Cardiac amyloidosis: Treatment and prognosis

INTRODUCTION — Amyloidosis refers to the extracellular deposition of fibrils arising from a variety of serum proteins. These fibrils adopt a beta-pleated sheet configuration that leads to characteristic histologic changes. Amyloid deposits can occur in a variety of organs, but morbidity and mortality from amyloid deposition most commonly occur when the heart, kidney, liver, or autonomic nervous system are affected. (See "Overview of amyloidosis".)

This topic will review the treatment and prognosis of cardiac amyloidosis.

The pathophysiology of amyloid formation and the clinical manifestations and diagnosis of cardiac amyloidosis are discussed separately. (See "Overview of amyloidosis", section on 'Pathogenesis' and "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis".)

SPECIFIC COMPLICATIONS OF CARDIAC AMYLOIDOSIS

Atrial fibrillation — In patients with AL (light chain) or ATTR (transthyretin) cardiac amyloidosis, the approach to atrial fibrillation differs from patients with other forms of cardiomyopathy and the general population:

●Rate and rhythm control – In patients with atrial fibrillation, we prioritize rate control over rhythm control. For most patients, we suggest amiodarone for rate control. In patients in whom amiodarone is not an option for therapy, we use low-dose digoxin or low-dose beta blockers.

The use of amiodarone in this group of patients is consistent with professional guidelines and evidence from small studies [1].

Rhythm control of atrial fibrillation is difficult to achieve, which may be due to infiltration of the atrium by amyloid fibrils and the atrial enlargement often seen in cardiac amyloidosis. Our approach is based on our experience and the higher likelihood of adverse effects of agents used to treat heart rate in patients with cardiac amyloidosis. There are few data to guide the choice of rate or rhythm control agents [2]. The experience with catheter ablation for atrial arrhythmias in patients with cardiac amyloidosis is limited [3]. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".)

●Anticoagulation – In patients with cardiac amyloidosis and atrial fibrillation or atrial flutter, we recommend anticoagulation. We do not use standard risk estimators (eg, CHA₂DS₂VASC).

Although amyloidosis is associated with increased hemorrhagic risk due to amyloid angiopathy, intestinal or bladder amyloid, or coagulopathy, major bleeding in patients with amyloidosis does not seem to exceed that seen in other patients with similar nonamyloid degrees of illness. (See "Atrial fibrillation in adults: Use of oral anticoagulants".)

This approach is motivated by the high rate of atrial thrombus detected in patients with cardiac amyloidosis, which exceeds the highest risk predicted by commonly used risk scores (eg, approximately 12 percent in the CHA2DS2VASC score) (calculator 1):

•Among patients with cardiac amyloidosis who underwent transesophageal echocardiography (TEE) prior to cardioversion, 81 percent had a cardiac thrombus [4].

•In a prospective cohort of patients with cardiac amyloidosis who underwent cardiovascular magnetic resonance imaging, the overall prevalence of intracardiac thrombus was 13.1 percent [5].

•Among patients with cardiac amyloidosis who underwent echocardiography at a single center, the prevalence of cardiac thrombus was 27 percent [6].

•In a series of patients with and without cardiac amyloidosis who underwent autopsy, patients with cardiac amyloidosis were more likely to have an intracardiac thrombus (51 versus 16 percent) [7].

●Cardioversion – In patients with AL or ATTR cardiac amyloidosis who require cardioversion for symptomatic management, we recommend TEE prior to cardioversion rather than no TEE prior to cardioversion. This recommendation applies regardless of the duration of anticoagulation prior to cardioversion and regardless of the duration of atrial fibrillation or flutter prior to cardioversion.

This approach is consistent with professional guidelines [1].

Our recommendation is motivated by observational studies that show a rate of rate of atrial thrombus between 13 and 81 percent in patients with cardiac amyloidosis; these studies are describe above [4-7].

Conduction system disease — Patients with cardiac amyloidosis are at risk of conduction system disease (eg, atrioventricular block) and may benefit from pacemaker therapy. In patients with cardiac amyloidosis, we use the general indications for cardiac pacing. (See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Cardiac involvement' and "Permanent cardiac pacing: Overview of devices and indications".)

