[PDF] - Hospitalist Ronald Witteles, M.D. Stanford University School of PDF Document

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“Cardiology Pearls for the Hospitalist”

Ronald Witteles, M.D. Stanford University School of Medicine October 20, 2018

@Ron_Witteles

Outline

 A common patient scenario… – It might seem standard but… – Can we do better?  News hot off the presses  A diagnosis not to be missed

anymore… and one you certainly see!

 Final thoughts

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A Familiar Patient

78 y.o. man with dilated nonischemic

cardiomyopathy

Diagnosis: 4 years ago, normal coronary

angiogram, LBBB present

Echo at diagnosis (not significantly changed

since then): Moderately dilated LV, LVEF 25%, 3+ MR

Course over 4 years:
3 hospitalizations for ADHF (last 6 months

ago)

Generally adherent with meds
Usually NYHA 2-3 symptoms
BP typically runs in 105/70 range
NT-proBNP 4 months ago = 3000 pg/ml

Outpatient Medications

Furosemide 40 mg bid
Metoprolol tartrate 25 mg bid
Lisinopril 10 mg qd
Digoxin 0.5 mg qd
Rosuvastatin 10 mg qhs
KCl 20 mEq qd

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A Familiar Patient

Now – admitted to hospital
7 kg weight gain over last 3 weeks
Worsening DOE, now SOB with a few

steps

No chest pain, dizziness, or any other

symptoms

Exam & Labs

Exam (pertinent):
Afebrile, HR 72, BP 105/70, RR 16, SaO2 95% RA
JVP 15 cm H2O
Laterally displaced PMI, RRR with 2/6 systolic murmur at apex
Scattered bibasilar rales
3+ bilateral LE edema
Labs:
Na 136, K 4.4
BUN 26, Cr 1.4 (baseline 1.4)
NT-pro-BNP 6500 pg/mL
Troponin I: <0.1
Digoxin: 0.9 (therapeutic)
Lipids: LDL 115, HDL 45, TG 115

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Hospital Course

EKG/Echo – EF 25%, 3+MR, LBBB (similar to baseline)
Diuresed with IV furosemide over 4 days
Symptoms improve to close to baseline
Discharged home – same meds, augmented furosemide/K
Labs on day of discharge:
Na 134
K 4.2
BUN 35
Cr 1.6
NT-pro-BNP 5500 pg/ml
Digoxin 0.9 (therapeutic)
Could we have done any better for this patient?

What Do You Do?

What about the lisinopril?

1) Continue lisinopril unchanged 2) Uptitrate lisinopril dose to 20 mg qd 3) Change lisinopril to ARB 4) Stop lisinopril & start sacubitril/valsartan next day 5) Change lisinopril to ARB x 36 hours, then change to sacubitril/valsartan

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What Do You Do?

What about the lisinopril?

1) Continue lisinopril unchanged 2) Uptitrate lisinopril dose to 20 mg qd 3) Change lisinopril to ARB 4) Stop lisinopril & start sacubitril/valsartan next day 5) Change lisinopril to ARB x 36 hours, then change to sacubitril/valsartan

PARADIGM-HF

Neprilysin: Breaks down natriuretic peptides &

angiotensin II

Trial: Sacubitril-valsartan vs. Enalapril
Double-blind, randomized trial of 8442 patients
LVEF ≤ 40%
NYHA II-IV
Primary end-point: Time to CV death or HF

hospitalization

Stopped early after median follow-up of 27 months
ACC/AHA/HFSA Guidelines:
SWITCH NYHA Class 2-3 HFrEF patients

from ACEi or ARB to sacubitril-valsartan (Class 1 recommendation!)

Adapted from McMurray et al. New Engl J Med. 2014;371:993-1004.

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Breakdown of Outcomes

Adapted from McMurray et al. New Engl J Med. 2014;371:993-1004.

Breakdown of Outcomes

Adapted from McMurray et al. New Engl J Med. 2014;371:993-1004.

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Breakdown of Outcomes

Adapted from McMurray et al. New Engl J Med. 2014;371:993-1004.

