heart failure medications update - dcpa · heart failure medications update alga s. ramos morales,...

12/21/2015

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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

� 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.

Heart Failure

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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

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.

Heart Failure

NYHA ClassificationFunctional 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.

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.

NYHA=New York Heart Association

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Heart Failure Treatment

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.

Beta Blocker

ARB

ACE-IAll volume overload

Class II-IV

Persistently symptomatic AfricanAmerican,Class III-IV

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

Loop Diuretics

Hydral-Nitrates

Aldosterone Antagonists

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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� Reduce the risk of cardiovasculardeath and hospitalization for heartfailure in patients with chronic heartfailure (NYHA Class II-IV) andreduced ejection fraction in place ofan ACEI or ARB

FDA= U.S. Food and Drug Administration

Entresto ® (sacubitril/valsartan)FDA Indications


� Adult patients for treatment ofsymptomatic chronic heart failurewith reduced ejection fraction

EMA = European Medicines Agency

Entresto ® (sacubitril/valsartan)EMA Indication

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

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Entresto ® (sacubitril/valsartan)Mechanism of Action

Neprisylin

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� 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

Entresto ® (sacubitril/valsartan)Dosing

ACEI=angiotensin converting enzyme inhibitor; ARB=angiotensin II receptor blockerEntresto label. Retrieved from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Orig1s000lbl.pdf

� Hypersensitivity

� History of angiodema with ACEI/ARB

� Concomitant use of ACEI

� Concomitant use with aliskiren in patients with diabetes

Entresto ® (sacubitril/valsartan)Contraindications


� Angioedema

� Hypotension

� Renal impairment

� Hyperkalemia

� Severe hepatic impairment

� Lactation/Pregnancy

Entresto ® (sacubitril/valsartan)Warnings & Precautions


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Adverse ReactionsSacubitril/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 ® (sacubitril/valsartan)Adverse Reactions


Entresto ® (sacubitril/valsartan)Pharmacokinetics

Absorption

Bioavailability > 60%

Peak 0.5hr, 2hr, 1.5hr

With or without food

Distribution

Protein Binding 94-97%

0.28% of sacubitril reaches blood brain barrier

Vd 75L; 103L

Metabolism

Sacubitril is metabolized to LBQ657 by esterases

Elimination

Urine: 52-68% sacubitril; 13% valsartan

T1/2 1.4hrs;11.5hrs/9.9hrs

Pharmacokinetics


Drug Interactions

RAAS drugs

Lithium

NSAIDs

K sparring diuretic

Entresto ® (sacubitril/valsartan)Drug Interactions

RAAS=renin-angiotensin-aldosterone system;

K=potassium; NSAIDS=non-steroidal anti-

inflammatory 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




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OutcomesEnalapril(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)

Total CV Death693 (16.5) 558 (13.3) 0.80 (0.71-0.89; 0.00004)


� Cost

� NOT YET AVAILABLE

Entresto ® (sacubitril/valsartan)Cost Analysis


doi:10.1016/j.jacc.2013.05.019.

Entresto ® (sacubitril/valsartan)Place in Therapy

Beta Blocker

ARB


Class II-IV



Loop Diuretics

Hydral-Nitrates


Sacubitril/valsartan

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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 worseningheart failure in patients with stable, symptomaticchronic heart failure with left ventricular ejectionfraction ≤ 35%, who are in sinus rhythm withresting heart rate ≥ 70 beats per minute andeither are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use

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

� 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 beta-blockers

EMA = European Medicines Agency

Corlanor® (ivabradine)EMA Indication

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. 8 904-915.

� 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® (ivabradine)Dosing


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� 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® (ivabradine)Contraindications


� 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® (ivabradine)Warnings & Precautions


Corlanor® (ivabradine)Pharmacokinetics

Absorption

Bioavailability ~40%

AUC increased 20-40% with food

Distribution

Vd ~100L

Protein Binding ~70%

Metabolism

CYP3A4

Major metabolite

N-desmethylated derivative

Excretion

First pass elimination in gut and liver

Urine ~4% unchanged drug

Pharmacokinetics


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� CYP3A4 inhibitors

� CYP3A4 inducers

� Negative chronotropes

� Pacemakers: Not recommended for use with demand pacemakers set to rates ≥ 60 beats per minute

Corlanor® (ivabradine)Drug Interactions


Adverse Reactions

Ivabradine(n=3,260)

Placebo (n=3,278)

Bradycardia 10% 2.2%

Hypertension 8.9% 7.8%Atrial fibrillation 8.3% 6.6%

Phosphenes 2.8% 0.5%

Corlanor® (ivabradine)Adverse Effects


Corlanor® (ivabradine)Pivotal Trial: SHIFT


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� Cost

� 5mg (60): $450.00

� 7.5mg (60): $450.00

Corlanor® (ivabradine)Cost Analysis

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Corlanor® (ivabradine)Place in Therapy


doi:10.1016/j.jacc.2013.05.019.