AL CARDIAC AMYLOIDOSIS

Therapies to avoid or use with caution — We avoid treatment with agents that may cause significant hypotension, bradycardia, or worsening of heart failure (HF) in patients with AL cardiac amyloidosis. The causes of adverse effects in patients with AL cardiac amyloidosis include binding of drugs to amyloid fibers, unmasking of underlying autonomic neuropathy, and poor hemodynamic reserve characteristic of HF [1]. Regardless of the cause, patients with AL cardiac amyloidosis can have a pronounced and prolonged effect from even low doses of cardiovascular medications, and, in the case of digoxin, toxicity may occur at serum levels typically considered therapeutic [8].

The likelihood of adverse effects from medications with hemodynamic effects is related to the patient's clinical findings:

●Hypotension, conduction system disease, or severe HF – In patients with AL cardiac amyloidosis who have hypotension, conduction system disease (eg, atrioventricular block), or who have signs of advanced HF, medications that cause vasodilation, decrease heart rate, or have negative inotropic effects are contraindicated. (See "Clinical manifestations and diagnosis of advanced heart failure", section on 'When to suspect advanced heart failure'.)

●Less severe cardiac involvement – In patients with AL cardiac amyloidosis who do not have hypotension, conduction system disease, or signs of severe HF, agents with hemodynamic effects can be used with caution. The risk of adverse effects depends on the clinical scenario:

•Atrial fibrillation – In patients with AL cardiac amyloidosis and atrial fibrillation, beta blockers and digoxin can be used if no other agents are tolerable or effective for rate or rhythm control. The approach to atrial fibrillation is presented elsewhere in this topic. (See 'Atrial fibrillation' above.)

We avoid use of calcium channel blockers in patients with AL cardiac amyloidosis. In our experience these agents are likely to cause hypotension and atrioventricular block.

This approach to patients with AL cardiac amyloidosis and atrial fibrillation is consistent with professional guidelines [1].

In our experience, beta blockers and digoxin can be used with caution (eg, low dose, frequent monitoring) in atrial fibrillation, while calcium channel blockers are likely to cause adverse effects. However, there are few data to guide practice. There is low quality evidence of adverse effects with digoxin in patients with AL cardiac amyloidosis (see below) [8].

•Heart failure – Most patients with symptomatic HF should avoid medications with vasodilatory or conduction system effects. Therapies to avoid include:

-ACE inhibitors and ARBs – We avoid use of angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) in patients with AL cardiac amyloidosis. In our experience, these agents often cause profound hypotension in patients with AL cardiac amyloidosis and HF; the efficacy of these agents in patients with AL cardiac amyloidosis is unknown.

-Beta blockers – We avoid beta blockers in patients with AL cardiac amyloidosis; these agents can cause marked bradycardia, atrioventricular block, or hypotension in patients with HF. In our experience, patients undergoing high-dose chemotherapy are more likely to have adverse effects from beta blockers compared with patients who are undergoing maintenance chemotherapy or who have completed chemotherapy.

-Digoxin – In select patients with AL cardiac amyloidosis with HF, we use digoxin with caution. Amyloid fibrils bind to digoxin, which may increase its on-target effects and the likelihood of toxicity regardless of its serum level [8]. In our experience, digoxin can be safely used in highly selected patients. However, an observational study that included patients with AL cardiac amyloidosis found that digoxin was frequently discontinued (16 percent) and resulted in numerous arrhythmic events (11 percent) of which approximately 5 percent were terminal [8].

Disease-specific therapy for AL amyloidosis — In patients with AL cardiac amyloidosis, the underlying hematologic disorder should be appropriately treated. The treatment regimen is based on the hematologic disorder and the severity of AL cardiac amyloidosis. The goals of treatment and the approach to treatment of diseases that lead to AL cardiac amyloidosis are discussed separately. (See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis", section on 'General concepts' and "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis", section on 'Initial treatment'.)

Therapy for heart failure — In patients with AL cardiac amyloidosis, the approach to therapy of HF is different from other patients with HF:

●Systolic heart failure – In patients with AL cardiac amyloidosis and reduced systolic function, the goal of pharmacologic therapy is to relieve HF symptoms and avoid adverse drug effects. Treatment consists of general measures used to treat HF (eg, salt and water restriction) and use of a diuretic for volume management. (See "Use of diuretics in patients with heart failure".)

There is no specific regimen of agents for use in patients with AL cardiac amyloidosis and HF with reduced ejection fraction (HFrEF). Many agents typically used to treat HFrEF should be avoided in patients with AL cardiac amyloidosis. (See 'Therapies to avoid or use with caution' above.)

This approach is consistent with professional guidelines [1].

