Cardiac amyloidosis medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]; Aarti Narayan, M.B.B.S [3]; Cafer Zorkun, M.D., Ph.D. [4]; Lakshmi Gopalakrishnan, M.B.B.S. [5]


Major cardiac manifestations of systemic amyloidosis include heart failure and fatal arrhythmias. Therefore, in addition to treating the underlying disease, the treatment of cardiac amyloidosis includes the treatment of heart failure and arrhythmias. Treatment of heart failure associated with cardiac amyloidosis differs from therapy usually administered in patients with systolic or diastolic dysfunction. Loop diuretics are the drugs of choice in the treatment of heart failure in cardiac amyloidosis.

Medical Therapy

Treatment of Underlying Disease

ATTR Amyloidosis

Tafamidis (ATTR stabilization molecule) has been approved by regulatory agencies for treatment of patients with ATTR cardiomyopathy and NYHA functional class I-III symptoms. The ATTR-ACT study randomized 441 patients with ATTR amyloid cardiomyopathy (mutant or while type) to tafamidis 80 mg, 20 mg, or placebo, and followed the patients for 30 months.[1] Compared with placebo, tafamidis reduced mortality (29.5 vs 42.8% HR 0.70; 95% CI 0.51 to 0.86) and cardiovascular hospitalizations (0.48 vs 0.70 per year; RR 0.68; 95% CI 0.56 to 0.81).

AL Amyloidosis

The definitive treatment of AL amyloidosis includes antiplasma cell therapy aimed at halting the process of paraprotein production responsible for the formation of amyloid. Major treatment strategies include:[2][3]


Most common chemotherapy regimens used in the treatment of AL amyloidosis are:

Of all the chemotherapy regimens, treatment with IV melphalan has shown the highest success rate, with a complete hematologic response in ≈40% of patients. However patients with advanced heart failure, pleural effusion, markedly thickened ventricular wall and elevated troponin levels are associated with poor prognosis in patients treated with chemotherapy. In patients with cardiac amyloid, an ejection fraction of <40% is considered an absolute contraindication for high dose chemotherapy. A standard regimen of melphalan includes pulsed dose administration of melphalan and prednisone for 3 to 5 days every 6 weeks. An alternative regimen is monthly injection of slow continuous low-dose melphalan. Bortezomib, a novel proteasome inhibitor, has been shown to be associated with higher response rates similar to that of HSCT.[12][13] Frequent assessment of plasma free light chains and cardiac biomarkers should be a part of the treatment strategy, to optimize risk/benefit ratio and to prevent chemotherapy related toxicity.[14]

Autologous Hematopoietic Stem Cell Transplantation (HSCT)

HSCT is one of the two widely used regimens in the treatment of AL amyloidosis, the other being a combination of melphalan and dexamethasone. This treatment strategy includes administration of high-dose IV melphalan followed by stem cell rescue.[15][16] In selected patients response rates can approach 60%.[17][18][19] Although HSCT has been shown to be associated with reduced mortality, selection of patients remains a critical step while employing this method in the treatment of AL amyloidosis. Reports indicate best results were obtained in patients with one or two organ involvement, no cardiac dysfunction and in those with nephrotic syndrome as the predominant manifestation of systemic amyloidosis. On the contrary, patients with multi-organ involvement, cardiac dysfunction and renal insufficiency are at high risk for morbidity and mortality when treated with HSCT. Poor prognostic predictors include:

Treatment related mortality limits the use of HSCT in every patient and thus warrants a need for the careful selection of patients.

In a randomized controlled trial conducted by the French Myeloma Collaborative Group comparing high dose melphalan followed by HSCT with melphalan and dexamethasone combination regimen, it was found that there exists no significant differences in the treatment outcomes between the two regimens.[24]

Investigational Agents

Several investigational products are currently being studied in clinical trials. These include small interfering RNA (siRNA) molecules which reduce the production of the amyloid precursor misfolded protein and ATTR stabilization molecules.

Treatment of Heart Failure

Heart failure in cardiac amyloidosis (CA) is due to extracellular deposition of amyloid fibrils which results in reduced myocardial compliance and myonecrosis. This extensive infltration of amyloid results in non-compliant, small ventricles leading to impaired filling. Infiltration of the atria further worsens the situation as it impairs atrial contraction.

Acute Pharmacotherapy

Pharmacotherapy in heart failure associated with amyloidosis is different from heart failure due to other causes in that loop diuretics are the main stay of treatment and beta-blockers and ACE inhibitors may be harmful. TTR CA responds better to pharmacotherapy than AL cardiac amyloidosis.

  • Loop diuretics are the drugs of choice in the treatment of heart failure in cardiac amyloidosis. Higher doses of diuretics are used if concomitant nephrotic syndrome is present.
  • Hospitalization and IV diuretics are recommended in the presence of severe symptoms. Careful monitoring of blood pressure and renal function is warranted as rigorous use of diuretics can progress to azotemia. Addition of an aldosterone antagonist such as spironolactone to loop diuretics is well tolerated. Patients with anasarca have reduced absorption rate for the drugs and hence are given intravenous medications.
  • Beta-blockers have been shown to have no proven benefit in the treatment of heart failure associated with amyloidosis. Moreover their use may worsen the condition in patients in whom cardiac output is dependent on heart rate due to presence of a low, fixed stroke volume.
  • Clinical experience with ACE inhibitors in this scenario has shown that these agents are often associated with profound hypotension in AL type CA. The reason for that is possibly by exposing a subclinical neuropathy.
  • Calcium channel blockers bind to the amyloid fibrils and thereby have been reported to increase the incidence of congestive heart failure and produce arrhythmias. Because of this abnormal binding to amyloid fibrils patients with cardiac amyloidosis may be exceptionally sensitive to the negative inotropic effects of these drugs and hence, these drugs are contraindicated in patients with both AL and TTR cardiac amyloidosis.[25][26][27][28][29]
  • Digoxin also binds to amyloid fibrils and is associated with increased risk of digitalis toxicity.

Treatment of Atrial Fibrillation

Involvement of the atria in CA increases the risk for developing atrial fibrillation (AFib). Interstitial deposition of amyloid fibrils makes the atria less compliant and forms a substrate for the development of AFib. [32] AFib with rapid ventricular rate can be treated using the following drugs:

  • Low dose beta-blockers: Should be used with caution and with constant blood pressure monitoring
  • Digoxin: Digoxin should be used with caution in patients with CA as these patients are more prone for digitalis toxicity.
  • Amiodarone: Amiodarone is used for rhythm control and is proved to be well tolerated in these patients.


Occurrence of intracardiac thrombi is frequent in patients with cardiac amyloidosis especially in the AL type. Atrial fibrillation, poor left ventricular diastolic function and atrial mechanical dysfunction have been shown to be associated with increased risk for developing intracardiac thrombi. Thrombi can be present even when the patient is in sinus rhythm.[33][34] Indications for anticoagulation with warfarin include:

  • Presence of AFib
  • Diminutive transmitral A wave and depressed left atrial appendage velocity on echo signalling atrial failure, especially in AL type CA

Because of the increased risk for thromboembolism and subsequent stroke in patients with CA, anticoagulation is not withheld once indicated unless an absolute contraindication exists.

Supportive Measures

  • Physical activity may continue as long as the patient can tolerate it.
  • Diet restrictions vary with the extent of cardiomyopathy and heart failure. These may include salt and/or fluid restrictions.


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