11/02/2020 1 Cardiac Amyloidosis General Medicine for Palliative Physicians Conference 2020 Dr Eleanor Wicks Clinical Lead of Inherited Cardiac Diseases Service Consultant Cardiologist and Honorary Senior Clinical Lecture in Heart Failure, Imaging, Inherited and Acquired Cardiac Diseases Oxford University Hospitals @eleanorwicks @HeartFailureOUH @OxfordICC @Cardiomyopathy Disclosures • Consultancy and speaker fees • Novartis, Servier, Alnylam • Advisory services • James Lind Alliance Project Steering Partnership • Cardiomyopathy UK, BHF, Takeda • Membership and advisory committees • ESC myocardial and pericardial diseases working group • Association for Inherited Cardiac Conditions • Cardiomyopathy UK and BHF Charity involvement • Inherited cardiac conditions (ICC) curriculum and training working group 1 2
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Cardiac Amyloidosis
General Medicine for Palliative Physicians Conference 2020
Dr Eleanor Wicks
Clinical Lead of Inherited Cardiac Diseases Service
Consultant Cardiologist and Honorary Senior Clinical Lecture in Heart Failure, Imaging, Inherited and Acquired
• James Lind Alliance Project Steering Partnership
• Cardiomyopathy UK, BHF, Takeda
• Membership and advisory committees
• ESC myocardial and pericardial diseases working group
• Association for Inherited Cardiac Conditions
• Cardiomyopathy UK and BHF Charity involvement
• Inherited cardiac conditions (ICC) curriculum and training working group
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Amyloidosis
• Aims:
– Improve awareness and update your knowledge &
understanding of amyloidosis
– Reinforce knowledge of epidemiology, red flags and
challenges in the diagnosis, assessment (and staging) of
cardiac amyloidosis
– Overview new treatment options
– Think about a coordinated, multi-disciplinary approach
Case 1
6MWT, 6-minute walk test; BJP, Bence Jones protein; CMR, cardiac magnetic resonance imaging; eGFR, estimated glomerular filtration rate; FLC, free light chain; NT-proBNP, N-terminal pro-B-type natriuretic peptide; SAP, serum amyloid P; TnT, troponin T; UPT, urine preservative transport
• 46-year old lady presented with nephrotic syndrome in January 2017• Renal biopsy – minimal change disease• Treated with prednisolone – no response• Cyclosporine A added – no response• June 2017, repeat renal biopsy – amyloid• Cr 143, eGFR 35ml/min, serum albumin 17g/L, 24hr UPT 13.2 g• NT-proBNP 465 ng/L, TnT 38 ng/L• κ FLC 72.5, λ FLC 172.4, κ/λ ratio 0.42, lambda BJP 0.4 g/24hr• Bone marrow biopsy – 7% lambda restricted plasma cells• Echocardiogram – no definite evidence of amyloid• Non-contrast CMR – likely early cardiac amyloid• SAP scan – moderate visceral amyloid load in the spleen and kidneys• 6MWT – 438 metres (82% of normal for age)
Dispenzieri A, et al. J Clin Oncol 2004;22(18):3751–3757
Stage 1: both markers low (NT-proBNP <332, TnT <0.035, TnI <0.1) median survival 26.4 monthsStage 2: one or other marker high survival 10.5 monthsStage 3: both markers high survival 3.5 months
Stage 1: both markers low (NT-proBNP <332, TnT <0.035, TnI <0.1) median survival 26.4 monthsStage 2: one or other marker high survival 10.5 monthsStage 3: both markers high survival 3.5 months
Case 2
• 77-year-old male
• Admitted with congestive cardiac failure
• Bilateral carpal tunnel decompressions 15 years ago
• Hx of AF and longstanding HTN
• No FH of note
• CKD (creatinine 180), proteinuria ++
• Resistant to diuretics +++
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CXR
ECG
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CMR
DPD Scintigraphy: Perugini stage
Perugini et al, JACC 2005
Huff et al, EHJ 2014
Grade 2 – cardiac uptake with intensity similar or greater than bone signal
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Diagnostic workup
Clinical Suspicion(Hx, ECG, echo +/- CMR)
DPD scan + serum, urine IFE + FLCs
+ve DPD, -ve screen +ve DPD, +ve screen
TTR cardiac amyloid likely
1. Offload2. Refer ICC clinic/NAC3. Discharge
AL amyloid possible
