do new drugs signify a paradigm shift? - mayo clinic pgr hf 10.18 final.pdf2016 acc/aha/hfsa focused...
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©2016 MFMER | slide-1
Do New Drugs SIGNIFY a PARADIGM SHIFT? Medication Updates in Heart Failure
Melissa Laub, PharmDPGY1 Pharmacy ResidentPharmacy Grand RoundsOctober 18, 2016
©2016 MFMER | slide-2
Objectives• Explain the impact of heart failure with reduced
ejection fraction in the United States. • Review the 2016 ACC/AHA/HFSA guideline
updates on new pharmacological therapy for heart failure.
• Describe the literature supporting guideline recommendations for the new medication classes (angiotensin receptor-neprilysininhibitor and If current inhibitor).
©2016 MFMER | slide-3
Heart Failure Disease Classifications
NYHA Functional Classification
Class Symptoms
I No limitation of physical activity.
II Slight limitation of physical activity. Comfortable at rest.
III Marked limitation of physical activity. Comfortable at rest.
IV Unable to carry out physical activity without discomfort. Symptoms at rest.
ACCF/AHA StagesStage Description
A At risk for HF but without structural heart disease or symptoms of HF.
B Structural heart disease but withoutsigns or symptoms of HF.
C Structural heart disease with prior orcurrent symptoms of HF.
D Refractory HF requiring specialized interventions.
Yancy CW. Circulation. Circulation. 2013 Oct 15;128(16):e240-327.ACCF: American College of Cardiology Foundation AHA: American Heart AssociationNYHA: New York Heart AssociationHF: Heart failure
• Heart failure with reduced ejection fraction (HFrEF): Ejection fraction < 40%
• Heart failure with preserved ejection fraction (HFpEF): Ejection fraction > 50%
©2016 MFMER | slide-4
QuestionIt is estimated what percentage of people with heart failure will die within 5 years of diagnosis?A. 10B. 30C. 50D. 70
©2016 MFMER | slide-5
Impact of Heart Failure
• 50% of people die within 5 years of diagnosis
• Lifetime risk in adults > 40 years old is 20%
• More than 14,500 heart failure patients receive care at Mayo Clinic, Rochester each year
Graphic from: http://CDC.gov.Mozaffarian D. Circulation. 2016 Jan 26;133(4):e38-360.
http://mayoclinic.org.
©2016 MFMER | slide-6
Eras of Heart Failure Pharmacotherapy
ACE-I: Angiotensin converting enzyme inhibitor, ARB: Angiotensin receptor blocker, -B: Beta blocker, Ald antag: Aldosterone antagonistRCT: Randomized control trial
Graphic modified from: Mentz, et al. Heart Failure, a Companion to Braunwald’s Heart Disease. 2014.
Fonarow GC. Am Heart J. 2011 Jun;161(6):1024-30.
0% -
10% -
20% -
30% -
40% -
50% -
60% -
70% -
Rel
ativ
e R
isk
Red
uctio
n (%
) in
Mor
talit
y:
Land
mar
k R
CTs
ACE-I or ARB
-B
Aldost.Antag.
ACE-I or ARB+
BB+
Aldost. Antag.
CONSENSUS, SOLVD, Val-HeFT
CIBIS, MERIT-HF,CORPERNICUS RALES,
EMPHASIS-HF
?
New Agents
©2016 MFMER | slide-7
Patient Case #1 Mr. GH• 61 year old Caucasian male diagnosed with HFrEF in 2011
• Admitted for urinary tract infection, but also has worsening edema and dyspnea
• Stage C Class III
• Home medications:• Lisinopril 40 mg daily• Metoprolol succinate 200 mg daily• Eplerenone 25 mg daily• Torsemide 10 mg daily
• Lab values:• EF: 30%• HR: 65 bpm• BP: 110/60 mmHg• SCr: 1.3 mg/dL• Potassium: 4.8 mEq/L
How can we advance his heart failure therapy?
