Detection and management of preclinical heart failure

Director, Menzies Research Institute Tasmania

Tom Marwick

Overt heart failure

(Stages C and D)

Risk factors including social

determinants and behaviour (Stage A)

Preclinical disease

Stage B

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Preclinical heart failure

Hunt SA, et al. J Am Coll Cardiol 2009;53:e1-e90

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HF stages

Stage BStructural heart

disease but without signs or symptoms of HF

Stage AAt high risk for HF without structural heart disease or

symptoms

Stage CStructural heart

disease with prior or current

symptoms of HF

Stage DRefractory HF

requiring specialized intervention

Patient with:-Previous MI-LV remodeling including LVH and low EF-Asymptomatic valvular disease

Patient with:-Hypertension-Atherosclerosis-Diabetes-Metabolic syndrome-Cardiotoxins-With FHx CM

1. Why - The epidemiology of heart failure

2. Detection - is HF screening an option?a. Right population

b. Right test

c. Rx strategy

d. Measuring outcomes

e. Quantifying risk, FP and FN results

3. Proof of Principle – TasELF study

4. Lessons about community-based RCTs

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TCF funding – Rural HF project

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What is heart failure?

Acute heart failure

Chronic heart failure

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

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Magnitude of the Problem

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The heart failure epidemic

Hospital admissions per 1,000 population per year for heart failure (Kannel WG. Br Heart J 1994)

Why is HF increasing?- Aging- Survival from heart attack- Risk factors

- BP- diabetes- obesity

Chance of getting HF?- About 30%

HF IS THE SINGLE MOST EXPENSIVE DIAGNOSIS IN HEALTH SYSTEM

Wellcome Museum, London

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Metabolic drivers of the HF epidemic

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HF – Survival rate at 5 years

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) 315-322

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

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Heart Failure - Quality of Life

Lynn J. JAMA 1997; 277:1633-40

PF: Physical functionRP: Role limitationBP: Body painGH: General health perceptionsVT: VitalitySF: Social functionRE: Emotional ProblemsMH: Mental Health

Focus on early disease to change trajectory

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HF is bad! What can we do about it?

1. Why - The epidemiology of heart failure

2. Detection - is HF screening an option?a. Right population

b. Right test

c. Rx strategy

d. Measuring outcomes

e. Quantifying risk, FP and FN results

3. Proof of Principle – TasELF study

4. Lessons about community-based RCTs

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TCF funding – Rural HF project

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Screening for HF

• Prevalence: 10% (> 65 yrs)

• At June 2010, there were 79,100 people aged 65 years and over in Tasmania - 15.6% of the population

• Can we afford to screen ~80,000 people in order to find ~8,000 with HF?

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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

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Essentials of screening

Thomas Bayes, 1702-61

1. Choosing the right population

2. Having the right test

3. Absolute vs relative risk

4. Defining the phenotype

5. Having a treatment strategy

6. Knowing how to manage false positive and false negative tests

1. Why - The epidemiology of heart failure

2. Detection - is HF screening an option?a. Right population

b. Right test

c. Rx strategy

d. Measuring outcomes

e. Quantifying risk, FP and FN results

3. Proof of Principle – TasELF study

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Rural HF project

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Shrink the haystack

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Framingham HF Risk Score

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Health ABC HF Score

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ARIC HF Risk Score

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PRISMA- A Meta AnalysisTotal 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:1)Study in

unselected population, community

2)Reporting risk effect size in RR/OR/HR

3)Outcome: incident heart failure

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Studies included

Author Study (Trial)Total(n)

F-U(year)

HF(n)

1Ho; Kannel ; Ho et al

Framingham study (Framingham and Offspring) 9450 40 652

2ButlerKalogeroul

Health ABC study (Health Aging and Body Composite Study)

2934 6.5 258

3 HeNHANES (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 5 4001

7 Dunlay Population based CC-Mayo 1924 　 962

8 Bahrami MESA (Multi-Ethnic Study of Atherosclerosis) 6814 4 79

9Gottdiener; Mujib

Cardio Vascular Health 5625 12 597

10 Chen YTEPESE (Established Population for Epidemiologic Studies of the Elderly program)

1749 10 173

11 Wilhelmsen MPPS (Sweden) 7495 27 937

12 Bibbins-DCARDIA (Coronary Artery Risk Development in Young Adults)

5115 20 27

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 14 112

17 Kenchaiah Physician’s heart (US) 21094 21 1109

18 Brouwers PREVEND (Netherlands)　 8592 12　 374

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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

Risk Variable -

Hypertension

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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• < 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

Inclusion

Exclusion

1. Why - The epidemiology of heart failure

2. Detection - is HF screening an option?a. Right population

b. Right test

c. Rx strategy

d. Measuring outcomes

e. Quantifying risk, FP and FN results

3. Proof of Principle – TasELF study

4. Lessons about community-based RCTs

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Rural HF project

myocyte

preproBNP (134 aa)

proBNP (108 aa) signal peptide (26 aa)

secretion

NT-proBNP (1-76) BNP (77-108)

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BNP release from Cardiac Myocytes

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BNP to ER presentation with dyspnea

Maisel A. J Am Coll Cardiol 2001

38+/-4141+/-31

1076+/-138

0

200

400

600

800

1000

1200

BN

P p

g/m

l

No CHF LV DysfunctionNo acute CHF

CHF

N=139 N=14 N=97

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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/strainBNP is not a good marker of subclinical disease (no substitute for the echo lab!)

