Management of Cardiac Amyloidosis

Management of Cardiac

AmyloidosisMeredith Sigler, PharmD, BCPS

Assistant Professor of Pharmacy PracticeTexas Tech University Health Sciences

Center, Jerry H. Hodge School of PharmacyApril 10, 2021

TSHP Annual Seminar 1

Disclosures

°Served on advisory board for Alnylam Pharmaceuticals


Learning Objectives

° Pharmacist Objectives: • Define ATTR-cardiomyopathy• Compare treatment options for ATTR-cardiomyopathy• Analyze literature for the treatment of ATTR-cardiomyopathy• Identify ongoing trials for ATTR-cardiomyopathy

° Technician Objectives: • Identify ATTR-cardiomyopathy in a patient’s medical record• List treatment options for ATTR-cardiomyopathy• Interpret outcomes from ATTR-cardiomyopathy trials for treatment• Identify ongoing trials for ATTR-cardiomyopathy


Amyloidosis

°20 different amyloidogenic proteins

°Misfolding of these various proteins leads to disease

°Wide range of organ involvement:•Amyloid light chain (AL): numerous organ involvement•Amyloid transthyretin (ATTR): nervous system and cardiac•Amyloid beta (Aβ): Alzheimer’s disease


Longo DL, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 20e. McGraw-Hill; Accessed February 26, 2021. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2129&sectionid=192018356.

Cardiac Amyloidosis

Two important distinctions

AL

Misfolded monoclonal immunoglobulin light chains (AL) from an abnormal clonal proliferation of plasma cells

Managed by Hematology/Oncology

ATTR

Transthyretin (TTR) amyloidosis (ATTR), a liver-synthesized protein

Managed by Cardiology and/or Neurology


Kittleson M, et al. Circulation. 2020 Jul 7;142(1):e7-e22. doi: 10.1161/CIR.0000000000000792. Epub 2020 Jun 1.

ATTR Overview

°Discussion today focused on transthyretin amyloid cardiomyopathy°ATTR presentation is a neurologic and/or cardiac disease

•Wide spectrum of manifestation•Age-related or inherited


Griffin JM, et al. Trends Cardiovasc Med. 2021 Jan;31(1):59-66. doi: 10.1016/j.tcm.2019.12.003.

Neuropathic Phenotype

Mixed Phenotype

Cardiac Phenotype

Hereditary ATTR

ATTR-Cardiomyopathy

°Extracellular deposition of transthyretin in the myocardium leads to a restrictive cardiomyopathy

°Inherited: autosomal dominant, variant in transthyretin gene (ATTRv)•Untreated median survival (due to TTR Val122IIE): 2.5 years

°Age: wild-type (ATTRwt)•Untreated median survival: 3.6 years



Stable tetramer Dissociated tetramer Folded monomer Misfolded monomer

Oligomer Amyloid fibril


ATTR fibril formation

ATTR-Cardiomyopathy Presentation° Present with typical heart failure signs and symptoms: dyspnea; fatigue; and/or edema

° Echocardiogram: moderate to severe left ventricular wall thickness, ≥ 14 mm; most with preserved ejection fraction (EF ≥50%)•Restrictive cardiomyopathy

° May see low-voltage on ECG

° Family history: genetic variants, ATTRv

° Noncardiac clues: carpal tunnel syndrome, lumbar spinal stenosis, biceps tendon rupture, sensory polyneuropathy and/or autonomic neuropathy•Systemic infiltrative disease



Diagnostic Work-up: Cardiac Amyloidosis° Ensure no other infiltrative disease process

° Screen for monoclonal light chain:•Serum kappa/lambda free light chain ratio (normal: 0.26

– 1.65)•Serum and urine immunofixation electrophoresis if

monoclonal protein detected

° Tc-99m-PYP•Grade 2/3 uptake OR heart/contralateral chest ratio

(H/CL) >1.5

° Endomyocardial biopsy with Congo Red stain


If positive, send to Hematology/

Oncology


ATTR-Cardiomyopathy Treatment

Manage heart failure symptoms

Manage arrhythmias

Start disease-modifying therapies




°Manage heart failure symptoms•Diuresis

•Difficult to fully decongest

°No evidence for, “traditional therapies,” even if reduced ejection fraction•ACEi/ARBs may cause hypotension•Beta-blockers often not tolerated•*Nondihydropyridine calcium channel blockers may bind to amyloid fibrils*




°Management of arrhythmias•Anticoagulation recommended regardless of CHA2DS2-VASc score