1. Offload 2. Liaise NAC and Haem as IP3. Consider endomyocardial biopsy4. Look for other organ involvement
-ve DPD, +ve screen -ve DPD, -ve screen
Consider alternative diagnosis
Treatment
• Diuretics as needed -> offload acutely
• Long term usual fluid balance advice
• Little role for ACEi, ARBs, BBs, rate limiting CCBs
• Digoxin controversial – generally avoid
Novel therapies considered:
• Transthyretin tetramer stabilising agents (diflusinal and tafamidis)
• Antisense and interfering RNA therapeutics (reduce TTR
production by 80-90%)
• Monoclonal anti-SAP antibodies (clearance of established amyloid)
Maurer et al, Circ Heart Fail 2015; Sekijima et al, Society of Amyloidosis 2006; Coelho et al, NEJM 2013; Ackermann et al, the International Society of Amyloidosis 2012; Richards et al, NEJM 2015.
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Case 3
• 68-year old lady, previously fit and well
• Gradual worsening of SOB
• She had several investigations, including an ECG and echo → significant LVH and voltage criteria for LVH on ECG
• Aortic stenosis and was planned for aortic valve surgery
• Before surgery she was scheduled for a CMR scan – she had pulmonary oedema during cardiac MRI → scan interrupted before LGE
• Emergency surgery and had mechanical aortic valve replacement
• Struggled thereafter with SOB
Case 3
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Echo 5 years later
Features of HCM: In an adult, HCM is defined by a wall thickness ≥15 mm in one or more LV myocardial segments – as measured by any imaging technique (echo, CMR or CT), that is not explained solely by loading conditions
CMR 5 years later
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CMR 5 years later: typical features of amyloid
Classic extensive ‘zebra’ scar pattern on late enhancement
Suspected cardiac amyloidosis -> Immunofixation serum and urine FL and electrophoresis-> negative
• Present in up to 15% of patients with AS and up to 30% of low-flow, low gradient AS
• In AS, CA is associated with increased risk of HF, mortality, treatment futility with AVR
• Look for specific red flags and confirm the diagnosis
• Transcatheter rather than surgical AVR preferred
• Start treatment for TTR amyloid as soon as diagnosis confirmed
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CHAD-STOP mnemonic for initial steps in CA:C: conduction and rhythm disorder prevention (amiodarone = ok, pacemaker)H: high heart rate maintenance A: anticoagulationD: diureticsSTOP: STOP betablockers and calcium channel blockers (to optimize HR, CO and preload), STOP digoxin and STOP renin-angiotensin-aldosterone inhibitors (to minimize severe hypotension, esp in autonomic dysfunction)
CHAD-STOP mnemonic for initial steps in CA:C: conduction and rhythm disorder prevention (amiodarone = ok, pacemaker)H: high heart rate maintenance A: anticoagulationD: diureticsSTOP: STOP betablockers and calcium channel blockers (to optimize HR, CO and preload), STOP digoxin and STOP renin-angiotensin-aldosterone inhibitors (to minimize severe hypotension, esp in autonomic dysfunction)
WHAT IS AMYLOIDOSIS?
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Amyloidosis
• Extracellular deposition of abnormally folded protein
• Over 30 different proteins
• Accumulate in tissues as amyloid fibrils which leads to progressive dysfunction
Bind Congo red and SAP
Unusual stability
Damage tissue structure
and organ function Serum Amyloid P (SAP) scintigraphy
Types of amyloidosis (differential diagnoses)
• Cardiac AL (light chain) amyloidosis
• Cardiac transthyretin (ATTR) amyloidosis
– Wild-type ATTR (Senile Systemic/Senile Cardiac)
– Hereditary transthyretin amyloidosis (hATTR) mutation of TTR gene e.g. V122I, T60A
• AA amyloidosis
• Rare (genetic)
• Apo A1/A2
• Lysozyme
Gonzalez-Lopez E, et al. Eur Heart J 2015;36:2585-94
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Amyloid fibril proteins
Amyloid fibril protein (circulating)
• Light chain of immunoglobulin
• Amyloid A protein
• ‘Normal’ TTR
• ‘Mutated’ TTR
There are more than 30 known amyloid fibril proteins!
