professor richard troughton south/sun_plenary_0730_trougton...• 23% cv mortality or hf...
TRANSCRIPT
Professor Richard TroughtonCardiologist
Christchurch Heart Institute
University of Otago
Christchurch
7:15 - 8:25 Breakfast Session: Novartis Breakfast Session
An Update on Heart Failure
Heart Failure Update
Richard Troughton
Christchurch Heart Institute
19 August 2018
Take Home Points
• Heart Failure is increasingly common
• BNP and Echocardiography are key tools for diagnosis
• Defining LV ejection fraction is important
• Preserved (PEF) versus Reduced (REF)
• Co-morbidities are common
• There are exciting new therapies for HFrEF including Entresto
• Treatment of HFpEF is more challenging (…. but there is hope)
Overview
• What’s happening with Heart Failure epidemiology?
• Importance of LV Ejection Fraction - HFpEF versus HFrEF
• Recent Guideline Updates
• New Treatments
• Comorbidities
• Take Home Points
Overview
• What’s happening with Heart Failure epidemiology?
• Importance of LV Ejection Fraction - HFpEF versus HFrEF
• Recent Guideline Updates
• New Treatments
• Comorbidities
• Take Home Points
Lifetime Risk of Heart Failure
Lloyd-Jones et al, Circulation 2002.
Attributable Risk for Heart Failure
Other Other
Preserved versus Reduced LV Ejection Fraction
HF-PEF
Vascular / Ventricular Stiffness
Loss of diastolic reserve
HF-REF
Systolic impairment
Distribution of left ventricular ejection fraction
in incident heart failure
Dunlay, S. M. et al. (2017) Epidemiology of heart failure with preserved ejection fraction
Nat. Rev. Cardiol. doi:10.1038/nrcardio.2017.65
Prevalence of HFpEF and HFrEF in community cohorts
Dunlay, S. M. et al. (2017) Nat. Rev. Cardiol. doi:10.1038/nrcardio.2017.65
Projected population burden of heart failure
Dunlay, S. M. et al. (2017) Epidemiology of heart failure with preserved ejection fraction
Nat. Rev. Cardiol. doi:10.1038/nrcardio.2017.65
(10
,00
0)
(10
,00
0)
(10,000’s)
Mortality: HFpEF vs. HFrEF
Dunlay, S. M. et al. (2017) Nat. Rev. Cardiol. doi:10.1038/nrcardio.2017.65
Combination ACEI, -Blocker and MRA are now the cornerstone of therapy for HFrEF
ACEI
ARB
BB
ACEI + BB
ACEI + ARB
ARB + BB
ACEI +MRA
ACEI + ARB +BB
ACEI +BB + MRA
0.83 (0.66, 1.01)
0.88 (0.61, 1.26)
0.57 (0.33, 0.94)
0.57 (0.41, 0.72)
0.83 (0.51, 1.24)
0.47 (0.23, 0.86)
0.57 (0.35, 0.91)
0.52 (0.31, 0.80)
0.44 (0.26, 0.66)
HR (95% credible interval) for treatment vs. placebo*
0 0.5 1 1.5
*HR<1 favors treatment
Results are based on random-effects network meta-analysis using Bayesian models2
Studies included: 57 RCTs, Phase II/III (Jan 1987- April 2015) assessing guideline-recommended drug classes for HFrEF
Patient population: Patients (aged ≥18 years) with chronic HFrEF (LVEF <45%) and NYHA class II–IV of varying etiology presenting in the
outpatient department were included
1. McMurray et al. Eur Heart J 2012;33:1787–847;.2. Burnett H et al. Circ Heart Fail. 2017;10:e003529
Differential response to treatment in HFpEF
Borlaug B A , Redfield M M Circulation 2011;123:2006
Overview
• What’s happening with Heart Failure epidemiology?
