12/21/2015

Heart Failure Medications Update Alga S. Ramos Morales, Pharm.D., M.S. PGY1 Pharmacy Resident Miami VA Healthcare System

Objectives 1.

Describe recent FDA approvals and study data for heart failure management and cardiovascular risk reduction

2.

Identify place in therapy for these new agents in conjunction to current treatments

3.

Apply pharmacology aspects in selecting therapies for heart failure patients

Heart Failure Pathophysiologic state in which the heart fails to pump blood at a rate commensurate with the requirements of the metabolizing tissues or is able to do so only with an elevated diastolic filling pressure. According to the AHA, heart failure affects nearly 5.7 million Americans of all ages

Roger VL, Go AS, Lloyd-Jones DM, et al, for the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2011 update: a report from the American Heart Association. Circulation. 2011 Feb 1. 123(4):e18-e209.

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Causes of Death in the U.S. Heart disease: 611,105 Cancer: 584,881 Chronic lower respiratory diseases: 149,205 Accidents (unintentional injuries): 130,557 Stroke (cerebrovascular diseases): 128,978 Centers for Disease Control (2015). Leading Causes of Death. Last updated: September 30, 2015. Retrieved from: http://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm

Heart Failure

Adapted from: Maron B.A., Rocco T.P. (2011). Chapter 28. Pharmacotherapy of Congestive Heart Failure. In Brunton L.L., Chabner B.A., Knollmann B.C. (Eds), Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e. Retrieved November 22, 2015 from http://accesspharmacy.mhmedical.com/content.aspx?bookid=374&Sectionid=41266235.

NYHA Classification Functional Capacity Class I. Patients with cardiac disease but without resulting limitation of physical activity. Class II. Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Class III. Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Class IV. Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. NYHA=New York Heart Association Adapted from: The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256.

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Heart Failure Treatment ACE-I

All volume overload Class II-IV

Loop Diuretics

ARB

Persistently symptomatic AfricanAmerican,Class III-IV

Hydral-Nitrates

Beta Blocker

eGFR > 30ml/min and K < 5.0mEq/dL, Class II-IV

Aldosterone Antagonists

Adapted from: Yancy CW, Jessup M, Bozkurt B, 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. J Am Coll Cardiol. 2013;62(16):e147-e239. doi:10.1016/j.jacc.2013.05.019.

Treatment

Adapted from: Maron B.A., Rocco T.P. (2011). Chapter 28. Pharmacotherapy of Congestive Heart Failure. In Brunton L.L., Chabner B.A., Knollmann B.C. (Eds), Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e. Retrieved November 22, 2015 from http://accesspharmacy.mhmedical.com/content.aspx?bookid=374&Sectionid=41266235.

Entresto ® (sacubitril/valsartan) Approved on 07/07/2015

Entresto label. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Orig1s000lbl.pdf

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Entresto ® (sacubitril/valsartan) FDA Indications

Reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction in place of an ACEI or ARB

FDA= U.S. Food and Drug Administration Entresto label. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Orig1s000lbl.pdf

Entresto ® (sacubitril/valsartan) EMA Indication

Adult patients for treatment of symptomatic chronic heart failure with reduced ejection fraction

EMA = European Medicines Agency European Medicines Agency (2015). Entresto (sacubitril/valsartan). Last accessed: 12/21/2015. Retrieved from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004062/human_med_001929.jsp&mid=WC0b01ac058001d1 24

Entresto ® (sacubitril/valsartan) Mechanism of Action

Neprisylin

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Entresto ® (sacubitril/valsartan) Dosing Sacubitril/valsartan 49/51 mg twice daily Increase in 2-4 weeks to 97/103mg 24/26mg in the following patients: Not currently on ACEI/ARB or history of low doses Severe renal impairment Moderate hepatic impairment ACEI=angiotensin converting enzyme inhibitor; ARB=angiotensin II receptor blocker Entresto label. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Orig1s000lbl.pdf

Entresto ® (sacubitril/valsartan) Contraindications Hypersensitivity History of angiodema with ACEI/ARB Concomitant use of ACEI Concomitant use with aliskiren in patients with diabetes

Entresto label. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Orig1s000lbl.pdf

Entresto ® (sacubitril/valsartan) Warnings & Precautions Angioedema Hypotension Renal impairment Hyperkalemia Severe hepatic impairment Lactation/Pregnancy

Entresto label. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Orig1s000lbl.pdf

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Entresto ® (sacubitril/valsartan) Adverse Reactions

Adverse Reactions

Sacubitril/Valsartan (n=4,203)

Enalapril (n=4,229)

Hypotension

18%

12%

Hyperkalemia

12%

14%

Cough

9%

13%

Dizziness

6%

5%

Renal failure

5%

5%

Entresto label. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Orig1s000lbl.pdf

Entresto ® (sacubitril/valsartan) Pharmacokinetics Absorption

Distribution

Bioavailability > 60%

Protein Binding 94-97%

Peak 0.5hr, 2hr, 1.5hr

0.28% of sacubitril reaches blood brain barrier

With or without food

Vd 75L; 103L Pharmacokinetics

Elimination

Metabolism Sacubitril is metabolized to LBQ657 by esterases

Urine: 52-68% sacubitril; 13% valsartan T1/2 1.4hrs;11.5hrs/9.9hrs

Entresto label. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Orig1s000lbl.pdf

