter.org/cme Earn Up To 52 Credits Per Year Choose CME from The Medical Letter in the format that’s right for you! ▶ Comprehensive Exam – Available online or in print to Medical Letter subscribers, this 78 question test enables you to earn 13 credits immediately upon successful completion of the test A score of 70% or greater is required to pass the exam Our comprehensive exams allow you to test at your own pace in the comfort of your home or office Comprehensive tests are offered every January and July enabling you to earn up to 26 credits per year Starting with our January 2015 comprehensive exam, there will be 130 questions, enabling you to earn 26 credits upon successful completion of the test (or up to 52 credits if also taking the July 2015 exam) $49/exam ▶ Free Individual Exams – Free to active subscribers of The 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increase the participant’s ability to know, or apply knowledge into practice after assimilating, information presented in materials contained in The Medical Letter The Medical Letter will strive to continually improve the CME program through periodic assessment of the program and activities The Medical Letter aims to be a leader in supporting the professional development of healthcare providers through Core Competencies by providing continuing medical education that is unbiased and free of industry influence The Medical Letter is supported solely by subscription fees and accepts no advertising, grants, or donations GOAL: Through this program, The Medical Letter expects to provide the healthcare community with unbiased, reliable, and timely educational content that they will use to make independent and informed therapeutic choices in their practice LEARNING OBJECTIVES: Activity participants will read and assimilate unbiased reviews of FDA-approved and off-label uses of drugs and other treatment modalities Activity participants will be able to select and prescribe, or confirm the appropriateness of the prescribed usage of, the drugs and other therapeutic modalities discussed in The Medical Letter with specific attention to clinical trials, pathophysiology, dosage and administration, drug metabolism and interactions, and patient management Activity participants will make independent and informed therapeutic choices in their practice Upon completion of this program, the participant will be able to: Explain the current approach to the management of chronic heart failure Discuss the pharmacologic options available for treatment of chronic heart failure and compare them based on their efficacy, dosage and administration, and potential adverse effects Determine the most appropriate therapy given the clinical presentation of an individual patient with chronic heart failure Review the efficacy and safety of metreleptin (Myalept) for treatment of leptin deficiency in patients with congenital or acquired generalized lipodystrophy Privacy and Confidentiality: The Medical Letter guarantees our firm commitment to your privacy We not sell any of your information Secure server software (SSL) is used for commerce transactions through VeriSign, Inc No credit card information is stored IT Requirements: Windows XP/Vista/7/8, Mac OS X+; current versions of Microsoft IE, Mozilla Firefox, Google Chrome, Safari, or any other compatible web browser Highspeed connection Have any questions? Call us at 800-211-2769 or 914-235-0500 or e-mail us at: custserv@medicalletter.org Questions start on next page The Medical Letter ® Online Continuing Medical Education DO NOT FAX OR MAIL THIS EXAM To take CME exams and earn credit, go to: medicalletter.org/CMEstatus Issue 1460 Questions (Correspond to questions #11-20 in Comprehensive Exam #72, available July 2015) Drugs for Chronic Heart Failure In patients with heart failure with reduced ejection fraction, ACE inhibitors have been shown to: a improve symptoms b decrease hospitalizations c prolong survival d all of the above The most common adverse effect of ACE inhibitors is: a cough b angioedema c hypokalemia d dizziness ARBs: a are less effective than ACE inhibitors for treatment of chronic heart failure b are more likely than ACE inhibitors to cause angioedema c not cause cough d all of the above Potential advantages of extended-release metoprolol succinate over carvedilol include: a less hypotension b a lower risk of bronchospasm c once-daily dosing d all of the above Hyperkalemia can occur with: a ACE inhibitors b ARBs c aldosterone antagonists d all of the above In patients with heart failure, digoxin has not been shown to: a improve symptoms b decrease hospitalizations c prolong survival d all of the above A 59-year-old white man presents post-MI with heart failure symptoms and a LVEF of 29% He is currently being treated with an ACE inhibitor and extended-release metoprolol succinate Addition of which of the following drugs has been shown to prolong survival in such a patient? a digoxin b hydrochlorothiazide c eplerenone d hydralazine and isosorbide dinitrate A 68-year-old white man with heart failure with reduced ejection fraction being treated with enalapril and carvedilol comes to your office complaining of shortness of breath On physical examination, he has bilateral rales and edema in both lower extremities Which of the following would you recommend for acute relief of symptoms in this patient? a a combination of hydralazine and isosorbide dinitrate b valsartan c a loop diuretic d digoxin Metreleptin (Myalept) – A Leptin Analog for Generalized Lipodystrophy Metreleptin (Myalept) has been approved by the FDA for treatment of: a any partial lipodystrophy b lipodystrophy associated with use of protease inhibitors in patients with HIV c congenital or acquired generalized lipodystrophy d all of the above 10 Adverse effects of metreleptin have included: a hypoglycemia b weight loss c abdominal pain d all of the above ACPE UPN: Per Issue Exam: 0379-0000-15-460-H01-P; Release: January 19, 2015, Expire: January 19, 2016 Comprehensive Exam 72: 0379-0000-15-072-H01-P; Release: July 2015, Expire: July 2016 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 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: The Medical Letter, Inc 145 Huguenot St Ste 312 New Rochelle, NY 10801-7537 www.medicalletter.org Customer Service: Call: 800-211-2769 or 914-235-0500 Fax: 914-632-1733 E-mail: custserv@medicalletter.org Permissions: To reproduce any portion of this issue, please e-mail your request to: permissions@medicalletter.org Copyright 2015 ISSN 1523-2859 Subscriptions (US): year - $98; years - $189; years - $279 $49 per year for students, interns, residents, and fellows in the US and Canada Reprints - $12 each Site License Inquiries: E-mail: info@medicalletter.org Call: 800-211-2769 ext 315 Special rates available for bulk subscriptions ... once/d 2.5-5 mg once/d 40 mg once/d 40 mg once/d mg once/d 16 mg once/d mg bid 20 mg bid 1.25-2.5 mg once/d 10 mg once/d mg once/d mg once/d 40-80 mg once/d 4-8 mg once/d 80 mg once/d 32 mg once/d... information presented in materials contained in The Medical Letter The Medical Letter will strive to continually improve the CME program through periodic assessment of the program and activities The Medical. .. 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