What You Should Be Asking Yourself… Which systolic HF patients should I not be putting on sacubitril/valsartan?

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Practicalities of Use

Greater BP drop than with ACEi or ARB

alone

Must be off of ACEi for at least 36 hours

(angioedema risk)

All the more reason to get away from ACEi for

new heart failure patients

Make sure insurance approval in place!

Adapted from McMurray et al. New Engl J Med. 2014;371:993-1004.

What Should You Do with the Metoprolol 25 mg bid?

1) Stop the beta-blocker (ADHF admission) 2) Change to carvedilol 6.25 mg bid 3) Change to carvedilol 25 mg bid 4) Continue metoprolol tartrate 25 mg bid 5) Change to metoprolol succinate 50 mg qd

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What Should You Do with the Metoprolol 25 mg bid?

1) Stop the beta-blocker (ADHF admission) 2) Change to carvedilol 6.25 mg bid 3) Change to carvedilol 25 mg bid 4) Continue metoprolol tartrate 25 mg bid 5) Change to metoprolol succinate 50 mg qd

COMET Trial

3029 patients
LVEF < 35%
NYHA Class II-IV
HF Admission within last 2 years
Randomized to:
Carvedilol 3.125 mg bid  25 mg bid vs.
Metoprolol tartrate 5 mg bid  50 mg bid
Mean follow-up: 4.8 years

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10 COMET: Mortality

Adapted from Poole-Wilson et al. Lancet. 2003;362:7-13.

P= 0.0017

COMET: Heart Rates

Adapted from Poole-Wilson et al. Lancet. 2003;362:7-13.

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What should you do with the digoxin 0.5 mg/day?

1) Get rid of it. 2) Continue at a lower dose. 3) Continue unchanged.

What should you do with the digoxin 0.5 mg/day?

1) Get rid of it. 2) Continue at a lower dose. 3) Continue unchanged.

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Digoxin – DIG Trial (1997)

6800 patients with EF ≤ 45%
Digoxin vs. placebo
All patients in sinus rhythm
Outcomes:
Primary: All-cause mortality
Secondary: CV death, worsened HF &

hospitalizations

All-Cause Mortality

Adapted from NEJM. 1997;336:525-33.

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Death or HF Hospitalization

Adapted from NEJM. 1997;336:525-33.

placebo digoxin

Cochrane Review: Risk of Clinical Deterioration if Stop Dig

Adapted from Hood et al. Cochrane Library. 2004, Issue 4.

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An Inevitable Sequence of Events...

Well-meaning physician targets digoxin levels for

treatment of HF or atrial fibrillation

A patient with eggerthella lenta ends up on an

extremely high dose of digoxin

Patient receives antibiotics (Z-pack, etc.)
Patient gets dig-toxic
NOTE: This is the reason for antibiotic-digoxin

medication interactions!

How to Avoid This?

Step 1: Recognize we live in a world of antibiotics.
It is not realistic to think your patient will not

ultimately get an antibiotic prescription.

Step 2: Don’t target digoxin levels!
You can estimate daily dose by 2 main things:
GFR
Amiodarone use
Nobody should require a maintenance dose > 0.25 mg
Remember: For the most part, low levels are okay!
Particularly true if using for heart failure

indication rather than rate control

Reasons for checking digoxin levels:
You suspect toxicity
To check medication adherence

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DIG Trial: Post-hoc Analysis of Mortality

vs. 1-month Digoxin Levels

Adapted from Adams et al. J Am Coll Cardiol. 2005;46:497-504.

What Should You Do With the Rosuvastatin 10 mg?

1) Get rid of it. 2) Continue rosuvastatin 10 mg 3) Increase to rosuvastatin 40 mg 4) Switch to atorvastatin 40 mg 5) Switch to PCSK9 inhibitor

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What Should You Do With the Rosuvastatin 10 mg?

