The effectiveness and value of disease-modifying therapies for transthyretin amyloid cardiomyopathy

Transthyretin amyloidosis is a condition in which misfolded proteins (transthyretin) build up in various body tissues. When this occurs in the heart, it can cause cardiomyopathy (transthyretin amyloid cardiomyopathy [ATTR-CM]), as the buildup of transthyretin can cause the heart muscle to stiffen. ¹ This leads to a range of cardiac symptoms, including arrhythmia, heart failure, and shortened lifespan. ² Estimates suggest that approximately 50,000 to 150,000 Americans live with ATTR-CM; this is likely an underestimate given the heterogeneous nature of symptoms and lack of awareness among clinicians, which can lead to delayed or missed diagnoses. ²

Treatment options have evolved from symptomatic treatment of heart failure and cardiac/liver transplantation to include tafamidis, a transthyretin stabilizer that was approved in 2019 as the first ATTR-CM–specific treatment. ³ Another transthyretin stabilizer agent, acoramidis, was approved in November 2024, with another drug, vutrisiran, an RNA silencer, currently under US Food and Drug Administration review for ATTR-CM. ⁴ Prior to the availability of disease-specific therapies, the annual cost of care for a patient in the United States with ATTR-CM could exceed $60,000, predominantly attributed to inpatient hospital care. ⁵ The availability of new therapies has added new cost concerns, both to the health system and to individual patients. For instance, an earlier economic modeling analysis found tafamidis to be not cost-effective at its list price of $225,000 in 2019, a price that has since gone up. ⁶

The Institute for Clinical and Economic Review (ICER) evaluated 3 disease-modifying therapies (DMTs) for ATTR-CM. This report presents the summary of our systematic literature review and cost-effectiveness analyses and highlights the key policy recommendations discussed at the Midwest Comparative Effectiveness Public Advisory Council’s (Midwest CEPAC) public meeting on September 20, 2024. The ICER Final Evidence Report on DMTs for ATTR-CM is available at https://icer.org/wp-content/uploads/2024/03/ICER_ATTR-CM_Final-Report_For-Publication_10212024.pdf.

Summary of Findings

CLINICAL EFFECTIVENESS

We evaluated the efficacy and safety of tafamidis, acoramidis, and vutrisiran for the treatment of adults with ATTR-CM. We were not able to compare the agents with each other because of key differences in the trials. Instead, these agents were evaluated separately and compared with no disease-specific treatment as defined in the respective pivotal trials.

The ATTR-ACT trial studied 2 doses of tafamidis (20 mg or 80 mg) vs placebo in 441 patients who were in early to mid-stages of disease, as measured by the New York Heart Association (NYHA) Functional Classification. ⁷ NYHA functional classes range from I to IV, with later stages indicating heart failure and greater limitation in physical activity. ⁸ The trial included patients in NYHA functional class I, II, and III (8.4%, 59.6%, and 31.9%, respectively). ⁷ Over a follow-up period of 30 months, the hazard ratio (HR) for all-cause mortality with tafamidis (pooled doses) was 0.67 (95% CI = 0.49-0.94), with survival curves diverging at approximately 18 months after treatment initiation. ⁷ There was no significant difference in all-cause mortality reduction between the 20-mg and 80-mg doses during the randomized portion of the trial, but a longer follow-up analysis found a significant difference in favor of the 80-mg dose. ⁹ Patients taking tafamidis 80 mg experienced fewer cardiovascular-related hospitalizations compared with placebo (0.49 vs 0.70 hospitalizations per year; relative risk [RR] = 0.70; 95% CI = 0.57-0.85). ⁷

The ATTRibute-CM trial evaluated acoramidis vs placebo in 632 patients who were in NYHA functional class I, II, and III (10.8%, 72%, and 17.2%, respectively). ¹⁰ Survival at 30 months was numerically higher in the acoramidis group compared with placebo (80.7% vs 74.3%), although early mortality curves crossed multiple times, violating the proportional hazards assumption, and it appears that this difference was not statistically significant. ¹⁰ The risk of cardiovascular hospitalization was significantly lower in the acoramidis group (RR = 0.50; 95% CI = 0.36-0.70). ¹⁰