Entresto ® (sacubitril/valsartan) Drug Interactions RAAS drugs

K sparring diuretic

Drug Interactions

NSAIDs

Lithium

RAAS=renin-angiotensinaldosterone system; K=potassium; NSAIDS=non-steroidal antiinflammatory drug

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Entresto ® (sacubitril/valsartan) Pivotal Trial: PARADIGM-HF

Center for Drug Evaluation and Research (2015). Medical Review. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000MedR.pdf

Entresto ® (sacubitril/valsartan) PARADIGM-HF and IMPROVE-HF

Center for Drug Evaluation and Research (2015). Medical Review. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000MedR.pdf

Entresto ® (sacubitril/valsartan) Pivotal Trial: PARADIGM-HF

Center for Drug Evaluation and Research (2015). Medical Review. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000MedR.pdf

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Entresto ® (sacubitril/valsartan) Pivotal Trial: PARADIGM-HF

Outcomes

Enalapril (n=4212) n(%)

Entresto® (n=4187) n(%)

Hazard Ration (95% CI, 1-sided p-value)

Primary Composite Endpoint

1117 (26.5)

914 (21.8)

0.80 (0.73-0.87; 0.0000002)

CV Death

459 (10.9)

377 (9.0)

HF Hospitalization

658 (15.6)

537 (12.8)

0.79 (0.71-0.89; 0.00004)

693 (16.5)

558 (13.3)

0.80 (0.71-0.89; 0.00004)

Total CV Death

Center for Drug Evaluation and Research (2015). Medical Review. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000MedR.pdf

Entresto ® (sacubitril/valsartan) Cost Analysis Cost NOT YET AVAILABLE

Entresto ® (sacubitril/valsartan) Place in Therapy All volume overload Class II-IV

Loop Diuretics

ARB

Persistently symptomatic AfricanAmerican,Class III-IV

Hydral-Nitrates

Beta Blocker

eGFR > 30ml/min and K < 5.0mEq/dL, Class II-IV

Aldosterone Antagonists

ACE-I Sacubitril/valsartan

Adapted from: Yancy CW, Jessup M, Bozkurt B, 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. J Am Coll Cardiol. 2013;62(16):e147-e239. doi:10.1016/j.jacc.2013.05.019.

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Corlanor ® (ivabradine) Approved on 04/15/2015

Corlanor label. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206143Orig1s000lbl.pdf

Corlanor® (ivabradine) FDA Indication

Reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction ≤ 35%, who are in sinus rhythm with resting heart rate ≥ 70 beats per minute and either are on maximally tolerated doses of betablockers or have a contraindication to betablocker use

FDA= U.S. Food and Drug Administration Corlanor label. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206143Orig1s000lbl.pdf

Corlanor® (ivabradine) EMA Indication Used to treat the symptoms of long-term stable angina in adults with coronary artery disease with a heart rate of at least 70 beats per minute Used in patients with long-term heart failure whose heart rate is at least 75 beats per minute Used in combination with standard therapy including beta-blockers, or in patients who cannot be treated with betablockers EMA = European Medicines Agency European Medicines Agency (2015). Corlentor (ivabradine). Last accessed: 12/21/2015. Retrieved from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000598/human_med_000727.jsp&mid=WC0b01a c058001d124

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Corlanor® (ivabradine) Mechanism of Action

McGraw-Hill Companies, Inc. Retrieved from: www.biologyaspoetry.com

Adapted from: Nattel and Carlsson 2006 Nature Reviews; Drug Discovery 5:1034-1049. David S. Park and Glenn I. Fishman (2011). The Cardiac Conduction System. Circulation March 1, 2011 vol. 123 no. 8 904915.

Corlanor® (ivabradine) Dosing Initial dose – 5mg twice daily Titrate based on patient’s heart rate in two weeks Maximum dose 7.5mg twice daily Consider initiating 2.5mg daily in patients with conduction defects or in whom bradycardia could lead to hemodynamic compromise Corlanor label. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206143Orig1s000lbl.pdf

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Corlanor® (ivabradine) Contraindications Acute decompensated heart failure Blood pressure less than 90/50mmHg Sick sinus syndrome, sinoatrial block or 3rd degree AV block, unless a functioning demand pacemaker is present Resting heart rate less than 60bpm prior to treatment Severe hepatic impairment Pacemaker dependence Corlanor label. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206143Orig1s000lbl.pdf

Corlanor® (ivabradine) Warnings & Precautions Monitor patients for atrial fibrillation Monitor heart rate decreases and bradycardia symptoms during treatment Not recommended in patients with 2nd degree AV Block Fetal toxicity: Females should use effective contraception Lactation Corlanor label. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206143Orig1s000lbl.pdf

