Download Detection and management of preclinical heart failure

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