•Amiodarone preferred

•*Digoxin may bind to amyloid fibrils*



Treatment Options

Disease-modifying therapies


TTR silencers

TTR stabilizers

TTR disrupters


TTR Silencers


STOPTargets hepatic synthesis of TTR

• >85% decrease in circulating TTR proteinPatisiran

• siRNA that degrades TTR mRNA• Intravenous infusion every 21 days

• < 100kg: 0.3mg/kg; ≥ 100 kg: 30mgInotersen

• Single-stranded antisense oligonucleotide that binds to TTR mRNA, causing degradation

• Subcutaneous weekly injection (284mg)

Kittleson M, et al. Circulation. 2020 Jul 7;142(1):e7-e22. doi: 10.1161/CIR.0000000000000792. Epub 2020 Jun 1.Kapoor M, et al. J Neuromuscul Dis. 2019;6(2):189-199. doi: 10.3233/JND-180371.ONPATTRO (patisiran) [prescribing information]. Cambridge, MA: Alnylam Pharmaceuticals Inc; February 2020.TEGSEDI (inotersen) [prescribing information]. Boston, MA: Akcea Therapeutics, Inc; September 2020.

TTR Silencers

°Infusion-related reaction (patisiran)°Thrombocytopenia (inotersen)

•Regular platelet monitoring advised (weekly)°Glomerulonephritis (inotersen)°REMS program for inotersen

°Thyroid function should be monitored°All patients should receive vitamin A supplementation


Kittleson M, et al. Circulation. 2020 Jul 7;142(1):e7-e22. doi: 10.1161/CIR.0000000000000792. Epub 2020 Jun 1.Kapoor M, et al. J Neuromuscul Dis. 2019;6(2):189-199. doi: 10.3233/JND-180371.Tegsedi (inotersen) [prescribing information]. Boston, MA: Akcea Therapeutics, Inc; September 2020.Onpattro (patisiran) [prescribing information]. Cambridge, MA: Alnylam Pharmaceuticals Inc; February 2020.

Patisiran ~ $414,162/yearInotersen ~ $359,840/year

TTR Stabilizers

°Diflunisal•Non-steroidal anti-inflammatory, stabilizes TTR in vitro via binding to the thyroxine binding site ultimately decreasing misfolding and reduction in fibrils

•250 mg PO BID•Contraindication: thrombocytopenia and eGFR < 40 mL/min/1.73m2

°Tafamidis•Binds the thyroxine-binding site•20, 61, 80 mg PO daily

•Lacks efficacy: severe aortic stenosis, NYHA Class IV, eGFR < 25 mL/min/1.73m2



TTR Stabilizers

°Advised to give diflunisal with a proton-pump inhibitor

°Tafamidis relatively benign•The 61 mg may have more GI upset compared to placebo



Diflunisal ~ $720/yearTafamidis ~ $225,000/year

TTR Disrupters

°Doxycycline and tauroursodeoxycholic acid (TUDCA)•Remove amyloid deposits•Large amount of side effects, mixed results with efficacy




°Start disease-modifying therapies•Patisiran and inotersen do not currently have an indication for cardiac amyloidosis•Secondary outcomes in neuropathy trials of the ATTR-CM subgroup suggest possible benefit

•Tafamidis is the only agent approved by the FDA for cardiac amyloidosis

°Key is to start early to prevent further progression


Tafamidis


Tafamidis

°FDA approved in May 2019•Wild-type and hereditary

°VYNDAQEL®•20mg capsule of tafamidis meglumine

°VYNDAMAX™•61mg capsule of tafamidis


Park J, et al. Ann Pharmacother. 2020 May;54(5):470-477. doi: 10.1177/1060028019888489. Epub 2019 Nov 18.

Tafamidis


Tetramer stabilized by binding of tafamidis at the

thyroxine binding site

Park J, et al. Ann Pharmacother. 2020 May;54(5):470-477. doi: 10.1177/1060028019888489. Epub 2019 Nov 18.

Evidence for TafamidisTafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT)

°Phase III•Multicenter, international, randomized, placebo-controlled, double-blind

°N = 441

°Randomized: 2:1:2 of 80mg:20mg:placebo•Tafamidis meglumine•Duration: 30 months


Maurer MS, et al. N Engl j Med. 2018 Sep 13:379(11):1007-1016. doi: 10.1056/NEJMoa1805689.

