1. Detection and management of preclinical heart failure
Tom Marwick
Director, Menzies Research Institute Tasmania

2. EARLY HEART FAILURE Preclinical heart failure
Overt heart failure
(Stages C and D)
Preclinical disease
Stage B
Risk factors including social determinants and behaviour (Stage A)

3. EARLY HEART FAILURE HF stages
Stage A
At high risk for HF without structural heart disease or symptoms
Stage B
Structural heart disease but without signs or symptoms of HF
Stage C
Structural heart disease with prior or current symptoms of HF
Stage D
Refractory HF requiring specialized intervention
Patient with:
-Hypertension
-Atherosclerosis
-Diabetes
-Metabolic syndrome
-Cardiotoxins
-With FHx CM
Patient with:
-Previous MI
-LV remodeling including LVH and low EF
-Asymptomatic valvular disease
Hunt SA, et al. J Am Coll Cardiol 2009;53:e1-e90

4. EARLY HEART FAILURE TCF funding – Rural HF project
Why - The epidemiology of heart failure
Detection - is HF screening an option?
Right population
Right test
Rx strategy
Measuring outcomes
Quantifying risk, FP and FN results
Proof of Principle – TasELF study
Lessons about community-based RCTs

5. EARLY HEART FAILURE What is heart failure?
Chronic heart failure
Acute heart failure

6. EARLY HEART FAILURE Magnitude of the Problem
Australia (National Heart Foundation of Australia-HF guideline)
Prevalence: 10% (> 65 yrs); 50% (> 85 yrs )
Annual Incident HF: 30,000
Annual admissions: 100,000
Annual cost of care: $411 million (0.4% )
USA (Hunt SA ,2009)
Prevalence: 5,800,000
Incident rate: 500,000 /year
Annual cost of care: 39 billion (1-2%)
Worldwide (McMurray JJ 1998)
Prevalence: 23,000,000
Why is HF increasing?
- Aging
- Survival from heart attack
- Risk factors BP
diabetes
obesity

7. EARLY HEART FAILURE The heart failure epidemic
HF IS THE SINGLE MOST EXPENSIVE DIAGNOSIS IN HEALTH SYSTEM
Hospital admissions per 1,000 population per year for heart failure (Kannel WG. Br Heart J 1994)
Chance of getting HF?
- About 30%
Why is HF increasing?
- Aging
- Survival from heart attack
- Risk factors BP
diabetes
obesity

8. EARLY HEART FAILURE Metabolic drivers of the HF epidemic
Wellcome Museum, London

9. EARLY HEART FAILURE HF – Survival rate at 5 years
Five-year survival following a first admission to any Scottish hospital in 1991 for heart failure, myocardial infarction and the four most common of cancer specific to men and women.
Stewart S, et al. More malignant than cancer? Five-year survival following a first admission for heart failure in Scotland. European Journal of Heart Failure 3 (2001)

10. Heart Failure - Quality of Life
EARLY HEART FAILURE
Heart Failure - Quality of Life
PF: Physical function
RP: Role limitation
BP: Body pain
GH: General health perceptions
VT: Vitality
SF: Social function
RE: Emotional Problems
MH: Mental Health
Lynn J. JAMA 1997; 277:
Juenger J et al. Health related quality of life in patients with congestive heart failure: comparison with other chronic disease and relation to functional variables.
Heart 2001; 87: 235

11. EARLY HEART FAILURE HF is bad! What can we do about it?
Focus on early disease to change trajectory

12. EARLY HEART FAILURE TCF funding – Rural HF project
Why - The epidemiology of heart failure
Detection - is HF screening an option?
Right population
Right test
Rx strategy
Measuring outcomes
Quantifying risk, FP and FN results
Proof of Principle – TasELF study
Lessons about community-based RCTs

13. EARLY HEART FAILURE Screening for HF
Prevalence: 10% (> 65 yrs)
At June 2010, there were 79,100 people aged 65 years and over in Tasmania % of the population
Can we afford to screen ~80,000 people in order to find ~8,000 with HF?