©2016 MFMER | slide-8
Standards of Care: 2013 ACCF/AHA Guideline
Digoxin
Hydralazine + Isosorbide Dinitrate
Aldosterone Antagonist
ACE-I or ARB +-Blocker
Persistently symptomatic
NYHA class II-IV (CrCl >30ml/min +
<5.0 mEq/dL)
All HFrEF Stage C, Class I-IV
African Americans NYHA class III-IV
Loop diuretics(Symptom
management)
Yancy CW. Circulation. 2013 Oct 15;128(16):e240-327.ACCF: American College of Cardiology Foundation AHA: American Heart AssociationACE-I: Angiotensin converting enzyme inhibitorARB: Angiotensin receptor blocker
©2016 MFMER | slide-9
ACC: American College of CardiologyAHA: American Heart Association, HFSA: Heart Failure Society of AmericaACE-I: Angiotensin converting enzyme inhibitorARB: Angiotensin receptor blocker
Digoxin
If Current Inhibitor
Hydralazine + Isosorbide Dinitrate
Aldosterone Antagonist
ACE-I, ARB, or ARNI +-Blocker
Persistently symptomatic
NYHA class II-IV (CrCl >30ml/min +
<5.0 mEq/dL)
All HFrEF Stage C, Class I-IV
African Americans NYHA class III-IV
2016 ACC/AHA/HFSA Focused Update
NYHA class II-III (NSR, resting HR >70 bpm)
ARNI: Angiotensin receptor-neprilysin inhibitor
Loop diuretics(Symptom
management)
Yancy CW. J Am Coll Cardiol. 2016 Sep 27;68(13):1476-88.
©2016 MFMER | slide-10
ARNI: Sacubitril-ValsartanRenin-Angiotensin-Aldosterone System Natriuretic Peptide System
Angiotensin I
Angiotensin II
Angiotensin II Type 1
Receptor
• Vasoconstriction• Increased aldosterone• Increased sympathetic tone• Cardiac fibrosis
Valsartan Sacubitril
Pro-BNP
BNP: B-type natriuretic peptideARNI: Angiotensin receptor-neprilysin inhibitor
BNP
Heart Failure
NT-pro-BNP
Neprilysin
Inactive fragments
• Vasodilation• Decreased aldosterone• Decreased sympathetic tone• Decreased cardiac fibrosis
Graphic adapted from Langenickel TH. Drug Discovery Today. 2012.
Neprilysin
Inactive fragments
©2016 MFMER | slide-11
QuestionSacubitril-valsartan has been shown to improve which of the following outcomes in patients with HFrEF?A. Hospitalization rates for HFB. Death from cardiovascular causesC. A & B independentlyD. None of the above
©2016 MFMER | slide-12
PARADIGM-HF Design• RCT of 8,442 patients NYHA class II-IV HF with EF < 40%
and elevated BNP
• Randomized to
Baseline DemographicsAge 64 years oldGender 79% maleRace 66% CaucasianNYHA Class II 72%NYHA Class III 24%Systolic BP 120 + 15 mmHg
Baseline Therapy Continued-Blocker 93%
Diuretics 80%
Aldosterone Antagonist 55%
ICD 15%
Sacubitril-valsartan 200 mg BID
Enalapril 10 mg BID
Mcmurray JJ. N Engl J Med 2014; 371:993-1004..RCT: Randomized control trialICD: Implantable cardioverter difibrilator
©2016 MFMER | slide-13
PARADIGM-HF ResultsEfficacy
All p values <0.0001
Mcmurray JJ. N Engl J Med 2014; 371:993-1004..
0%
5%
10%
15%
20%
25%
30%
Composite** CV death** HF hospitalization**
21.8%
26.5%
13.3%16.5%
12.8%
15.8%
Sacubitril-valsartan (N=4187)Enalapril (N=4212)
Composite (CV death +
HF hospitalization)
CV death HF hospitalization
©2016 MFMER | slide-14
PARADIGM-HF Results
All p values <0.01
Safety
0%
2%
4%
6%
8%
10%
12%
14%
16%
Symptomatichypotension**
SCr > 2.5 mg/dL** Serum K+ > 6mmol/L**
Cough**
9.2%
3.3%4.5% 4.3%
5.6%
11.3%
14.3%
Sacubitril-valsartan (N=4187)Enalapril (N=4212)
14%
Mcmurray JJ. N Engl J Med 2014; 371:993-1004..
Symptomatic hypotension
SCr >2.5 mg/dL Serum K + >6mmol/L
Cough
©2016 MFMER | slide-15
Additional Support• Compared to enalapril, sacubitril-valsartan:
• Decreased 30-day hospital readmission rates for any cause
• Prevented clinical progression of surviving patients
• No difference in effectiveness regardless of:• Ejection fraction (5%-42%)• Background therapy
Packer M. Circulation. 2015 Jan 6;131(1):54-61. Desai AS. J Am Coll Cardiol. 2016 Jul 19;68(3):241-8.Soloman SD. Circ Heart Failure. 2016 Mar;9(3):e002744.
