Download A Modest Proposal - We are Overdue for an International Fontan

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Brian W. McCrindle
I have the following financial relationships to disclose:
Consultant /investigator for:
Aegerion
Daichii Sankyo
Janssen
Merck
I will not discuss off label use and/or investigational use
in my presentation.
CHSS Work Weekend – November 18-20, 2016
A Modest Proposal:
We are Overdue for
an International Fontan Registry
Brian W. McCrindle, MD MPH
Labatt Family Heart Centre, The Hospital for Sick Children
Department of Pediatrics, University of Toronto
A Modest Proposal
Jonathan Swift - 1729
Saturn Devouring His Son
Francisco Goya - 1823
An Uncertain Reality
Donald Trump - 2016
The Fontan Procedure
Promise and Reality
Single ventricle palliation
Natural history:
- rare long-term adult survivors, balanced circulations
Early palliations:
- arterial shunts, ductal stent, SVC connections
- pulmonic outflow procedures, pulmonary banding
- systemic outflow procedures, DKS
- atrial septostomy
- Norwood, hybrid procedures
Pulmonary Atresia
with Intact Ventricular Septum
Single ventricle palliation
Tricuspid atresia (Wilder et al. JTCVS 2015):
6 year survival: arterial shunt 85%, PA band 93%, SCPC 93%
Systemic right venticle (Ohye et al. NEJM 2011):
12 month survival: Norwood RVPA 74%, MBT 64%
Norwood interstage mortality 12% (Ghanayem et al, JTCVS
2012)
Outcomes after SCPC (Alsoufi et al. EJCTS 2012):
6 year competing risks: 17% dead, 76% Fontan, 7% still
waiting
Single ventricle palliation
Cavopulmonary connections:
1958 Glenn – SVC to distal RPA shunt
1971 Fontan/Baudet – “Fontan” procedure
1971-73 Bjork, Kreutzer – modifications
1972 Azzolina – bidirectional SVC anastomosis
1988 DeLeval – lateral tunnel
1989 Norwood/Jacobs – hemi-Fontan
1990 Marcelletti – extracardiac conduit
40 year follow-up after the Fontan operation: Longterm outcomes of 1,052 patients.
Pundi et al. JACC 2015; 66:1700-10
n=1,052 patients with Fontan from 1973-2012
Type of Fontan operation
Atriopulmonary connection
Lateral tunnel
Extracardiac conduit
Other
59%
25%
11%
5%
40 year follow-up after the Fontan operation: Longterm outcomes of 1,052 patients.
Pundi et al. JACC 2015; 66:1700-10
n=1,052 patients with Fontan from 1973-2012
Pre-operative anatomy
Tricuspid atresia
Double inlet LV
Heterotaxy
Pulmonary atresia/ IVS
HLHS
Other
26%
26%
13%
3%
2%
30%
40 year follow-up after the Fontan operation: Longterm outcomes of 1,052 patients.
Pundi et al. JACC 2015; 66:1700-10
Overall survival
71%
61%
43%
40 year follow-up after the Fontan operation: Longterm outcomes of 1,052 patients.
Pundi et al. JACC 2015; 66:1700-10
Causes of death known for 281 of 426 patients
Primary cardiac cause
83% (4 malignancies)
Contributing factors
Respiratory failure
Renal insufficiency
Sudden death/arrhythmia
Bleeding complications
DIC / sepsis
PLE
Hepatic insufficiency
36%
30%
19%
18%
17%
11%
10%
40 year follow-up after the Fontan operation: Longterm outcomes of 1,052 patients.
Pundi et al. JACC 2015; 66:1700-10
40 year follow-up after the Fontan operation: Longterm outcomes of 1,052 patients.
Pundi et al. JACC 2015; 66:1700-10
Overall survival by surgical era
1991-2000
< 1990
2001+
40 year follow-up after the Fontan operation: Longterm outcomes of 1,052 patients.
Pundi et al. JACC 2015; 66:1700-10
Overall survival by Fontan type
Extracardiac conduit
Other
AP connection
Lateral tunnel
40 year follow-up after the Fontan operation: Longterm outcomes of 1,052 patients.
Pundi et al. JACC 2015; 66:1700-10
Overall survival by lesion
40 year follow-up after the Fontan operation: Longterm outcomes of 1,052 patients.
Pundi et al. JACC 2015; 66:1700-10
Trends in Fontan surgery and risk factors for early
adverse outcomes: ANZ Fontan Registry.
Iyengar et al. JTCVS 2014; 148:566-75
Australia and New Zealand Fontan Registry 1975-2010
n=1095 Fontans, 1071 with sufficient data
1989 previous palliations in 990 patients
Trends in Fontan surgery and risk factors for early
adverse outcomes: ANZ Fontan Registry.
