updates in heart failure (hf) 2016: acc / aha and … update - mcbride.pdf1 updates in heart failure...
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Updates in Heart Failure (HF) 2016:
ACC / AHA and ESC
Patrick McBride, MD, MPH
Professor of Medicine & Family Medicine, UW
School of Medicine and Public Health
Special thanks to:
Clyde W. Yancy, MD, MSc
Professor of Medicine, Chief, Cardiology
Northwestern University, Deputy Editor, JAMA Cardiology
Patrick E. McBride, MD, MPH
Professor of Medicine and Family Medicine
Associate Director, Preventive Cardiology
Interim, Associate Dean for Faculty Affairs
Senior Research Director, Research Networks
ICTR
I have no conflicts of interest to disclose
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Objectives:The diagnosis and treatment of
HFrEF*
New Epidemiology 2016
•Prevention
•New Guidelines
•New Therapies
•New Phenotype
*HFrEF = heart failure reduced ejection
fraction
Copyright © 2016 American Medical Association. All rights reserved.
From: A Contemporary Appraisal of the Heart Failure Epide mic in Olmsted County, Minnesota, 2000 to 2010
JAMA Intern Med. 2015;175(6):996-1004. doi:10.1001/jamainternmed.2015.0924
Temporal Trends in Heart Failure Incidence Rates Overall and by Reduced or Preserved Ejection Fraction Among Women and Men in Olmsted County, Minnesota, 2000 to 2010Yearly rates (smoothed using 3-year moving average) per 100 000 persons have been standardized by the direct method to the age distribution of the US population in 2010. HFpEF indicates heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.
Figure Legend:
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A Contemporary Appraisal of the HF Epidemic
• Age and sex-specific incidence of heart failure has declined
− 315/100,000 to 219/100,000
• Rate reduction of 37.5%
• Incidence decline was greater for HFrEF – 45.1% vs. HFpEF -27.9%
• Risk for CV death was lower for HFpEF but the same for non-CV
death
• Hospitalizations have increased 34%
• Most hospitalizations, 63%, were due to non-cardiovascular
causes
• Thus today’s epidemic of heart failure is defined by a marked
increase in hospitalizations, predominance of non-CV death rate,
and persistence and predominance of HFpEF
Roger VL et al. JAMA Intern Med. 2015; April 20.
Stages, Phenotypes and Treatment of HF
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The treatment of HFrEF;
2016- Update
New Epidemiology
•Prevention
•New Guidelines
•New Therapies
•New Phenotype
Survival (years)
Ammar et al. Circulation 2007; 115:1563
Prevalence and prognostic significance of HF Stages
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Comparison of short-term vs lifetime cumulative risks of CHF for men and
women at selected index ages
FRAMINGHAM Donald M. Lloyd-Jones et al Circulation 2002;106:3068
ONE IN FIVE INDIVIDUALS WILL DEVELOP HF
Lifetime risk for HF; indexed to blood pressure & sex
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STAGE A HF:
Hypertension as a Risk Factor for HF in African Ame ricans
Bibbins-Domingo et al. N Engl J Med. 360(12):1179-1190
Incidence of heart failure in young Americans
Bibbins-Domingo et al. New England Journal of Medicine. 360(12):1179-1190
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SPRINT Hypertension Trial
• Study Design: Randomized Single Blind
Primary Outcome Measures: First occurrence of a
myocardial infarction (MI), acute coronary
syndrome (ACS), stroke, heart failure (HF), or CVD
death [ Time Frame: 6 years ]
Secondary Outcome Measures: All-cause mortality ;
Development of end stage renal disease (ESRD),
Dementia, Decline in cognitive function, Small
vessel cerebral ischemic disease
• Estimated Enrollment: 9250
Increased CV risk as defined by SPRINT:
•clinical or subclinical cardiovascular disease other than stroke;
•chronic kidney disease, excluding polycystic kidney disease, with an estimated glomerularfiltration rate (eGFR) of 20 to less than 60 ml per minute per 1.73 m 2 of body-surface area, calculated with the use of the four-variable Modification of Diet in Renal Disease equation;
• a 10-year risk of cardiovascular disease of 15% or greater on the basis of the Framingham risk score;
•or an age of 75 years or older
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Systolic Blood Pressure in the Two Treatment Groups over the Course of the Trial
The SPRINT Research Group. N Engl J Med 2015;373:21 03-2116
Primary Outcome and Death from Any Cause
The SPRINT Research Group. N Engl J Med 2015;373:2103-2116
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Primary and Secondary Outcomes and Renal Outcomes
TheSPRINT Research Group. N Engl J Med 2015;373:2103 -2116
38%RR
The diagnosis and treatmentof HFrEF
•New Epidemiology
•Prevention
New Guidelines
•New Therapies
•New Phenotype
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Stages, Phenotypes and Treatment of HF
Yancy, C. Jessup M, Bozkurt B. et al. JACC 2013
Pharmacologic Treatment for Stage C HFrEF
Yancy, C et al. JACC 2013
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New Guidelines Have Emerged- 2016
RAASi in Heart Failure and Post-MI LV Dysfunction
Post-MI
Low EF
Mild-Mod CHF
Low EF
CHF
Severe HF
CHF
Preserved EF
ACEi1 AIRE
SAVE
SOLVD CONSENSUS PEP-CHF
(perindopril)
MRAEPHESUS1
(eplerenone)
EMPHASIS1
(eplerenone)
RALES1
(spironolactone)
TOPCAT2
(spironolactone)
ARB1 OPTIMAAL
VALIANT
ELITE-II
HEALL
VAL-HeFT
CHARM
CHARM-Preserved
I-PRESERVE
ARNI3 PARADIGM-HF
(LCZ-696)
1. Mentz RJ, et al. Int J Cardiol. 2013:167:1677-1687. 2. Pitt B, et al. N Engl J Med. 2014;370(15):1383-1392. 3. McMurray JJV, et al. N Engl J Med 2014;371:993-1004.
