Treatment of Cardiac Transthyretin Amyloidosis: An Update

Michele Emdin; Alberto Aimo; Claudio Rapezzi; Marianna Fontana; Federico Perfetto; Petar M. Seferović; Andrea Barison; Vincenzo Castiglione; Giuseppe Vergaro; Alberto Giannoni; Claudio Passino; Giampaolo Merlini


Eur Heart J. 2019;40(45):3699-3706. 

In This Article

Supportive Treatment of Cardiac Involvement

Drug Therapies

The application of guideline-recommended therapeutic algorithms for HF[44] to cardiac ATTR, with regard to therapies targeting cardiac damage and its direct consequences may yield a partial benefit. Beta-blockers may be poorly tolerated or contraindicated, for example because of hypotension, conduction disturbances, or impossibility of adequately increasing cardiac output, especially in cases with overt restrictive pathophysiology, when cardiac output becomes critically dependent on heart rate.[45] Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARBs) may be poorly tolerated as well, particularly in hypotensive patients. Nonetheless, almost 30% of patients in the ATTR-ACT trial were on beta-blockers or ACEi/ARB.[12] Because of the lack of evidence on their prognostic impact in cardiac ATTR, no specific recommendation can be made, and these drugs might be considered in the absence of clear contraindications, starting from low doses, with slow up-titration and close monitoring. Mineralocorticoid receptor antagonists are frequently and safely used. Diuretic therapy is essential for dyspnoea relief and is often needed in high doses to reduce pulmonary and peripheral congestion, particularly in patients with severe diastolic dysfunction, although care should be taken to avoid worsening renal function and excessive preload reduction. Digoxin has been traditionally contraindicated because of old reports of increased toxicity in patients with amyloid cardiomyopathy,[10] but a recent report suggests that it may be cautiously utilized in AL amyloidosis, at low doses and with frequent drug concentration monitoring, while no data are available in TTR amyloidosis.[46] Finally, non-dihydropyridine calcium channel blockers are contraindicated because of their negative inotropic effect.

Patients with cardiac amyloidosis have an increased risk of atrial thrombosis even in sinus rhythm, likely because of a loss of atrial mechanical function.[47] Anticoagulation with either warfarin or the novel oral anticoagulants can usually be safely prescribed to patients with ATTR, with the same indications than in other disease settings because of the absence of any specific evidence. In a recent study on 58 patients with cardiac amyloidosis (50% with ATTR) referred to direct-current cardioversion for atrial arrhythmias, there was a high cancellation rate because of intracardiac thrombi even among patients who received adequate anticoagulation; performing a transoesophageal echocardiogram before DDCV is then advisable.[48]

Implantable Cardioverter-defibrillator

Sudden cardiac death has a high incidence and may result from tachyarrhythmias, but more often from electromechanical dissociation or arrhythmias not amenable to implantable cardioverter-defibrillator (ICD) therapy. This point has been most extensively studied in cardiac AL amyloidosis.[49] In a study on 53 patients with cardiac amyloidosis (33 AL, 10 ATTRwt, and 9 ATTRv), who received an ICD for either primary (n = 41) or secondary prevention (n = 12), the rate of appropriate ICD shocks was 32% in the first year and was observed almost exclusively in patients with AL amyloidosis.[50] Appropriate ICD shocks were more frequent in patients implanted for secondary prevention, and did not translate into overall survival benefit. Higher defibrillation thresholds and complication rates represent further concerns.[51]

Cardiac Pacing

The infiltration of myocardial tissue by amyloid fibres predisposes to bradyarrhythmias. In a large series of patients with ATTRv-related polyneuropathy (n = 262), prophylactic pacemaker was implanted in patients (n = 100) with His-ventricular interval ≥70 ms, His-ventricular interval >55 ms associated with a fascicular block, a first-degree atrioventricular (AV) block, or a Wenckebach anterograde point ≤100 b.p.m. Over a mean 45-month follow-up, a high-degree AV block was documented in 24 of the 95 patients (25%). The risk of high-degree AV block was higher in patients with first-degree AV block or Wenckebach anterograde point ≤100 b.p.m. (hazard ratio 3.5; 95% confidence interval 1.2–10).[52] Although a screening electrophysiological study cannot be proposed to all TTR patients, these findings suggest that any conduction disturbance on 12-lead electrocardiogram (ECG) warrant further investigations, including at least ECG long-term Holter monitoring and close follow-up.

Left Ventricular Assist Device and Cardiac Transplantation

Left ventricular assist device therapy is technically feasible in patients with cardiac amyloidosis but is associated with high short-term mortality and worse outcome than in dilated cardiomyopathy, as in other forms of restrictive cardiomyopathy.[53,54]

Isolated cardiac transplantation is a valuable option for patients with end-stage HF when significant extracardiac disease is excluded. In a case report, no recurrence of amyloid in the cardiac allograft and no systemic abnormalities were reported 5 years after heart transplantation.[55] A second patient with the same mutation was well 3 years later, with no evidence of allograft or systemic amyloid deposition.[56] Among 10 patients (2 ATTRwt, 7 ATTRv, 1 undetermined), there was only one episode of amyloid recurrence in the cardiac graft.[57] The Stanford cardiac transplantation evaluation guidelines for ATTR summarize the screening examinations for transplantation candidates.[58]