Amyloid type
• AL
• AA
• ATTRwt
• hATTR
AA, amyloid A amyloidosis; AL, amyloidosis light chain; hATTR, hereditary; TTR amyloidosis; TTR, transthyretin; wt, wild-type. Data courtesy of National Amyloidosis Centre data 2018 (unpublished)
Terminology and classification
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Key facts 1: Cardiac Amyloidosis
• Rare form of cardiomyopathy, challenging to diagnose, often associated with poor prognosis
• Amyloidosis = a collection of disorders of protein mis-folding
• Mis-folded protein forms aggregates within a cell which are potentially toxic
• Excess of protein or impairment of clearance of abnormal protein can lead to amyloidosis
Knowles TP, et al. Nat Rev Mol Cell Biol. 2014;15:384–96.
Key facts 2
• Two types account for 95% of all cardiac amyloidosis:
• AL (light chain) fibril deposits
– Clonal plasma cell dyscrasia (disorder) that results in overproduction and misfolding of light chain antibody fragments
• TTR (transthyretin) deposits
– Due to misfolding of the liver-derived precursor protein transthyretin (TTR, previously called prealbumin)
AL, light chain; TTR, transthyretin. Donnelly J, Hanna M. Cleve Clin J Med 2017;84(12 Suppl 3):12–26.
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CARDIAC AL AMYLOIDOSIS
Cardiac AL amyloidosis
• Commonest diagnosed form of cardiac amyloidosis
• Cardiac involvement in 50-90% of systemic AL amyloidosis, often HF
• Derived from monoclonal immunoglobulin light chain
• Poor prognosis - median survival 12 months
• Median age at diagnosis is 50-60yrs
• May co-exist with multiple myeloma (10-15%) or any B-cell dyscrasia
but >80% due to subtle or ‘benign’ gammopathies
• Full clinical evaluation and investigations (ECG, Echo, CMR, biomarkers,
biopsy, SAP ± DPD scan, immunofixation of urine and serum, serum
immunoglobulin FLC, urine electrophoresis, bone marrow biopsy
– Hereditary transthyretin amyloidosis (hATTR) mutation of TTR gene e.g. V122I, T60A (inherited)
• Wild-type ATTR amyloidosis:
– Predominant cardiomyopathy and presents with symptoms of heart failure, arrhythmias, syncope, AS
– Risk factors for ATTRwt: Predominantly male (95%), increasing age, ?being historically fit
– 40-50% previous CTS, 50% atrial fibrillation at presentation
– Median survival >3 years(h)ATTR-CM, (hereditary) TTR amyloidosis cardiomyopathy; HF, heart failure; TTR, transthyretin; wt, wild-typeGertz MA, et al. J Am Coll Cardiol 2015;66(21):2451–2466; Conceição et al, J Peripher Nerv Syst 2016;21(1):5–9; Tanskanen M, et al. Ann Med 2008;40(3):232–239; Grogan M, et al. J Am Coll Cardiol 2016;68(10):1014–20; Pinney JH, et al. J Am Heart Assoc 2013;2(2):e000098
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Wild type transthyretin (ATTR) Amyloidosis
• Autopsy studies indicate cardiac ATTR amyloid deposits are present in up to 25% of men over 80 years of age
• 13% of hospitalised patients with HFpEF (and +++ more with AS ?32%) have been shown to have amyloidosis…for which there are now disease specific treatments
– but majority not diagnosed with amyloidosis in life
– Misdiagnosis - poor sensitivity and specificity of echocardiography
– Deposits clinically significant?
