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.