• Importance of LV Ejection Fraction - HFpEF versus HFrEF
• Recent Guideline Updates
• New Treatments
• Comorbidities
• Take Home Points
BNP / NT-ProBNP
1
108
H2N
COOH76
77
1H2N
108
COOHCOOH 76
77H2N
Pro-BNP
NT-pro-BNPBNP
Corin
Adapted from Lam et al, JACC 2007; 49:1193
Major stimulus for secretion is wall stretch
Modifiers: ischemia, neurohormones
Cardiomyocyte
Peripheral Circulation
BNP / NT-ProBNP
Roche Elecsys
1
108
H2N
COOH76
77
1H2N
108
COOHCOOH 76
77H2N
Pro-BNP
NT-pro-BNPBNP
Abbott
Adapted from Lam et al, JACC 2007; 49:1193
Cardiomyocyte
Peripheral Circulation
BNP/NT-proBNP - Take Home
• Guideline endorsed for diagnosis and monitoring
o Low levels rule out heart failure
o High levels indicate HF is likely (or functionally important heart disease)
o Levels fall with effective HF treatment
o Persisting high levels are associated with high mortality and hospitalisation risk
Alaa Mabrouk Salem Omar et al. Circ Res. 2016;119:357-374
Echo - Take Home
• Single most important test in HF
• Key indices :o LV ejection fraction
oPresence of LVH (increased mass or wall thickness)
o LV diastolic dysfunction (elevated filling pressures)
o Left atrial dilatation
oMore than moderate valve disease
o Elevated right heart pressures (RVSP > 30mmHg)
Overview
• What’s happening with Heart Failure epidemiology?
• Importance of LV Ejection Fraction - HFpEF versus HFrEF
• Recent Guideline Updates
• New Treatments
• Comorbidities
• Take Home Points
ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; ARNI=angiotensin receptor neprilysin inhibitor; BB=beta blocker; CV=cardiovascular; HF=heart failure; HFrEF=heart failure with reduced ejection fraction; MRA=mineralocorticoid receptor antagonist. See notes for definitions of study names
1. SOLVD Investigators. N Engl J Med 1991;325:293–302 2. MERIT-HF study group, Lancet, 1999, 353:2001-7 3. Granger et al. Lancet 2003;362:772−6 4.
McMurray et al. Lancet 2003;362:767–771; 5. Swedberg et al. Lancet 2010;376:875–85 6. Zannad et al. N Engl J Med 2011;364:11–21; 7. McMurray et al. N Engl J Med
2014;371:993–1004 8 CIBIS-II Investigators. Lancet 1999;353:9–13
Landmark trials in HFrEF
MERIT-HF2 (1999)3991 patients
Metorprolol vs placebo:
• 34% all-cause mortality
EMPHASIS-HF6 (2011)2,737 patients
Eplerenone (MRA) vs
placebo:
• 37% CV mortality or HF
hospitalization
SHIFT5 (2010)6,558 patients
Isvabradine (If inhibitor) vs
placebo:
• 18% CV death or HF
hospitalization
PARADIGM-HF7
(2014)
8,442 patients
Sacubitril/valsartan
(ARNI) vs enalapril:
SOLVD-T1 (1991)2,569 patients
Enalapril (ACEI) vs placebo:
• 16% all-cause mortality
CHARM-Alternative3 (2003)2,028 patients
Candesartan (ARB) vs
placebo:
• 23% CV mortality or HF
hospitalization
CHARM-Added4 (2003)2,548 patients
Candesartan (ARB) vs
placebo:
• 15% CV mortality or HF
hospitalization
1990s 2000s 2010s
CIBIS-II8 (1999)2,647 patients
Bisoprolol (BB) vs placebo:
• 34% all-cause mortality
Vasoconstrictor
Salt and H2O
retaining
Neurohumoral Balance and the Circulation
Endothelin
Angiotensin II
Aldosterone
Norepinephrine
BNP
ANP
Urocortin
Adrenomedullin
Vasodilator
Diuretic
Adapted from Shah M et al. Rev Cardiovasc Med. 2001;2(suppl 2):S2–S6.