Evidence for Tafamidis

°NYHA Class IV°AL (amyloidosis light chain)°eGFR < 25 mL/min/1.73m2

°Liver transaminase levels exceeding 2x ULN

°History of liver or heart transplant

°Implanted cardiac device°Severe malnutrition, mBMI(< 600: albumin [gm] x BMI)

°Taking: NSAIDs, TUDCA, doxycycline, CCBs, digitalis



Excluded if:


°Age: mean 74 years°NYHA

•Class I: 8.4%•Class II: 59.6%•Class III: 32.0%

°Median age: 75 years°Race: Black: 14%, White: 80%°ATTRv: 24%



Baseline characteristics:



All-cause mortality lower

•29.5% versus 42.9%•HR: 0.7 (95% CI: 0.51 to 0.96)

CVD-related hospitalization lower

•0.48 versus 0.70 per year•RRR: 0.68 (95% CI: 0.56 – 0.81)

Pooled-analysis for tafamidis

Hospitalizations higher for NYHA Class III on tafamidis

ATTRv subgroup was not statistically significant


No difference in rates of adverse events reported

Primary Outcome


Months since First Dose




Rapezzi C, et al. JACC: Heart Fail. 2021 Feb:9(2). DOI: 10.1016/j.jchf.2020.09.011.

Characteristic Tafamidis,ATTTRwt(n=201)

Placebo,ATTRwt(n = 134)

Tafamadis,ATTRv(n = 63)

Placebo,ATTRv(n = 43)

Age, yrsMean ± SD

75.5 ± 6.7 74.9 ± 6.0 71.6 ± 8.0 71.4 ± 8.1

Male, n (%) 194 (9.5) 128 (95.5) 47 (74.6) 29 (67.4)

NHYA function class, n (%)IIIIII

19 (9.5)133 (66.2)49 (24.4)

11 (8.2)79 (59.0)44 (32.8)

5 (7.9)49 (46)29 (46)

2 (4.7)22 (51.2)19 (44.2)

1-year mortality: ATTRwt 6.6% and ATTRv: 22%


All-cause mortality and frequency of CV-related hospitalizations, ATTRwt = with tafamidis• Win ratio: 1.74, 95% CI: 1.26 to 2.41

All-cause mortality and frequency of CV-related hospitalizations, ATTRv = with tafamidis• Win ratio: 1.30, 95% CI: 0.79 to 2.14


Rapezzi C, et al. JACC: Heart Fail. 2021 Feb:9(2). DOI: 10.1016/j.jchf.2020.09.011.


°Long-term extension of ATTR-ACT°Treated for up to an additional 60 months°Placebo -> randomized to tafamidis 80mg or 20mg (2:1)

°All patients eligible to transition to tafamidis free acid 61mg (equivalent to tafamidis 80mg)•Median length of exposure to prior to transition: 39 months


Damy T, et al. Eur J Heart Fail. 2020 Oct 18. doi: 10.1002/ejhf.2027.


Tafamidis 80 mgn = 176


Placebon = 177



Tafamidis 80mgn = 154

Tafamidis 20mgn = 28

Tafamidis free acid 61 mg

All patients

30 monthsATTR-ACT

+ 9 months (median)ATTR-ACT LTE

+ 12 monthsATTR-ACT LTE



ATTR-ACT 80mg (n = 176) vs 20mg (n = 88)•No difference in all-cause mortality•HR: 0.95 (95% CI: 0.59 – 1.55)

LTE 80mg (n = 230) vs 20mg (n = 115)•Lower all-cause mortality with 80mg•HR: 0.70 (95% CI: 0.50 – 0.98)



Key Takeaways

°Tafamidis can slow the progression of disease•Decreased mortality and CVD hospitalizations compared to placebo

°Important to start early

°Difficult to conclude whether 80mg is superior to 20mg


Management of Fluid Status

°Single-center assessment at an ambulatory diuresis clinic in the management of heart failure, assessing outcomes for cardiac amyloidosis

°Run by certifiedheart failurenurse practitioners


Vaishnav J, et al. Am Heart J. 2020 Dec 22;233:122-131. doi: 10.1016/j.ahj.2020.12.009.