In our experience, patients with AL cardiac amyloidosis and HF have a low tolerance of agents typically used to treat HFrEF. In contrast to other causes of HFrEF (eg, coronary artery disease, dilated cardiomyopathy), it is unclear whether the regimen of agents (eg, ACE inhibitors) typically used to treat most patients with HFrEF is effective or safe in patients with AL cardiac amyloidosis; such patients were underrepresented in large trials of neurohormonal therapy for HFrEF.

●Restrictive cardiomyopathy or diastolic heart failure – In patients with AL cardiac amyloidosis who present with a restrictive physiology or diastolic dysfunction and HF symptoms, the goals of management are to control volume status and avoid therapies likely to cause adverse effects. Thus, diuretics are the mainstay of therapy, and agents typically used to treat HF with preserved ejection fraction (eg, mineralocorticoid receptor antagonists, sodium-glucose co-transporter 2 inhibitors) are of unclear benefit and safety. (See 'Therapies to avoid or use with caution' above.)

Refractory heart failure therapy — Patients with AL cardiac amyloidosis who have refractory HF symptoms should be offered palliative care and be evaluated for the feasibility of continuous inotropic support, heart transplantation, and mechanical circulatory support (MCS):

●Palliative care – Palliative care should be offered to all patients with refractory HF. (See "Palliative care for patients with advanced heart failure: Decision support and management of symptoms".)

●Heart transplantation – In patients with AL cardiac amyloidosis, heart transplantation is only feasible if the underlying hematologic disorder can be successfully treated prior to or early after heart transplantation. However, many patients with cardiac AL cardiac amyloidosis have significant noncardiac organ dysfunction (eg, chronic kidney disease) that precludes treatment of the underlying hematologic disorder or precludes heart transplantation. While remission of plasma cell disorders can occur, relapses are common and are associated with lower survival after heart transplantation:

•In one series, only 4 percent of patients with AL cardiac amyloidosis had clinically isolated cardiac disease [9].

•In a retrospective study, 10 patients with AL cardiac amyloidosis had a five-year survival of 20 percent [10]. Among those who received chemotherapy after heart transplantation, survival was 36 percent. Amyloid recurred in all of these patients at a median of 11 months after heart transplantation.

•In a single-center study that included nine patients with AL cardiac amyloidosis, there were no deaths recorded after approximately four years, and one patient had amyloid infiltration of the graft [11]. Most of these patients underwent chemotherapy or stem cell transplantation before or after transplantation. Thus, these patients were highly selected.

●Mechanical circulatory support – In general, patients with AL cardiac amyloidosis have worse survival after placement of a left ventricular assist device (LVAD) compared with other patients undergoing LVAD placement [12].

●Inotropic support – Inotropic support may be feasible in patients with AL cardiac amyloidosis who can tolerate the vasodilatory properties of agents used for continuous inotropic support (eg, milrinone, dobutamine). (See "Inotropic agents in heart failure with reduced ejection fraction", section on 'Inotropic agents in use'.)

Sudden death prevention — In patients with AL cardiac amyloidosis whose prognosis (see 'Prognosis' below) is acceptable (eg, >50 percent chance of one-year survival) and who had an episode of sudden cardiac death (SCD) or sustained ventricular tachycardia or ventricular fibrillation, it is reasonable to place an implantable cardioverter-defibrillator (ICD) for secondary prevention, as discussed separately. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".)

The role of ICD placement for primary prevention is uncertain.

This approach is consistent with professional guidelines [1].

Based on limited data, patients with AL cardiac amyloidosis are less likely to have SCD averted with an ICD; they are more likely to die suddenly from pulseless electrical activity. In addition, patients with AL cardiac amyloidosis were underrepresented in large trials of ICDs for primary and secondary prevention of SCD. Examples of studies that addressed SCD in patients with cardiac amyloidosis include:

●In a study that included 19 patients with AL cardiac amyloidosis who received an ICD, four had a history of syncope, 10 had a history of high-grade ventricular arrhythmias, and five patients had both [13]. There were six cardiac deaths, which were all sudden in nature and classified as electromechanical dissociation (ie, pulseless electrical activity) despite the ICD. Only one patient received appropriate ICD shocks with long-term survival. Two patients subsequently underwent cardiac transplantation, and one patient died of an unrelated disease.