Neurohormonal Imbalance in Heart Failure
Endothelin
Aldosterone
Vasopressin
Angiotensin II
Norepinephrine
Exce
ss v
aso
co
nstric
tion
Compensation
Excess vasodilation
BNP
ANP
Urocortin
Adrenomedullin
LCZ696
LCZ696: Angiotensin Receptor Neprilysin Inhibition
Angiotensinreceptor blocker
Inhibition of neprilysin
Sacubitril/Valsartan (Entresto)first in class dual AT1 receptor and neprilysin inhibitor (ARNI)
Antoni Bayes-Genis et al. JACC 2016;68:639-653
Neprilysin / Neutral Endopeptidase
NEP is 749-AA, membrane-bound, zinc-dependent endopeptidase
Acts on multiple substrates
Widely present in kidneys, heart, brain, gut and lungs
Natriuretic peptides
Endothelin
Substance P
Bradykinin
Angiotensin II
Adrenomedullin
Angiotensin I
NEP
Inactive
fragments
or metabolites
N Engl J Med 2014; 371:993-1004 DOI: 10.1056/NEJMoa1409077
Prospective comparison of ARNI with ACEI to
Determine Impact on Global Mortality and
morbidity in Heart Failure trial (PARADIGM-HF)
SPECIFICALLY DESIGNED TO REPLACE CURRENT USE
OF ACE INHIBITORS AND ANGIOTENSIN RECEPTOR
BLOCKERS AS THE CORNERSTONE OF THE
TREATMENT OF HEART FAILURE
Aim of the PARADIGM-HF Trial
LCZ696400 mg daily
Enalapril20 mg daily
• NYHA class II-IV heart failure
• LV ejection fraction ≤ 40% 35%
• BNP ≥ 150 (or NT-proBNP ≥ 600)
• Any use of ACE inhibitor or ARB, but able to tolerate stable dose equivalent to at least enalapril 10 mg daily for 4 weeks
• Guideline-recommended use of beta-blockers and mineralocorticoid receptor antagonists
• Systolic BP ≥ 95 mm Hg, eGFR ≥ 30 ml/min/1.73 m2 and serum K ≤ 5.4 mEq/L at randomization
PARADIGM-HF: Entry Criteria
2 weeks 1-2 weeks 2-4 weeks
Single-blind run-in period Double-blind period
(1:1 randomization)
Enalapril
10 mgBID
100 mgBID
200 mgBID
Enalapril 10 mg BID
LCZ696 200 mg BID
PARADIGM-HF: Study Design
Randomization
LCZ696
N Engl J Med 2014; 371:993-1004 DOI: 10.1056/NEJMoa1409077
N Engl J Med 2014; 371:993-1004 DOI: 10.1056/NEJMoa1409077
In heart failure with reduced ejection fraction, when compared
with recommended doses of enalapril:
LCZ696 was more effective than enalapril in . . .
• Reducing the risk of CV death and HF hospitalization
• Reducing the risk of CV death by incremental 20%
• Reducing the risk of HF hospitalization by incremental 21%
• Reducing all-cause mortality by incremental 16%
• Incrementally improving symptoms and physical limitations
LCZ696 was better tolerated than enalapril . . .
• Less likely to cause cough, hyperkalemia or renal impairment
• Less likely to be discontinued due to an adverse event
• More hypotension, but no increase in discontinuations
• Not more likely to cause serious angioedema
PARADIGM-HF: Summary of Findings
Entresto Available in NZ from 1 October 2018 (?)
• Special Authority for Subsidy – Retail pharmacy
• Initial application from any relevant practitioner. Approvals valid for 12 months for applications meeting all of the following criteria:
1. Patient has heart failure; and is in NYHA/WHO functional class II-IV; and
2. Patient has a documented left ventricular ejection fraction (LVEF) ≤ 35%; and
3 Patient is receiving concomitant optimal standard chronic HF treatments.
• Renewal from any relevant practitioner. Approvals valid for 12 months for applications where the treatment remains appropriate and the patient is benefiting from treatment.