The HELIOS-B trial evaluated vutrisiran vs placebo in 655 patients who were in NYHA functional class I, II, and III (12.8%, 77.7%, and 9.5%, respectively), with a portion of participants (40%) treated with tafamidis at baseline. ¹¹ After 33 to 36 months of follow-up, vutrisiran reduced all-cause mortality compared with placebo (16% vs 21%; HR = 0.69; 95% CI = 0.49-0.98), with mortality reductions persisting through 42 months (HR = 0.65; 95% CI = 0.46-0.90). ¹¹ A similar trend was seen in the subgroup who were not already receiving tafamidis (monotherapy) but was not statistically significant. ¹¹ Vutrisiran also demonstrated superiority in reducing recurrent cardiovascular events in both monotherapy (HR = 0.68; 95% CI = 0.53-0.86) and overall populations (HR = 0.73; 95% CI = 0.61-0.88). ¹¹

All 3 DMTs had a favorable safety profile, with similar rates of adverse events among patients treated with the intervention vs placebo. Owing to its mechanism of action, vutrisiran-treated patients require vitamin A supplementation. ¹²

UNCERTAINTIES BECAUSE OF LIMITATIONS IN THE CLINICAL EVIDENCE

Direct comparisons between tafamidis, acoramidis, and vutrisiran were not possible owing to different study populations, with the added complexity that tafamidis was used by many patients in the acoramidis and vutrisiran trials after tafamidis became available in real-world practice. There is some uncertainty in the treatment benefit of tafamidis in a more contemporary ATTR-CM population, which is more likely to contain individuals in earlier stages of disease (NYHA class I or II vs III) than the ATTR-ACT trial. However, subgroup analysis data from the pivotal trial and survival data from an observational trial suggest that tafamidis may have an increased benefit, if anything, in earlier-stage patients. Acoramidis showed only a small mortality benefit of questionable statistical significance, possibly owing to being studied in a healthier population. Although vutrisiran demonstrated a significant mortality reduction, this could be partially attributed to its longer trial duration (33 to 36 months vs 30 months of the tafamidis and vutrisiran pivotal trials). Lastly, there are no clinical trial data for patients with advanced disease (NYHA class IV), and guidelines conflict regarding treatment of NYHA class III patients, creating uncertainty about optimal therapy in more severe cases.

COST-EFFECTIVENESS

The comparative clinical evidence on acoramidis and tafamidis was insufficient to conduct separate cost-effectiveness analyses for the 2 drugs. Thus, we conducted the evaluation as a drug class added to best supportive care, compared with best supportive care alone, employing effectiveness estimates derived from ATTR-ACT, where more comprehensive data were available, and patient demographics from ATTRibute-CM, a more recently studied patient population. At the time of analysis, there were insufficient data to incorporate vutrisiran into our economic model.

The model used the health states from NYHA class I to class IV and death, as well as a transient state for cardiovascular-related hospitalizations. Transition probabilities between NYHA classes were derived from the ATTR-ACT trial data, assuming equal efficacy between transthyretin-stabilizing agents. Mortality was modeled with disease-specific hazards and treatment-specific rates obtained by calibrating modeled survival to the ATTR-ACT trial observed mortality. Individuals remained in the model until death and could discontinue treatment based on rates observed in the ATTRibute-CM trial. Outcomes calculated were life-years, quality-adjusted life-years, equal-value life-years, costs, and time in NYHA class I/II.

The economic model included several assumptions. Treatment was discontinued for individuals in the NYHA class IV state. We also assumed health state utilities were equal between treatment and control arms. Furthermore, adverse reactions were generally mild and similar between treatment and control groups; therefore, adverse reactions were assumed to be reflected in disease progression and discontinuation rates, and we did not include an additional cost or disutility in the model. Treatment with a transthyretin-stabilizing agent plus best supportive care resulted in greater costs, increased life-years, higher quality-adjusted life-years, and more time spent in NYHA class I and II compared with best supportive care alone (Table 1). At a placeholder price of $194,291 per year (the annual net price of tafamidis), the incremental cost-effectiveness ratios for the transthyretin-stabilizing agents plus best supportive care, compared with best supportive care alone, greatly exceeded commonly accepted cost-effectiveness thresholds (Table 2). Results were sensitive to the modeled utility values for NYHA classes II and IV, and the mortality HR for NYHA class II vs class I. In the probabilistic sensitivity analysis, no iterations using tafamidis pricing generated incremental cost-effectiveness ratios that fell within the commonly used thresholds.

