Cost-Effectiveness of Tafamidis Therapy for Transthyretin Amyloid Cardiomyopathy

Abstract

Background: In patients with transthyretin amyloid cardiomyopathy, tafamidis reduces all-cause mortality and cardiovascular hospitalizations and slows decline in quality of life compared with placebo. In May 2019, tafamidis received expedited approval from the US Food and Drug Administration as a breakthrough drug for a rare disease. However, at $225 000 per year, it is the most expensive cardiovascular drug ever launched in the United States, and its long-term cost-effectiveness and budget impact are uncertain. We therefore aimed to estimate the cost-effectiveness of tafamidis and its potential effect on US health care spending.

Methods: We developed a Markov model of patients with wild-type or variant transthyretin amyloid cardiomyopathy and heart failure (mean age, 74.5 years) using inputs from the ATTR-ACT trial (Transthyretin Amyloidosis Cardiomyopathy Clinical Trial), published literature, US Food and Drug Administration review documents, healthcare claims, and national survey data. We compared no disease-specific treatment ("usual care") with tafamidis therapy. The model reproduced 30-month survival, quality of life, and cardiovascular hospitalization rates observed in ATTR-ACT; future projections used a parametric survival model in the control arm, with constant hazards reduction in the tafamidis arm. We discounted future costs and quality-adjusted life-years by 3% annually and examined key parameter uncertainty using deterministic and probabilistic sensitivity analyses. The main outcomes were lifetime incremental cost-effectiveness ratio and annual budget impact, assessed from the US healthcare sector perspective. This study was independent of the ATTR-ACT trial sponsor.

Results: Compared with usual care, tafamidis was projected to add 1.29 (95% uncertainty interval, 0.47-1.75) quality-adjusted life-years at an incremental cost of $1 135 000 (872 000-1 377 000), resulting in an incremental cost-effectiveness ratio of $880 000 (697 000-1 564 000) per quality-adjusted life-year gained. Assuming a threshold of $100 000 per quality-adjusted life-year gained and current drug price, tafamidis was cost-effective in 0% of 10 000 probabilistic simulations. A 92.6% price reduction from $225 000 to $16 563 would be necessary to make tafamidis cost-effective at $100 000/quality-adjusted life-year. Results were sensitive to assumptions related to long-term effectiveness of tafamidis. Treating all eligible patients with transthyretin amyloid cardiomyopathy in the United States with tafamidis (n=120 000) was estimated to increase annual healthcare spending by $32.3 billion.

Conclusions: Treatment with tafamidis is projected to produce substantial clinical benefit but would greatly exceed conventional cost-effectiveness thresholds at the current US list price. On the basis of recent US experience with high-cost cardiovascular medications, access to and uptake of this effective therapy may be limited unless there is a large reduction in drug costs.

Keywords: amyloidosis; cost-benefit analysis; economics; heart failure.

Figure 1.. Schematic of Model and Model Calibration.

We developed a state-transition Markov model to evaluate the cost-effectiveness of tafamidis therapy compared with usual care among patients with symptomatic heart failure due to transthyretin amyloid cardiomyopathy (ATTR-CM, panel A). In monthly cycles, patients could experience cardiovascular hospitalizations (some proportion of which were fatal), or die from other causes (Panel B). In the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT), treatment with tafamidis compared with usual care reduced the risk of cardiovascular hospitalizations throughout the course of therapy, and the risk of death after the first 18 months of treatment. Over the initial 30 months, the model reproduced survival rates seen in the tafamidis and control arms in the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT, Panel C). The model used a parametric (Weibull) model to project long-term survival in the control arm beyond 30 months. The base case assumed that the effectiveness of tafamidis would be preserved beyond 30 months (best-case scenario). In sensitivity analyses, we modeled an intermediate-case scenario that assumed that the effectiveness of tafamidis gradually would wane beyond 30 months so that there would be no meaningful differences between the control and intervention groups beyond 90 months, and a worst-case scenario that assumed a complete loss of effectiveness of tafamidis beyond 30 months (Panel C). See text for additional modeling details. Abbreviations: ATTR-ACT = Transthyretin Amyloidosis Cardiomyopathy Clinical Trial, ATTR-CM = transthyretin amyloid cardiomyopathy.

Figure 2.. One-Way Sensitivity Analysis by Price of Tafamidis.

We evaluated the effect of varying the annual cost of tafamidis on the incremental cost-effectiveness ratio (ICER) of tafamidis compared with usual care, holding all other input parameters at their base-case value. At the 2019 annual price of $225,000, tafamidis does not meet conventional cost-effectiveness thresholds. An 86.7% reduction in price to $29,925 would be needed to achieve a threshold of $150, 000 per quality-adjusted life year (QALY) gained, a 92.6% reduction in price to $16,563 would be needed to meet a cost-effectiveness threshold of $100,000 per QALY gained, and a 98.6% reduction to $3,200 would be needed to achieve a cost-effectiveness threshold of $50,000 per QALY gained.

Figure 3.. Cost-Effectiveness Acceptability Curves.

In probabilistic sensitivity analyses, we ran 10,000 iterations of the model after sampling key input parameters from pre-specified statistical distributions (with replacement). The results are shown below as acceptability curves, which indicate the proportion of simulations (y-axis) in which a given strategy is the optimal strategy at various cost-effectiveness thresholds (x-axis). Under our base case assumptions and assuming a societal cost-effectiveness threshold of $100,000 per quality-adjusted life year (QALY), treatment with tafamidis was cost-effective compared with usual care in 0% of the simulations.