1) Get rid of it. 2) Continue rosuvastatin 10 mg 3) Increase to rosuvastatin 40 mg 4) Switch to atorvastatin 40 mg 5) Switch to PCSK9 inhibitor

GISSI-HF Trial

4574 patients with HF (ischemic or nonischemic)
NYHA Class II-IV
EF <40% or EF>40% but HF hospitalization in past 12

months

Ischemic (40%), Nonischemic (60%)
Randomized: Rosuvastatin 10 mg daily vs.

placebo

Primary endpoints:
Survival
Mortality or CV hospitalization

Adapted from GISSI-HF Investigators. Lancet. 2008;372:1231-9.

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GISSI-HF: Mortality

Adapted from GISSI-HF Investigators. Lancet. 2008;372:1231-9.

GISSI-HF: Mortality or CV Hospitalization

Adapted from GISSI-HF Investigators. Lancet. 2008;372:1231-9.

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A Mental Exercise

You’re a highly-paid executive at a big

pharmaceutical company which makes an on-patent statin.

You have been tasked with designing a heart failure

clinical trial to test your statin’s efficacy.

#1 concern: Get a positive result!
What type of study would you pitch?
Large
Placebo-controlled (not versus alternative lipid-

lowering agent!)

Only patients with ischemic cardiomyopathy
Primary endpoint: Vascular events!
Only one problem…
No way this would ever be considered ethical…
Right?

CORONA

5011 patients ≥ 60 years
All with ischemic, systolic HF
NYHA II: EF ≤ 35%
NYHA III-IV: EF ≤ 40%
Rosuvastatin 10 mg daily vs. placebo
Primary endpoint : A vascular endpoint (!)
CV death, nonfatal MI, nonfatal stroke

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CORONA: Primary Endpoint

Adapted from Kjekshus et al. NEJM. 2007;357:2248-61. Adapted from Kjekshus et al. NEJM. 2007;357:2248-61.

CORONA: All-Cause Mortality

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So What to Do With Statins in HF?

For nonischemic heart failure  forget it!
For ischemic heart failure…
If angina, PVD, etc.  still use
Otherwise  consider not using
Polypharmacy issues are real!
Let’s focus on what makes a real difference…

You are doubling the outpatient furosemide & plan to check a BMP within 5 days of discharge. What should you do with the potassium?

1) Get rid of it. 2) Increase KCl to 40 mEq/day. 3) Switch to spironolactone.

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You are doubling the outpatient furosemide & plan to check a BMP within 5 days of discharge. What should you do with the potassium?

1) Get rid of it. 2) Increase KCl to 40 mEq/day. 3) Switch to spironolactone.

RALES Trial

1663 patients with LVEF ≤ 35%
NYHA Class III-IV
Had been NYHA Class IV within 6 months of

enrollment

Excluded if Cr>2.5 mg/dl or K>5.0 mmol/L
Randomized to spironolactone 25 mg qd vs.

placebo

Primary outcome: All-cause mortality

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RALES Trial: Survival

Adapted from Pitt et al. NEJM. 1999;341:709-17.

EMPHASIS-HF Trial

2737 patients
Age >55 years, NYHA II
EF<30% (or 30-35% with QRS>130 ms)
Cardiac hospitalization in last 6 months or high

BNP

Excluded if K > 5.0 or GFR <30 mL/min
Randomized to eplerenone 50 mg qd vs.

placebo

Primary endpoint: CV Death or HF

hospitalization

Stopped early (21 months) due to + result

Adapted from Zannad et al. NEJM. 2011;364:11-21.

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EMPHASIS-HF: Primary Endpoint

Adapted from Zannad et al. NEJM. 2011;364:11-21.

EMPHASIS-HF: Overall Mortality

Adapted from Zannad et al. NEJM. 2011;364:11-21.

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Caution: Beware Unintended Consequences

Examined the impact of the RALES trial
n spironolactone prescriptions & events in

Canada between 1993-2001 (before/after RALES)

Spironolactone Prescriptions vs. Time

Adapted from Juurlink et al. NEJM. 2004;351:543-51.