CTS: carpel tunnel syndrome
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Key facts 3: Modern epidemiology of ATTR amyloidosis
Frequency of cardiac ATTR amyloidosis deposits in different settings
• Amyloid deposits in autopsied subjects (mean age 69 years) without HF 16%
• Unexpected bone tracer myocardial uptake in patients >75 years undergoing 2.7%
scintigraphy for non-cardiac reasons 2
• Unexpected TTR mutations in patients with supposed sarcomeric HCM 3 5%
• Hospitalised patients with HFpEF 4 13%
• Amyloid deposits in autopsied elderly patients (mean age 76 years) with HFpEF 1 16%
• Elderly patients with severe degenerative aortic stenosis 5 32%
HCM: hypertrophic cardiomyopathy; HF: heart failure; HFpEF: heart failure with a preserved ejection fraction.1 Mohammed SF, et al. JACC Heart Fail 2014;2:113-22; 2 Longhi et al. JACC Cardiovasc Imaging 2014;7:531-23 Damy T et al. Eur Heart J 2016;37:1826-34; 4 Gonzalez-Lopez E, et al. Eur Heart J 2015;36:2585-94;5 Castano A, et al. Eur Heart J 2017;38:2879-87; 6 Grogan M, et al. J Am Coll Cardiol 2016;68:1014-20.
Hereditary ATTR amyloidosis
• Amyloid fibril protein is variant transthyretin (TTR)
• Spectrum of hereditary ATTR amyloidosis:– More than 130 genetic amyloidogenic variants of TTR– Autosomal dominant inheritance– Variable penetrance and phenotype, including:
Several single amino acid substitutions associated:• V30M-associated ATTR amyloidosis most prevalent worldwide (Portugal, Sweden,
Japan)• T60A-associated ATTR amyloidosis most prevalent in British and Irish Caucasians • V122I TTR variant present in ~4% of African-Americans
ATTR, TTR amyloidosis; TTR, transthyretin. Reilly MM, et al. J Neurol Neurosurg Psychiatry 1995;59(1):45–49; Carr AS, et al. J Neurol Neurosurg Psychiatry 2016;87(6):620–627
47%
14%
5%
6%
6%
22% T60A
V30M
G47V
V122I
E89K
Other
46 TTR mutations in the UK70.5% T60A CTS (-7.5, 13-0)
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TTR mutations
TTR, transthyretin
• TTR is a single polypeptide chain of 127 amino acids encoded by single gene on chromosome 18 with 4 exons, inherited as AD trait with variable penetrance
• TTR is a tetrameric plasma transport protein for thyroid hormone and retinol-binding protein/vitamin A synthesized in the liver
• Most TTR mutations are single nucleotide substitutions
Genotypic-phenotypic correlation in ATTR amyloidosis
Most prevalent variants in UK:2
T60A: 30%V122I: 64%
V30M and V122I: most
common mutations
worldwide1
Figure adapted from Rapezzi C. et al. Eur Heart J 2013;34:520–8 by permission of Oxford University Press1. Ando Y, et al. Orphanet J Rare Dis 2013;8:31; 2. Lane T, et al. Orphanet J Rare Dis 2015;10(Suppl 1):O26
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Key facts 4: TTR Thr60Ala amyloidosis
• Most common in UK and Ireland
• Later onset (average 61)
• Autonomic involvement early
• Cardiac involvement common
• No vitreous deposits
• Reduced penetrance (related to late onset)
Key facts 5: Transthyretin V122i: AD cause in elderly African Americans
Buxbaum JN, et al. Genet Med 2017; 19: 933:742.