TABLE 1.

Discounted Results for the Base Case for Transthyretin-Stabilizing Agent Plus Best Supportive Care Treatment Compared With Best Supportive Care Alone

Treatment	Drug a	Hospital cost	Nondrug cost b	Total cost a	Life-years	QALYs	evLYs	Years in NYHA class I and II
Transthyretin-stabilizing agent + best supportive care	$744,000	$69,000	$45,000	$858,000	4.4	2.9	3.2	2.7
Best supportive care alone	$0	$45,000	$31,000	$76,000	3.0	2.0	2.0	1.8

^a Based on tafamidis pricing.

^b Including supportive care and nonstabilizing therapy costs.

evLY = equal value of life-years gained; NYHA = New York Heart Association; QALY = quality-adjusted life-year.

TABLE 2.

Incremental Cost-Effectiveness Ratios for the Base Case

Treatment	Comparator	Cost per QALY gained a	Cost per LY gained a	Cost per evLY gained a	Cost per additional year in NYHA class I and II a
Transthyretin-stabilizing agent + best supportive care	Best supportive care alone	$873,000	$566,000	$627,000	$871,000

^a Based on tafamidis pricing.

evLY = equal value of life-years gained; LY = life-year; NYHA = New York Heart Association; QALY = quality-adjusted life-year.

KEY UNCERTAINTIES IN THE MODELING OF COST-EFFECTIVENESS

Key uncertainties in this analysis include being unable to differentiate the cost-effectiveness of acoramidis and tafamidis because of limited acoramidis-specific data, using trial data that may not reflect current ATTR-CM populations, and challenges in obtaining contemporary ATTR-CM–specific data on mortality, disease progression, and costs. The analysis relied on combining efficacy data from the ATTR-ACT (tafamidis) trial, as stage-specific transition probabilities were only available for tafamidis, and population characteristics from the ATTRibute-CM (acoramidis) trial. Cost estimates were derived from obstructive hypertrophic cardiomyopathy owing to a lack of ATTR-CM–specific data. Additionally, we currently have insufficient data on the HELIOS-B trial, and because vutrisiran is not the same class of treatments as acoramidis and tafamidis, we are not able to incorporate it into the structure of our current model.

Policy Discussion

The Midwest CEPAC convened on September 20, 2024, to publicly deliberate on the clinical effectiveness and cost-effectiveness of tafamidis, acoramidis, and vutrisiran for ATTR-CM. The Midwest CEPAC is an independent appraisal committee composed of medical evidence experts, including clinicians, methodologists, and patient advocates. Their deliberations included input from clinical experts, patient representatives with ATTR-CM expertise, and formal comments from the public. Following the discussion, the Midwest CEPAC panel members deliberated on key questions raised by ICER’s report.

All panelists found that current evidence is adequate to demonstrate that the net health benefit of tafamidis (14-0), acoramidis (15-0), and vutrisiran (14-0) are greater than that of no disease-specific treatment. Additionally, despite an “A” rating from the ICER research team about the added benefit of vutrisiran to tafamidis, all panelists found that current evidence is not adequate to demonstrate that the net health benefit of vutrisiran added to tafamidis is greater than that of tafamidis alone (15-0). The panel also found that the evidence was inadequate to distinguish the net health benefit among the interventions (tafamidis, acoramidis, vutrisiran) when used as monotherapy (15-0) (Table 3).

TABLE 3.

Votes on Comparative Clinical Effectiveness Questions

Question	Yes	No
For adults with ATTR-CM, is the current evidence adequate to demonstrate that the net health benefit of tafamidis is greater than that of no disease-specific treatment?	14 a	0
For adults with ATTR-CM, is the current evidence adequate to demonstrate that the net health benefit of acoramidis is greater than that of no disease-specific treatment?	15	0
For adults with ATTR-CM, is the current evidence adequate to demonstrate that the net health benefit of vutrisiran is greater than that of no disease-specific treatment?	14 a	0
For adults with ATTR-CM, is the current evidence adequate to demonstrate that the net health benefit of vutrisiran added to tafamidis is greater than that of tafamidis alone?	0	15
Is the currently available evidence adequate to distinguish the net health benefit among the interventions when used as monotherapy (tafamidis, acoramidis, vutrisiran)?	0	15

Patient population for all questions: adults with ATTR-CM.