Okumura N. Circ Heart Fail. 2016;9:e003212.
©2016 MFMER | slide-16
Patient Case #1Mr. GH
• 61 year old Caucasian male diagnosed with HFrEF in 2011 admitted for urinary tract infection. Now stable and being discharged.
• Home medications:• Lisinopril 40 mg daily• Metoprolol succinate 200 mg daily• Eplerenone 25 mg daily• Torsemide 10 mg daily
Cardiology recommended to start sacubitril-valsartan after discharge and follow up with his primary care doctor. What is your initiation recommendation?
©2016 MFMER | slide-17
Sacubitril-Valsartan Dosing PearlsDescription DoseStarting Dose 49/51 mg (100 mg) BIDTarget/Max Dose
Adjusted Starting Dose• ACE-I/ARB naïve or on equivalent of < 10
mg/day enalapril or < 160 mg/day valsartan• CrCl < 30 ml/min• Moderate hepatic impairment
Entresto [package insert]. Novartis 2015.Senni M. Europ J Heart Fail. 2016 Sep;18(9):1193-202.
©2016 MFMER | slide-18
Sacubitril-Valsartan Dosing PearlsDescription DoseStarting Dose 49/51 mg (100 mg) BIDTarget/Max Dose 97/103 mg (200 mg) BID
Adjusted Starting Dose• ACE-I/ARB naïve or on equivalent of < 10
mg/day enalapril or < 160 mg/day valsartan• CrCl < 30 ml/min• Moderate hepatic impairment
Entresto [package insert]. Novartis 2015.Senni M. Europ J Heart Fail. 2016 Sep;18(9):1193-202.
©2016 MFMER | slide-19
Sacubitril-Valsartan Dosing PearlsDescription DoseStarting Dose 49/51 mg (100 mg) BIDTarget/Max Dose 97/103 mg (200 mg) BID
Adjusted Starting Dose• ACE-I/ARB naïve or on equivalent of < 10
mg/day enalapril or < 160 mg/day valsartan• CrCl < 30 ml/min• Moderate hepatic impairment
24/26 mg (50 mg) BID
Entresto [package insert]. Novartis 2015.Senni M. Europ J Heart Fail. 2016 Sep;18(9):1193-202.
©2016 MFMER | slide-20
Sacubitril-Valsartan Dosing Pearls
• Titration• Conservative: low dose x 2 weeks medium dose x 3
weeks target dose • Condensed: medium dose x 2 weeks target dose
• All patients:• At least 36 hour washout period between ACE-I therapy
Description DoseStarting Dose 49/51 mg (100 mg) BIDTarget/Max Dose 97/103 mg (200 mg) BID
Adjusted Starting Dose• ACE-I/ARB naïve or on equivalent of < 10
mg/day enalapril or < 160 mg/day valsartan• CrCl < 30 ml/min• Moderate hepatic impairment
24/26 mg (50 mg) BID
Entresto [package insert]. Novartis 2015.Senni M. Europ J Heart Fail. 2016 Sep;18(9):1193-202.
©2016 MFMER | slide-21
Question• Following discontinuation of his lisinopril, which
dose of sacubitril-valsartan should Mr. GH be started on?
A. 24/26 mg BIDB. 49/51 mg BIDC. 97/103 mg BID
©2016 MFMER | slide-22
Patient Case #1 - Three Months LaterMr. GH• 61 year old Caucasian male diagnosed with HFrEF in 2011 admitted for
acute decompensated heart failure
• Stated he never started sacubitril-valsartan
• Home medications:• Lisinopril 40 mg daily• Metoprolol succinate 200 mg daily• Eplerenone 25 mg daily• Torsemide 10 mg daily
• Lab values:• EF: 25%• HR: 60 bpm• BP: 95/50 mmHg
Why hasn’t sacubitril-valsartan gained more popularity?