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Prognosis of cardiac amyloidosis
0 12 24 36 48 600
20
40
60
80
100ATTRwt
ATTR T60A
ATTR V122IAL
Time (months)
Perc
en
t su
rviv
al
Median survival in cardiac AL ~12 monthsMedian survival in cardiac ATTR >3 years P<0.001
DIAGNOSIS OF CARDIAC AMYLOIDOSIS
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A form of Restrictive Cardiomyopathy
Restrictive Cardiomyopathy
Primary Restrictive Cardiomyopathy
Secondary Restrictive Cardiomyopathy
Endomyocardial Fibrosis
Loeffler’s Cardiomyopathy
Idiopathic Restrictive Cardiomyopathy
Infiltrative Disease Storage Disease
Amyloidosis
Sarcoidosis
Postirradiation Therapy
Hemochromatosis
Glycogen Storage Disease
Fabry’s Disease
Leung DY & Klein AL. In: Topol EJ, Califf RM, Isner JM, et al, eds. Textbook of
6MWT, 6-minute walk test; DPD, diphosphono-1,2-propanodicarboxylic acid; ECG, electrocardiography; eGFR, estimated glomerular filtration rate; MRI, magnetic resonance imaging; NT-proBNP, N-terminal pro brain-type natriuretic peptide;
QoL, quality of life; SAP, serum amyloid P; TnT, troponin T; uACR, urine albumin-to-creatinine ratio; uPCR, urine protein-to-creatinine ratio
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Diagnosis
• Clinical history
– Symptoms…carpel tunnel!
– Other medical conditions
– Medications - any side effects?
• Family history
• Physical examination
RCM symptoms
Maybe none or only minor symptoms which may progress:
• Breathlessness• Fatigue • Inability to exercise• Chest pain or pressure• Swelling of legs, feet or tummy bloating• Weight loss or gain if fluid +++• Waking at night feeling breathless or needing more pillows to sleep• Palpitations or irregular heart beat• Dizzy spells or fainting…pacemaker• Nausea, poor appetite• Numbness/tingling or carpel tunnel syndrome• …
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Key facts 6: Clinical manifestations of amyloidosis
*Very suggestive of AL amyloidosisAL, amyloidosis light chain; CNS, central nervous system; GI, gastrointestinal; UTI, urinary tract infectionBased on Conceição et al. J Peripher Nerv Syst 2016;21(1):5–9
Myopathy
*Macroglossia
GI manifestations
• *Organomegaly
• Nausea and vomiting
• Changes in GI motility
(i.e. diarrhoea, constipation,
gastroparesis, early satiety)
• Unintentional weight loss
CNS manifestations
• Progressive dementia
• Headache
• Ataxia
• Seizures
• Spastic paresis
• Stroke-like episodes
Renal manifestations
• Proteinuria
• Renal failure
Connective tissue
• Carpal tunnel syndrome
• Spinal Stenosis
Ocular manifestations
• Vitreous opacification
• *Periorbital ecchymosis• Glaucoma
• Abnormal conjunctival vessels
• Papillary abnormalities
Cardiovascular manifestations
• Conduction blocks
• Cardiomyopathy
• Palpitations and arrhythmia
• Mild regurgitation
• Shortness of breath
• Oedema
Peripheral sensory motor neuropathy
• Neuropathic pain
• Altered sensation (i.e. change in
sensitivity to pain and temperature)
• Numbness and tingling
• Muscle weakness
• Impaired balance
• Difficulty walking
Autonomic neuropathy
• Orthostatic hypotension
• Recurrent UTI (due to urinary retention)
• Sexual dysfunction
• Sweating abnormalities
Key facts 6: Diagnostic red flags
• Clinical suspicion
• Neuropathy
• Autonomic dysfunction (in absence of diabetes)
• Cardiac features (pacemaker)
• Irish/Portuguese
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Diagnostic Pathway of Cardiac Amyloidosis: Investigations and diagnosis
Constellation of clinical, laboratory and imaging findings
• History and examination
• Electrocardiogram (ECG)
• Echocardiography (TTE)
• Blood tests: including serum immunofixation, serum free light chains, eGFR, albumin, TnT and NT-proBNP
• Urine tests, including urine immunofixation, 24-hour albuminuria, uPCR and uACR
• Holter monitor for 24-48 hours
• Exercise test or cardiopulmonary exercise test (CPET) ± 6MWT
