MEDICAL SURGICAL NURSING

1. Dr Andrew Ludman
Cardiology Consultant
Royal Devon & Exeter NHS Foundation Trust
University of Exeter Medical School
a.ludman@nhs.net

2. Declarations
• Support for educational events: Astra Zenaca, Bayer, Boehringer
Ingelheim, Daiichi-Sankyo, Pfizer, Sanofi, Servier, Shire
• Speaker fees: Novartis, Sanofi, Astra Zenaca.
• Grant for HF service support: Servier

4. What is heart failure?
• A structural cardiac abnormality leading to failure of the
heart to provide adequate oxygen to metabolising tissues
despite normal filling pressures.
• A syndrome in which patients have typical symptoms (e.g.
breathlessness, ankle swelling, and fatigue) and signs (e.g.
elevated jugular venous pressure, pulmonary crackles, and
displaced apex beat) resulting from an abnormality of cardiac
structure or function.
2012 ESC HF guidelines
‘Acute’ ‘Chronic’ ‘Hospitalised’ ‘De novo’ ‘Decompensated’ ‘Right’ ‘Left’

5. Epidemic of Heart Failure?
Or just hyperbole?

6. Global age standardised mortality rates by
sociodemographic index
Lancet 2017, 390;10110: pg1084-1150

7. Global number of deaths by cause 1990 - 2016
Lancet 2017, 390;10110: pg1151-1210

8. Leading causes of lost years of life
Lancet 2017, 390;10110: pg1151-1210

9. Projected increasing burden of common risk factors for
heart failure in the USA
Dunlay, S. M. et al. (2017) Nat. Rev. Cardiol. doi:10.1038/nrcardio.2017.65

10. Classification of heart failure
Sutherland 2010- Bridging the quality gap: Heart failure

11. Trends in incident HFpEF and
HFrEF in Olmsted County,
Minnesota, USA
Dunlay, S. M. et al. (2017) Nat. Rev. Cardiol. doi:10.1038/nrcardio.2017.65
Is heart failure incidence increasing?
Sex-standardized trends in incidence of
heart failure, by age group: Ontario,
Canada
Darwin F. Yeung et al. CMAJ 2012;184:E765-E773

12. CVD in the UK
BHF CVD Statistics Compendium 2017

13. Prevalence of HF in the UK
• ~550,000 people in the
UK with heart failure
BHF CVD Statistics Compendium 2017
QOF
0.8%
Bhatnager et al. 2014 Heart

14. Increasing inpatient episodes for CVD
BHF CVD Statistics Compendium 2017

15. Hospitalised Heart Failure in the UK
NICOR UK HF Audit 2015-16

16. Hospitalised Heart Failure in the UK – how are doing?
NICOR UK HF Audit 2015-16
Inpatient mortality ↓ to
8.9% from 9.6% (2014/15)
1 in 3 dead at 1 year

17. High hospital readmission rates
www.escardio.org/communities/HFA/Pages/global-heart-failure-awareness-programme.aspx

18. What can we do to improve outcomes?

19. What can we do to improve outcomes?
NICE Quality Standard on Acute HF. 2015. Available at: https://www.nice.org.uk/guidance/qs103
Last accessed: Sept 2017.

20. Don’t miss the diagnosis – use serum natriuretic peptide testing
Griffin et al. 2017 Value In Health. In press Roberts et al. BMJ 2015
AHF QS 1. Adults presenting to hospital with new suspected acute heart failure
have a single measurement of natriuretic peptide.