©2016 MFMER | slide-23
PARADIGM-HFLimitations & Controversies
• Comparative dose of enalapril = 10 mg BID• Extended run-in phase criteria• Under-representation of certain ethnicities• Under-representation of advanced disease• Unknown long-term effects
©2016 MFMER | slide-24
Summary: Sacubitril-Valsartan• Reduces risk of CV death, symptom
progression, and hospitalization in HFrEF• Promising new class in HF despite slow
adoption• Eligible Patients:
• Established disease already on background therapy
• Newly diagnosed• Not for decompensated patients
©2016 MFMER | slide-25
Patient Case #2 Mrs. BC• 53 year old Caucasian female diagnosed with HFrEF in 2009
• Presents to clinic with worsening sleep orthopnea
• Stage C Class III
• Home medications:• Lisinopril 20 mg daily• Carvedilol 6.25 mg twice daily• Spironolactone 50 mg daily• Furosemide 60 mg daily• Digoxin 250 mcg daily
• Lab values:• EF: 33%• HR: 75 bpm, NSR• BP: 95/57 mmHg• SCr: 1.4 mg/dL• Potassium: 5.0 mEq/L
How can we advance her heart failure pharmacotherapy?
©2016 MFMER | slide-26
Digoxin
If Current Inhibitor
Hydralazine + Isosorbide Dinitrate
Aldosterone Antagonist
ACE-I, ARB, or ARNI +-Blocker
Persistently symptomatic
NYHA class II-IV (CrCl >30ml/min +
<5.0 mEq/dL)
All HFrEF Stage C, Class I-IV
African Americans NYHA class III-IV
2016 ACC/AHA/HFSA Focused Update
NYHA class II-III (NSR, resting HR >70 bpm)
ARNI: Angiotensin receptor-neprilysin inhibitor
Loop diuretics(Symptom
management)
Yancy CW. J Am Coll Cardiol. 2016 Sep 27;68(13):1476-88..ACC: American College of CardiologyAHA: American Heart Association, HFSA: Heart Failure Society of AmericaACE-I: Angiotensin converting enzyme inhibitorARB: Angiotensin receptor blocker
©2016 MFMER | slide-27
If Current Inhibitor: Ivabradine
HCN: Hyperpolarization-activated cyclic nucleotide-gated channelSA node: Sinoatrial node
HCN Channel
Na+K+
Intracellular
Extracellular
Pacemaker cell in SA node
If Current
©2016 MFMER | slide-28
If Current Inhibitor: Ivabradine
HCN: Hyperpolarization-activated cyclic nucleotide-gated channelSA node: Sinoatrial node
HCN Channel
Na+K+
Intracellular
Extracellular
Pacemaker cell in SA node
Ivabradine
©2016 MFMER | slide-29
QuestionIvabradine has been shown to improve which of the following outcomes in certain patients with HFrEF?A. Hospitalization rates for HFB. Death from cardiovascular causesC. A & B independentlyD. None of the above
©2016 MFMER | slide-30
BEAUTIFUL Trial• RCT 12,473 patients with coronary artery disease and EF <40%
• Randomized to
• Did not meet significance for composite endpoint
• Did reduce hospitalizations for myocardial infarction in subgroup patients with heart rate > 70 bpm
Fox K. Lancet. 2008 Sep 6;372(9641):807-16.
Ivabradine (titrated to HR of 50-60 bpm)
Placebo
©2016 MFMER | slide-31
SHIFT Design• RCT of 6,558 patients EF < 35%, in NSR with resting HR >70 bpm on β-blocker
• Randomized to
Swedberg K. Lancet. 2010 Sep 11;376(9744):875-85.EF: Ejection fractionCV: CardiovascularNSR: Normal sinus rhythm, HR: heart rate
Baseline DemographicsAge 60 years oldGender 76% maleEthnicity 89% CaucasianNYHA Class II 49%NYHA Class III 50%Heart Rate 80 + 10 bpm
Baseline Therapy Continued-Blocker 89%
ACE-I 79%
ARB 14%
Diuretics 84%
Aldosterone Antagonist 61%
Ivabradine (titrated to HR of 50-60 bpm)
Placebo
©2016 MFMER | slide-32
SHIFT ResultsMean heart rate during the study
90 -
80 -
70 -
60 -
50 -
0 0 2 wks 1 4 8 12 16 20 24 28 32
64
7580
67
75
Follow-up (months)
Hea
rt ra
te (b
pm)
Ivabradine (N=3241)Placebo (N=3264)
Swedberg K. Lancet. 2010 Sep 11;376(9744):875-85.
