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May 3, 2022 Circulation. 2022;145:e895–e1032. DOI: 10.1161/CIR.0000000000001063 e954

CLINICAL STATEMENTS AND GUIDELINES 7.8.2 Treatment of Cardiac Amyloidosis

Recommendations for Treatment of Cardiac Amyloidosis Referenced studies that support the recommendations are summarized in the Online Data Supplements.

COR LOE Recommendations

1 B-R 1.	 In select patients with wild-type or variant transthyretin cardiac amyloidosis and NYHA class I to III HF symptoms, transthyretin tetramer stabilizer therapy (tafamidis) is indicated to reduce cardiovascular morbidity and mortality.1

Value Statement: Low Value (B-NR) 2.	 At 2020 list prices, tafamidis provides low economic value (>$180 000 per QALY gained) in patients with HF with wild-type or variant transthyretin cardiac amyloidosis.2

2a C-LD 3.	 In patients with cardiac amyloidosis and AF, anticoagulation is reasonable to reduce the risk of stroke regardless of the CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischemic attack [TIA], vascular disease, age 65 to 74 years, sex category) score.3,4

Synopsis For patients with ATTR-CM and EF ≤40%, GDMT may be poorly tolerated. The vasodilating effects of ARNi, ACEi, and ARB may exacerbate hypotension, especially with amyloid-associated autonomic dysfunction. Beta blockers may worsen HF symptoms as patients with AT- TR-CM rely on heart rate response to maintain cardiac output. The benefit of ICDs in ATTR-CM has not been studied in randomized trials, and a case-control study showed unclear benefit.5 CRT has not been studied in ATTR-CM with HFrEF. Disease-modifying therapies include TTR silencers (disrupt hepatic synthesis via mRNA inhibition/degradation: inotersen and patisiran), TTR stabilizers (prevent misfolding/deposition: diflunisal and tafamidis), and TTR disruptors (target tissue clearance: doxycycline, tauroursodeoxycholic acid [TUDCA], and epigallocatechin-3-gallate [EGCG] in green tea). Light chain cardiac amyloidosis is managed by hematologyoncology specialists and beyond the scope of cardiologists, but diagnosis is often made by cardiologists when cardiac amyloid becomes manifest (Figure 13). AL amyloidosis is treatable, and patients with AL amyloidosis with cardiac involvement should promptly be referred to hematology-oncology for timely treatment. Inotersen and patisiran are associated with slower progression of amyloidosis-related polyneuropathy in ATTRv-CM.6,7 There are ongoing trials of the impact of inotersen and patisiran and newer generation mRNA inhibitors-degraders on cardiovascular morbidity or mortality. There is limited benefit of diflunisal,8 doxycycline plus TUDCA,9,10 and EGCG,11 on surrogate endpoints such as LV mass, but the impact of these agents on cardiovascular morbidity and mortality has not been assessed. Evaluation and management of autonomic dysfunction, volume status, and arrhythmia are important. Recommendation-Specific Supportive Text

1.	 Tafamidis is currently the only therapy to improve cardiovascular outcomes in ATTR-CM.1 Tafamidis binds the thyroxin-binding site of TTR. In the ATTR-ACT (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy) clinical trial, a randomized trial of patients with ATTRwt-CM or ATTRv-CM and NYHA class I to III symptoms, tafamidis had lower all-cause mortality (29.5% versus 42.9%) and lower cardiovascular-related hospitalization (0.48 versus 0.70 per year) after 30 months.1 There was a higher rate of cardiovascular-related hospitalizations in patients with NYHA class III HF, potentially attributable to longer survival during a more severe period of disease. Given that tafamidis prevents but does not reverse amyloid deposition, tafamidis is expected to have greater benefit when administered early in the disease course. As the survival curves separate after 18 months, patients for whom noncardiac disease is not expected to limit survival should be selected. Benefit has not been observed in patients with class IV symptoms, severe aortic stenosis, or impaired renal function (eGFR <25 mL·min−1·1.73 m−2 body surface area). Tafamidis is available in 2 formulations: tafamidis meglumine is available in 20-mg capsules; and the FDA-approved dose is 80 mg (4 capsules) once daily. Tafamidis is also available in 61-mg capsules; the FDA-approved dose for this new formulation is 61 mg once daily. 2.	 One model-based analyses used the results of the ATTR-ACT study1 to evaluate the cost-effectiveness of chronic tafamidis compared with no amyloidosis-specific therapy among patients with wild-type or variant transthyretin amyloidosis and NYHA class I to III HF.2 With assumptions that tafamidis remained effective beyond the clinical trial duration, they estimated tafamidis increased average survival by 1.97 years and QALY by 1.29. Despite these large clinical benefits, tafamidis (with an annual cost of $225 000) had an incremental cost-effectiveness ratio >$180 000 per QALY gained, the benchmark used by this guideline for low value. The cost of tafamidis would need to decrease by approximately 80% for it to be intermediate value with a cost per QALY <$180 000. 3.	 Intracardiac thrombosis occurs in approximately one-third of patients with cardiac amyloidosis, in some cases in the absence of diagnosed AF3,4,12 and regardless of CHA2DS2-VASc score.13 The use of anticoagulation reduced the risk of intracardiac thrombi in a retrospective study.4 The choice of direct oral anticoagulants (DOAC)

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