●Similar findings were reported in a single-center cohort study of 53 patients with cardiac amyloidosis (33 with AL cardiac amyloidosis confirmed by endomyocardial biopsy) who had undergone ICD implantation (77 percent for primary prevention) [14]. Over a mean follow-up of 23 months, 15 patients (12 with cardiac AL amyloidosis) received at least one appropriate ICD shock; none of these shocks occurred in patients who received the ICD strictly for primary prevention.

Prognosis — With contemporary management, the median survival for AL cardiac amyloidosis with cardiac involvement is approximately 5.5 years after diagnosis [15]. Detailed prognosis can be estimated using staging methods (table 1 and table 2), which are discussed separately. (See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis", section on 'Staging'.)

ATTR AMYLOIDOSIS

Disease-specific therapy for ATTR amyloidosis — In patients with ATTRwt (wild-type transthyretin amyloidosis) or ATTRv (where "v" indicates "variant") cardiac amyloidosis and New York Heart Association (NYHA) functional class I to III HF symptoms, we recommend treatment with tafamidis rather than no disease-specific therapy, and we suggest tafamidis rather than diflunisal. Diflunisal is poorly tolerated and has unclear efficacy in patients with cardiac amyloidosis.

Tafamidis is given as tafamidis meglumine 80 mg daily or as tafamidis 61 mg daily. Tafamidis (either formulation) does not require specific monitoring and is continued indefinitely [16]. The high cost of tafamidis is a major barrier to therapy.

This approach to therapy for ATTR cardiac amyloidosis is consistent with professional society recommendations [1].

There are no direct comparisons between disease-specific therapies that target amyloid deposition. However, a randomized trial found that tafamidis reduced the risk of cardiovascular events and improved quality of life compared with placebo [17]. While diflunisal may improve symptoms of polyneuropathy, the benefits of diflunisal on cardiovascular outcomes in patient with cardiac amyloidosis is uncertain; the available data suggest that it is poorly tolerated.

●Tafamidis – Tafamidis prevents cleavage of transthyretin tetramers and may reduce deposition of amyloid [18,19]. In the ATTR-ACT trial, 441 patients with ATTR (variant or wild-type) cardiac amyloidosis were randomly assigned in a 2:1:2 ratio to receive tafamidis 80 mg, tafamidis 20 mg, or placebo once daily for 30 months [17]. Exclusion criteria included NYHA functional class IV HF symptoms or an estimated glomerular filtration rate (eGFR) less than 25 mL/min per 1.73 m².

Tafamidis reduced the rate of mortality compared with placebo (29.5 versus 42.9 percent; hazard ratio [HR] 0.70, 95% CI 0.51-0.96) and reduced the rate of cardiovascular-related hospitalizations (0.48 versus 0.70 per year; risk ratio 0.68, 95% CI 0.56-0.81). Tafamidis also reduced the rate of decline in six-minute walk distance and Kansas City Cardiomyopathy Questionnaire-Overall Summary. The incidence of adverse events was similar in the tafamidis and placebo groups.

Consistent effects on mortality and cardiovascular hospitalization were observed across subgroups of TTR type (ATTRwt, ATTRv), tafamidis dose, and NYHA functional class at baseline, except for patients with NYHA class III at baseline, in whom the risk of cardiovascular-related hospitalization was higher with tafamidis.

●Diflunisal – Diflunisal is a nonsteroidal antiinflammatory agent that prevents cleavage of amyloid tetramers. Its chemical structure is similar to that of tafamidis [1]. However, the efficacy of diflunisal is unclear, and it is poorly tolerated. A trial of diflunisal assessed its effect on polyneuropathy symptoms, and an observational study assessed its effect on cardiovascular outcomes:

•In a trial that included 130 patients with ATTRv polyneuropathy both with or without cardiomyopathy, assignment to treatment with diflunisal resulted in less progression of neuropathy (Neuropathy Impairment Score 8.7 versus 16.3 points) and higher quality of life (Short-Form Health Survey score 1.5 versus 4.9 points) compared with placebo [20]. Cardiovascular event rates were not reported.

•In a retrospective study from a single center that included patients with ATTRwt cardiac amyloidosis, patients who were treated with diflunisal had lower mortality compared with those not treated with diflunisal (adjusted HR 0.13, 95% CI 0.05-0.36) [21]. Diflunisal was discontinued in 40 percent of patients. The favorable effect of diflunisal observed in this study is most likely due to bias or unmeasured confounders.