21. AHF QS 2. Adults admitted to hospital with new suspected acute heart failure
and raised natriuretic peptide levels have a transthoracic Doppler 2D
echocardiogram within 48 hours of admission.
• Heart failure with reduced
ejection fraction (HFREF)
• Heart failure with preserved
ejection fraction (HFPEF)

22. Type of heart failure?
Heart failure with reduced ejection fraction
(HFREF)
Heart failure with preserved ejection fraction
(HFPEF)

23. AHF QS 3. Adults admitted to hospital with acute heart failure
have input within 24 hours of admission from a dedicated
specialist heart failure team

24. AHF QS 4. Adults with acute heart failure due to left ventricular systolic dysfunction
are started on, or continue with, beta-blocker treatment during their hospital
admission.
AHF QS5. Adults admitted to hospital with acute heart failure and reduced left
ventricular ejection fraction are offered an ACE inhibitor and an aldosterone
antagonist.
More drugs…better outcome

25. Discharge planning and specialist follow up reduce mortality
NICOR UK HF Audit 2015-16
AHF QS 6. Adults with acute heart failure have a follow-up clinical assessment by a
member of the community- or hospital-based specialist heart failure team within
2 weeks of hospital discharge.

26. Diuretics – an old dog?

27. Outcome for 1-year death or urgent heart transplantation (Tx) (left) and for the combined end point of 1-
year death, urgent heart transplantation, or heart failure (HF) readmission (right) for the patients subdivided
on the basis of the development of worsening renal function (WRF) and on the presence of signs of
congestion (Cong) at discharge.
Marco Metra et al. Circ Heart Fail. 2012;5:54-62
Don’t underestimate the importance of diuretics -
decongestion is really important

28. A new trick?

29. Sympatheticnervoussystem
Renin-angiotensin-aldosteronesystem
Vasoconstriction
 Blood pressure
 Sympathetic tone
 Aldosterone
 Hypertrophy
 Fibrosis
Natriureticpeptidesystem
Vasodilation
 Blood pressure
 Sympathetic tone
 Natriuresis/diuresis
 Vasopressin
 Aldosterone
 Fibrosis
 Hypertrophy
Vasoconstriction
 RAAS activity
 Vasopressin
 Heart rate
 Contractility

NPRs
Natriuretic
peptide
receptors
NPs
Natriuretic peptides
Epinephrine
(adrenaline)
Norepinephrine
(noradrenaline)
α1, β1, β2
receptors

Ang II AT1R

Neurohormonal activation in heart failure
Ang=angiotensin; AT1R=angiotensin II type 1 receptor; NPs=natriuretic peptides; NPRs=natriuretic peptide receptors; RAAS=renin-angiotensin-
aldosterone system.
1. Levin E, et al. N Engl J Med. 1998;339:321–8. 2. Nathisuwan S, Talbert RL. Pharmacotherapy. 2002;22:27–42.
3. Kemp CD, Conte JV. Cardiovascular Pathology. 2012;365–71. 4. Schrier RW, Abraham WT. N Engl J Med. 2009;341:577–85.
HF SYMPTOMS and PROGRESSION

30. Entresto (sacubitril/valsartan) simultaneously inhibits neprilysin (via
sacubitril) and blocks AT1 receptors (via valsartan)1–5
*Neprilysin substrates listed in order of relative affinity for NEP: ANP, CNP, Ang II, Ang I, adrenomedullin, substance P, bradykinin, endothelin-1,
BNP.
Ang=angiotensin; ANP=atrial natriuretic peptide; AT1=angiotensin II type 1; BNP=brain natriuretic peptide; CNP=C-type natriuretic peptide.
1. Levin E, et al. N Engl J Med 1998;339:321–8. 2. Nathisuwan and Talbert. Pharmacotherapy. 2002;22:27–42.3. Schrier and
Abraham. N Engl J Med. 1999;341:577–85. 4. Langenickel TH, Dole WP. Drug Discov Today: Ther Strateg. 2012;9:e131–9.
5. Feng et al. Tetrahedron Letters. 2012;53:275–6.