6MWT, 6-minute walk test; DPD, diphosphono-1,2-propanodicarboxylic acid; ECG, electrocardiography; eGFR, estimated glomerular filtration rate; MRI, magnetic resonance imaging; NT-proBNP, N-terminal pro brain-type natriuretic peptide;
QoL, quality of life; SAP, serum amyloid P; TnT, troponin T; uACR, urine albumin-to-creatinine ratio; uPCR, urine protein-to-creatinine ratio
Additional basic investigations
• To derive type of amyloid
• To assess risk from amyloid
• To assess symptom limitation
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Cardiac biomarkers ATTR: NT-proBNP
A raised NT-proBNP and TnT or TnI are predictive of adversity
Stage 1: both markers low (NT-proBNP <332, TnT <0.035, TnI <0.1) median survival 26.4 monthsStage 2: one or other marker high survival 10.5 monthsStage 3: both markers high survival 3.5 months
Stage 1: both markers low (NT-proBNP <332, TnT <0.035, TnI <0.1) median survival 26.4 monthsStage 2: one or other marker high survival 10.5 monthsStage 3: both markers high survival 3.5 months
Diagnosis – CMR, ETT, Holter
Exercise ECG MRI scan
Holter monitor
CPET
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Diagnostic Pathway of Cardiac Amyloidosis: Investigations and diagnosis
Constellation of clinical, laboratory and imaging findings
• History and examination
• Electrocardiogram (ECG)
• Echocardiography (TTE)
• Blood tests: including serum immunofixation, serum free light chains, eGFR, albumin, TnT and NT-proBNP
• Urine tests, including urine immunofixation, 24-hour albuminuria, uPCR and uACR
• Holter monitor for 24-48 hours
• Exercise test or cardiopulmonary exercise test (CPET) ± 6MWT
6MWT, 6-minute walk test; DPD, diphosphono-1,2-propanodicarboxylic acid; ECG, electrocardiography; eGFR, estimated glomerular filtration rate; MRI, magnetic resonance imaging; NT-proBNP, N-terminal pro brain-type natriuretic peptide;
QoL, quality of life; SAP, serum amyloid P; TnT, troponin T; uACR, urine albumin-to-creatinine ratio; uPCR, urine protein-to-creatinine ratio
CMR: What to look for
• LGE imaging is used to identify amyloid infiltration directly1
Transmural LGESubendocardial LGENo LGE
CMR, cardiac magnetic resonance imaging; LGE, late gadolinium enhancementFigure reproduced with permission from Fontana M, et al. Circulation 2015;132(16):1570–15791. Fontana M, et al. Circulation 2015;132(16):1570–1579
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Native T1 (mapping) in amyloidosis
AL, amyloidosis light chain; ATTR, TTR amyloidosis; LGE, late gadolinium enhancement; TTR, transthyretinFontana M, et al. JACC Cardiovasc Imaging 2014;7(2):157–165
Native T1 in the hypertrophic phenotype
HCM, hypertrophic cardiomyopathySado DM, et al. Circ Cardiovasc Imaging 2013;6(3):392–398
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Diagnostic Pathway of Cardiac Amyloidosis: Investigations and diagnosis
Constellation of clinical, laboratory and imaging findings
• History and examination
• Electrocardiogram (ECG)
• Echocardiography (TTE)
• Blood tests: including serum immunofixation, serum free light chains, eGFR, albumin, TnT and NT-proBNP
• Urine tests, including urine immunofixation, 24-hour albuminuria, uPCR and uACR
• Holter monitor for 24-48 hours
• Exercise test or cardiopulmonary exercise test (CPET) ± 6MWT
6MWT, 6-minute walk test; DPD, diphosphono-1,2-propanodicarboxylic acid; ECG, electrocardiography; eGFR, estimated glomerular filtration rate; MRI, magnetic resonance imaging; NT-proBNP, N-terminal pro brain-type natriuretic peptide;
QoL, quality of life; SAP, serum amyloid P; TnT, troponin T; uACR, urine albumin-to-creatinine ratio; uPCR, urine protein-to-creatinine ratio
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TREATMENT OF CARDIAC AMYLOIDOSIS
General Treatments
• Treat underlying cause (if identified)• Diuretics as needed -> offload acutely• Long term usual fluid balance advice, daily weights• Little role for ACEi, ARBs, BBs, rate limiting CCBs• Digoxin controversial• Rhythm control - Amiodarone• Anticoagulation• Autonomic neyropathy therefore tend to avoid ACEi or