Iyengar et al. JTCVS 2014; 148:566-75
Early outcomes by era
1975-90
1991-2000
2001-10
Early mortality
8%
4%
1%
Early failure
9%
7%
4%
Prolonged effusions
4%
8%
8%
LOS >30 days
16%
12%
10%
Composite outcomes
26%
20%
12%
* Similar breakdown by Fontan type (AP > LT > ECC)
Outcomes associated with AP connection type, age at Fontan,
underlying morphology (HLHS, heterotaxy), high PA pressures
Redefining expectations of long-term survival after
the Fontan procedure: ANZ Fontan Registry.
D’Udekem et al. Circulation 2014; 130:S32-S38
Follow-up of 1006 survivors of 1089 patients
Redefining expectations of long-term survival after
the Fontan procedure: ANZ Fontan Registry.
D’Udekem et al. Circulation 2014; 130:S32-S38
Overall survival by Fontan type
Extracardiac conduit
Lateral tunnel
AP connection
Redefining expectations of long-term survival after
the Fontan procedure: ANZ Fontan Registry.
D’Udekem et al. Circulation 2014; 130:S32-S38
Redefining expectations of long-term survival after
the Fontan procedure: ANZ Fontan Registry.
D’Udekem et al. Circulation 2014; 130:S32-S38
Freedom from late Fontan failure
Non-HLHS RV
HLHS
NYHA III/IV, PLE/plastic bronchitis, Fontan conversion
or takedown, transplantation, death
LV
Redefining expectations of long-term survival after
the Fontan procedure: ANZ Fontan Registry.
D’Udekem et al. Circulation 2014; 130:S32-S38
Redefining expectations of long-term survival after
the Fontan procedure: ANZ Fontan Registry.
D’Udekem et al. Circulation 2014; 130:S32-S38
Freedom from late adverse events
Failure, SVT, stroke, pulmonary embolism, pacemaker
Redefining expectations of long-term survival after
the Fontan procedure: ANZ Fontan Registry.
D’Udekem et al. Circulation 2014; 130:S32-S38
Redefining expectations of long-term survival after
the Fontan procedure: ANZ Fontan Registry.
D’Udekem et al. Circulation 2014; 130:S32-S38
Freedom from supraventricular tachycardia
Extracardiac conduit
Lateral tunnel
AP connection
NIH Pediatric Heart Network
Fontan Cross-sectional Study
Initial PI – BJ Clark (Anderson, Atz)
7 clinical centres; data collection 2003-2004
Inclusion:
6-18 years of age
Minimum participation: echo, BNP, parent CHQ
Followed at study centre (or affiliate)
Exclusion:
Important disorder precluding participation
NIH Pediatric Heart Network
Fontan Cross-sectional Study
NIH Pediatric Heart Network
Fontan Cross-sectional Study
Limitations:
Undefined denominator; not an inception cohort
Incomplete participation; representativeness and
generalizability
Fewer Hispanics
Fewer with dev. delay / learning disability
Retrospective collection of medical history
NIH Pediatric Heart Network
Fontan Cross-sectional Study
Contemporary outcomes after the Fontan procedure: a
Pediatric Heart Network Study. Anderson et al. J Am Coll
Cardiol 2008; 52:85.
Main findings:
–FHS within normal range for 80%
–BNP low (median 13 pg/mL)
–Ejection fraction normal for 73%
–Evidence of diastolic dysfunction in 72%
–Peak VO2 66% of normal (many sub-max)
–Lower EF, more AVVR in single RV’s
NIH Pediatric Heart Network
Fontan Cross-sectional Study
Relationships of patient and medical characteristics to health
status in children and adolescents after the Fontan
procedure. McCrindle et al. Circulation 2006; 113:1123.
NIH Pediatric Heart Network
Fontan Cross-sectional Study
NIH Pediatric Heart Network
Fontan Cross-sectional Study
NIH Pediatric Heart Network
Fontan Cross-sectional Study
NIH Pediatric Heart Network
Fontan Cross-sectional Study
NIH Pediatric Heart Network
Fontan Cross-sectional Study
NIH Pediatric Heart Network
Fontan Cross-sectional Study
Laboratory measures of exercise capacity and ventricular
characteristics and function are weakly associated with
functional health status after Fontan procedure. McCrindle et
al. Circulation 2010; 121:34.
Overall, more associations with physical FHS than
psychosocial FHS; weak associations in general.
–Higher BNP, but R2=0.01.
–Physical FHS and exercise (max work rate; R2=0.09), echo
(Tei index [interaction], end-systolic volume, AVVR;
R2=0.14), MRI (mass/EDV, ESV; R2=0.11)
NIH Pediatric Heart Network
Fontan Cross-sectional Study
Clinical perspective:
1. The impact of treatment strategies targeted toward those
with important laboratory abnormalities in the pathological
range may influence FHS to an unknown degree but should
be an important component of future studies.
2. Strategies targeting FHS and its non-cardiac determinants
directly, such as through rehabilitation programs and by
addressing psychosocial morbidities, may have a greater
impact on health-related quality of life.
3. Such programs should be developed and evaluated for
these high-risk and complex patients.
