Heart failure with preserved lvef and senile amyloidosis
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Transcript of Heart failure with preserved lvef and senile amyloidosis
Heart Failure with a Preserved Ejection Fraction and Senile
Amyloidosis: Under Appreciated and Often Overlooked
Mat Maurer, MD
Columbia University Medical Center
March 15, 2015
Disclosures
• I have research support from several pharmaceutical companies and device companies that are working on TTR amyloid: – Foldrx Pharmaceuticals, Inc. –Pfizer, Inc. – ISIS Pharmaceuticals –Alnylam Pharmaceuticals
• I will discuss unapproved investigational therapies for TTR amyloidosis.
5 Things we know about Senile (ATTRwt) Cardiac Amyloidosis
1. Senile cardiac amyloid (ATTRwt) is the most common form of cardiac amyloidosis.
2. ATTRwt cardiac amyloid is an under-appreciated cause of HFpEF
3. An EKG is not a good screening test for ATTRwt.
4. SCA is a great masquerader but there are clues
5. Non-invasive bone scintigraphy is highly specific for ATTR cardiac amyloid
5 Things we know about Senile (ATTRwt) Cardiac Amyloidosis
1. Senile cardiac amyloid (ATTRwt) is the most common form of cardiac amyloidosis.
2. ATTRwt cardiac amyloid is an under-appreciated cause of HFpEF
3. An EKG is not a good screening test for ATTRwt.
4. SCA is a great masquerader but there are clues
5. Non-invasive bone scintigraphy is highly specific for ATTR cardiac amyloid
Cardiac Amyloid: A Rare Condition? Incidence/Prevalence
Type Incidence/Prevalence 1◦ AL Amyloid ~2500 Cases per year
50% have cardiac involvement
ATTRmutant 4% of African Americans are carriers
25,000-120,000 US patients
ATTRwt (SCA) ~10-25% of adults >80 years
~1 million
TTR (Prealbumin)
Transthyretin - TTR • Tetramer of subunits of 127 amino
acids each • TTR is a plasma transport protein for
thyroxine (T4) and for retinol.
ATTR Amyloidosis in United States: THAOS Registry
• Most common type is ATTRwt
• 76±7 years
• 97% Males
• Echo; – IVS = 18±3 mm
– EF = 51±12%
• Survival: 58.5% at 3 years
N= 390
5 Things we know about Senile (ATTRwt) Cardiac Amyloidosis
1. Senile cardiac amyloid (ATTRwt) is the most common form of CA.
2. ATTRwt cardiac amyloid is an under-appreciated cause of HFpEF
3. An EKG is not a good screening test for ATTRwt.
4. SCA is a great masquerader but there are clues
5. Non-invasive bone scintigraphy is highly specific for ATTR cardiac amyloid
TTR Cardiac Amyloidosis: A underappreciated cause of HFpEF
JACC Heart Fail. 2014;2(2):113-22.
8%
92%
< 75 years
Amyloid No Amyloid
32%
68%
> 75 years
Amyloid No Amyloid
Transthyretin Cardiac Amyloid in Afro-Caribbean Patients with ADHF
• 1,142 ADHF patients • 170 (14.9%) Afro-
Caribbean patients – 17 (10%) were confirmed to
have cardiac ATTR V122I.
• Survival worse in amyloid compared to non-amyloid cardiomyopathy – 34 vs 59 months,
p<0.01.
JACC 2012; 59 (13): E993
Black Patients (n=170)
All Other Patients (n=972)
P value
Age (years) 71 (53-77) 73 (63-81) <0.01
Male 64.7% 67.1% <0.01
Non-ischemic 87.1% 58.2% <0.01
ATTR V122I 10% 0.4% <0.01
HTN disease 18.8% 7% <0.01
TTR cardiac amyloidosis among elderly patients with HFpEF (=120)
Parameter Result
Age (years) 83±9
% Female 61%
NT-proBNP (pg/L) 3524
LVH by EKG 13%
MWT (mm) 14
EF (%) 61±8
European Heart Journal (2014) 35: S1025
5 Things we know about Senile (ATTRwt) Cardiac Amyloidosis
1. Senile cardiac amyloid (ATTRwt) is the most common form of CA.
2. ATTRwt cardiac amyloid is an under-appreciated cause of HFpEF
3. An EKG is not a good screening test for ATTRwt.
4. SCA is a great masquerader but there are clues
5. Non-invasive bone scintigraphy is highly specific for ATTR cardiac amyloid
Both of them
Which patient has Cardiac Amyloid?