31. PARADIGM-HF: Design
RANDOMISATION
n=8442
2 Weeks 1–2 Weeks 2–4 Weeks
SINGLE-BLIND ACTIVE
RUN-IN PERIOD
DOUBLE-BLIND
TREATMENT PERIOD
On top of standard HFrEF therapy (excluding ACEIs and ARBs)
Median of 27 months’ follow-up
Sacubitril/
valsartan
200 mg BID‡
Sacubitril/
valsartan
100 mg BID†
Enalapril
10 mg BID*
Enalapril 10 mg BID§
Sacubitril/valsartan 200 mg BID‡
Randomised, double-blind trial with a single-blind run-in period1–3
*Enalapril 5 mg BID (10 mg TDD) for 1–2 weeks followed by enalapril 10 mg BID (20 mg TDD) as an optional starting run-in dose for those patients who are treated
with ARBs or with a low dose of ACEI; †200 mg TDD; ‡400 mg TDD; §20 mg TDD. BID=twice daily; TDD=total daily dose.
1. McMurray J, et al. Eur J Heart Fail. 2013;15:1062–73.
2. McMurray J, et al. Eur J Heart Fail. 2014;16:817–25.
3. McMurray J, et al. N Engl J Med. 2014; 371:993–1004.

32. PARADIGM-HF: Primary endpoint
Death from CV causes or first hospitalisation for HF1,2
249
236
896
853
1544
1488
2257
2123
3018
2922
3663
3579
3922
3883
4187
4212
Days since randomisation
1.0
0.6
0.4
0.2
0
0 180 360 540 720 900 1080 1260
Cumulative
probability
21.8% (Entresto) vs. 26.5% (Enalapril)
Hazard ratio=0.80 (95% CI: 0.73–0.87)
p<0.0000002;2 ARR=4.7%; NNT=21.*
No. at risk
Entresto
(sacubitril/valsartan):
Enalapril:
Enalapril
Entresto (sacubitril/valsartan)
ARR=absolute risk reduction NNT=numbers needed to treat . *Events rates, ARR and NNT are all based on median F/U at 27 months.
1. McMurray J, et al. N Engl J Med. 2014;371(11): 993-1004.
2. Entresto Summary of Product Characteristics.

33. PARADIGM-HF: Components of primary endpoint
Death from CV causes1
280
279
1005
994
1716
1726
2478
2410
3282
3231
3891
3860
4056
4051
4187
4212
Days since randomisation
1.0
0.6
0.4
0.2
0
0 180 360 540 720 900 1080 1260
Cumulative
probability
13.3% (Entresto) vs. 16.5% (Enalapril)
Hazard ratio=0.80 (95% CI: 0.71–0.89)
p<0.001; ARR=3.2%; NNT=32.*
Enalapril
Entresto (sacubitril/valsartan)
ARR=absolute risk reduction NNT=numbers needed to treat. *Events rates, ARR and NNT are all based on median F/U at 27 months.
1. McMurray J, et al. N Engl J Med. 2014;371(11): 993-1004.
No. at risk
Entresto
(sacubitril/valsartan):
Enalapril:

34. PARADIGM-HF: Components of primary endpoint
First hospitalisation for HF1
249
236
896
853
1544
1488
2257
2123
3018
2922
3663
3579
3922
3883
4187
4212
Days since randomisation
1.0
0.6
0.4
0.2
0
0 180 360 540 720 900 1080 1260
Cumulative
probability
12.8% (Entresto) vs. 15.6% (Enalapril)
Hazard ratio=0.79 (95% CI: 0.71–0.89)
p<0.001; ARR=2.8%; NNT=36.*
Enalapril
Entresto (sacubitril/valsartan)
ARR=absolute risk reduction NNT=numbers needed to treat. *Events rates, ARR and NNT are all based on median F/U at 27 months.
1. McMurray J, et al. N Engl J Med. 2014;371(11): 993-1004.
No. at risk
Entresto
(sacubitril/valsartan):
Enalapril:

35. Time to first hospitalisation for HF reduced within 30 days of
randomisation1,2*
1.5
1.0
0.5
0
0 10 20 30
Kaplan-Meier
estimate
of
Cumulative
rate
Enalapril
Entresto (sacubitril/valsartan)
4140
4143
4153
4166
4174
4192
4187
4212
Time since randomisation (days)
Hazard ratio=0.60 (95% CI: 0.38-0.94)
p=0.027; ARR=0.5%
No. at risk
Entresto
(sacubitril/valsartan):
Enalapril:
1. Packer M, et al. Circulation. 2015;131(1):54-61.
2. Entresto Summary of Product Characteristics
3. Novartis Data on file. [LCZ15-C025-1128] October 2015
*ARR=absolute risk reduction (at median F/U 30 days).
Time to first hospitalisation was not a primary or secondary endpoint in PARADIGM-HF.

