The treatment of cardiac transthyretin amyloidosis (ATTR-CM) has two major goals: to slow the formation and deposition of new transthyretin (TTR) amyloid fibrils and to prevent and treat the cardiovascular complications of the disease. Current disease-modifying therapies primarily slow further amyloid formation; they do not rapidly remove established myocardial amyloid deposits. Therefore, early diagnosis and initiation of specific therapy before advanced irreversible cardiac damage has occurred are particularly important.
Symptomatic Treatment of Heart Failure
Volume Management
Careful control of volume status is the cornerstone of symptomatic therapy. Loop diuretics, such as furosemide or torasemide, are the most important drugs for treating pulmonary congestion and peripheral edema. Mineralocorticoid receptor antagonists may be added when appropriate.
Volume management can be challenging because patients with restrictive amyloid cardiomyopathy often have a relatively fixed stroke volume and may be highly dependent on adequate ventricular filling. Excessive diuresis can therefore cause hypotension, renal dysfunction, dizziness, and worsening fatigue. Body weight, blood pressure, renal function, and serum electrolytes should be monitored regularly.
Beta-Blockers
The standard treatment algorithm for conventional heart failure with reduced ejection fraction (HFrEF) cannot simply be transferred to ATTR-CM. Beta-blockers are not automatically indicated solely because the left ventricular ejection fraction (LVEF) is ≤40%.
Patients with advanced amyloid cardiomyopathy often depend on a relatively high heart rate to maintain cardiac output. Beta-blockers can therefore worsen bradycardia, hypotension, fatigue, and exercise intolerance. Nevertheless, low-dose beta-blockers may be useful in selected patients, particularly those with LVEF ≤40%, ischemic heart disease, or a need for ventricular rate control in atrial fibrillation. Observational data suggest a possible survival benefit of low-dose beta-blockers in ATTR-CM patients with LVEF ≤40%, but randomized ATTR-specific trials are lacking.
ACE Inhibitors, ARBs, and ARNI
ACE inhibitors, angiotensin II receptor blockers (ARBs), and angiotensin receptor–neprilysin inhibitors (ARNI) are fundamental components of conventional HFrEF therapy. In cardiac amyloidosis, however, these drugs are often less well tolerated because of low blood pressure, reduced stroke volume, and, particularly in hereditary ATTR amyloidosis, autonomic dysfunction.
No consistent ATTR-specific survival benefit has been demonstrated for ACE inhibitors or ARBs. Their use should therefore be individualized according to blood pressure, renal function, concomitant conditions, and tolerability rather than routinely prescribed solely because of a reduced LVEF.
Mineralocorticoid Receptor Antagonists
Mineralocorticoid receptor antagonists (MRAs), such as spironolactone or eplerenone, appear to be relatively well tolerated in many patients with ATTR-CM. Large observational analyses have associated MRA therapy with lower all-cause mortality. However, this evidence is observational and has not yet been confirmed in dedicated randomized controlled ATTR-CM trials.
SGLT2 Inhibitors
Sodium–glucose cotransporter 2 (SGLT2) inhibitors are increasingly used in patients with ATTR-CM and heart failure. Observational studies indicate that these agents are generally well tolerated and are associated with fewer heart-failure hospitalizations and potentially lower cardiovascular and all-cause mortality.
However, patients with cardiac amyloidosis were generally excluded from the major randomized SGLT2 inhibitor heart-failure trials. The available ATTR-CM evidence is therefore encouraging but should not yet be interpreted as definitive proof of an ATTR-specific mortality benefit.
Atrial Fibrillation and Other Arrhythmias
Atrial fibrillation and atrial flutter are very common in cardiac amyloidosis. Because atrial mechanical dysfunction and amyloid infiltration substantially increase the risk of intracardiac thrombus formation and systemic embolism, oral anticoagulation is generally recommended in patients with atrial fibrillation or atrial flutter unless contraindicated.
Rate-control therapy must be used cautiously because excessive reduction of heart rate may decrease cardiac output. Conduction abnormalities are also frequent, and some patients eventually require permanent pacemaker implantation. Rhythm control, including cardioversion or amiodarone in selected patients, may be considered individually.