14. EARLY HEART FAILURE What’s wrong with screening?
The risk of false positive results
Lead to further unnecessary diagnostic testing, over-treatment, some can be invasive
Cause psychological distress and anxiety in asymptomatic people
Need of evidence that screening and detection changes management outcomes
Screening for Heart Failure has not been recommended by the US Preventive Services Task Force

15. EARLY HEART FAILURE Essentials of screening
Thomas Bayes,
Choosing the right population
Having the right test
Absolute vs relative risk
Defining the phenotype
Having a treatment strategy
Knowing how to manage false positive and false negative tests

16. EARLY HEART FAILURE Rural HF project
Why - The epidemiology of heart failure
Detection - is HF screening an option?
Right population
Right test
Rx strategy
Measuring outcomes
Quantifying risk, FP and FN results
Proof of Principle – TasELF study

17. EARLY HEART FAILURE Shrink the haystack

18. EARLY HEART FAILURE Framingham HF Risk Score

19. EARLY HEART FAILURE Health ABC HF Score

20. EARLY HEART FAILURE
ARIC HF Risk Score

21. EARLY HEART FAILURE PRISMA- A Meta Analysis
Total articles identified
(n=2947)
Articles reviewed by title or abstract
(n=1974)
Articles included for meta-analysis
(n=23)
Articles included in systematic review
(n=29)
18 additional articles from bibliographies included. Articles for full text review
(n=111)
Articles eligible for review
(n=94)
Excluded duplicates
(n=973)
Excluded by title or abstract
(n=1880)
Excluded articles not reporting characteristics of inclusion criteria
(n=83)
Excluded articles reporting risk inconsistent with inclusion criteria
(n=6)
Inclusion:
Study in unselected population, community
Reporting risk effect size in RR/OR/HR
Outcome: incident heart failure

22. EARLY HEART FAILURE Studies included
Author
Study (Trial)
Total
(n)
F-U
(year) HF 1
Ho;
Kannel ;
Ho et al
Framingham study (Framingham and Offspring)
9450 40
652 2
Butler
Kalogeroul
Health ABC study (Health Aging and Body Composite Study)
2934
6.5
258 3 He
NHANES (National Health Nutrition Examination Survey
13643 19
1382 4
Eriksson
Men born in 1913 (Sweden)
973 17
311 5
Agarwal
ARIC (The Atherosclerosis Risk in Communities)
13555
15.5
1487 6
Goyal
One Million Person-Year
359947
4001 7
Dunlay
Population based CC-Mayo
1924
962 8
Bahrami
MESA (Multi-Ethnic Study of Atherosclerosis)
6814 79 9
Gottdiener; Mujib
Cardio Vascular Health
5625 12
597 10
Chen YT
EPESE (Established Population for Epidemiologic Studies of the Elderly program)
1749
173 11
Wilhelmsen
MPPS (Sweden)
7495 27
937
Bibbins-D
CARDIA (Coronary Artery Risk Development in Young Adults)
5115 20 13
Ingelsson
ULSAM
2321 29
259 14
Wang J
Kuopio (Finland)
1032
20.7
303 15
Aronow
Mt Sinai
2902
3.58
794 16
Smith JG
MDCS (Sweden)
5187
112
Kenchaiah
Physician’s heart (US)
21094 21
1109 18
Brouwers
PREVEND (Netherlands)　
8592
12　
374

23. EARLY HEART FAILURE Risk variables identified
Clinical Risks
Clin Risks (uncontrollable)
Lab risk markers
Age
Gender (male)
Fasting Glucose
Obesity
Smoking, COPD
C-reactive protein
Diabetes
Low Physical Activity
Renal dysfunction
Family History
Coffee, Alcohol
Albumin
Hypertension
Sleep disorder
Dyslipidemia
Education, race
Abnormal ECG (LVH)
Resting Heart Rate
NT-proBNP, BNP
Atrial Fibrillation
Troponin
Valvular Heart disease
LVEF (echo, MRI)
Coronary artery disease (CAD)
BP medication
CVA or TIA
Other medication

