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

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)

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

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

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

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

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

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

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) 315-322

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; 277:1633-40 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

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

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

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 - 15.6% of the population Can we afford to screen ~80,000 people in order to find ~8,000 with HF?

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

EARLY HEART FAILURE Essentials of screening Thomas Bayes, 1702-61 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

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

EARLY HEART FAILURE Shrink the haystack

EARLY HEART FAILURE Framingham HF Risk Score

EARLY HEART FAILURE Health ABC HF Score

EARLY HEART FAILURE ARIC HF Risk Score

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

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

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

Risk Variable -Hypertension

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

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

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)

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

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

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

EARLY HEART FAILURE Progressive miniaturization

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

EARLY HEART FAILURE Measurement of strain

EARLY HEART FAILURE Strain and sick heart muscle

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

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

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 = .80-1.07). 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 - 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 = .80-1.07).

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

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 2010 26; 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

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

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

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”

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.

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. Primary Secondary New onset of heart failure; 6 minutes walk test distance

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

EARLY HEART FAILURE How we will screen for HF

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)

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

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)

EARLY HEART FAILURE The Big Picture 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.

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

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

Thank you

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

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 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 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

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.

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