• Note: Due to the angiotensin II receptor blocking activity of sacubitril with valsartan it should not be co-administered with an ACE inhibitor or ARB.
https://www.pharmac.govt.nz/news/consultation-2018-07-02-multiproduct-novartis/
New Treatments being evaluated for HF
Sodium-Glucose coTransporter 2 (SGLT-2) Inhibitors
EMPA-REG Outcomes
EMPA-REG Outcomes – key findings
SGLT-2 Inhibitors – how do they work?
SGLT-2 Inhibitors – Pending trials
New Treatments being evaluated for HF
Overview
• What’s happening with Heart Failure epidemiology?
• Importance of LV Ejection Fraction - HFpEF versus HFrEF
• Recent Guideline Updates
• New Treatments
• Comorbidities
• Take Home Points
Multimorbidity in heart failure in the community
Dunlay, S. M. et al. (2017) Nat. Rev. Cardiol. doi:10.1038/nrcardio.2017.65
Iron Homeostasis
Alain Cohen-Solal et al. Heart 2014;100:1414-1420
Iron Deficiency in Heart Failure
• Iron Deficiency (with or without anaemia) is common
American Heart Journal 2013 165, 575-582
Iron Deficiency in Heart Failure
• Iron Deficiency (with or without anaemia) is common
• In HFrEF, treatment of iron deficiency with IV iron improves symptoms, QOL and functional status
CONFIRM-HF study, Ponikowski et al. Eur Heart J. 2015
Iron Deficiency in Heart Failure
• Iron Deficiency (with or without anaemia) is common
• In HFrEF, treatment of iron deficiency with IV iron improves symptoms, QOL and functional status
• Oral iron supplementation is ineffective
IRON-OUT Study
0
100
200
300
0
10
20
30
40
Week 0 16 Week 0 16Ferr
itin
(n
g/m
l)Ts
at (
%)
Week 0 16 Week 0 16
+3% p=0.003
IRONOUT-HF
Normalrange
Normalrange
+11ng/mlP=0.056
Iron Placebo
Week 0 240
100
200
300
0
10
20
30
40
Week 0 24
Week 0 24Week 0 24
+238ng/mlP<0.001
+12%P<0.001
vs. FAIR-HF (IV Iron)
Iron Placebo
JAMA. 2017;317(19):1958-1966. doi:10.1001/jama.2017.5427
Iron Deficiency in Heart Failure
• Iron Deficiency (with or without anaemia) is common
• In HFrEF, treatment of iron deficiency with IV iron improves symptoms, QOL and functional status
• Oral iron supplementation is ineffective
• IV iron now appears safe (carboxymaltose formulation) but whether it reduces hospitalisation or death is uncertain
New Mortality / Morbidity trials with IV Iron
Overview
• What’s happening with Heart Failure epidemiology?
• Importance of LV Ejection Fraction - HFpEF versus HFrEF
• Recent Guideline Updates
• New Treatments
• Comorbidities
• Take Home Points
Take Home Points
• Heart Failure is increasingly common
• BNP and Echocardiography are key tools for diagnosis
• Defining LV ejection fraction is important
• Preserved (PEF) versus Reduced (REF)
• Co-morbidities are common
• There are exciting new therapies for HFrEF including Entresto
• Treatment of HFpEF is more challenging (…. but there is hope)
Thank You
• Questions?
Take Home Points
• Heart Failure is increasingly common
• BNP and Echocardiography are key tools for diagnosis
• Defining LV ejection fraction is important
• Preserved (PEF) versus Reduced (REF)
• Co-morbidities are common
• There are exciting new therapies for HFrEF including Entresto
• Treatment of HFpEF is more challenging (…. but there is hope)