24. Risk Variable -Hypertension

25. EARLY HEART FAILURE Inclusion/ Exclusion
> 65 years
Diabetes
High blood pressure /on treatment
Overweight
Family history of heart failure
Past history of chemotherapy
Past history of heart disease
Inclusion
< 65 years
> Moderate valve disease
History of heart failure
Already on BB and ACEi
Contraindications to BB or ACEi
Oncologic life expectancy <12 month
Inability to acquire adequate images
Exclusion

26. EARLY HEART FAILURE Rural HF project
Why - The epidemiology of heart failure
Detection - is HF screening an option?
Right population
Right test
Rx strategy
Measuring outcomes
Quantifying risk, FP and FN results
Proof of Principle – TasELF study
Lessons about community-based RCTs

27. BNP release from Cardiac Myocytes
EARLY HEART FAILURE
BNP release from Cardiac Myocytes
preproBNP (134 aa)
myocyte
proBNP (108 aa)
signal peptide (26 aa)
secretion
NT-proBNP (1-76)
BNP (77-108)

28. EARLY HEART FAILURE BNP to ER presentation with dyspnea
N=139 N=14 N=97
Maisel A. J Am Coll Cardiol 2001

29. Preclinical disease and BNP
EARLY HEART FAILURE
Preclinical disease and BNP
n=101 apparently normal diabetic subjects (asymptomatic, normal EF)
BNP in LVH pts was higher than those without LVH
But only 4 had elevated BNP (using age and gender-specific normal ranges) - only 1 had low velocity/strain
BNP is not a good marker of subclinical disease (no substitute for the echo lab!)
Fang ZY. Am Heart J 2005
p<0.05
NT-proBNP (pg/ml)
Taylor A. Am Heart J 2006

30. EARLY HEART FAILURE Echo is essential in HF diagnosis
My field of research is understanding the genes contributing to disease in particular famililial cancers
Siemens
SC2000
Philips
ie33 GE
Vivid e9

31. EARLY HEART FAILURE Progressive miniaturization

32. EARLY HEART FAILURE Early HF – Standard tests normal
LA volume
32ml/m2

33. EARLY HEART FAILURE Measurement of strain

34. EARLY HEART FAILURE Strain and sick heart muscle

35. EARLY HEART FAILURE Other diagnostic markers?
Central Blood Pressure
ECG
6 Minute-walk Test (6MW)
Assessment of Activity and quality of life
Minnesota MLHFQ score
Charlson comorbidity index
Duke Activity Status Index (DASI)
EQ5D
SOF frailty score

36. EARLY HEART FAILURE Rural HF project
Why - The epidemiology of heart failure
Detection - is HF screening an option?
Right population
Right test
Rx strategy
Measuring outcomes
Quantifying risk, FP and FN results
Proof of Principle – TasELF study

37. Stage B Heart failure cardio-protective Treatment (SOLVD trial)
SOLVD – Prevention Trial
Study of Left Ventricular Dysfunction
There was no difference between the carvedilol and placebo groups in the primary endpoint of all-cause mortality or hospital admission for cardiovascular problems (HR = .92 ; CI = ).
percentage of event, defined as death or hospitalization for congestive Heart Failure, occurring in the placebo and Enalapril (ACEi) Groups

38. Cardio-protective Treatment of Stage B Heart failure (SAVE trial)
SAVE Trial - Captopril
Study of Survival and Ventricular Enlargement Trial
There was no difference between the carvedilol and placebo groups in the primary endpoint of all-cause mortality or hospital admission for cardiovascular problems (HR = .92 ; CI = ).