beta-blockers unless already taking them and asymptomatic
• Advanced HF therapies • ?Disease-modifying meds
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Treatments
• Treat underlying cause (if identified)• Diuretics as needed -> offload acutely• Long term usual fluid balance advice• Little role for ACEi, ARBs, BBs, rate limiting CCBs• Digoxin controversial• Rhythm control
– Amiodarone• ?Disease-modifying meds unproven• Anticoagulation• Autonomic neyropathy therefore tend to avoid ACEi or beta-
blockers unless already taking them and asymptomatic • Advanced HF therapies
CHAD-STOP mnemonic for initial steps in CA:C: conduction and rhythm disorder prevention (amiodarone = ok, pacemaker)H: high heart rate maintenance A: anticoagulationD: diureticsSTOP: STOP betablockers and calcium channel blockers (to optimize HR, CO and preload), STOP digoxin and STOP renin-angiotensin-aldosterone inhibitors (to minimize severe hypotension, esp in autonomic dysfunction – unless already taking them and they are asymptomatic)
CHAD-STOP mnemonic for initial steps in CA:C: conduction and rhythm disorder prevention (amiodarone = ok, pacemaker)H: high heart rate maintenance A: anticoagulationD: diureticsSTOP: STOP betablockers and calcium channel blockers (to optimize HR, CO and preload), STOP digoxin and STOP renin-angiotensin-aldosterone inhibitors (to minimize severe hypotension, esp in autonomic dysfunction – unless already taking them and they are asymptomatic)
Minimise and manage side effects
• Low blood pressure
• Urinary frequency
• Fatigue
• Dizzy spells + fainting on exertion
• Erectile dysfunction
• Orthostatic hypotension, esp with autonomic neuropathy
In reactive systemic (inflammatory disease, AA) treated vigorouslyReducing the supply of the amyloid fibril precursor protein ->
amyloid regression
Gillmore JD, et al. Lancet 2001;358(9275):24–29; Lachmann HJ, et al. N Eng J Med 2007:356(23);2361–2371; Lachmann HJ, et al. Br J Haematol 2003;122(1):78–84; Palladini G, et al. J Clin Oncol 2012;30(36):4541–4549
Maurer et al, Circ Heart Fail 2015; Sekijima et al, Society of Amyloidosis 2006; Coelho et al, NEJM 2013; Ackermann et al, the International Society of Amyloidosis 2012; Richards et al, NEJM 2015.
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Other treatments for amyloidosis
• Antisense and interfering RNA therapeutics (reduce
Maurer et al, Circ Heart Fail 2015; Sekijima et al, Society of Amyloidosis 2006; Coelho et al, NEJM 2013; Ackermann et al, the International Society of Amyloidosis 2012; Richards et al, NEJM 2015.
TTR-lowering therapy: Alnylam & Ionis/AkceaReduce pre-cursor supply of amyloid through RNAi
ATTR, TTR amyloidosis; LFT, liver function test; RNA interference (RNAi), TTR, transthyretinCoelho T, et al. N Engl J Med 2013;369(9):819–829
Inotersen (Ionis/Akcea)
• A 2′-O-methoxyethyl–modified antisense oligonucleotide, inhibits hepatic production of transthyretin
• Phase 1 – healthy volunteer study
• 80% reduction in plasma TTR concentration
• Transient inflammation, abnormal LFTs
Patisiran (Alnylam)
• Phase 1 – healthy volunteer study
• 85% reduction in plasma TTR concentration
• Mild injection site reactions only toxicity
Rapid, dose-dependent, and durable lowering of mutant and non-mutant
transthyretin levels
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Statistically Significant Benefit in Neuropathy Disease Progression
• mNIS+7 Primary Endpoint
Placebo Inotersen
Baseline (absolute value) 74.12 79.35
Change from baseline to month 15
25.53 5.80
Statistically significant difference was observed at both 8 months and 15 months
LSM = Least Squares Method
02
04
06
08
0
0
5
1 0
1 5
2 0
2 5
3 0
S t u d y W e e k
mN
IS+
7
Ch
an
ge
fr
om
Ba
se
lin
e
(L
SM
S
EM
)
P la c e b o
I n o t e r s e n
1 9 . 7 3
( p = 0 . 0 0 0 0 0 0 0 4 )
8 . 6 9
( p = 0 . 0 0 0 5 )
mNIS+7: Modified neuropathy impairment score +7 neurophysiology tests; The Norfolk Quality of Life‐Diabetic Neuropathy (QOL‐DN) questionnaire
Benson et al. NEJM. 2018; 379: 22-31.
