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Heart Failure
Cardiology – what’s new and what’s changed
Professor Andrew Clark Academic Cardiology Hull York Medical School
Hull: city of culture
Hull: city of culture
CHRONIC HEART FAILURE Cardiology – what’s new and what’s changed
0
20
40
60
80
100
0 2 4 6 8 10 Years
Mor
talit
y
placebo
enalapril
average life increment 260 days (up 50%
from 521 to 781 days)
Eur Heart J 1999;20:136
Months 0 6 18 12
50
80
70
60
90
100
Surv
ival
P=0.00013 P=0.0014 (adjusted)
carvedilol
placebo
N Engl J Med 2001;344:1651
0.4
0.6
0.8
1
0 12 24 36 Months
Surv
ival
placebo
spironolactone
N Engl J Med 1999;341:709
Days
0 500 1000 1500
100
75
50
25
0
N Engl J Med 2005;352:1539–49
P<0.002
CRT
no CRT
Why research matters
Reasons to be cheerful, part 3
J Am Heart Assoc 2012;1:16
Nested case-control study 1376 cases and 2752 propensity-matched controls Age 72; 72% ♂ LVEF 25%
Data from IMPROVE-HF registry
SLEEP DISORDERED BREATHING Cardiology – what’s new and what’s changed
Sleep disordered breathing
Need to think clever …
Am J Respir Crit Care Med 2001;164:614
SERVE-HF
N=1325 ; LVEF ≤45% AHI ≥15 h-1 (mostly central) BMT v BMT+ASV Death; lifesaving CV intervention; HF hospitalisation
ACE/ARB
BB
MRA
92%
92%
48%
Diuretic 85%
AHI 31 h-1
CSA 45%
SaO2 <90% 53 m
Data from SERVE-HF
N Engl J Med 2015: DOI: 10.1056/NEJMoa1506459
N=1325 ; LVEF ≤45% AHI ≥15 h-1 (mostly central) BMT v BMT+ASV Death; lifesaving CV intervention; HF hospitalisation
Data from SERVE-HF
SERVE-HF
N Engl J Med 2015: DOI: 10.1056/NEJMoa1506459
All cause death CV death
SERVE-HF
N=1325 ; LVEF ≤45% AHI ≥15 h-1 (mostly central) BMT v BMT+ASV Death; lifesaving CV intervention; HF hospitalisation
Data from SERVE-HF
N Engl J Med 2015: DOI: 10.1056/NEJMoa1506459
IS TREATING T2DM WORTHWHILE? Cardiology – what’s new and what’s changed
ACCORD
N Engl J Med 2008;358:2545
N=10 251 age 62.2; 38%♀ Hba1 8.1% Randomised to intensive therapy <6.0% (42 mmol.mol-1) standard therapy 7.0 - 7.9% 1° EP: nonfatal MI or CVA; cardiovascular death
Nonfatal MI or CVA; CV death Death
P=0.16 P=0.04
Blood Urine
Na+
K+
glucose glucose Glut SGLT 2 Na+
SGLT=sodium-glucose linked transporter
gliflozin
EMPA-REG
N Engl J Med 2015;373:2117
N=7020; age 63; 71%♂ T2DM+established CVD MI, UA CAD (angio) CVA, PVD Median follow up 3.1 years 1° EP CV death, MI, CVA
EMPA-REG
N Engl J Med 2015;373:2117
N=7020; age 63; 71%♂ T2DM+established CVD MI, UA CAD (angio) CVA, PVD Median follow up 3.1 years 1° EP CV death, MI, CVA
EMPA-REG
Systolic blood pressure Weight
N Engl J Med 2015;373:2117
N=7020; age 63; 71%♂ T2DM+established CVD MI, UA CAD (angio) CVA, PVD Median follow up 3.1 years 1° EP CV death, MI, CVA
NEUROENDOCRINE REVISITED Cardiology – what’s new and what’s changed
kinins
(breakdown products)
AT2
Aldosterone
Ang I
Ang II
AT1
ACE
Angiotensinogen
Renin
ACEI
ARB
DRI (aliskiren)
MRA
Physiology
Cardiac myocyte stretch Chamber enlargement
ANP, BNP
NPRA
Natriuresis (Na+, H2O)
↓ blood volume ↑ pooling ↓ BP
vasodilation
Decreased aldosterone levels Inhibition of RAAS Inhibition of sympathetic nervous activity
Ang II
(breakdown products)
ANP, BNP
(breakdown products)
NEP
kinins
(breakdown products)
Amino-peptidase P candoxatril omapatrilat