39. EARLY HEART FAILURE Rural HF project
Why - The epidemiology of heart failure
Detection - is HF screening an option?
Right population
Right test
Rx strategy
Measuring outcomes
Quantifying risk, FP and FN results
Proof of Principle – TasELF study

40. EARLY HEART FAILURE Stage B HF - Progression to overt HF
Aaron M. From et al. The development of Heart Failure in Patients with Diabetes Mellitus and Preclinical Diastolic Dysfunction: A Population Based Study. JACC ; 55(4)
Natural history of SBHF
Olmsted County study (n=1760)
LV dysfunction in T2DM
25% HF in 2 years, 36.9% in 5 years, twice the rate of HF in patients without LV dysfunction

41. TASELF Process Measures
EARLY HEART FAILURE
TASELF Process Measures
(n)

42. EARLY HEART FAILURE Rural HF project
Why - The epidemiology of heart failure
Detection - is HF screening an option?
Right population
Right test
Rx strategy
Measuring outcomes
Quantifying risk, FP and FN results
Proof of Principle – TasELF study

43. EARLY HEART FAILURE Changes needed
Medicare
Tasmania Medicare Local
DHHS
THOs
“55113 – Cardiac M-mode and 2 dimensional real time echocardiographic examination of the heart … for the investigation of symptoms or signs of cardiac failure, or
suspected or known ventricular hypertrophy or dysfunction, or chest pain”

44. EARLY HEART FAILURE
Research Questions
1. What is the prevalence of Stage B Heart Failure (LVSD & LVDD) in at risk population in Tasmanian community
2. How does functional capacity (6MW test) correlates with echo systolic and diastolic parameters
3. How does central blood pressure associate with diastolic dysfunction and LV mass
4. What is a better echo marker LVEF, GLS and diastology in stage B heart failure.
5. How does screening and early treatment affect quality of life?
6. Is community screening cost effective?
7. What are the main constrains of a community screening model? Main constrains of treatment delivery.

45. TASELF - Study design
Title
Tasmanian Study of Echocardiographic detection of Left ventricular dysfunction
Trial acronym
TAS-ELF (H )
Trial ID
ACTRN
Study Type
Interventional (Prospective Randomized Open Blinded Endpoint-Probe)
Allocation
Randomized Controlled (Adaptive)
Sample size
400 x 400 (=0.044, β=0.8; 7.8% annual loss); 25% versus 12.5% in 2 yrs
Random seq. Masking/blind
Enrollment followed by randomization (central web-based program).
Masked: those involved in recruiting, randomization, analyzing data.
Participants
Eligibility: (>65 year, Stage A[ACC/AHA guideline]); Exclusion: BB + ACEi
Recruitment
18 months. Self-referred (by advertising and recommendation by GP)
Follow Up
Phone tracking on 1st, 6th,12th,18th,24th month. Repeat assessment: 24th month.
Primary
Secondary
New onset of heart failure;
6 minutes walk test distance

46. TASELF Planned sites Hobart Huonville Oatlands Geeveston Longford
Deloraine
Launceston
Smithton
Ulverstone
George Town
Devonport
New Norfolk
Sorrell
Kingston
Scottdale
Queenstown
St Helen’s

47. EARLY HEART FAILURE How we will screen for HF

48. EARLY HEART FAILURE Planned protocol
Apparently healthy subject with HF risk
Exclusion of known HF, co-morbidities, CAD
Subclinical LVD – start ACEi and BB
(n=120)
Normal LV
2 year follow-up for HF and functional capacity
Clinically suitable for randomization
Clinical questionnaires
Usual care
Exclusion of reduced EF (<40%), valve disease, CAD
BNP in borderline
Baseline echo
Randomize
1:1 (n=800)
Echo strain, diastology
HF 25%
HF 10%
HF 5%
Aim to study 800 subjects in the 1st year (400 subjects with HF screening and therapy vs 400 controls)
~16 studies per week (ie 2 trips/week)

49. Venn diagram TASELF risk profile
Missing
T2DM – Chemo : 3
Chemo- T2DM-Obe: 3
T2DM
Obese 5 2 78 20 6 31 1 55 7 4 DM
31%
Obese
49%
HTN
87%
Chemo
10%
FHx Ht
37%
Past Ht dis
12%
Total (n=220)
HYT
Chemo

50. TASELF Registry – updated May 2014
Assessed for eligibility
(n=511)
Randomized
(n=220)
Allocation
Allocated to intervention (=104)
- Treatment (n=76)
- Observation (Normal echo) (n=28)
Allocated to observation (n=116)
- Treatment (n=2)
- Observation (n=114)
Excluded (n=178)
Not meeting inclusion
Participant registered (n=828)

51. EARLY HEART FAILURE The Big Picture
At June 2010, there were 79,100 people aged 65 years and over in Tasmania % of the population
The prevalence of people in this age group with diabetes (T2DM), obesity, high blood pressure, past cancer therapy or known cardiac disease is about 50% - roughly 40,000 people (100 times the number in the study)
An effective program on a state-wide basis would avoid/delay heart failure in 2,400 people.