●Investigational agents – Patisiran and inotersen are agents that alter hepatic TTR synthesis via ribonucleic acid (RNA) interference, which may reduce the availability of misfolded monomers that form amyloid deposits [22,23]. The only efficacy data come from a subgroup analysis of patients with cardiac amyloidosis enrolled in a trial of patisiran:

•Patisiran – Patisiran is an anti-TTR small interfering ribonucleic acid (siRNA) formulation of lipid nanoparticles. A randomized trial that compared patisiran with placebo in 225 patients with ATTRv and polyneuropathy included a subgroup of patients with cardiac amyloidosis [23]. In this subgroup of patients, patisiran reduced N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and LV wall thickness and slowed the progression of LV systolic dysfunction. The drug was generally well tolerated.

Therapy for heart failure — In patients with ATTR cardiac amyloidosis, we use general measures to treat HF and avoid exposure to agents that may cause adverse hemodynamic effects:

●General measures – The general measures used to treat HF, such as sodium restriction, alcohol avoidance, and self-care, are described separately. (See "Heart failure self-management".)

●Diuretics for volume management – In patients with ATTR cardiac amyloidosis and HF, diuretics are required to relieve symptoms and maintain fluid balance. (See "Use of diuretics in patients with heart failure".)

●Medical regimens for HF treatment – In patients with ATTR cardiac amyloidosis with either HF with reduced ejection fraction or HF with preserved ejection fraction (including restrictive physiology), we have no specific recommendations for HF therapy other than general HF treatment measures and diuretics for volume overload. Similar to patients with AL cardiac amyloidosis, in patients with evidence of hypotension, heart block, or severe HF, we avoid vasodilators and medications with negative chronotropic or inotropic effects. (See 'Therapies to avoid or use with caution' above.)

This approach is consistent with professional guidelines [1].

In our experience and based on limited data, the efficacy of neurohormonal therapies is unclear, and many patients discontinue therapy due to intolerance. Some retrospective data suggest a possible benefit with mineralocorticoid receptor antagonist (MRA) and beta blocker therapy:

•In a retrospective study that included 2371 patients with ATTR cardiac amyloidosis, approximately 50 percent of patients were treated with an angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB), 50 percent were treated with a beta blocker, and 40 percent were treated with an MRA [24]. After a median follow-up of 28 months, the ACE inhibitor or ARB was discontinued in 33 percent, beta blockers were discontinued in 22 percent, and MRAs were discontinued in 8 percent. Mortality was lower in patients with a left ventricular ejection fraction (LVEF) <40 percent who were treated with a beta blocker and in patients with an LVEF ≥40 percent treated with an MRA, but these findings are hypothesis-generating due to the retrospective nature of the study.

•In another study that included 309 patients with ATTR cardiac amyloidosis, ACE inhibitor or ARB use (35 percent), beta blocker use (50 percent), and MRA use (24 percent) were not associated with the outcome of death [25].

Refractory heart failure — Options for patients with refractory HF include:

●Palliative care – Palliative care should be offered to all patients with refractory HF. (See "Palliative care for patients with advanced heart failure: Decision support and management of symptoms".)

●Transplantation – Transplantation may be an option for some patients with ATTR cardiac amyloidosis and refractory HF symptoms. Patient characteristics and the type of amyloid influences the approach to transplantation, which may include liver transplantation, heart transplantation, or combined heart-liver transplantation:

•ATTRwt – Patients with ATTRwt amyloidosis generally have disease that is isolated to the heart, and as such, may benefit from isolated heart transplantation. However, patients with ATTRwt often present at an age beyond that which is usually acceptable for transplantation. The published experience with heart transplantation in this group of patients is limited [26].

•ATTRv – In patients with ATTRv cardiac amyloidosis, amyloidosis is caused by abnormal production of amyloid in the liver. Heart transplantation may treat the cardiac disorder, but systemic amyloidosis is likely to progress without liver transplantation. With isolated liver transplantation, progression of HF may occur.

Thus, combined heart and liver transplantation may have advantages compared with isolated heart or liver transplantation. As examples:

-Fourteen patients in a single center had combined heart-liver transplantation for familial cardiac amyloidosis between 1999 and 2012. Survival was 93 percent at one year and 82 percent at five years. No recurrent amyloid was reported [27].

-Among seven patients with ATTRv who underwent isolated liver transplantation, all seven patients showed clinical progression of cardiomyopathy and four died within five years [28].

