Tafamidis Should Be Accessible for all Patients With Transthyretin Amyloid Cardiomyopathy

Mitchell A. Psotka, MD, PHD


JACC Heart Fail. 2021;9(2):124-126. 

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a traditionally under-recognized etiology of heart failure that occurs in 2 forms: hereditary (hATTR-CM), in which the TTR gene has an autosomal dominant pathogenic sequence mutation responsible for transthyretin protein misfolding (also known as variant ATTR-CM), and wild-type (wtATTR-CM), in which there is no TTR gene mutation.[1] In both forms of ATTR-CM, the normal circulating transthyretin protein tetramer destabilizes and misassembles into aggregations termed amyloid fibrils. These fibrils infiltrate the myocardium and worsen diastolic and eventually systolic function, although they can also affect other tissues, including the nervous system, causing consequent neuropathy. The clinical course of the cardiomyopathy is variable but progressive, often worse with hATTR-CM than with wtATTR-CM, and overall characterized by a median untreated survival of 2.5 to 3.5 years from diagnosis.

Although ATTR-CM is currently classified as a rare disease, with an estimated prevalence of <200,000 persons in the United States, some investigations suggest that it may be substantially more common. It has been reported in ~10% of patients with heart failure and a preserved ejection fraction or those undergoing aortic valve replacement.[1,2] Autopsy studies have identified myocardial ATTR accumulations in >20% of people >80 years of age. The most common TTR mutation associated with hATTR-CM is Val122Ile; although with low penetrance, Val122Ile is present in >1 million individuals in the United States. Finally, as noninvasive diagnosis with technetium pyrophosphate scintigraphy has become the proven and accepted method, pushing aside the restraining gold standard of endomyocardial biopsy in all but rare cases, the identified prevalence of ATTR-CM continues to increase.

Thankfully, patients with ATTR-CM can potentially benefit from decades of basic science and clinical research that have produced approved therapeutics with clinically meaningful effects. The easiest to administer of these is tafamidis, a daily, orally available medication that binds and slows dissociation of the transthyretin tetramers, the rate-limiting step in amyloid fibril formation.[1] In the primary analysis of the ATTR-ACT (Transthyretin Amyloidosis Cardiomyopathy Clinical Trial), a Phase III multicenter international randomized controlled clinical trial, 264 patients with ATTR-CM treated with tafamidis had lower rates of all-cause mortality and cardiovascular hospitalizations compared with the 117 patients receiving placebo, over 30 months of follow-up.[3] The primary analysis used the hierarchical Finkelstein-Schoenfeld, or "win ratio," method for p < 0.001 in favor of tafamidis; the hazard ratio by proportional hazards modeling for all-cause mortality was 0.70 for tafamidis, with a 95% confidence interval (CI) of 0.51 to 0.96. According to Poisson regression, tafamidis also reduced the rate of cardiovascular hospitalizations, with a relative risk ratio of 0.68 (95% CI: 0.56 to 0.81). In addition, tafamidis improved functional capacity measured by the 6 min walk test and quality of life measured by using the Kansas City Cardiomyopathy Questionnaire.

In this issue of JACC: Heart Failure, Rapezzi et al.[3] closely interrogates the efficacy of tafamidis among genetic subgroups: the 335 patients from ATTR-ACT with wtATTR-CM and 106 patients with hATTR-CM were assessed for the primary and multiple prespecified secondary and post hoc outcomes. These data are highly relevant to clinicians managing the common mix of patients with wtATTR-CM and hATTR-CM, although these analyses are sometimes underpowered due to the smaller size of the hATTR-CM population. The authors report that patients with hATTR-CM had more advanced disease at trial enrollment, including higher New York Heart Association functional class and lower 6 min walk distance, and more rapid progression with higher event rates during the trial, than patients with wtATTR-CM. Of the included patients with hATTR-CM, 57.5% had the Val122Ile mutation. I derived survival estimates from the presented Kaplan-Meier data (Stata 14.2, StataCorp, College Station, Texas). The 1-year mortality was 22% in the hATTR-CM population and only 6.6% in the wtATTR-CM population, giving an approximate risk ratio for 1-year all-cause mortality of 0.30 (95% CI: 0.18 to 0.52) for wtATTR-CM compared with hATTR-CM. The frequency of annual cardiovascular hospitalizations was 0.81 (95% CI: 0.62 to 1.07) for hATTR-CM and 0.67 (95% CI: 0.58 to 0.78) for wtATTR-CM.