52. EARLY HEART FAILURE Stakeholders
Impact of project on stakeholders
Prof Marwick and Ms Yang
Support of their research activities
Menzies Research Institute Tasmania
Leadership of a community-based initiative that aligns with the mission of the Institute
Rural GPs
Access to diagnostic testing that may help identify and avoid patients developing a potential problem with heart failure
Rural communities
Access to a service that will reduce the risk of serious illness and hospital admission far away from their family/social support
Consultants/hospitals
Reduction of urgent heart failure admissions
Wider community
If successful, the proposed strategy will be of value in all practices and not restricted to the rural community

53. EARLY HEART FAILURE Support
Item
Amount
Source
Contribution to Echo equipment
$150,000
Tas Community Fund
$105,000
Siemens
Sonographer PhD scholarship
$75,000
National Heart Foundation
Supervision – Principal investigator, cardiologists, GPs
$50,000+
Menzies, THO-S, practices
Support of travel, research assistants
$50,000
$40,000
Diabetes Australia
vTAHSP
Total
~$500k

54. Thank you

55. EARLY HEART FAILURE Rural HF project
Why - The epidemiology of heart failure
Detection - is HF screening an option?
Right population
Right test
Rx strategy
Measuring outcomes
Quantifying risk, FP and FN results
Proof of Principle – TasELF study
Lessons about community-based RCTs

56. EARLY HEART FAILURE Time frame
Tasks
Responsible person
Start date
Due date
Milestones
Communication with GPs, advertising to communities
Prof Tom Marwick, Dr Michael Lees
1st July 2013
30th June 2014
Recruitment of ~10 communities
Ethics application
Prof Tom Marwick
17th July 2014
Approval
Screening and imaging in communities
Ms Hilda Yang, other members of Prof Tom Marwick’s team
Screening of subjects in 12 months
Treatment of patients with undiagnosed disease
Dr Michael Lees, GPs in other communities, supported by Dr Jeff Evans, Prof Marwick, RHH and LGH cardiologists
30th July 2016
Appropriate management of identified patients
Follow-up at 12, 24, 36 months
1st July 2014
30th June 2016
Follow-up of screened subjects
Data analysis
Prof Tom Marwick, Hilda Yang
1st July 2016
Complete analysis
Dissemination of results
December 2016
Submission to Australian and international symposia and publication
Translation of science to practice
Implementation of screening programme Statewide

57. HEART FAILURE IN RURAL COMMUNITIES Risk evaluation
Likelihood
Seriousness
Mitigation plan
Failure to recruit practices in other towns
Low
Serious
Contacts already being made
Failure to recruit appropriate patients
Direct approaches to communities
Loss of patients to follow-up
Less then expected
incidence of eligible pts fitting screening criteria
Moderate
Increase recruitment
Less incidence of early stage HF than expected
Very unlikely - that would be an excellent outcome!
Lower success than anticipated in reducing % that develop late stage HF
None – this would be a negative study. The community still have the benefit of vascular screening.
Lack of buy-in from Government Agencies to implement programme
Moderate if the effect is less than anticipated
Involvement of the Heart Foundation and Diabetes Australia to help make our case with government.

58. EARLY HEART FAILURE Implications of Early HF
1,760 diabetic pts with assessment of cardiac function; 411 (23%) abnormal
Every 1-U increase in E/e' ratio a/w increase of HF hazard ratio of 3%
Diastolic dysfunction a/w HF after adjustment for age, sex, BMI, HT, CAD and echo parameters (HR: 1.61; p = 0.003).
From AM et al. J Am Coll Cardiol 2010