There is inconclusive evidence that the benefits of heart or heart-liver transplantation are influenced by the presence of specific mutations. As examples:

-In the study noted above, all patients had the Thr60Ala mutation [28].

-In a single center report that included patients with ATTRv cardiac amyloidosis who had the Val122Ile mutation and underwent isolated heart transplantation, cardiac amyloidosis and systemic amyloidosis did not recur after five years of follow-up [29].

-In a series of 11 patients with ATTRv cardiac amyloidosis who underwent isolated liver transplantation, four patients with Glu42Gly mutation and one patient with Ala36Pro mutation showed clinical evidence of progressive HF, while six patients with Val30Met mutation did not show clinical evidence of progressive HF [30].

●Mechanical circulatory support – In patients with ATTR cardiac amyloidosis, ventricular assist device therapy is rare due to technical difficulties with implantation in patients with a restrictive cardiac morphology and the severity of comorbidities typically caused by noncardiac amyloid deposition [31].

●Continuous inotropic support – In patients with ATTR cardiac amyloidosis and systolic LV dysfunction, continuous home infusion of an inotrope may be an option for therapy.

We do not routinely use inotropes to treat patients with restrictive physiology caused by ATTR. Theoretically, dobutamine and milrinone have lusitropic properties that could be helpful in patients with restrictive physiology, but, in our experience, these agents have few beneficial effects.

The details on inotropic support are discussed separately. (See "Inotropic agents in heart failure with reduced ejection fraction", section on 'Inotropic agents in use'.)

Liver transplantation — The role of liver transplantation in patients with ATTRv cardiac amyloidosis is described separately. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation", section on 'Metabolic disorders'.)

Prognosis — Two staging systems have been proposed in patients with ATTR amyloidosis:

●ATTRwt staging – The first published staging system for patients with ATTRwt cardiac amyloidosis is based on serum levels of NT-proBNP and cardiac troponin T [32]. Thresholds of troponin T (0.05 ng/mL) and NT-proBNP (3000 pg/mL) were used. The respective four-year overall survival estimates were 57, 42, and 18 percent for stage I (both values below cutoff), stage II (one above), and stage III (both above), respectively.

●ATTRwt or ATTRv staging – The second staging system, validated in patients with ATTRwt or ATTRv, is based on serum levels of NT-proBNP and eGFR [33]. Stage I is defined as NT-proBNP ≤3000 pg/mL and eGFR ≥45 mL/min per 1.73 m², Stage III is defined as NT-proBNP >3000 pg/mL and eGFR <45 mL/min per 1.73 m², and the remainder were Stage II. Median survival among Stage I patients was 69.2 months, Stage II patients 46.7 months, and Stage III patients 24.1 months [33].

AA AND OTHER AMYLOIDOSES — In patients with either serum amyloid A amyloidosis (AA cardiac amyloidosis) or other amyloidoses who have cardiac involvement, treatment is focused on the underlying condition causing AA cardiac amyloidosis, if available. The diagnosis and treatment of these rare amyloidoses are discussed separately. (See "Overview of amyloidosis", section on 'Types of amyloidosis' and "Pathogenesis of AA amyloidosis" and "Causes and diagnosis of AA amyloidosis and relation to rheumatic diseases" and "Treatment of AA (secondary) amyloidosis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac amyloidosis" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Heart failure in adults" and "Society guideline links: Immunoglobulin light chain (AL) amyloidosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: AL amyloidosis (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Specific complications of cardiac amyloidosis

•Atrial fibrillation

-Rate and rhythm control – In patients with atrial fibrillation, we prioritize rate control over rhythm control. For most patients, we suggest amiodarone for rate control (Grade 2C). In patients in whom amiodarone is not an option for therapy, we use low-dose digoxin or low-dose beta blockers. (See 'Atrial fibrillation' above.)

-Anticoagulation – In patients with cardiac amyloidosis and atrial fibrillation or atrial flutter, we recommend anticoagulation (Grade 1B). We do not use standard risk estimators (eg, CHA₂DS₂VASC). (See 'Atrial fibrillation' above.)

-Cardioversion – In patients with AL (light chain) or ATTR (transthyretin) cardiac amyloidosis who require cardioversion for symptomatic management, we recommend transesophageal echocardiography (TEE) prior to cardioversion rather than no transesophageal echocardiography prior to cardioversion. (See 'Atrial fibrillation' above.)