©2016 MFMER | slide-33
SHIFT Results
CV: CardiovascularHF: Heart failure
Efficacy
0%
5%
10%
15%
20%
25%
30%
35%
Composite** CV death HF hospitalization**
24%
29%
14% 15% 16%
21%
Ivabradine (N=3241)Placebo (N=3264)
**p <0.05
Composite(CV death +
HF hospitalization)**
Swedberg K. Lancet. 2010 Sep 11;376(9744):875-85.
©2016 MFMER | slide-34
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
10%
Symptomatic bradycardia** Asymptomatic bradycardia** Blurred vision** Atrial fibrillation**
1%
6%
1% 1% <1%
9%
8%
Symptomaticbradycardia
SHIFT ResultsSafety
Ivabradine (N=3241)Placebo (N=3264)
All p values <0.05
Asymptomaticbradycardia
5%
Swedberg K. Lancet. 2010 Sep 11;376(9744):875-85.
Blurred vision Atrial fibrillation
©2016 MFMER | slide-35
Patient Case #2Mrs. BC• 53 year old Caucasian female diagnosed with HFrEF in 2009
• Presents to clinic with worsening sleep orthopnea
• Home medications:• Lisinopril 20 mg daily• Carvedilol 6.25 mg twice daily• Spironolactone 50 mg daily• Furosemide 60 mg daily• Digoxin 250 mcg daily
• Lab values:• HR: 75 bpm, NSR• BP: 95/57 mmHg
How do we start ivabradine?
©2016 MFMER | slide-36
Ivabradine Dosing Pearls
Heart Rate Dose Adjustment> 60 bpm Increase by 2.5 mg BID50-60 bpm Maintain< 50 bpm or symptoms of bradycardia
Decrease by 2.5 mg BID or discontinue
• Starting dose: 5 mg BID with meals• Maximum dose: 7.5 mg BID
Corlanor [package insert]. Amgen 2015.Swedberg K. Lancet. 2010 Sep 11;376(9744):875-85.
©2016 MFMER | slide-37
Summary: Ivabradine• Reduces risk of hospitalization in certain
HFrEF patients• Potential add on for stable HFrEF patients
with:• Resting heart rate > 70 bpm and in NSR
AND• Maximized or contraindication to
beta-blocker therapyAND
• Intolerance or contraindication to digoxin
©2016 MFMER | slide-38
Ivabradine: Beyond Heart Failure
Tardif J. Eur Heart J 2005. 2005 Dec;26(23):2529-36.Cappato R. J Am Coll Cardiol. 2012 Oct 9;60(15):1323-9.
Fox K. N Engl J Med. 2014 Sep 18;371(12):1091-9.
Trial Disease State Comparator Result
INITIATIVE Stable angina Atenolol Non-inferior
Cappato et al. Inappropriate sinus tachycardia Placebo Improved
symptoms
SIGNIFY Stable CAD withoutHF Placebo Did not improve
outcomes
CAD: Coronary artery disease
©2016 MFMER | slide-39
Future Directions
http://www.clinicaltrials.gov
• PARAGON-HF: Sacubitril-valsartan vs. valsartan (Mortality) NCT01920711
• Digoxin vs. ivabradine in HFpEF (Symptoms)NCT01796093
HFpEF
• Ivabradine + -blockers in patients with atrial fibrillationPreliminary results: International Journal of Cardiology
Atrial Fibrillation
• Sacubitril-valsartan vs. olmesartan for essential hypertension NCT01785472
• Sacubitril-valsartan vs. placebo in patients with essential hypertension NCT01193101
Hypertension
HFpEF: Heart failure with preserved ejection fraction
©2016 MFMER | slide-40
Questions & Discussion
©2016 MFMER | slide-41
Sacubitril/Valsartan: Cost Effectiveness• Estimated price = $380.00 per month• Added approximately 0.6 QALYs compared to
enalapril• Estimated $50,000 per QALY• Estimated 9% discount would keep within
budget impact threshold• Similar to other popular brand name drugs
• Advair $320.00• Crestor $300.00
QALY: Quality adjusted life year Ollendorf DA. JAMA 2016. Sandhu. Annals of Int. Med 2016.
Gaziano TA. JAMA Card 2016.
©2016 MFMER | slide-42
Ivabradine: Cost Effectiveness• Estimated price= $375.00 per month• Added approximately 0.24 QALYs compared to
placebo• Estimated $8,594 savings over 10 years with
private insurance based on single cost-effectiveness trial
QALY: Quality adjusted life year Kansal AR. J Am Heart Assoc. 2016 May 6;5(5).