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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 Patient with: Patient with: -Hypertension -Atherosclerosis -Diabetes -Metabolic syndrome -Cardiotoxins -With FHx CM -Previous MI -LV remodeling including LVH and low EF -Asymptomatic valvular disease Stage C Structural heart disease with prior or current symptoms of HF Stage D Refractory HF requiring specialized intervention Hunt SA, et al. J Am Coll Cardiol 2009;53:e1-e90 EARLY HEART FAILURE TCF funding – Rural HF project 1. Why - The epidemiology of heart failure 2. Detection - is HF screening an option? a. b. c. d. e. Right population Right test Rx strategy Measuring outcomes Quantifying risk, FP and FN results 3. Proof of Principle – TasELF study 4. 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 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 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 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 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 Lynn J. JAMA 1997; 277:1633-40 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 1. Why - The epidemiology of heart failure 2. Detection - is HF screening an option? a. b. c. d. e. Right population Right test Rx strategy Measuring outcomes Quantifying risk, FP and FN results 3. Proof of Principle – TasELF study 4. 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, overtreatment, 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 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 Thomas Bayes, 1702-61 EARLY HEART FAILURE Rural HF project 1. Why - The epidemiology of heart failure 2. Detection - is HF screening an option? a. b. c. d. e. Right population Right test Rx strategy Measuring outcomes Quantifying risk, FP and FN results 3. 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) Excluded duplicates (n=973) Articles reviewed by title or abstract (n=1974) Excluded by title or abstract (n=1880) Articles eligible for review (n=94) 18 additional articles from bibliographies included. Articles for full text review (n=111) Excluded articles not reporting characteristics of inclusion criteria (n=83) Articles included in systematic review (n=29) Excluded articles reporting risk inconsistent with inclusion criteria (n=6) Articles included for metaanalysis (n=23) Inclusion: 1) Study in unselected population, community 2) Reporting risk effect size in RR/OR/HR 3) Outcome: incident heart failure EARLY HEART FAILURE Studies included Author 3 Ho; Kannel ; Ho et al Butler Kalogeroul He 4 Eriksson 5 1 2 Study (Trial) Total (n) F-U (year) HF (n) Framingham study (Framingham and Offspring) 9450 40 652 2934 6.5 258 13643 19 1382 Health ABC study (Health Aging and Body Composite Study) NHANES (National Health Nutrition Examination Survey 973 17 311 Agarwal Men born in 1913 (Sweden) 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 8 Bahrami Gottdiener; Mujib MESA (Multi-Ethnic Study of Atherosclerosis) 6814 4 79 Cardio Vascular Health 5625 12 597 1749 10 173 7495 27 937 5115 20 27 2321 29 259 9 962 13 Ingelsson EPESE (Established Population for Epidemiologic Studies of the Elderly program) MPPS (Sweden) CARDIA (Coronary Artery Risk Development in Young Adults) ULSAM 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 10 Chen YT 11 Wilhelmsen 12 Bibbins-D 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 Inclusion Diabetes High blood pressure /on treatment Overweight Family history of heart failure Past history of chemotherapy Past history of heart disease • • • • • • • < 65 years Exclusion > 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 EARLY HEART FAILURE Rural HF project 1. Why - The epidemiology of heart failure 2. Detection - is HF screening an option? a. b. c. d. e. Right population Right test Rx strategy Measuring outcomes Quantifying risk, FP and FN results 3. Proof of Principle – TasELF study 4. Lessons about community-based RCTs 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 1200 1076+/-138 BNP pg/ml 1000 800 600 400 200 141+/-31 38+/-4 0 No CHF LV Dysfunction No acute CHF CHF N=139 N=14 N=97 Maisel A. J Am Coll Cardiol 2001 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!) NT-proBNP (pg/ml) 2500 p<0.05 p<0.05 2000 1500 1000 500 0 Obese Non-obese Ischemic Dilated Taylor A. Am Heart J 2006 Fang ZY. Am Heart J 2005 EARLY HEART FAILURE Echo is essential in HF diagnosis 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 1.3 S-1 0.7 S-1 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 1. Why - The epidemiology of heart failure 2. Detection - is HF screening an option? a. b. c. d. e. Right population Right test Rx strategy Measuring outcomes Quantifying risk, FP and FN results 3. Proof of Principle – TasELF study Stage B Heart failure cardio-protective Treatment (SOLVD trial) SOLVD – Prevention Trial Study 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 - Captopril Study of Survival and Ventricular Enlargement Trial EARLY HEART FAILURE Rural HF project 1. Why - The epidemiology of heart failure 2. Detection - is HF screening an option? a. b. c. d. e. Right population Right test Rx strategy Measuring outcomes Quantifying risk, FP and FN results 3. 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 EARLY HEART FAILURE Rural HF project 1. Why - The epidemiology of heart failure 2. Detection - is HF screening an option? a. b. c. d. e. Right population Right test Rx strategy Measuring outcomes Quantifying risk, FP and FN results 3. 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. Enrollment followed by randomization (central web-based program). Masking/blind 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 New onset of heart failure; Secondary 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 Clinical questionnaires Apparently healthy subject with HF risk Baseline echo Clinically suitable for randomization Exclusion of known HF, co-morbidities, CAD Exclusion of reduced EF (<40%), valve disease, CAD BNP in borderline HF 25% Usual care Randomize 1:1 (n=800) Normal LV HF 10% Echo strain, diastology Subclinical LVD – start ACEi and BB (n=120) 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) 2 year follow-up for HF and functional capacity Planned protocol TASELF Registry – updated May 2014 Participant registered (n=828) Assessed for eligibility (n=511) Excluded (n=178) Not meeting inclusion 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) 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 Stakeholder Prof Marwick and Ms Yang Menzies Research Institute Tasmania Rural GPs Rural communities Consultants/hospitals Wider community Impact of project on stakeholders Support of their research activities Leadership of a community-based initiative that aligns with the mission of the Institute Access to diagnostic testing that may help identify and avoid patients developing a potential problem with heart failure Access to a service that will reduce the risk of serious illness and hospital admission far away from their family/social support Reduction of urgent heart failure admissions 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 Contribution to Echo equipment $150,000 Tas Community Fund $105,000 Siemens Sonographer PhD scholarship $75,000 National Heart Foundation Supervision – Principal investigator, cardiologists, $50,000+ Menzies, THO-S, GPs practices Support of travel, research assistants $50,000 Diabetes Australia $40,000 vTAHSP Total ~$500k Thank you EARLY HEART FAILURE Rural HF project 1. Why - The epidemiology of heart failure 2. Detection - is HF screening an option? a. b. c. d. e. Right population Right test Rx strategy Measuring outcomes Quantifying risk, FP and FN results 3. Proof of Principle – TasELF study 4. 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 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 1st July 2013 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 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 HEART FAILURE IN RURAL COMMUNITIES Risk evaluation Risk Likelihood Seriousness Mitigation plan Failure to recruit practices Low in other towns Failure to recruit Low appropriate patients Loss of patients to follow-up Low Serious Contacts already being made Serious Less then expected incidence of eligible pts fitting screening criteria Low Moderate Direct approaches to communities Direct approaches to communities 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. Serious 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