•Conduction system disease – In patients with cardiac amyloidosis, we use the general indications for cardiac pacing. (See "Permanent cardiac pacing: Overview of devices and indications".)

●AL amyloidosis

•Therapies to avoid – The clinical scenario influences which therapies to avoid (see 'Therapies to avoid or use with caution' above):

-Hypotension, conduction system disease, or severe heart failure – In patients with AL cardiac amyloidosis who have hypotension, conduction system disease (eg, atrioventricular block), or who have signs of advanced heart failure (HF), medications that cause vasodilation, decrease heart rate, or have negative inotropic effects are contraindicated.

-Heart failure – Most patients with symptomatic HF should avoid medications with hemodynamic effects such as angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta blockers, and digoxin.

-Atrial fibrillation – In patients with AL cardiac amyloidosis and atrial fibrillation, beta blockers and digoxin can be used if no other agents are tolerable or effective for rate or rhythm control.

We avoid use of calcium channel blockers in patients with AL cardiac amyloidosis.

•Specific therapy for AL amyloidosis – In patients with AL cardiac amyloidosis, the underlying hematologic disorder should be appropriately treated. (See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis", section on 'General concepts' and "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis", section on 'Initial treatment'.)

•Therapy for heart failure with reduced ejection fraction – Treatment consists of general measures used to treat HF (eg, salt and water restriction) and use of a diuretic for volume management. (See 'Therapy for heart failure' above and "Use of diuretics in patients with heart failure".)

There is no specific regimen of agents for use in patients with AL cardiac amyloidosis and HF with reduced ejection fraction (HFrEF). Many agents typically used to treat HFrEF should be avoided in patients with AL cardiac amyloidosis. (See 'Therapies to avoid or use with caution' above.)

•Restrictive cardiomyopathy or diastolic heart failure – Diuretics are the mainstay of therapy for volume overload, and agents typically used to treat HF with preserved ejection fraction (HFpEF) are of unclear benefit or safety. (See 'Therapy for heart failure' above.)

•Sudden death prevention – In patients with AL cardiac amyloidosis whose prognosis is acceptable (eg, >50 percent chance of one-year survival), it is reasonable to place an implantable cardioverter-defibrillator (ICD) for secondary prevention; placement of an ICD for primary prevention is controversial. (See 'Prognosis' above and 'Sudden death prevention' above.)

•Prognosis – With contemporary management, the median survival for AL cardiac amyloidosis with cardiac involvement is approximately 5.5 years after diagnosis. Detailed prognosis can be estimated using staging methods (table 1 and table 2), which are discussed separately. (See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis", section on 'Staging'.)

●ATTR amyloidosis

•Medical therapy – In patients with ATTRwt (wild-type transthyretin amyloidosis) or ATTRv (where "v" indicates "variant") cardiac amyloidosis and New York Heart Association (NYHA) functional class I to III HF symptoms, we recommend treatment with tafamidis rather than no disease-specific therapy (Grade 1B), and we suggest tafamidis rather than diflunisal (Grade 2C). Diflunisal is poorly tolerated and has unclear efficacy in patients with cardiac amyloidosis. (See 'Disease-specific therapy for ATTR amyloidosis' above.)

•Therapy for heart failure – In patients with ATTR cardiac amyloidosis with either HFrEF or HFpEF (including restrictive physiology), there are no specific recommendations for HF therapy other than general HF treatment measures and diuretics for volume overload. (See 'Therapy for heart failure' above.)

In patients with refractory HF, options for therapy include palliative care, heart or combined heart and liver transplantation, mechanical circulatory support, and continuous inotrope infusion. (See 'Refractory heart failure' above.)

•Liver transplantation – The role of liver transplantation in patients with ATTRv is described separately. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation", section on 'Metabolic disorders'.)

•Prognosis – Two staging systems have been proposed in patients with ATTR amyloidosis. (See 'Prognosis' above.)

●AA and other amyloidoses – In patients with either serum amyloid A amyloidosis (AA cardiac amyloidosis) or other amyloidoses who have cardiac involvement, treatment is focused on the underlying condition causing AA cardiac amyloidosis, if available. (See "Overview of amyloidosis", section on 'Types of amyloidosis' and "Pathogenesis of AA amyloidosis" and "Causes and diagnosis of AA amyloidosis and relation to rheumatic diseases" and "Treatment of AA (secondary) amyloidosis".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledge Rodney H Falk, MD, who contributed to earlier versions of this topic review.