RAASi=renin-angiotensin-aldosterone inhibitor; MI=myocardial infarction; EF: ejection fraction; CHF=chronic heart failure; ACEi=angiotensin-converting enzyme inhibitor; MRA=mineralocorticoid receptor antagonist; ARB=angiotensin II receptor blocker; ARNI=angiotensin receptor-neprilysin inhibitor.
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RAAS inhibition- 2016
ACE-I & ARB - 2016
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ARNI 2016
ARNI – (Harm) 2016
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Ivabradine 2016
ESC HF Guidelines 2016
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ESC HFrEF Treatment Algorithm
The treatment of HFrEF: 2016 - Update
•New Epidemiology•Prevention•New Guidelines
New Therapies•New Phenotype
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Endogenousvasoactive peptides
(natriuretic peptides, adrenomedullin,bradykinin, substance P,
calcitonin gene-related peptide)
Inactive metabolites
Neurohormonal activation
Vascular tone
Cardiac fibrosis, hypertrophy
Na+ retention
Neprilysin Neprilysininhibition
McMurray JJV, et al. N Engl J Med. 2014;371:993-1004 .
Effects of Neprilysin Inhibition in Heart Failure
Sac/Val = Sacubitril/Valsartan. McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.
Number needed to treat = 21
PARADIGM-HF: Primary Endpoint of CV Death or Heart Failure Hospitalization
Number at RiskSac/ValEnalapril
0 180 540 900Days since Randomization
0
0.1
0.2
0.4
0.6
1.0
Enalapril1117 events (26.5%)
Sac/Val914 events (21.8%)
1260
Cum
ulat
ive
Pro
babi
lity
41874212
36633579
22572123
15441488
896853
360 720 1080
0.3
0.5
39223883
30182922
249236
HR 0.80 (95% CI, 0.73–0.87), p<0.001
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Sac/Val(n=4187)
Enalapril(n=4212)
Hazard Ratio(95% CI)
p-Value
Primary endpoint914
(21.8%)1117
(26.5%)0.80
(0.73–0.87)<0.001
Cardiovascular death
558(13.3%)
693(16.5%)
0.80(0.71–0.89)
<0.001
Hospitalization for heart failure
537(12.8%)
658(15.6%)
0.79(0.71–0.89)
<0.001
Sac/Val = Sacubitril/Valsartan.
McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.
PARADIGM-HF: Effect of Sac/Val vs. Enalapril on the Primary Endpoint and Its Components
McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.
Sac/Val vs. Enalapril on Primary Endpoint and on CV Death by Subgroups
All PatientsAge
<65 years≥65 years
SexMaleFemale
NYHA ClassI or IIIII or IV
Estimated GFR<60 mL/min/1.73 m2
≥60 mL/min/1.73 m2
Ejection fraction≤35%>35%
NT-proBNP≤Median>Median
HypertensionNoYes
Prior use of ACE inhibitorNoYes
Prior use of aldosterone antagonistNoYes
Prior hospitalization for heart failureNoYes
Death from Cardiovascular Causes
1.70.3
Sac/Val Better
Primary EndpointHazard Ratio
(95% CI)p-Value forInteraction
Hazard Ratio(95% CI)
p-Value forInteractionNo.