ECG is Relatively Insensitive
0%
25%
50%
75%
100%
AtrialFibrillation
Pseudoinfarct PPWRP Low Limb LeadVoltage
Low PrecordialLead Voltage
Sokolow Criteria AbnormalVoltage to
Masss Ratio
Overall (n=210) AL (n=110)
ATTRmt (n=45) ATTRwt (n=45)
Am J Cardiol. 2014;114(7):1089-93
5 Things we know about Senile (ATTRwt) Cardiac Amyloidosis
1. Senile cardiac amyloid (ATTRwt) is the most common form of CA.
2. ATTRwt cardiac amyloid is an under-appreciated cause of HFpEF
3. An EKG is not a good screening test for ATTRwt.
4. SCA is a great masquerader but there are clues
5. Non-invasive bone scintigraphy is highly specific for ATTR cardiac amyloid
You’ve Got to Think of IT to Diagnose IT!!!
History/ Exam Clues
• HFPEF without hypertension,
particularly in men
• Evidence of right-sided heart
failure (e.g. hepatomegaly, ascites,
and lower extremity edema)
• Intolerance of ACE, Beta-blockers.
• Bilateral carpal tunnel syndrome
Imaging Clues • Thick septum and granular
sparkling on 2D TTE
• Low voltage to mass ratio
• Low tissue Doppler velocities,
strain, or strain rate
• Apical sparring on strain rate
imaging
• Delayed gadolinium enhancement
on CMRI
Preserved Apical Strain Echocardiographic Clue
Delayed Enhancement in Amyloid
5 Things we know about TTR Cardiac Amyloidosis
1. TTR amyloid is the most common form of CA.
2. TTR cardiac amyloid is an under-appreciated cause of HFpEF
3. An EKG is not a good screening test for TTR amyloidosis
4. Clues to TTR Cardiac Amyloidosis are available
5. Non-invasive bone scintigraphy is highly specific for TTR amyloid
Noninvasive Diagnosis of TTR Cardiac Amyloidosis Using 99mTc-DPD Scintigraphy
J Am Coll Cardiol 2005;46:1076–84
Differences in Cardiac Retention with Tc-99
in Controls, AL and ATTR Amyloid
Circ Cardiovasc Imaging. 2013;6(2):195-201.
PYP Scanning for Cardiac Amyloid Sensitivity and Specificity
Semi-Quantitative Sensitivity Specificity
91% 90%
Positive
Predictive
Value
Negative
Predictive
Value
95% 82%
Scoring 0 = absent cardiac uptake and
normal bone uptake
1 = mild cardiac uptake,
inferior to bone uptake
2 = moderate cardiac uptake
equal to bone or attenuated
bone uptake;
3 = strong cardiac uptake
greater than bone or with
mild/absent bone uptake
PYP Scanning for Cardiac Amyloid Sensitivity and Specificity
Quantitative Sensitivity Specificity
91% 90%
Positive
Predictive
Value
Negative
Predictive
Value
95% 82%
Methods
• Heart: Whole body
• Heart: CL Ratio
• Heart: Blood Pool
What we don’t know about Senile Cardiac Amyloidosis
1. How early does cardiac amyloid develop?
2. Does senile cardiac amyloid cause age related cardiovascular disorders?
3. What is the role of cardiac biomarkers?
4. Are there effective treatments for ATTRwt amyloid?
What we don’t know about Senile Cardiac Amyloidosis
1. How early does cardiac amyloid develop?
2. Does senile cardiac amyloid cause age related cardiovascular disorders?
3. What is the role of cardiac biomarkers?
4. Are there effective treatments for ATTRwt amyloid?
Age Dependent Penetrance
Journal of Cardiac Failure, 2011; 17 (8), S69
What we don’t know about Senile Cardiac Amyloidosis
1. How early does cardiac amyloid develop?
2. Does senile cardiac amyloid cause age related cardiovascular disorders?
3. What is the role of cardiac biomarkers?
4. Are there effective treatments for ATTRwt amyloid?
TTR Amyloid as a Cause of Age Related Cardiac and Non-Cardiac Disorder
• HFpEF (aka DHF)