Ang I
Ang II
ACE
omapatrilat
kinins
(breakdown products)
AT2
Aldosterone
Ang I
Ang II
AT1
ACE
ANP, BNP
(breakdown products)
NEP
Angiotensinogen
Renin
LCZ696
sacubitril valsartan
PARADIGM-HF • NYHA class II, III, or IV
symptoms • LVEF ≤ 40% (reduced to
≤35% by amendment)
• BNP≥150 pg.ml-1 or NT-proBNP ≥600 pg.ml-1
or, if HF hospitalisation in last year
• BNP of ≥ 100 pg.ml-1 or NT-proBNP ≥400 pg.ml-1
• Systolic BP <100 mm Hg at screening or 95 mm Hg at randomization,
• eGFR < 30 ml.min-1.1.73 m-2 or decrease in eGFR >25% between screening and randomization
• K+ > 5.2 mmol.l-1 at screening (or > 5.4 mmol.l-1 at randomization)
• history of angioedema or unacceptable ACEI/ARB side effects
N Engl J Med 2014;371:993
PARADIGM-HF
N Engl J Med 2014;371:993
LCZ N=4187
Enalapril N=4212
PARADIGM-HF
N Engl J Med 2014;371:993
PARADIGM-HF
N Engl J Med 2014;371:993
- 6
- 5
- 4
- 3
- 2
- 1
0 LCZ Enal
KCCQ (8 m)
PARADIGM-HF
N Engl J Med 2014;371:993
Quality of life deteriorates less
NNT to prevent one primary endpoint event 21
NNT to prevent one CV death
32
N Engl J Med 2014;371:993
PARADIGM-HF
Age ...
Eur Heart J 2015;36:2576
Mode of death ...
Eur Heart J 2015;36:1990
Sudden death Death from HF
HF hospitalisation ...
Circulation 2015;131:54
1st hospitalisation Cumulative hospitalisations
Severity of HF ...
J Am Coll Cardiol 2015;66:2059
Severity of HF ...
J Am Coll Cardiol 2015;66:2059
10 15 20 25 30 35 40Ejection fraction (%)
Haza
rd ra
tio (9
5%CI
)
1
0.8
0.7
0.5
1.2
1.5 P for interaction =0.83
Enalapril better
Sacubitril/valsartan better
LVEF ...
Lancet 2012;380:1387 Data from PARAGON
The run-in phase
Eur J Heart Fail 2013;15:1062
Trial stopped March 2014
ESC presentation On-line publication August 2014
FDA: fast track status Sept 2014
EMA: accelerated assessment Nov 2014
FDA: approves Entresto July 2015
MHRA issues Early Access to Medicines Sept 15
EU approval Nov 15
UK launch Jan 2016
NICE STA ?
ORGANISATION OF CARE Cardiology – what’s new and what’s changed
Prevalence of Heart Failure Age at first hospital admission by sex (National Audit data 2013/14)
National HF audit 2013/14: www.ucl.ac.uk/nicor/audits/heartfailure/documents/annualreports/hfannual13-14.pdf.
Co-morbidity in CHF
0
2
4
6
8
10
12
14
16
18
0 1 2 3 4 5 6 7 8 9 10+
%
N of co-morbidities
J Am Coll Cardiol 2003;42:1226
QS 103
• Statement 3. Adults admitted to hospital with acute heart failure have input within 24 hours from a dedicated specialist heart failure team.
• Statement 6. Adults with acute heart failure have a follow-up clinical assessment ... within 2 weeks of hospital discharge.
• Statement 3. People referred ... either because of suspected heart failure and previous MI or high serum natriuretic peptide levels, are seen by a specialist within 2 weeks of referral.
• Statement 9. People with stable chronic heart failure receive a clinical assessment at least every 6 months.
The National Audit
National HF audit 2013/14: www.ucl.ac.uk/nicor/audits/heartfailure/documents/annualreports/hfannual13-14.pdf.
Best practice tariff
Monitor. 2015/16 National Tariff Payment System. Available at: www.gov.uk/government/uploads/system/uploads/attachment_data/file/332133/NationalTariff2015-16_EngagementOverview.pdf.