^a One council member was unable to vote, resulting in 14 total votes.

ATTR-CM = transthyretin amyloid cardiomyopathy.

The Midwest CEPAC also voted on “benefits beyond health” and “special ethical priorities” as part of a process intended to signal to policymakers whether there are important considerations when making judgments about the long-term value for money that are not adequately captured in analyses of clinical and/or cost-effectiveness (Table 4). The majority of the panel (13 out of 15) voted that tafamidis at its current price has “low long-term value for money at current pricing” compared with no disease-specific treatment (Table 5). Value votes were not taken for acoramidis and vutrisiran at the Midwest CEPAC Public Meeting because prices were not available at the time of the public meeting.

TABLE 4.

Votes on Benefits Beyond Health and Special Ethical Priorities

Benefits beyond health and special ethical priorities	Strongly disagree	Disagree	Neutral	Agree	Strongly agree
To help inform judgments of overall long-term value for money, please indicate your level of agreement with the following statements:
There is substantial unmet need despite currently available treatments.	0	0	4	5	6
This condition is of substantial relevance for people from a health/ethnic group that have not been equitably served by the health care system.	0	0	0	7	8 a
The TTR stabilizers are likely to produce substantial improvement in caregivers’ quality of life and/or ability to pursue their own education, work, and family life.	0	0	1	12	2
Acoramidis offers a substantial opportunity to improve access to effective treatment by means of its mechanism of action or method of delivery.	0	9	6	0	0

^a One council member had technical difficulties when voting and submitted a vote manually.

TTR = transthyretin.

TABLE 5.

Votes on Long-Term Value for Money at Current Price for Tafamidis

Question	High long-term value for money at current pricing	Intermediate long-term value for money at current pricing	Low long-term value for money at current pricing
Given the available evidence on comparative clinical effectiveness and incremental cost-effectiveness, and considering benefits beyond health and special ethical priorities, what is the long-term value for money of tafamidis compared with no disease-specific treatment at current pricing?	0	2	13

Following the discussion of the evidence, a policy roundtable was convened to deliberate on how best to translate the evidence and additional considerations on these therapies into clinical practice, pricing, and insurance coverage. The full set of policy recommendations can be found in the Final Evidence Report on the ICER website: https://icer.org/wp-content/uploads/2024/03/ICER_ATTR-CM_Final-Report_For-Publication_10212024.pdf.

Select key policy recommendations are as follows:

• •
  Payers should use trial inclusion criteria to develop coverage policy and engage clinical experts and patient representatives in considering how to address coverage issues for which there is limited or no evidence at the current time.

  • o
    Diagnosis: Payers should include confirmation of the diagnosis of ATTR-CM as part of coverage policy to avoid futile health spending as well as to avoid adverse clinical events.
  • o
    Clinical eligibility: Clinical experts at the Policy Roundtable felt that it was not unreasonable for payers to use specific inclusion/exclusion criteria from the pivotal trials as the basis for insurance coverage.
• •Given the high costs and uncertainty about the relative effectiveness of different medications, and the lack of evidence to help clinicians identify patients for whom one drug is more likely to be effective than another, it is not unreasonable for payers to consider preferring specific agents based on cost as part of a broader evidence-based approach to negotiating lower prices.
• •Manufacturers should set prices that will foster affordability and access for all patients by aligning prices with the patient-centered therapeutic value of their treatments.
• •Researchers and funding agencies should focus future research on efforts to establish the comparative effectiveness of tafamidis, acoramidis, and vutrisiran in similar populations.

Funding Statement

Drs Wasfy, Winn, Shah, Kim, and Touchette received funding from ICER for the work described in this summary.

Outside of the submitted work, Dr Wasfy reports grant funding from the National Institutes of Health and American Heart Association, past consulting fees from Biotronik and Pfizer, recent consulting fees from Path and Point32Health, and editorial roles at the Journal of the American College of Cardiology and Circulation: Cardiovascular Quality and Outcomes.