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No Change in HF Admissions

Adapted from Juurlink et al. NEJM. 2004;351:543-51.

More Hospitalizations for Hyperkalemia

Adapted from Juurlink et al. NEJM. 2004;351:543-51.

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More In-Hospital Hyperkalemic Death

Adapted from Juurlink et al. NEJM. 2004;351:543-51.

Aldosterone Antagonists: Take-Home Points

Two large trials with very + results in

advanced systolic heart failure patients, but…

You must make sure the patient is set

up for appropriate potassium monitoring as an outpatient (as was done in the trials).

Is there really any higher risk of

hyperkalemia than with supplemental K?

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Is Any EP Device Indicated?

1) Consult for implantable loop monitor placement 2) Consult for ICD placement 3) Consult for biventricular pacemaker/ICD placement 4) No device is indicated

Is Any EP Device Indicated?

1) Consult for implantable loop monitor placement 2) Consult for ICD placement 3) Consult for biventricular pacemaker/ICD placement 4) No device is indicated

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COMPANION Trial (2004)

1520 patients
NYHA Class III-IV
LVEF ≤ 35%
QRS ≥ 120 ms, PR > 150 ms
Median QRS duration 160 ms
Randomized to medical therapy vs. biventricular

pacemaker vs. biventricular pacemaker/ICD

Median f/u: 16 months
Primary endpoint: Survival without hospitalization

COMPANION Trial: Survival Without Hospitalization

Adapted from Bristow et al. NEJM. 2004;350:2140-50. P< 0.001

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COMPANION Trial: Survival

Adapted from Bristow et al. NEJM. 2004;350:2140-50. P< 0.001

CARE-HF Trial

813 patients
NYHA Class III-IV
LVEF ≤ 35%
QRS ≥ 150 ms or 120-149 ms with additional echo criteria
Most patients = LBBB, Median QRS = 160 ms
Randomized to resynchronization vs. no

resynchronization

No ICD therapy
Median f/u: 29.4 months
Primary endpoint: All-cause mortality or CV

hospitalization

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30 CARE-HF Trial: Survival Without CV Hospitalization

Adapted from Cleland et al. NEJM. 2005;352:1539-49. P< 0.001

CARE-HF Trial: Overall Survival

Adapted from Cleland et al. NEJM. 2005;352:1539-49. P< 0.002

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How About the NT-proBNP?

Reminder – NT-proBNP levels: 4 months PTA: 3000 pg/ml Admission: 6500 pg/ml Possible discharge: 5500 pg/ml What should you do based on this result?

1) Discharge the patient as planned 2) Push forward with further diuresis 3) Further uptitrate neurohormonal antagonists

How About the NT-proBNP?

Reminder – NT-proBNP levels: 4 months PTA: 3000 pg/ml Admission: 6500 pg/ml Possible discharge: 5500 pg/ml What should you do based on this result?

1) Discharge the patient as planned 2) Push forward with further diuresis 3) Further uptitrate neurohormonal antagonists

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TIME-CHF Trial

499 patients age >60 with NYHA II-IV HF
All with HF hospitalizations within past year
Intervention: Symptom-guided management
r NT-proBNP-guided therapy
Primary endpoints:
18 month survival free of hospitalization
Quality of life at 18 months

Adapted from Pfisterer et al. JAMA 2009;301:383-92.

No Difference in Hospital-Free Surivival

Adapted from Pfisterer et al. JAMA 2009;301:383-92.

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No Difference in QOL (If Anything – Better Without NT-BNP!)

Adapted from Pfisterer et al. JAMA 2009;301:383-92.

Minnesota Living with Heart Failure Score

BOT-AcuteHF Trial

271 patients hospitalized for ADHF
Patients first treated with usual care until clinical

stability, then randomized to:

Conventional treatment (blinded to NT-proBNP

measurement), or

NT-proBNP-guided treatment
If NT-proBNP ≥ 3000 ng/L  treatment

intensified (more neurohormonal blockade, inotrope treatment, and/or more loop diuretics)

Primary endpoint:
CV Death or CV rehospitalization at day 182
Mean furosemide discharge dose (P=0.077):
Control: 164 mg
NT-proBNP-guided: 198 mg

Adapted from Castrini et al. J Cardiovasc Med. 2016;828-839.