Statistically Significant Benefit in Quality of Life
• Norfolk QoL-DN Primary Endpoint
Statistically significant difference was observed at both 8 months and 15 months
* **
11.68
LSM = Least Squares Method*p = 0.032, **p = 0.0006
Placebo Inotersen
Baseline (absolute value) 48.60 48.57
Change from baselineto month 15
12.67 0.99
Benson et al. NEJM. 2018; 379: 22-31.
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NEURO-TTR: Inotersen - Safety Observations
• Overall death rate (2.9%)• 5 deaths in study: 5 (4.5%) in inotersen arm, 0 in placebo arm
– 4 deaths in the inotersen arm were associated with disease progression and considered unrelated to treatment• Cachexia (2)• Intestinal perforation due to sigmoid volvulus• Congestive heart failure following stoma revision surgery complications
– 1 fatal intracranial hemorrhage in conjunction with serious thrombocytopenia• No serious thrombocytopenia observed following implementation of more
frequent monitoring
• Inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis. Thrombocytopenia and glomerulonephritis were managed with enhanced monitoring.
*Approved by NICE May 2019 for stage 1 and stage 2 polyneuropathy in adults with hereditary transthyretin amyloidosis
Benson et al. NEJM. 2018; 379: 22-31.
Stages of familial amyloid polyneuropathy
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Patisiran Phase 3 APOLLO Study Results
• 87.8% mean serum TTR Reduction from baseline for patisiran over 18 months
SEM, standard error of mean; TTR, transthyretin. Adams D, et al. N Engl J Med 2018;379(1):11–21
Patisiran APOLLO study results (n=225)
NIS, neurological impairment score; QoL-DN, quality of life-diabetic neuropathy; SEM, standard error of mean; TTR, transthyretinAdams D, et al. N Engl J Med 2018;379(1):11–21
Primary endpoint: mNIS+7 change from baseline
Secondary endpoint: Norfolk QoL-DN change from baseline
TTR changeChange from baseline at 9 months Change from baseline at 18 months
adverse events; SOC, system organ class. Solomon SD, et al. Circulation 2019;139(4):431–443; Adams D, et al. Presented at American Academy of Neurology 2018; April 2018, Los Angeles, USA
• Mean cumulative function = average number of events per patient by a certain time
• Analysis of hospitalization/death data was conducted post-hoc based on data collected from AE CRFs; hospitalization/death events caused by SAEs within 28 days of last dose of study drug were included; hospitalization events caused by SAEs within SOC of cardiac disorder were classified as cardiac hospitalization
Recurrent hospitalization and death events by treatment arm (post-hoc analysis)*
• Diagnosis and typing of amyloid remains challenging
• Key to detection is a high level of suspicion
• ATTR amyloidosis is increasingly recognised & diagnosed
• Integrate all clinical information including patient demographics, race, gender, mode of presentation, ECG, echo and CMR, DPD and urine/serum analysis + FLC
• Diagnosis of ATTR-CM has been enhanced by CMR and bone scintigraphy
– More than two thirds of patients now diagnosed non-invasively
• But delays in diagnosis persist
– Earlier diagnosis of cardiomyopathy +/- via extra-renal manifestations
– Red flags & awareness, awareness (education)
• Simple staging systems can prognosticate and stratify enrolment of patients with ATTR amyloidosis into trials of novel ‘disease-modifying’ therapies
• Diagnosis is important to allow for effective patient management