Fang ZY. Am Heart J 2005

0

500

1000

1500

2000

2500

Obese Non-obese

Ischemic Dilated

p<0.05

p<0.05

NT-proBNP (pg/ml)

Taylor A. Am Heart J 2006

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Echo is essential in HF diagnosis

SiemensSC2000

Philipsie33

GEVivid e9

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Progressive miniaturization

LA volume32ml/m2

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Early HF – Standard tests normal

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Measurement of strain

1.3 S-1

0.7 S-1

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Strain and sick heart muscle

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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

1. Why - The epidemiology of heart failure

2. Detection - is HF screening an option?a. Right population

b. Right test

c. Rx strategy

d. Measuring outcomes

e. Quantifying risk, FP and FN results

3. Proof of Principle – TasELF study

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Rural HF project

Stage B Heart failurecardio-protective Treatment

(SOLVD trial)

SOLVD – Prevention TrialStudy of Left Ventricular Dysfunction

percentage of event, defined as death or hospitalization for congestive Heart Failure, occurring in the placebo and Enalapril (ACEi) Groups

Cardio-protective Treatment of Stage B Heart failure (SAVE trial)

SAVE Trial - CaptoprilStudy of Survival and Ventricular Enlargement Trial

1. Why - The epidemiology of heart failure

2. Detection - is HF screening an option?a. Right population

b. Right test

c. Rx strategy

d. Measuring outcomes

e. Quantifying risk, FP and FN results

3. Proof of Principle – TasELF study

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Rural HF project

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Stage B HF - Progression to overt HF

• 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

Aaron M. From et al. The development of Heart Failure in Patients with Diabetes Mellitus and Preclinical Diastolic Dysfunction: A Population Based Study. JACC 2010 26; 55(4)

1. Why - The epidemiology of heart failure

2. Detection - is HF screening an option?a. Right population

b. Right test

c. Rx strategy

d. Measuring outcomes

e. Quantifying risk, FP and FN results

3. Proof of Principle – TasELF study

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Rural HF project

“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”

DHHSTHOs

Tasmania Medicare Local

Medicare

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Changes needed

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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.

TASELF - Study design

Title Tasmanian Study of Echocardiographic detection of Left ventricular dysfunction

Trial acronym TAS-ELF (H00013333)

Trial ID ACTRN12614000080628

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.

PrimarySecondary

New onset of heart failure; 6 minutes walk test distance

TASELF Planned sites

HobartHuonvilleOatlands GeevestonLongfordDeloraine LauncestonSmithton Ulverstone George Town DevonportNew NorfolkSorrellKingstonScottdaleQueenstownSt Helen’s

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How we will screen for HF

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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 y

ear

follo

w-u

p f

or

HF

and f

unct

ional ca

paci

ty

Clinically suitable for randomization

Clinical questionnaires Usual

care

Exclusion of reduced EF (<40%), valve disease, CADBNP in borderline

Baseline echo

Randomize1:1 (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)

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)

• At June 2010, there were 79,100 people aged 65 years and over in Tasmania - 15.6% 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.

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The Big Picture

Stakeholder Impact of project on stakeholdersProf Marwick and Ms Yang Support of their research activitiesMenzies 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

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Stakeholders

Item Amount Source

Contribution to Echo equipment $150,000 Tas Community Fund

Contribution to Echo equipment $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 AustraliavTAHSP

Total ~$500k

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Support

Thank you

1. Why - The epidemiology of heart failure

2. Detection - is HF screening an option?a. Right population

b. Right test

c. Rx strategy

d. Measuring outcomes

e. Quantifying risk, FP and FN results

3. Proof of Principle – TasELF study

4. Lessons about community-based RCTs

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Rural HF project

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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 1st July 2013 17th July 2014 Approval

Screening and imaging in communities

Ms Hilda Yang, other members of Prof Tom Marwick’s team

1st July 2013 30th June 2014 Screening of 800 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

1st July 2013 30th July 2016 Appropriate management of identified patients

Follow-up at 12, 24, 36 months

Ms Hilda Yang, other members of Prof Tom Marwick’s team

1st July 2014 30th June 2016 Follow-up of screened subjects

Data analysis Prof Tom Marwick, Hilda Yang

1st July 2016 30th July 2016 Complete analysis

Dissemination of results Prof Tom Marwick, Hilda Yang

30th July 2016 December 2016 Submission to Australian and international symposia and publication

Translation of science to practice

Prof Tom Marwick 30th July 2016 December 2016 Implementation of screening programme Statewide

Risk Likelihood Seriousness Mitigation plan

Failure to recruit practices in other towns

Low Serious Contacts already being made

Failure to recruit appropriate patients

Low Serious Direct approaches to communities

Loss of patients to follow-up Low Serious Direct approaches to communities

Less then expectedincidence of eligible pts fitting screening criteria

Low Moderate Increase recruitment

Less incidence of early stage HF than expected

Low Low Very unlikely - that would be an excellent outcome!

Lower success than anticipated in reducing % that develop late stage HF

Low Low 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

Serious Involvement of the Heart Foundation and Diabetes Australia to help make our case with government.

HEART FAILURE IN RURAL COMMUNITIES

Risk evaluation

1,760 diabetic pts with assessment of cardiac function; 411 (23%) abnormalEvery 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

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Implications of Early HF