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Outcomes (at 182 Days)

Adapted from Castrini et al. J Cardiovasc Med. 2016;828-839.

PRIMA II Trial

405 patients, randomized 2011-2015
Inclusion criteria:
ADHF admission
NT-proBNP ≥ 1700 ng/L
Patients first treated with usual care until clinical

stability, then randomized to:

Conventional treatment (blinded to NT-proBP

measurement), or

NT-proBNP-guided treatment (targeting >30%

NT-proBNP reduction from admission to discharge)

Followed treatment algorithm if NT-proBNP

value <30% reduction at randomization

Primary endpoint:
All-cause mortality and HF readmissions in 180

days after randomization

Adapted from Steinen et al. Circulation. 2018;137:1671-83.

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Primary Endpoint

Adapted from Steinen et al. Circulation. 2018;137:1671-83.

Primary Endpoint

Adapted from Steinen et al. Circulation. 2018;137:1671-83.

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2 Months Later

Readmitted with declining exercise

tolerance, volume overload despite close

utpatient follow-up and medication

adherence

Repeat TTE: LVEF 25%, 4+ MR, RVSP

60 mmHg

Surgical consult:
Too high-risk for mitral valve surgery or

LVAD (age, frailty, severe LV dysfunction)

Patient states he is not ready for

hospice/bridge-to-hospice consideration.

Is there anything else to do about the

severe MR?

What is the best option?

1) Continue optimal medical therapy alone. 2) Refer for a second surgical opinion for MV repair/replacement. 3) Refer for Mitraclip consideration.

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What is the best option?

1) Continue optimal medical therapy alone. 2) Refer for a second surgical opinion for MV repair/replacement. 3) Refer for Mitraclip consideration.

MitraClip trial: Mitra-FR

304 patients with severe ‘secondary’ MR
Ischemic or nonischemic
EF 15-40%, NYHA 2-4
Nonsurgical candidates
Maximal medical therapy
Randomized to OMT or MitraClip +

OMT

Primary endpoint: Death or HF hospitalization

at 12 months

Adapted from Obadia et al. NEJM. 2018; online before print. Downloaded Sep 24, 2018.

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Survival Without HF Hospitalization

Adapted from Obadia et al. NEJM. 2018; online before print. Downloaded Sep 24, 2018.

MitraClip trial: COAPT

614 patients with 3-4+ ‘secondary’ MR
Ischemic or nonischemic
EF 20-50%, NYHA 2-4
Nonsurgical candidates
Maximal medical therapy
Randomized to OMT or MitraClip +

OMT

Primary endpoint: HF hospitalizations at 24

months

Adapted from Stone et al. NEJM. 2018; online before print. Downloaded Sep 23, 2018.

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All-Cause Mortality

Adapted from Stone et al. NEJM. 2018; online before print. Downloaded Sep 23, 2018.

HF Hospitalizations

Adapted from Stone et al. NEJM. 2018; online before print. Downloaded Sep 23, 2018.

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Mitra-FR & COAPT: Why the Differences?

COAPT trial:
Larger
Longer follow-up
More technical expertise of operators
More intensive requirements of enrollment
Extremely rigorous requirements for med uptitration, CRT if

appropriate, HF expert involved in care

Worse MR (ERO = 0.41 cm2 vs. 0.31 cm2)
Higher NT-BNP (5500 vs. 3350)

Adapted from Stone et al. NEJM. 2018; online before print. Downloaded Sep 23, 2018.