Sac/Val Enalapril
1.51.31.10.90.70.5
Enalapril Better
1.70.3
Sac/Val Better
1.51.31.10.90.70.5
Enalapril Better
4212
21682044
3259953
31301076
15202692
3722489
21162087
12412971
9463266
18122400
15452667
4187
21112076
3308879
31871002
15412646
3715472
20792103
12182969
9213266
19162271
15802607
0.47
0.63
0.03
0.91
0.36
0.16
0.87
0.09
0.10
0.10
0.70
0.92
0.76
0.73
0.36
0.33
0.14
0.06
0.32
0.19
Subgroup
18
Sac/Val(n=4187)
Enalapril(n=4212)
p-Value
Prospectively identified adverse events
Symptomatic hypotension 14.0% 9.2% <0.001
Serum potassium > 6.0 mmol/L 4.3% 5.6% 0.007
Serum creatinine ≥ 2.5 mg/dL 3.3% 4.5% 0.007
Cough 11.3% 14.3% <0.001
Discontinuation for adverse event 10.7% 12.3% 0.03
Discontinuation for hypotension 0.9% 0.7% 0.38
Discontinuation for hyperkalemia 0.3% 0.4% 0.56
Discontinuation for renal impairment 0.7% 1.4% 0.002
Angioedema (adjudicated)
Medications, no hospitalization 6 (0.1%) 4 (0.1%) 0.52
Hospitalized; no airway compromise 3 (0.1%) 1 (<0.1%) 0.31
Airway compromise 0 0 —
McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.
PARADIGM-HF: Adverse Events
New FDA-Approved Sacubitril / Valsartan
Sacubitril/ValsartanBrand name Entresto
Indication
The fixed-dose combination of the neprilysin inhibi tor sacubitriland the ARB valsartan is indicated to reduce the ri sk of CV death and HF hospitalization in patients with HF with red uced ejection fraction.
DosageStart with 49/51 mg twice daily. Double the dose af ter 2–4 weeks as tolerated to maintenance dose of 97/103 mg twice daily.
Renal/hepatic impairment
For patients not currently taking an ACEI or ARB, o r for those with severe renal impairment (eGFR <30 mL/min/1.73 m2) or moderate hepatic impairment, start with 24/26 mg tw ice daily.
Switching from an ACE inhibitor
Stop ACE inhibitor for 36 hours before starting tre atment.
ContraindicationsHistory of angioedema related to previous ACE inhib itor or ARB, concomitant use of ACE inhibitors, concomitant use of aliskiren in patients with diabetes. WARNING – pregnancy, hype rkalemia.
Side effectsHypotension, hyperkalemia, cough, dizziness, renal failure, and angioedema (0.5% Sac/Val vs. 0.2% Enalapril).
http://www.pdr.net/full-prescribing-information/ent resto?druglabelid=3756. Accessed October 20, 2015.
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Practical Points on Use of Sacubitril / Valsartan
• Starting dose is 24 / 26 mg twice daily, unless patient is currently tolerating full dose ACEI or ARB in which case start 49 / 51 mg twice daily
• Target dose is 97 / 103 mg twice daily
• After 2 - 4 weeks up-titrate to next dose with ultimate goal to achieve target dose
• Monitor SBP, renal function and K as you would with ACEI or ARB use
• Space out dosing from other vasoactive medications if needed
• Adjust diuretics doses based on volume status
Ivabradine• Acts by inhibiting the If
channel, present in the cardiac SA node
• Reduces elevated HR
• Evaluated as treatment of HFrEF who have a resting HR of at least 70 beats per minute, in sinus rhythm, and who are also taking the highest tolerable dose of a beta blocker
DiFrancesco D. Curr Med Res Opin. 2005;21:1115-1122 .
SA node
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SHIFT Study: Primary Endpoint of CV Death or Hospitalization for Worsening HF
Swedberg K, et al. Lancet. 2010;376:875-885.
0 12 18 24 30
40
10
0
Months
20
30
6
Ivabradine (n=3241)
Placebo (n=3264)
Pat
ient
s w
ithP
rimar
y E
ndpo
int (
%) −18%
Placebo937 events (29%)
Ivabradine793 events (24%)
HR 0.82 (95% CI, 0.75–0.90) p<0.0001 ARR = 5%, NNT = 20
SHIFT Study: Effect of Ivabradine on Outcomes
EndpointIvabradine(n=3241)
Placebo(n=3264)
HR p-Value
Primary endpoint 24% 29% 0.82 <0.0001
All-cause mortality 16% 17% 0.90 0.092
Death from HF 3% 5% 0.74 0.014
All-cause hospitalization 38% 42% 0.89 0.003
Any CV hospitalization 30% 34% 0.85 0.0002
CV death, hospitalization for worsening HF, or hospitalization for non-fatal MI
25% 30% 0.82 <0.0001
Swedberg K, et al. Lancet. 2010;376:875-885 .
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New FDA-Approved IvabradineIvabradine
Brand name Corlanor
Indication
To reduce the risk of hospitalization for worsening HF in patients with stable, symptomatic chronic HF with LVEF ≤35% who are in sinus rhythm with resting HR ≥70 bpm and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use.