Beta Blocker

ARB


Class II-IV



Loop Diuretics

Hydral-Nitrates


Sacubitril/valsartan

Ivabradine

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


doi:10.1016/j.jacc.2013.05.019.

Beta Blocker

ARB


Class II-IV



Loop Diuretics

Hydral-Nitrates


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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

Vamos M, Erath JW, Hohnloser SH. Digoxin-associated mortality: A systematic review and meta-analysis of the literature. Eur Heart J 2015; DOI:10.1093/EURHEARTJ/EHV143.

Indication for digoxin HR (95% CI) p-value

AF 1.29 (1.21-1.39) <0.01

HF 1.14 (1.06-1.22) <0.01

AF or HF 1.21 (1.07-1.38) <0.01

Drugs in Development

Drug Name Current Phase Target

C-Cure III Stem Cells/Other Cell Therapies

NeoFuse III Stem Cells/Other Cell Therapies

Aliskiren III Renin

Rivaroxaban III Coagulation Factor X

Finerenone IIb Mineralcorticoid Receptor

Eleclazine II/III Sodium Channels

Aladorian II Ryanodine Receptor (RyRs)

ARRY-797 II p38 MAP kinase (MAPK)

Vericiguat II Guanylate Cyclase (sGC)

JVS-100 IIChemokine (C-X-C motif) Ligand

12/Stromal Cell-Derived Factor 1

Neucardin II ErbB4/HER4^ HER2/neu or ErbB-2

Omecamtiv II Myosin ATPase

Perhexiline II Carnitine Palmitoyltransferase 1 (CPT1)

PL-3994 II Natriuretic Peptide Receptors

Serelaxin II Relaxin Family Peptide Receptors 1-4

Carvedilol II Beta Adrenergic Receptors

Albiglutide II GLP-1 Receptor

Vepoloxamer II Cell MembraneSagient Research Systems, Inc (2015). Congestive Heart Failure. Accessed: 12/18/2015. Retrieved from:

http://www.biomedtracker.com/IndicationReport.cfm?IndID=264

Cases

� AB is a 60y/o African-American woman with ejection fraction of 30% and NYHA III HF on: carvedilol 25mg twice daily, enalapril 20mg twice daily, spironolactone 50mg daily, and furosemide 40mg twice daily. Her current HR is 90 beats/min and has had 6 hospitalizations in the past year for CHF.

� How would you consider optimizing her treatment?

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Cases

� AB mentions she saw an interesting ad on television about a funny current and her heart failure.

� What would you consider discussing with AB in relation to this?

� Would you consider adding digoxin therapy?

Post-Assessment

� __ (T/F) Entresto® (sacubitril/valsartan) is indicated to reduce cardiovascular death and hospitalization in heart failure patients, including pregnant females.

� __ (T/F) Corlanor® (ivabradine) is the first medication in its class with FDA indication for the treatment of chronic heart failure and stable angina in adults.

� __ (T/F) Studies have shown that digoxin has a significant difference in the risk of hospitalization for heart failure patients versus placebo.

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References

1. 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

2. 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.

3. Sagient Research Systems, Inc (2015). Corlanor. Accessed on 11/20/2015. Retrieved from: http://www.biomedtracker.com/DrugReport.cfm?DrugID=17290

4. Sagient Research Systems, Inc (2015). Entresto. Accessed on 11/20/2015. Retrieved from: http://www.biomedtracker.com/DrugReport.cfm?DrugID=11089

5. 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.

6. Swedberg, Karl et al (2010). Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. The Lancet , Volume 376 , Issue 9744 , 875 - 885 .Retrieved from: http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736%2810%2961198-1.pdf

7. Akshay S. Desai, John J.V. McMurray, Milton Packer, Karl Swedberg, Jean L. Rouleau, Fabian Chen, Jianjian Gong, Adel R. Rizkala, Abdel Brahimi, Brian Claggett, Peter V. Finn, Loren Howard Hartley, Jiankang Liu, Martin Lefkowitz, Victor Shi, Michael R. Zile, Scott D. Solomon (2015). Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients. European Heart Journal Aug 2015, 36 (30) 1990-1997; DOI: 10.1093/eurheartj/ehv186. Retrieved from: http://eurheartj.oxfordjournals.org/content/ehj/36/30/1990.full.pdf

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

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

10. 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.

11. Eichhorn EJ, Gheorghiade M. Digoxin. Prog Cardiovasc Dis. 2002; 44: 251–266.

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

13. 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.

heart failure medications update - dcpa · heart failure medications update alga s. ramos morales,...

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