Corlanor® (ivabradine) Pharmacokinetics Absorption

Distribution

Bioavailability ~40% AUC increased 20-40% with food

Vd ~100L Protein Binding ~70%

Pharmacokinetics

Metabolism

Excretion

CYP3A4 Major metabolite

First pass elimination in gut and liver

N-desmethylated derivative

Urine ~4% unchanged drug

Corlanor label. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206143Orig1s000lbl.pdf

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Corlanor® (ivabradine) Drug Interactions CYP3A4 inhibitors CYP3A4 inducers Negative chronotropes Pacemakers: Not recommended for use with demand pacemakers set to rates ≥ 60 beats per minute

Corlanor label. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206143Orig1s000lbl.pdf

Corlanor® (ivabradine) Adverse Effects

Adverse Reactions

Ivabradine (n=3,260)

Placebo (n=3,278)

Bradycardia Hypertension Atrial fibrillation Phosphenes

10% 8.9% 8.3% 2.8%

2.2% 7.8% 6.6% 0.5%

Corlanor label. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206143Orig1s000lbl.pdf

Corlanor® (ivabradine) Pivotal Trial: SHIFT

Center for Drug Evaluation and Research (2015). Medical Review. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206143Orig1s000MedR.pdf

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Corlanor® (ivabradine) Pivotal Trial: SHIFT

Center for Drug Evaluation and Research (2015). Medical Review. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206143Orig1s000MedR.pdf

Corlanor® (ivabradine) Pivotal Trial: SHIFT

Center for Drug Evaluation and Research (2015). Medical Review. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206143Orig1s000MedR.pdf

Corlanor® (ivabradine) Cost Analysis Cost 5mg (60): $450.00 7.5mg (60): $450.00

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Corlanor® (ivabradine) Place in Therapy ACE-I

All volume overload Class II-IV

Loop Diuretics

Persistently symptomatic AfricanAmerican,Class III-IV

Hydral-Nitrates

eGFR > 30ml/min and K < 5.0mEq/dL, Class II-IV

Aldosterone Antagonists

Sacubitril/valsartan

ARB Ivabradine

Beta Blocker

Adapted from: Yancy CW, Jessup M, Bozkurt B, 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. J Am Coll Cardiol. 2013;62(16):e147-e239. doi:10.1016/j.jacc.2013.05.019.

Digoxin Oldest compound in cardiovascular medicine still in use Applied in the treatment of heart failure and arrhythmia “The only oral inotrope that does not increase long-term mortality in chronic heart failure” …? Withering W. An account of the foxglove and some of its medical uses with practical remarks on dropsy and other diseases. In: Willins FA, Keys TE, eds. Classics of Cardiology. New York, NY: Henry Schyuman, Dover Publications; 1941; 1: 231–252. Eichhorn EJ, Gheorghiade M. Digoxin. Prog Cardiovasc Dis. 2002; 44: 251–266.

Digoxin Mortality ACE-I

All volume overload Class II-IV

Loop Diuretics

ARB

Persistently symptomatic AfricanAmerican,Class III-IV

Hydral-Nitrates

Beta Blocker

eGFR > 30ml/min and K < 5.0mEq/dL, Class II-IV

Aldosterone Antagonists

Adapted from: Yancy CW, Jessup M, Bozkurt B, 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. J Am Coll Cardiol. 2013;62(16):e147-e239. doi:10.1016/j.jacc.2013.05.019.

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Digoxin Mortality Class IIa Digoxin can be beneficial in patients with HFrEF, unless contraindicated, to decrease hospitalizations for heart failure (Level of Evidence: B)

Yancy CW, Jessup M, Bozkurt B, 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. J Am Coll Cardiol. 2013;62(16):e147-e239. doi:10.1016/j.jacc.2013.05.019.

Death and Digoxin Use in AF Patients AFFIRM study Outcome

HR (95% CI)

p-value

All-cause mortality

1.41 (1.19-1.67)

0.001

CV mortality

1.35 (1.06-1.71)

0.016

Arrhythmic mortality

1.61 (1.12-2.30)

0.009

Whitbeck MG, Charnigo RJ, Khairy P, et al. Increased mortality among patients taking digoxin--analysis from the AFFIRM study. Eur Heart J 2012: DOI:10.1093/eurheartj/ehs348. Available at: http://eurheartj.oxfordjournals.org.

Digoxin Mortality Digoxin (n=529) vs. No digoxin (n=2363) for recent-onset systolic heart failure Population

All-cause mortality

HF hospitalization

Overall cohort

1.72 (1.25-2.36)

1.05 (0.82-1.34)

On beta-blockers

1.55 (1.11-2.18)

1.08 (0.83-1.42)

Not on beta-blockers

2.49 (1.20-5.17)

0.88 (0.46-1.69)

Freeman JV, Yang J, Sung SH, et al. Effectiveness and safety of digoxin among contemporary adults with incident systolic heart failure.Circ Cardiovasc Qual Outcomes 2013; DOI:10.1161/CIRCOUTCOMES.111.000079. Available at: http://circoutcomes.ahajournals.org.

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Digoxin Mortality Vamos, M et al (2015). European Heart Journal. Risk for all-cause mortality in patients with and without digoxin Indication for digoxin

HR (95% CI)

p-value

AF

1.29 (1.21-1.39)