• Atrial fibrillation
• Conduction disease
• Subdural hematoma
• Lumbar Spinal Stenosis
Ups J Med Sci. 2014 Aug;119(3):223-8, JACC Heart Fail. 2014;2(2):113-22
What we don’t know about Senile Cardiac Amyloidosis
1. How early does cardiac amyloid develop?
2. Does senile cardiac amyloid cause age related cardiovascular disorders?
3. What is the role of cardiac biomarkers?
4. Are there effective treatments for ATTRwt amyloid?
Biomarkers for TTR Cardiac Amyloid
What we don’t know about Senile Cardiac Amyloidosis
1. How early does cardiac amyloid develop?
2. Does senile cardiac amyloid cause age related cardiovascular disorders?
3. What is the role of cardiac biomarkers?
4. Are there effective treatments for ATTRwt amyloid?
Disease modifying therapeutic opportunities for TTR amyloidosis
Tafamidis Open Label Study: Baseline Demographics / Medical History
Parameter Overall N=35 V122I
N=4 Wild-Type
N=31 Mean age, years (SD) 76.4 (4.65) 72.8 (3.38) 76.9 (4.62)
Gender (% male) 32 (91.4) 3 (75.0) 29 (93.5)
Black 4 (11.4) 4 (100.0) 0
NYHA (I / II / III ) 5 / 28/ 2 0 / 3 / 1 5 / 25/ 1
Duration of TTR-CM symptoms, months (SD) 92.5 (92.34) 74.5 (34.24) 94.8 (97.46)
NT-proBNP, pg/mL 4934.2 (4324.9) 5317.5 (343.0) 4909.5 (4465.1)
Troponin I, ng/mL 0.135 (0.080) 0.140 (0.000) 0.134 (0.082)
Atrial fibrillation*, n (%) 21 (60.0) 1 (25.0) 20 (64.5)
Cardiac pacemaker/ ICD. n (%) 14 (40.0%) 1 (25.0%) 13 (41.9%)
Circ Heart Failure: Accepted for publication
TTR Stabilization* with Tafamidis 20 mg QD
Visit Wild-Type
N=31
Week 6* Patients evaluated, n
Patients stabilized, n (%)
95% CI
31
30 (96.8)
83.3–99.9
Month 6 Patients evaluated, n
Patients stabilized, n (%)
95% CI
30
27 (90.0)
73.5–97.9
Month 12 Patients evaluated, n
Patients stabilized, n (%)
95% CI
28
25 (89.3)
71.8–97.7
*Primary endpoint.
Clinical Stabilization with Tafamidis* Considered stabilized if: • Alive and
• Did not have 2 of the following parameters – TTR not stabilized
– Increase in NT-proBNP ≥1000 pg/mL from baseline
– Increase in troponin I ≥0.1 ng/mL from baseline
– ≥10% unit decrease in EF from baseline
– >2 mm increase in IVS thickness from baseline
74%
26%
Stabilization Clinically with Tafamidis
Stabilized
NotStabilized
* Investigational - not approved
Tafamidis* in Patients With Transthyretin Cardiomyopathy (ATTR-ACT)
• Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy (ATTR-ACT) – NCT01994889
– Phase III study in 400 subjects randomized to 80 mg (n=160), 20 mg (n=80) or placebo (n=160).
– 30 Months duration
– Primary endpoint is all-cause mortality and frequency of cardiovascular-related hospitalization
– Analysis: hierarchical combination of the endpoints for a pooled analysis of the tafamidis treatment groups in comparison to placebo
* Investigational - not approved
Personalized Medicine for Adopting Dose of Tafamidis
Biochemistry. 2014;53(12):1993-2006. Amyloid – under review
Revusiran (ALN-TTRSC) in Patients With Transthyretin (TTR) Cardiac Amyloidosis
• Phase 2, Open-Label Trial
• Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Exploratory Clinical Activity of ALN-TTRSC in Patients With Transthyretin (TTR) Cardiac Amyloidosis – N= 26
– 35 day duration – 10 doses
• Primary Outcome – % experiencing adverse events (AEs), serious adverse events
(SAEs) and study drug discontinuation.
• Secondary Outcome: – Pharmacokinetics (PK) of ALN-TTRSC (revusiran)
– Effect of ALN-TTRSC (revusiran) on transthyretin (TTR)
Therapeutic Hypothesis for Revusiran in TTR Cardiac Amyloid
Production of mutant and wild type TTR
Neuropathy, cardiomyopathy
Organ deposition of monomers, amyloid
(β-pleated) fibril
Unstable circulating TTR tetramers
Stabilization of cardiomyopathy/neuropathy
(and potential recovery)
Prevention of organ deposition of TTR monomers and amyloid fibrils
(and potential clearance)
Reduction of unstable circulating
TTR tetramers
Revusiran acts to knock
down hepatic mutant and
wild-type TTR production
Revusiran Phase 2 Study Results Serum TTR Lowering at 5.0 mg/kg by TTR Type
Summary
• ATTRwt cardiac amyloid is an unrecognized and potentially modifiable cause of HFpEF.
• Early identification is essential and facilitated by
–Non-invasive imaging (echo and MRI)
–Bone Scintigraphy
• Emerging novel therapies are entering into early and late phase clinical trials.