Dosage
Start with 5 mg twice daily. After 2 weeks of treat ment, adjust dose based on HR. Max is 7.5 mg twice daily. In pat ients with conduction defects or in whom bradycardia could lea d to hemodynamic compromise, start with 2.5 mg twice dai ly.
Contraindications
Acute decompensated HF; BP <90/50 mmHg; sick sinus syndrome or third-degree AV block, unless a functio ning demand pacemaker is present; resting HR <60 bpm prior to t reatment; severe hepatic impairment; pacemaker dependence. WA RNING –fetal toxicity.
Side effectsOccurring in ≥1% of patients are bradycardia, hypertension, atria l fibrillation, and luminous phenomena (phosphenes).
http://www.pdr.net/full-prescribing-information/cor lanor?druglabelid=3713. Accessed October 20, 2015.
Practical Use of Ivabradine• Starting dose is 5 mg twice daily
• Target HR is 50 - 60 bpm
• After 2 weeks:
− If HR >60 bpm: Increase dose to 7.5 mg twice daily (Max dose)
− If HR 50 - 60 bpm: Maintain initial dose
− If HR <50 bpm or symptomatic bradycardia: Lower dose to 2.5 mg twice daily
− If HR <50 bpm or symptomatic bradycardia and dose is 2.5 mg twice daily: Discontinue
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Pharmacologic Treatment for Stage C HFrEF
? Valsartan/Sacubutril? Ivabradine
Strategies:Disease ManagementRemote PA monitoringProcess ImprovementPatient EducationFrailty AssessmentPalliative CareGenetic Counseling
Date of download: 7/11/2016Copyright © 2016 American Medical
Association. All rights reserved.
From: Potential Mortality Reduction With Optimal Implemen tation of Angiotensin Receptor Neprilysin Inhibitor Therapy in Heart Failure
JAMA Cardiol. Published online June 22, 2016. doi:10.1001/jamacardio.2016.1724
Demonstrated Benefits of Evidence-Based Therapies for Patients With Heart Failure and Reduced Ejection Fraction
Table Title:
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The treatment of HFrEF:2016 - Update
•New Epidemiology
•Prevention
•New Guidelines
•New Therapies
New Classification
A new classification?
ESC HF GUIDELINES 2016
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Definition of Heart Failure -ACC/AHA 2013
Classification Ejection Fraction
Description
I. Heart Failure with
Reduced Ejection Fraction (HFrEF)
≤40% Also referred to as systolic HF. Randomized clinical trials have
mainly enrolled patients with HFrEF and it is only in these patients that efficacious therapies have been demonstrated to date.
II. Heart Failure with
Preserved Ejection Fraction (HFpEF)
≥50% Also referred to as diastolic HF. Several different criteria have been
used to further define HFpEF. The diagnosis of HFpEF is challenging because it is largely one of excluding other potential
noncardiac causes of symptoms suggestive of HF. To date, efficacious therapies have not been identified.
a. HFpEF, Borderline 41% to 49% These patients fall into a borderline or intermediate group. Their
characteristics, treatment patterns, and outcomes appear similar to those of patient with HFpEF.
b. HFpEF, Improved >40% It has been recognized that a subset of patients with HFpEF
previously had HFrEF. These patients with improvement or recovery in EF may be clinically distinct from those with persistently
preserved or reduced EF. Further research is needed to better characterize these patients.
Yancy C et al, JACC 2013
Taking the failure out of HF - 2016
• ***We can prevent the progression of HF
− Greater use of – PREVENTION, DIAGNOSIS, imaging, prognosis
& treatment ; early introduction of RAAS inhibitors
• Quality Improvement
− Still with untapped effectiveness – MAXIMIZE THERAPY!
− Device therapy (ICD/CRT) as indicated
• New drug therapies-
− ARNI (Sacubitril / Valsartan); Ivabradine
• Personalized Therapy driven by Pharmacogenomics
• - Future?
− Stem cells
− Gene Transfer; Growth Factors, Gene Editing
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Thank You!
Date of download: 7/11/2016Copyright © 2016 American Medical
Association. All rights reserved.
From: Characteristics and Outcomes of Adult Outpatients W ith Heart Failure and Improved or Recovered Ejection Fraction
JAMA Cardiol. Published online July 06, 2016. doi:10.1001/jamacardio.2016.1325
Kaplan-Meier Curves, Adjusted for Age and Sex, Across the 3 Heart Failure GroupsThe stratified log-rank χ22 was 15.0 (P < .001) for
difference in mortality between groups. HFpEF indicates heart failure with preserved ejection fraction; HFrecEF, heart failure with recovered ejection fraction; and HFrEF, heart failure with reduced ejection fraction.
Figure Legend: