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
TSHP Annual Seminar 2
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
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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
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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§ionid=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
TSHP Annual Seminar 7
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
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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
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Kittleson M, et al. Circulation. 2020 Jul 7;142(1):e7-e22. doi: 10.1161/CIR.0000000000000792. Epub 2020 Jun 1.
Stable tetramer Dissociated tetramer Folded monomer Misfolded monomer
Oligomer Amyloid fibril
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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
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Kittleson M, et al. Circulation. 2020 Jul 7;142(1):e7-e22. doi: 10.1161/CIR.0000000000000792. Epub 2020 Jun 1.
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
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If positive, send to Hematology/
Oncology
Kittleson M, et al. Circulation. 2020 Jul 7;142(1):e7-e22. doi: 10.1161/CIR.0000000000000792. Epub 2020 Jun 1.
ATTR-Cardiomyopathy Treatment
Manage heart failure symptoms
Manage arrhythmias
Start disease-modifying therapies
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Kittleson M, et al. Circulation. 2020 Jul 7;142(1):e7-e22. doi: 10.1161/CIR.0000000000000792. Epub 2020 Jun 1.
ATTR-Cardiomyopathy Treatment
°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*
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Kittleson M, et al. Circulation. 2020 Jul 7;142(1):e7-e22. doi: 10.1161/CIR.0000000000000792. Epub 2020 Jun 1.
ATTR-Cardiomyopathy Treatment
°Management of arrhythmias•Anticoagulation recommended regardless of CHA2DS2-VASc score
•Amiodarone preferred
•*Digoxin may bind to amyloid fibrils*
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Kittleson M, et al. Circulation. 2020 Jul 7;142(1):e7-e22. doi: 10.1161/CIR.0000000000000792. Epub 2020 Jun 1.
Treatment Options
Disease-modifying therapies
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TTR silencers
TTR stabilizers
TTR disrupters
Kittleson M, et al. Circulation. 2020 Jul 7;142(1):e7-e22. doi: 10.1161/CIR.0000000000000792. Epub 2020 Jun 1.
TTR Silencers
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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
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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
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Kittleson M, et al. Circulation. 2020 Jul 7;142(1):e7-e22. doi: 10.1161/CIR.0000000000000792. Epub 2020 Jun 1.
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
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Kittleson M, et al. Circulation. 2020 Jul 7;142(1):e7-e22. doi: 10.1161/CIR.0000000000000792. Epub 2020 Jun 1.
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
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Kittleson M, et al. Circulation. 2020 Jul 7;142(1):e7-e22. doi: 10.1161/CIR.0000000000000792. Epub 2020 Jun 1.
ATTR-Cardiomyopathy Treatment
°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
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Tafamidis
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Tafamidis
°FDA approved in May 2019•Wild-type and hereditary
°VYNDAQEL®•20mg capsule of tafamidis meglumine
°VYNDAMAX™•61mg capsule of tafamidis
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Park J, et al. Ann Pharmacother. 2020 May;54(5):470-477. doi: 10.1177/1060028019888489. Epub 2019 Nov 18.
Tafamidis
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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
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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
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Maurer MS, et al. N Engl j Med. 2018 Sep 13:379(11):1007-1016. doi: 10.1056/NEJMoa1805689.
Excluded if:
Evidence for Tafamidis
°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%
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Maurer MS, et al. N Engl j Med. 2018 Sep 13:379(11):1007-1016. doi: 10.1056/NEJMoa1805689.
Baseline characteristics:
Evidence for Tafamidis
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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
Maurer MS, et al. N Engl j Med. 2018 Sep 13:379(11):1007-1016. doi: 10.1056/NEJMoa1805689.
No difference in rates of adverse events reported
Primary Outcome
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Months since First Dose
Maurer MS, et al. N Engl j Med. 2018 Sep 13:379(11):1007-1016. doi: 10.1056/NEJMoa1805689.
Evidence for Tafamidis
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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%
Evidence for Tafamidis
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
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Rapezzi C, et al. JACC: Heart Fail. 2021 Feb:9(2). DOI: 10.1016/j.jchf.2020.09.011.
Evidence for Tafamidis
°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
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Damy T, et al. Eur J Heart Fail. 2020 Oct 18. doi: 10.1002/ejhf.2027.
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Tafamidis 80 mgn = 176
Tafamidis 20 mgn = 88
Placebon = 177
Tafamidis 80 mgn = 110
Tafamidis 20 mgn = 60
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
Damy T, et al. Eur J Heart Fail. 2020 Oct 18. doi: 10.1002/ejhf.2027.
Evidence for Tafamidis
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)
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Damy T, et al. Eur J Heart Fail. 2020 Oct 18. doi: 10.1002/ejhf.2027.
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
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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
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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
Management of Fluid Status
°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
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Vaishnav J, et al. Am Heart J. 2020 Dec 22;233:122-131. doi: 10.1016/j.ahj.2020.12.009.
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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
Vaishnav J, et al. Am Heart J. 2020 Dec 22;233:122-131. doi: 10.1016/j.ahj.2020.12.009.
Management of Fluid Status
°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%)
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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]
Vaishnav J, et al. Am Heart J. 2020 Dec 22;233:122-131. doi: 10.1016/j.ahj.2020.12.009.
Management of Fluid Status
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
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Vaishnav J, et al. Am Heart J. 2020 Dec 22;233:122-131. doi: 10.1016/j.ahj.2020.12.009.
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
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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
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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
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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
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It’s Time
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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