Disease-modifying treatment is particularly important in patients with early or moderately advanced disease, when preservation of cardiac function is still possible. Two major therapeutic strategies are currently available:
Comparison of Disease-Modifying Therapies
Drug |
Therapeutic strategy / mechanism |
Route and dose |
Main clinical evidence |
Current EU indication |
Tafamidis (Vyndaqel) |
Selective TTR tetramer stabilizer. Binds to the thyroxine-binding sites of TTR and reduces dissociation of the tetramer into amyloidogenic monomers. |
Oral: 61 mg once daily for ATTR-CM. |
ATTR-ACT: significantly reduced all-cause mortality and cardiovascular-related hospitalizations over 30 months and slowed deterioration in functional capacity and quality of life compared with placebo. |
Approved for wild-type or hereditary ATTR amyloidosis in adults with cardiomyopathy (ATTR-CM). |
Acoramidis (Beyonttra) |
High-affinity TTR tetramer stabilizer that markedly stabilizes both wild-type and variant TTR and prevents tetramer dissociation. |
Oral: 712 mg twice daily. |
ATTRibute-CM: significant benefit over placebo in a hierarchical four-component endpoint comprising all-cause mortality, cardiovascular hospitalization, NT-proBNP, and 6-minute walk distance. |
Approved for wild-type or variant ATTR amyloidosis in adults with cardiomyopathy (ATTR-CM). EU authorization since February 2025. |
Vutrisiran (Amvuttra) |
RNA interference (siRNA) therapy. GalNAc-conjugated siRNA targets hepatic TTR mRNA, reducing synthesis of both wild-type and variant TTR. |
Subcutaneous: 25 mg once every 3 months. |
HELIOS-B: significantly reduced the composite risk of all-cause mortality and recurrent cardiovascular events and slowed deterioration in functional capacity and quality of life. |
Approved in the EU for wild-type or hereditary ATTR amyloidosis in adults with cardiomyopathy. Also approved for hereditary ATTR amyloidosis with stage 1 or 2 polyneuropathy. |
Patisiran (Onpattro) |
RNA interference (siRNA) therapy delivered in lipid nanoparticles; reduces hepatic synthesis of both variant and wild-type TTR. |
Intravenous infusion: 0.3 mg/kg once every 3 weeks; maximum dose 30 mg in patients weighing ≥100 kg. |
APOLLO-B: preserved functional capacity, particularly 6-minute walk distance, and improved health status compared with placebo over 12 months. It did not provide the same randomized mortality/recurrent cardiovascular-event evidence demonstrated with vutrisiran in HELIOS-B. |
Not approved in the EU for ATTR-CM. EU indication is hereditary ATTR amyloidosis in adults with stage 1 or stage 2 polyneuropathy. |
Tafamidis
Tafamidis was the first disease-modifying therapy to demonstrate a substantial clinical benefit in ATTR-CM. It selectively binds to the thyroxine-binding sites of the TTR tetramer and stabilizes the protein, thereby reducing its dissociation into monomers. Tetramer dissociation is the critical initial step leading to TTR misfolding, aggregation, and amyloid fibril formation.
For ATTR-CM, tafamidis is administered at a dose of 61 mg orally once daily.
In the landmark ATTR-ACT trial, tafamidis was superior to placebo for the hierarchical combination of all-cause mortality and cardiovascular-related hospitalization. Treatment also slowed deterioration in the 6-minute walk distance and quality of life. Because tafamidis slows further disease progression rather than rapidly removing existing amyloid, the clinical benefit is generally greatest when treatment is initiated before advanced cardiac damage has developed.
Acoramidis
Acoramidis is a potent, highly selective stabilizer of the TTR tetramer. By maintaining TTR in its stable tetrameric configuration, it reduces dissociation into monomers and thereby inhibits the formation of amyloidogenic intermediates.
The recommended dose is 712 mg orally twice daily.
In the phase III ATTRibute-CM trial, acoramidis demonstrated a significant clinical benefit compared with placebo using a hierarchical four-component endpoint consisting of all-cause mortality, cardiovascular hospitalization, change in NT-proBNP, and change in 6-minute walk distance.
Acoramidis is approved in the European Union for adults with wild-type or variant ATTR amyloidosis with cardiomyopathy.
Vutrisiran
Vutrisiran uses a different therapeutic strategy. It is a small interfering RNA (siRNA) conjugated to N-acetylgalactosamine (GalNAc), which selectively delivers the drug to hepatocytes. The siRNA promotes degradation of TTR messenger RNA, markedly reducing hepatic production of both variant and wild-type TTR.
The recommended dose is 25 mg administered subcutaneously once every three months.
In the phase III HELIOS-B trial, vutrisiran significantly reduced the risk of the composite outcome of all-cause mortality and recurrent cardiovascular events compared with placebo. It also slowed deterioration in functional capacity and patient-reported health status.
Vutrisiran is now approved in the European Union for adults with wild-type or hereditary ATTR amyloidosis with cardiomyopathy. It is also approved for hereditary ATTR amyloidosis with stage 1 or stage 2 polyneuropathy.
Because reduction of circulating TTR also lowers retinol-binding protein and consequently serum vitamin A concentrations, vitamin A supplementation according to the product information is recommended during treatment.
Patisiran
Patisiran is another siRNA-based TTR-silencing therapy. Encapsulated in lipid nanoparticles and administered intravenously, it reduces production of both variant and wild-type TTR in the liver.
The recommended dose is 0.3 mg/kg intravenously every three weeks, with a maximum dose of 30 mg for patients weighing 100 kg or more. Premedication is required to reduce the risk of infusion-related reactions.
In the APOLLO-B trial involving patients with ATTR cardiac amyloidosis, patisiran significantly reduced deterioration in the 6-minute walk distance and improved health status compared with placebo at 12 months.
However, unlike tafamidis, acoramidis, and vutrisiran, patisiran does not currently have an EU indication for ATTR-CM. Its European indication remains hereditary ATTR amyloidosis in adults with stage 1 or stage 2 polyneuropathy.
Follow-Up
Patients with cardiac ATTR amyloidosis require structured long-term follow-up, ideally within a multidisciplinary amyloidosis program.
In clinically stable patients, assessment approximately every 3–6 months is reasonable and should include:
Echocardiography is generally repeated approximately every 6–12 months, although the interval should be adapted to disease severity and changes in clinical status. Additional rhythm monitoring, cardiac magnetic resonance imaging, or other investigations may be required in selected patients.
Patients receiving disease-modifying therapy should also be assessed for treatment-specific adverse effects and for evidence of continued disease progression
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