NIH Pediatric Heart Network
Fontan Cross-sectional Study
Longitudinal assessment:
Fontan 2
Follow-up of current cohort
Vital status, FHS, interim medical events, access to health care, and
self-reported availability and willingness to participate in future
studies
Fontan 3 (SVR 2 and 3)
Further follow-up of current cohort
Includes cardiopulmonary exercise testing, echo, ECG, BNP,
biorepository
Transition and access to adult heart care
The long-term management of children and adults
with a Fontan circulation: A systematic review.
Gnanappa et al. Pediatr Cardiol 2016 [Epub]
Systematic review using PRISMA guidelines:
- Reasonable quality evidence for non-inferiority of ASA over
warfarin for thromboprophylaxis in standard risk Fontans
- No strong evidence for routine use of ACE inhibitors, beta
blockers, pulmonary vasodilators
- Little evidence for arrhythmia treatment, exercise
restriction/prescription, routine fenestration closure, elective
Fontan conversion, screening/management of liver
abnormalities
Survey of cardiologists (ANZ – 50% response): no uniformity
Pulmonary Atresia
with Intact Ventricular Septum
No simple answers
Pre-Fontan optimization
Preservation of optimal ventricular function
Preservation of low pulmonary vascular resistance (systemic
vascular resistance, vascular function, inflammation)
Systemic venous / lymphatic hypertension
Hepatic cirrhosis, PLE, plastic bronchitis
Thrombosis, arrhythmia, renal dysfunction, sarcopenia,
osteoporosis, lymphopenia
Neurodevelopmental / psychosocial / functional outcomes /
poor growth (short stature) / pregnancy
Need for data
Uniform (and deep) institutional data collection
Single ventricle survivorship programs
The relentless effects of the Fontan.
Rychik. Semin Thorac CV Surg 19:37-43
Why doesn’t everyone do this?
We don’t/can’t measure some of these things.
It’s way too complicated / expensive / resource-intensive.
My patients won’t do it.
My patient has unique features.
I followed it and didn’t believe (ie. agree with) the results,
or didn’t use it, or didn’t know what to do.
- Our results are better with ….
- Our results are better than ….
-
The traditional approach to risk stratification
and prediction
Relationships between factors and outcomes:
Causal
Confounder
Mediators
Effect modifiers / interaction
Random error
Based on probability theory – aimed at confidence
Univariable to multivariable approach
The traditional approach to risk stratification
and prediction
More complex stats to address more complex
questions – yields more complex answers, shades of
grey or “it depends”.
- Longitudinal models
- Multiple phases of risk
- Competing outcomes
- Repeating and interim events
- Time-varying covariates
Nonetheless, the overall R2 remains low.
The complexity of the Fontan pathway
- Underlying heterogeneity, unknown genetic and
environmental influences.
- Multiple procedures / impact of management.
- Operator dependence.
- Continuous evolution.
Human problem solving
- Flawed pattern recognition
- Reductionistic – reduce complexity, preference for
binary choices
- However, not rigorous
- Past experiences
- Errors in weighting
- Poor recognition of interaction
- Prone to suggestion
Factors in clinical decision-making
-
Mental state
The first patient I saw with this
The most recent patient I saw with this
My overall experience (impression or QA)
Literature, critical review, synthesis
Key influencers, authorities, CME
Individual patient characteristics, preferences
Practice environment, resources
A new approach
Biological systems are complex and based on many
associations.
Need to understand and model these complex
systems.
Define phenome-wide associations.
Necessary step towards personalized or precision
medicine.
Synergy and accelerated discovery; “in silico”
research.
Computational biology
Continuously define patterns in data.
eg. speech and face recognition, targeted advertising
BIG DATA – Deep and wide
Electronic medical record
Monitoring
Genetic / proteomic / biome data
Environmental / social data
Other external data sources
Patient reported data, social media
The nature of databases
Garbage – Some of the data for some of the patients
Registry – Some of the data for all of the patients
Academic database – All of the data for a defined
subset of patients
Integrated database – All of the data for all of the
patients
BIG ANALYTICS
- Logistic regression
- Support vector machine
- Deep learning, machine learning
- Artificial neural networks
On demand access to large, continuously updated
database + high performance computing.
EMR – phenotypic profiles – integrative predictive
models
Logistical challenges
Access, use agreements
Privacy, security
Linkages, translation, common terms
Need for data – The modest proposal
International Fontan Registry
Deep data and wide data
Computational biomedicine platform – big analytics
Discovery
Prediction
Nested mechanistic studies, clinical trials
Fontan BIG DATA
Systematic review, position paper
Education, EMBRACE COMPLEXITY
Prepare for BIG DATA
- Global unique identifier
- Standard diagnostic codes, definitions
- Standard data collection protocols
- Greater usability of EMRs
- Centralized biobanks
- Patient engagement
- Policy, funding for logistics
Interaction between inflammation, thrombin
generation and coagulation post -CPB
The modest proposal –
International Fontan Registry
1. Do we need this? Is now the time?
2. How do we do this?
– Who should build it?
– How deep / how wide?
– How should it be funded?
– How do we keep it going?
3. How do we use this?