Nonetheless, the effects of tafamidis were similar for patients with hATTR-CM and those with wtATTR-CM, as was the hierarchical Finkelstein-Schoenfeld analysis for the primary endpoint of all-cause mortality and frequency of cardiovascular hospitalizations.[3] The hazard ratio with tafamidis treatment for all-cause mortality was 0.71 (95% CI: 0.47 to 1.05) for patients with wtATTR-CM, and 0.69 (95% CI: 0.41 to 1.17) for those with hATTR-CM, although the survival curves may separate 6 months later for patients with hATTR-CM. In contrast, the difference in frequency of cardiovascular hospitalizations was less apparent for patients with hATTR-CM, with a relative risk ratio of 0.94 (95% CI: 0.66 to 1.34), compared with those with wtATTR-CM, with a relative risk ratio of 0.61 (95% CI: 0.49 to 0.75).

Functional and quality of life outcomes also benefited from tafamidis in both the wtATTR-CM and hATTR-CM populations. Tafamidis decreased the progressive reduction in 6 min walk test from baseline to 30 months' follow-up by 77 m (95% CI: 56 to 98) for wtATTR-CM and 80 m (95% CI: 21 to 138) for hATTR-CM. Similarly, the decline in Kansas City Cardiomyopathy Questionnaire overall summary scores was 12.7 (95% CI: 8.6 to 16.8) points less for wtATTR-CM and 18.2 (95% CI: 3.0 to 33.4) points less for patients with hATTR-CM. Finally, tafamidis decreased the mean increase in levels of N-terminal pro–B-type natriuretic peptide that occurred over the course of the study in both genotypic groups. The totality of the evidence supports the conclusion that patients with hATTR-CM and wtATTR-CM both merit treatment with tafamidis, even though those with hATTR-CM are often more ill when their disease is recognized.

With the established conclusion that patients with ATTR-CM should be treated with tafamidis, whether they possess the hereditary or wild-type genotype, the medical and patient community can refocus on whether patients can be treated with this effective therapeutic. The result of these analyses should again draw attention to the unreasonable pricing decisions made for this pharmaceutical, considerably above typically accepted cost-effectiveness thresholds.[4] At a current list price of $225,000 annually, it would require an estimated 92.6% price reduction to meet commonly accepted cost-effectiveness standards of $100,000 per quality-adjusted life year.[4] Appropriate use of tafamidis at its current price for all known eligible patients with ATTR-CM would increase total United States pharmaceutical spending by >9%.

Perhaps more critically, broad use of tafamidis would likely also cause substantial financial hardship for patients already experiencing this progressive and deadly disease. Multiple individual center reports describe how the excessive cost of tafamidis creates demanding barriers to patient access.[5] These include burdensome use management obstacles established by payers to restrict usage expenditures, such as prior authorization requirements, but also the need to navigate complicated financial assistance programs to secure sufficient and often time-limited help. In addition, despite copayment assistance from foundations or the manufacturer, the mean 30-day out-of-pocket cost for tafamidis at one center remained $250.

Tafamidis thus encapsulates both the crowning glory of scientific and medical achievement, the creation of a medical therapy for a previously untreatable disease, and the haunting dysfunction of the U.S. pharmaceutical pricing and payment system. The opportunity to help all patients in need of treatment unfortunately remains unrealized, and we should call on the manufacturer, as well as government agencies and representatives, to engage in changing the system to incentivize responsible pricing behaviors and equitable access for all.[2]