Patient #2

76 y.o. man with gradually worsening HFpEF over

last few years

PMH:
HTN (controlled on losartan 50 mg)
No obstructive CAD on cath 6 months ago
Baseline meds: Losartan 50 mg qd, furosemide 20

mg bid, spironolactone 25 mg qd

Admitted with worsening SOB/edema
Echo: Moderate-severe LVH, grade 3 diastolic

dysfunction, LVEF 65%, no significant valvular disease

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EKG Hospital Course

Diuresed with IV furosemide, transitioned to po
Cr stable in 1.6-1.8 range (baseline)
Getting ready for discharge

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Is Any Other Testing Indicated?

1) No 2) Yes – cardiac MRI with gadolinium contrast 3) Yes – technetium pyrophosphate (PYP) nuclear scan 4) Yes – exercise stress echo 5) Yes – coronary angiography

Is Any Other Testing Indicated?

1) No 2) Yes – cardiac MRI with gadolinium contrast 3) Yes – technetium pyrophosphate (PYP) nuclear scan 4) Yes – exercise stress echo 5) Yes – coronary angiography

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Amyloidosis: What is it?

Amylum – Starch (Latin)
Generic term for many diseases:
Protein misfolds into -sheets 
Forms into 8-10 nm fibrils 
Extracellular deposition into amyloid deposits

Types of Amyloid – Incomplete List

Systemic:
Light chains (AL) – “Primary”
Transthyretin (ATTR) – “Senile” or “Familial”
Serum amyloid A (AA) – “Secondary”
Localized – Not to be memorized!
Beta-2 microglobulin (A-2) – Dialysis (osteoarticular structures)
Apolipoprotein A-1 (AApoA-I) – Age-related (aortic intima, cardiac, neuropathic)
Apolipoprotein A-2 (AApoA-2) – Hereditary (kidney)
Calcitonin (ACal) – Complication of thyroid medullary CA
Islet amyloid polypeptide (AIAPP) – Age-related (seen in DM)
Atrial natriuretic peptide (AANF) – Age-related (atrial amyloidosis)
Prolactin (APro) – Age-related, pituitary tumors
Insulin (AIns) – Insulin-pump use (local effects)
Amyloid precursor protein (ABeta) – Age-related/hereditary (Alzheimers)
Prion protein (APrPsc) – Hereditary/sporadic (spongiform encephalopathies)
Cystatin-C (ACys) – Hereditary (cerebral hemorrhage)
Fibrinogen alpha chain (AFib) – Hereditary (kidney)
Lysozome (ALys) – Hereditary (Diffuse, especially kidney, spares heart)
Medin/Lactadherin – Age-related (medial aortic amyloidosis)
Gelsolin (AGel) – Hereditary (neuropathic, corneal)
Keratin – Cutaneous

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Transthyretin (TTR)

Transthyretin = “Transports thyroxine and retinol”
Prealbumin by any other name
Primary source: Liver
Almost completely circulates as a tetramer
In steady-state with monomeric form
Thyroxine binding  stabilizes tetramer
Monomeric TTR is inherently ‘amyloidogenic’
Mutations in TTR can make it even more

amyloidogenic

Some mutations favor cardiac deposition, others nerve

deposition

Study of wtTTR Amyloid Prevalence

Study from Mayo Clinic

published in April 2014

Reviewed autopsies from:
109 patients with antemortem

diagnosis of HFpEF without any clinical suspicion of amyloidosis

Age-matched control patients

without antemortem HF diagnosis

Blinded pathology review

Adapted from Mohammed et al. J Am Coll Cardiol HF. 2014;2:113-22.

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ATTR Among TAVR Patients

151 patients referred for TAVR, 68% men, mean age 84 years
PYP scans performed on all
Findings:
High incidence of undiagnosed ATTR amyloidosis!

Adapted from Castano et al. Eur Heart J. 2017;38:2879-2887..

Familial ATTR Amyloidosis

Mutant transthyretin protein  more

“amyloidogenic”

Predominant manifestations:
Cardiomyopathy
Peripheral neuropathy
Dozens of mutations described!
Type of mutation correlates with severity, age of onset,

and clinical manifestations of disease

V30M mutation: Most common in Portugal (1/600)
Familial amyloid polyneuropathy (“FAP”)
V122I mutation: Seen in 3+% of individuals of African

descent (!)

