professor richard troughton south/sun_plenary_0730_trougton...• 23% cv mortality or hf...

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)