professor richard troughton south/sun_plenary_0730_trougton...• 23% cv mortality or hf...
TRANSCRIPT
![Page 1: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/1.jpg)
Professor Richard TroughtonCardiologist
Christchurch Heart Institute
University of Otago
Christchurch
7:15 - 8:25 Breakfast Session: Novartis Breakfast Session
An Update on Heart Failure
![Page 2: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/2.jpg)
Heart Failure Update
Richard Troughton
Christchurch Heart Institute
19 August 2018
![Page 3: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/3.jpg)
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)
![Page 4: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/4.jpg)
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
![Page 5: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/5.jpg)
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
![Page 6: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/6.jpg)
Lifetime Risk of Heart Failure
Lloyd-Jones et al, Circulation 2002.
![Page 7: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/7.jpg)
Attributable Risk for Heart Failure
Other Other
![Page 8: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/8.jpg)
Preserved versus Reduced LV Ejection Fraction
HF-PEF
Vascular / Ventricular Stiffness
Loss of diastolic reserve
HF-REF
Systolic impairment
![Page 9: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/9.jpg)
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
![Page 10: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/10.jpg)
Prevalence of HFpEF and HFrEF in community cohorts
Dunlay, S. M. et al. (2017) Nat. Rev. Cardiol. doi:10.1038/nrcardio.2017.65
![Page 11: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/11.jpg)
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)
![Page 12: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/12.jpg)
Mortality: HFpEF vs. HFrEF
Dunlay, S. M. et al. (2017) Nat. Rev. Cardiol. doi:10.1038/nrcardio.2017.65
![Page 13: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/13.jpg)
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
![Page 14: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/14.jpg)
Differential response to treatment in HFpEF
Borlaug B A , Redfield M M Circulation 2011;123:2006
![Page 15: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/15.jpg)
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
![Page 16: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/16.jpg)
![Page 17: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/17.jpg)
![Page 18: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/18.jpg)
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
![Page 19: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/19.jpg)
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
![Page 20: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/20.jpg)
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
![Page 21: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/21.jpg)
Alaa Mabrouk Salem Omar et al. Circ Res. 2016;119:357-374
![Page 22: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/22.jpg)
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)
![Page 23: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/23.jpg)
![Page 24: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/24.jpg)
![Page 25: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/25.jpg)
![Page 26: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/26.jpg)
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
![Page 27: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/27.jpg)
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
![Page 28: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/28.jpg)
Vasoconstrictor
Salt and H2O
retaining
Neurohumoral Balance and the Circulation
Endothelin
Angiotensin II
Aldosterone
Norepinephrine
BNP
ANP
Urocortin
Adrenomedullin
Vasodilator
Diuretic
![Page 29: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/29.jpg)
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
![Page 30: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/30.jpg)
LCZ696
LCZ696: Angiotensin Receptor Neprilysin Inhibition
Angiotensinreceptor blocker
Inhibition of neprilysin
Sacubitril/Valsartan (Entresto)first in class dual AT1 receptor and neprilysin inhibitor (ARNI)
![Page 31: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/31.jpg)
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
![Page 32: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/32.jpg)
![Page 33: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/33.jpg)
N Engl J Med 2014; 371:993-1004 DOI: 10.1056/NEJMoa1409077
![Page 34: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/34.jpg)
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
![Page 35: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/35.jpg)
• 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
![Page 36: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/36.jpg)
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
![Page 37: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/37.jpg)
N Engl J Med 2014; 371:993-1004 DOI: 10.1056/NEJMoa1409077
![Page 38: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/38.jpg)
N Engl J Med 2014; 371:993-1004 DOI: 10.1056/NEJMoa1409077
![Page 39: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/39.jpg)
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
![Page 40: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/40.jpg)
![Page 41: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/41.jpg)
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/
![Page 42: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/42.jpg)
New Treatments being evaluated for HF
![Page 43: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/43.jpg)
Sodium-Glucose coTransporter 2 (SGLT-2) Inhibitors
![Page 44: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/44.jpg)
EMPA-REG Outcomes
![Page 45: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/45.jpg)
EMPA-REG Outcomes – key findings
![Page 46: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/46.jpg)
SGLT-2 Inhibitors – how do they work?
![Page 47: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/47.jpg)
SGLT-2 Inhibitors – Pending trials
![Page 48: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/48.jpg)
New Treatments being evaluated for HF
![Page 49: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/49.jpg)
![Page 50: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/50.jpg)
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
![Page 51: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/51.jpg)
Multimorbidity in heart failure in the community
Dunlay, S. M. et al. (2017) Nat. Rev. Cardiol. doi:10.1038/nrcardio.2017.65
![Page 52: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/52.jpg)
![Page 53: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/53.jpg)
Iron Homeostasis
Alain Cohen-Solal et al. Heart 2014;100:1414-1420
![Page 54: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/54.jpg)
Iron Deficiency in Heart Failure
• Iron Deficiency (with or without anaemia) is common
American Heart Journal 2013 165, 575-582
![Page 55: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/55.jpg)
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
![Page 56: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/56.jpg)
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
![Page 57: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/57.jpg)
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
![Page 58: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/58.jpg)
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
![Page 59: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/59.jpg)
New Mortality / Morbidity trials with IV Iron
![Page 60: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/60.jpg)
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
![Page 61: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/61.jpg)
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)
![Page 62: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/62.jpg)
Thank You
• Questions?
![Page 63: Professor Richard Troughton South/Sun_Plenary_0730_Trougton...• 23% CV mortality or HF hospitalization CHARM-Added4 (2003) 2,548 patients Candesartan (ARB) vs • 15% CV mortality](https://reader036.vdocuments.mx/reader036/viewer/2022071101/5fd9b84037f5685f010aa79e/html5/thumbnails/63.jpg)
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)