36. Entresto demonstrated significant clinical benefits
vs enalapril:
• 20% reduced risk of CV death or first HF hospitalisation (ARR=4.7%)
• 20% reduced risk of CV mortality (ARR=3.2%)
• 21% reduced risk of first HF hospitalisation (ARR=2.8%)
• Fewer HF symptoms and a better quality of life*
PARADIGM-HF: Summary of efficacy results1,2
ARR=absolute risk reduction (at median F/U 27 months). *According to analysis from the KCCQ sub-domains.
ARR=absolute Risk Reduction; CV=cardiovascular KCCQ=Kansas City Cardiomyopathy Questionnaire.
1. McMurray J, et al. N Engl J Med. 2014;371:993–1004.
2. Packer M, et al. Circulation 2015;131:54–61

37. PARADIGM-HF: Fewer adverse events leading to
permanent study drug discontinuation
McMurray et al. N Engl J Med 2014;371:993–1004.
10.7%
0.9% 0.7% 0.3%
12.3%
0.7%
1.4%
0.4%
0%
5%
10%
15%
Any adverse event Hypotension Renal impairment Hyperkalaemia
Patients
who
discontinued
study
drug
(%)
Entresto (sacubitril/valsartan;
N=4187)
Enalapril (N=4212)
p=0.03
p=0.38 p=0.002
p=0.56
n=10 n=5

38. NICE Technology Appraisal Guidance (TA388):
Sacubitril/valsartan is recommended as an option for treating people
with HF with reduced ejection fraction, only in people:1
NICE has reviewed sacubitril/valsartan (Entresto)



with NYHA class II to IV chronic heart failure and
who are already taking a stable dose of ACEI or ARBs and
with a left ventricular ejection fraction of 35% or less
ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; NYHA=New York Heart Association.
1. NICE Technology Appraisal Guidance (TA388). Appraisal consultation document. Sacubitril valsartan for treating symptomatic
chronic heart failure with reduced ejection fraction. April 2016 Available at: https://www.nice.org.uk/guidance/ta388 Last accessed
27 April 2016

39. NICE Technology Appraisal Guidance recommends that:
NICE TAG Recommendation
1. NICE Technology Appraisal Guidance (TA388). Sacubitril valsartan for treating symptomatic chronic heart failure with reduced ejection
fraction. April 2016 Available at: https://www.nice.org.uk/guidance/ta388 Last accessed 27 April 2016
2. NICE. Chronic HF Guideline. August 2010 Available at: https://www.nice.org.uk/guidance/cg108 Last accessed 27 April 2016
Treatment with sacubitril/valsartan should be started by a heart
failure specialist with access to a multidisciplinary heart failure team1
Dose titration and monitoring should be performed by the most
appropriate team member as defined in NICE’s guideline on chronic
heart failure in adults2

40. Where next for sacubitril/valsartan?
• Hospitalised/Acute heart failure
• Starting directly (no ACE-I)
• HF PEF
• Hypertension
• …..

41. Another new trick?
Sodium glucose co-transporter 2 (SGLT2) inhibitors
Singh 2014 - DOI: 10.4103/0975-9727.135761 Zinman B et al. N Engl J Med 2015;373:2117-2128

42. Sodium glucose co-transporter 2 (SGLT2) inhibitors
EMPA REG outcomes
Zinman B et al. N Engl J Med 2015;373:2117-2128

43. Sodium glucose co-transporter 2 (SGLT2) inhibitors
EMPA REG outcomes
Zinman B et al. N Engl J Med 2015;373:2117-2128

44. Conclusions
• Not sure about the HF epidemic yet
• Outcomes for hospitalised patients are improving
but remain poor
• Optimise fluid balance and medication pre-
discharge
• Specialist involvement and follow up
• Active drug development – watch this space

45. Additional resources for patients