By far the most common mutation encountered in USA
Familial amyloid cardiomyopathy (“FAC”)

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V-122I: How Common, How Important?

3856 black participants in Atherosclerosis

Risk in Community (ARIC) study recruited from 1987-1989

Note: Only 36% male, average age 52 at entry
Each participant genotyped for TTR gene
Findings:
Mutation in self-reported black population:

124/3732 (3.2%)

Mutation in non-black population: 2/10893

(0.02%)

More systolic/diastolic dysfunction, higher NT-

BNP in V-122I carriers

7% of carriers with overt amyloid CM

Adapted from Quarta et al. NEJM. 2015. 372:21-9.

Technetium Pyrophosphate (PYP) Scanning

 99mTc-pyrophosphate (PYP) – Old nuclear bone scan agent – Taken up by hearts infiltrated with ATTR but typically not AL amyloidosis

Adapted from Bokhari et al. Circ Cardiovasc Imaging. 2013;6:195-201 and Castano et al. JAMA Cardiol. 2016;1:880-9.

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Largest Study of Bone Scintigraphy

 Study across 8 centers in 5 countries

(N=1217)

 All patients with suspected or proven

ATTR amyloidosis received:

– Bone scintigraphy (PYP or DPD or HMDP) – SPIE/UPIE – Serum FLC  100% specificity for ATTR amyloidosis

when you combine scintigraphy & no monoclonal protein

Adapted from Gillmore et al. Circulation. 2016;133:2404-12.

Treatment: ATTR Amyloidosis

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Strategies to Prevent TTR Amyloid Deposition

Stabilize tetrameric form of TTR
Knock down production of TTR

in all forms

Adapted from Penchala et al. PNAS. 2013;110:9992-9997.

Patisiran: APOLLO Trial

225 patients with hATTR polyneuropathy
Randomized to patisirian (q3 week IV) vs.

placebo (2:1 randomization), double-blind

Premeds: Dexamethasone, acetaminophen,

diphenhydramine, H2 blocker

Primary endpoint
Change in mNIS+7 score at 18 months
Well-tolerated – only mild infusion

reactions

Results… Spectacular!

Data adapted from http://www.alnylam.com/wp-content/uploads/2017/11/EU-ATTR-2017_APOLLO- TRL_CAPELLA_FINAL_2Nov2017.pdf, and Adams et al, NEJM. 2018;379:11-21.

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APOLLO Results: mNIS+7

Data adapted from http://www.alnylam.com/wp-content/uploads/2017/11/EU-ATTR-2017_APOLLO- TRL_CAPELLA_FINAL_2Nov2017.pdf, and Adams et al, NEJM. 2018;379:11-21.

APOLLO Results: mNIS+7

Data adapted from http://www.alnylam.com/wp-content/uploads/2017/11/EU-ATTR-2017_APOLLO- TRL_CAPELLA_FINAL_2Nov2017.pdf, and Adams et al, NEJM. 2018;379:11-21.

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APOLLO Cardiac Subgroup Data

Data adapted from http://www.alnylam.com/wp-content/uploads/2017/11/EU-ATTR-2017_APOLLO- TRL_CAPELLA_FINAL_2Nov2017.pdf, and Adams et al, NEJM. 2018;379:11-21.

APOLLO Cardiac Subgroup: NTBNP

Data adapted from http://www.alnylam.com/wp-content/uploads/2017/11/EU-ATTR-2017_APOLLO- TRL_CAPELLA_FINAL_2Nov2017.pdf, and Adams et al, NEJM. 2018;379:11-21.

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APOLLO Cardiac Subgroup: NTBNP

Data adapted from http://www.alnylam.com/wp-content/uploads/2017/11/EU-ATTR-2017_APOLLO- TRL_CAPELLA_FINAL_2Nov2017.pdf, and Adams et al, NEJM. 2018;379:11-21.

ATTR-ACT Study – Tafamidis for ATTR Cardiomyopathy

Phase 3, Randomized, Placebo-