By Van Selby, MD

Assistant Professor of Medicine, University of California, San Francisco Cardiology Division, Advanced Heart Failure Section

Dr. Selby reports no financial relationships relevant to this field of study.

SYNOPSIS: Treatment with tafamidis in transthyretin amyloid cardiomyopathy patients produced reductions in all-cause mortality and cardiovascular hospitalizations. This was the first medical therapy to demonstrate improved survival for patients with this condition.

SOURCE: Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med 2018;379:1007-1016.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an under-recognized condition caused by myocardial deposition of amyloid fibrils composed of transthyretin. Currently, there are no approved therapies to treat ATTR-CM. Tafamidis is a transthyretin stabilizer that reduces the formation of pathologic amyloid fibrils in patients with ATTR-CM.

The authors of the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT) randomized 441 patients with confirmed ATTR-CM to tafamidis (20 mg or 80 mg daily) vs. placebo. The median age was 75 years. Most patients were male. Patients with both wild type (76%) and mutant (24%) ATTR-CM were enrolled. Investigators followed patients for 30 months. The primary outcome was all-cause mortality or cardiovascular hospitalization.

Tafamidis was associated with lower all-cause mortality compared to placebo (29.5% vs. 42.9%; hazard ratio, 0.7; 95% confidence interval [CI], 0.51-0.96) as well as a lower rate of cardiovascular hospitalization (relative risk ratio, 0.68; 95% CI, 0.56-0.81). The survival curves began to diverge at approximately 12-18 months, suggesting the drug takes time before demonstrating a favorable impact on outcomes. Tafamidis also was associated with significantly lower rates of decline in quality of life (P < 0.001) and six-minute walk distance (P < 0.001). Generally, tafamidis was well tolerated, with no significant differences in adverse events or discontinuation between the two groups.

The authors concluded treating patients with heart failure due to ATTR-CM with tafamidis reduces all-cause mortality and cardiovascular hospitalizations vs. placebo.


Generally, ATTR-CM affects patients > 60 years of age and is far more common in men. Amyloid fibrils form because of misfolded monomers or oligomers of the protein transthyretin. Transthyretin misfolding can occur either because of a mutation in the transthyretin gene (an autosomal dominant condition) or wild-type transthyretin that becomes unstable and misfolds (formerly referred to as senile amyloidosis). Amyloid fibrils deposit in the heart, leading to heart failure and arrhythmias. Tafamidis acts by binding to circulating transthyretin and stabilizing it in the tetramer form, preventing breakdown into pathologic, amyloid-forming monomers.

Long considered a rare disease, recent studies have demonstrated that ATTR-CM is much more common than previously believed, especially among older patients with heart failure and preserved ejection fraction. Patients often present with left ventricular thickening in the absence of significant hypertension, sometimes accompanied by low QRS voltage on ECG. A history of bilateral carpal tunnel syndrome, neuropathy, or autonomic dysfunction also should raise suspicion. Diagnosing ATTR-CM previously required tissue confirmation, usually through endomyocardial biopsy. However, technetium-labeled bone scintigraphy (such as technetium pyrophosphate scan) now allows providers to make a diagnosis of ATTR-CM without tissue biopsy in many cases.

Traditionally, treatment has been supportive, with no medical therapy shown to alter the underlying course of the disease. Without effective therapy, the prognosis generally was poor, with an average survival of approximately three years from diagnosis. Therefore, the results of ATTR-ACT mark a new era in the management of ATTR-CM, demonstrating impressive improvements in survival, hospitalizations, and quality of life. In a prespecified subgroup analysis, the benefit of tafamidis was not observed among patients with New York Heart Association (NYHA) functional class III heart failure. In fact, the rate of cardiovascular-related hospitalization among this subgroup was higher with tafamidis compared to placebo. Generally, subgroup analyses should be interpreted with caution. There is little reason to suspect tafamidis would worsen patients with NYHA class III symptoms. Maurer et al speculated that hospitalizations increased because of longer survival during a period with severe disease. In any case, this finding underscores the importance of early diagnosis of ATTR-CM, as the data suggest treatment is most efficacious when initiated before patients become markedly symptomatic.

The FDA has granted fast-track and breakthrough therapy designations for tafamidis, which could lead to the drug’s final approval in the coming months. Meanwhile, if patients are referred to a local amyloidosis specialty center, they may be able to obtain access to tafamidis through an open-label extension study that the drug’s manufacturer will offer. There are many more drugs in development for treatment of ATTR-CM, using several approaches to reduce amyloid deposition in the heart. In the coming years, we will see multiple options for this not-so-uncommon disease. It is more important than ever that providers maintain a high index of suspicion and know the red flag signs and symptoms.