• Draw pre-diuresis labs (BMP, Mg, NT-proBNP, whole blood creatinine and K+)

• Vital signs (BP, HR, weight)Administer IV diuretic and monitor first urine output

• Post-diuresis vital signs• Follow-up 7 days after diuresis

Workflow


°Followed for 6 months after index date

°IV diuresis completed with furosemide and dose determined by home oral regimen

°Contraindications for IV diuresis: symptomatic hypotension; acute kidney injury (SCr level twice baseline value)

°Referred to ED if clinically indicated




Characteristic AL-CMN = 17

ATTR-CMN = 27

Age, mean years ± SD 64.5 ± 7.1 75.6 ± 8.7

Male, n (%) 12 (71) 10 (37)

Race, n (%):African AmericanCaucasian

4 (23)12 (71)

17 (63)10 (37)

NYHA Class, n (%):IIIIIIV

5 (29)9 (53)1 (6)

6(22)21 (78)0 (0)

Ejection fraction, % ± SD 49 ± 14 44 ± 12

Loop diuretic, n (%)FurosemideTorsemideBumetanide

9 (69)3 (23)1 (8)

15 (56)10 (37)2 (7)

Furosemide dose equivalent, median (IQR) 20mg (18, 80) 40mg (20, 100)

eGFR, mL/min/1.73m2, median (IQR) 65.6 (46, 81.2) 57 (37, 76.9)

Blood pressure, mmHg, median (IQR) 104 (94, 116) / 70 (60,78)

Baseline Characteristics

AL-CA: light chain cardiac amyloidosis; ATTR-CA: transthyretin cardiac amyloidosis; NYHA: New York Heart Association; SD: standard deviation; IQR: interquartile range



°Average number of visits per patient = 4.6 (over 6 months)°Out of 203 visits, diuretic dose changed:

•Decreased: 29 (14%)•Increased: 67 (33%)•IV diuresis: 56 (28%)•Received metolazone: 12 (21%)


Ending dose AL-CMN = 17

ATTR-CMN = 27

Furosemide dose equivalent, median (IQR)

[Median change from baseline]

80mg (40, 200)

[+40mg]

120mg (40, 200)

[+80mg]



020406080

100120140160

30 days 90 days 180 days

Number of days hospitalized per 1000 patient days of follow-up

Pre-index visit Post-index visit



p-value < .001 for all time points

Ongoing trialsName Primary outcome Intervention Unique Identifier

AKCEA-TTR-LRx (CARDIO-TTRansform)

Phase 3Composite of CV mortality and recurrent CV events at week 120

TTR silencerSC injection every 4 weeks

NCT04136171

HELIOS-B Phase 3Composite: all-cause mortality and recurrent CV events

TTR silencerVutrisiranSC injection every 3 months

NCT04153149

Doxy/TUDCA Phase 3Survival at 18 months

TTR disrupterDoxycycline 100mg BIDTUDCA 250mg BID

NCT03481972

APOLLO-B Phase 3Change from baseline: 6 min walk test

TTR silencerPatisiranIV infusion

NCT03997383


https://www.clinicaltrials.gov

Ongoing trialsName Primary outcome Intervention Unique Identifier

ATTRIBUTE-CM Phase 3Change from baseline: 6 min walk testAll-cause death and CV-related hospitalization

TTR stabilizer,AG10 800mg BID

NCT03860935

Long-term safety of tafamidis in subjects with ATTR cardiomyopathy

Phase 3Open-labelAll-cause mortality and incidence of treatment emergent adverse events

TTR stabilizerTafamidis 61mg daily if available or tafamidis meglumine 80mg daily

NCT02791230

24 month open label study of the tolerability and efficacy of inotersen in ATTR cardiomyopathy patients

Open-labelChange from baseline in systolic strain imaging by echocardiography

TTR silencerInotersen 300mg SC weekly

NCT03702829

First-in-human study of NI006 in patients with ATTR cardiomyopathy

Phase 1 TTR removalRecombinant human antibody targeting TTR amyloid fibrils, with removal of fibrils in vivo

NCT04360434


https://www.clinicaltrials.gov

Key Unanswered Questions

°Efficacy of less costly diflunasil

°Efficacy of silencers versus stabilizers

°Role of using combination therapy of disease modifying agents


Summary

°ATTR-CM has a poor prognosis if left untreated and diagnosis can be difficult

°Treatment for ATTR-CM = diuresis, management of arrythmias, and disease-modifying agents

°Tafamidis is on the only disease-modifying agent, at this time, with evidence to reduce hospitalization and delay mortality

°Pharmacists can play key roles in providing relief from cardiac congestion and helping patients start on disease-modifying agents


It’s Time


Time to recognize signs and symptoms associated with ATTR-cardiomyopathy

Time to ensure adequate diuresis and treatment of arrhythmias

Time to start appropriate disease-modifying medications, preferably early to slow disease progression

Thank You

Twitter@SiglerMeredith

[email protected]


Management of Cardiac Amyloidosis

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