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

Which Therapy for ATTR Cardiomyopathy?

Table 1 summarizes evidence from clinical trials on the therapies for cardiac ATTR. The estimated prevalence of ATTR is increasing as a result of greater knowledge of the disease and more widespread availability of techniques for non-invasive assessment, such as diphosphonate scintigraphy. Cardiac involvement is a common feature of ATTR and a crucial determinant of morbidity and mortality, which justifies the current quest for safe and effective therapies. Until very recently, no evidence-based therapeutic options were available, also because patients with cardiac amyloidosis were systematically excluded from clinical trials on HF drugs, and dedicated, adequately powered trials were not performed. Liver transplantation (either alone or combined with heart transplantation) represented the only strategy impacting on patient prognosis, but was reserved to a small minority of patients because of the inherent limitations of transplantation and the uncertain benefit except for patients carrying the V30M mutation. A deeper understanding of ATTR pathogenesis has led to the assessment of other strategies to block transthyretin synthesis or to target other steps of the amyloidogenic cascade (Take home figure). Positive results in a phase 3 trial on the specific setting of ATTR cardiomyopathy have been found only for tafamidis. In the foreseeable future, this drug may become the first approved drug for ATTR cardiomyopathy and the standard of care for this condition, particularly in patients in NYHA Class I–II.[12] The other most promising approaches are patisiran and inotersen, which might prove even more effective than tafamidis as they block TTR synthesis, instead of stabilizing TTR tetramers. Hopefully, multiple therapeutic options will become available, allowing clinicians to tailor the therapeutic strategy on each patient, given the differential characteristics in terms of safety and efficacy. For instance, should patisiran and inotersen be proven equally effective, patisiran could be preferred for a patient receiving anticoagulants for atrial fibrillation, as therapy with inotersen may cause thrombocytopenia, and therefore increase the bleeding risk;[13,14] inotersen should generally not be initiated in patients with urinary protein to creatinine ratio ≥1000 mg/g or estimated glomerular filtration rate <45 mL/min/1.73 m2, as treatment with inotersen can cause glomerulonephritis that may result in dialysis-dependent renal failure.[14] Other perspectives for future research are combinations of drugs with complementary mechanisms of action, cost-effectiveness analyses on novel drugs, and well-designed studies to evaluate whether drugs for neurohormonal antagonism might have some role as adjunctive therapeutic strategies. For all these advances to occur, clinicians must become increasingly aware of red flags for ATTR cardiomyopathy and refer patients with suspected disease to specialized centres, where the diagnostic suspicion can either be confirmed or discarded, patients can receive state-of-the-art therapy and being enrolled in clinical trials.

Take home figure.

The pathogenetic cascade of cardiac transthyretin (TTR) amyloidosis and proposed therapeutic approaches for each step. The more promising approaches, for which a phase 3 study is available, are evidenced in bold, while the least established options are reported in brackets. Ab, antibody; ACEi/ARB, angiotensin converting enzyme inhibitor/angiotensin receptor blockers; ASO, antisense oligonucleotide; BB, beta-blockers; EGCG, epigallocatechin gallate; ICD, implantable cardioverter-defibrillator; LVAD, left ventricular assist device; ATTRv, variant transthyretin amyloidosis; MRA, mineralocorticoid receptor antagonists; PM, pacemaker; SAP, serum amyloid P component; siRNA, small interfering RNA; TUDCA, tauroursodeoxycholic acid.