The National Center for Health Research appreciates the opportunity to comment on the Centers for Medicare and Medicaid Services (CMS) proposal for Coverage with Evidence Development (CED) for transcatheter tricuspid valve replacement (TTVR). Based on the current evidence, including the TRISCEND II trial, we have concerns about the lack of clinically meaningful benefits and high rates of adverse events. Current data do not meet the required Medicare standard of “reasonable and necessary. However, if CED is finalized, the criteria should be strengthened, and the data should be analyzed after one year to determine if there is clear evidence that TTVR decreases mortality.
Key Concerns Regarding Outcome Data
The weaknesses of the study designs and analyses undermine the purported evidence that is currently available.
Mortality and Hospitalization. Despite the large sample, the TRISCEND II trial did not demonstrate a statistically significant reduction in mortality or hospitalization with TTVR compared to medical therapy (Hahn et al., 2024). Death is the most important outcome measure and mortality reduction should be a fundamental benchmark for evaluating the value of a high-risk, high-cost intervention. Hospitalization is also an important objective measure and the fact that TTVR patients are not showing a benefit is a major concern.
Quality-of-Life Outcomes. While TTVR showed improvements in quality-of-life measures, these outcomes were derived from unblinded assessments, leaving them vulnerable to placebo effects (Hahn et al., 2024; Spertus et al., 2020). For example, when patients are aware that they are being treated with a promising new surgery, they may have a more positive perspective when asked about their recovery and may also try harder on tests such as the 6-minute walk test. That is why subjective measures and those potentially influenced by lack of blinding must be interpreted cautiously and should not be combined with objective measures such as death and hospitalization in a composite outcome measure.
Composite measures can provide a broad assessment but, in this case, the most clinically meaningful outcomes are also less likely to be influenced by lack of blinding. Objective measures such as death and hospitalization should not be combined with subjective measures or with those that could be influenced by lack of blinding. We are pleased to see that CMS’ proposed CED would use a composite limited to death and hospitalization but urge that overall survival should be the primary outcome measure.
Adverse Events. Patients undergoing TTVR experienced significantly higher rates of severe complications:
- Severe Bleeding:4% in the TTVR group vs. 5.3% in the control group.
- Arrhythmias/Conduction Disorders Requiring NEW Permanent Pacemakers:8% in the TTVR group vs. 2.3% in the control group (Hahn et al., 2024).
These adverse event rates raise concerns about the safety profile of TTVR and its net benefit for patients, particularly since the Medicare population includes many frail individuals with multiple comorbidities. Medicare coverage seems impossible to justify given the results and the study’s shortcomings.
Underrepresentation of Key Medicare Populations
The data include appropriate age groups but lack the racial and ethnic diversity typical of Medicare beneficiaries.
Age. The TRISCEND II trial reported a mean patient age of 79.2 years, which is consistent with the older population likely to consider TTVR and with Medicare beneficiaries. However, outcomes for patients aged 80 and older, who are likely to be the most frail and with more comorbidities, should have been analyzed separately to determine what the benefits and risks are for those older patients that comprise a substantial segment of Medicare beneficiaries.
Demographic Representation. Most (75.5%) of the trial population were women, which is consistent with the higher prevalence of tricuspid regurgitation in women. The study included enough men to analyze the risks and benefits stratified by sex, but those analyses were not included in the published study. In contrast, there were too few patients representing racial and ethnic minorities to provide meaningful data on safety or effectiveness for those groups. Since Medicare patients are very diverse, this lack of diversity in the study raises concerns about the generalizability of the findings to all Medicare beneficiaries.
Recommendations for Strengthening CED Criteria
If CMS moves forward with CED for TTVR, we support the requirements that CMS has proposed and urge the inclusion of several more rigorous criteria to ensure that better evidence is collected to determine whether TTVR has benefits that outweigh the risks for Medicare beneficiaries, and that the procedure is thoroughly evaluated. Specifically:
- Require Randomized, Double blind, Sham-controlled Studies to Demonstrate a Mortality Benefit
- Require randomized, double blind, sham-controlled studies (Kodali et al, 2022) to show a statistically significant and clinically meaningful reduction in mortality as the primary endpoint.
- Require studies to show a statistically significant and clinically meaningful reduction in hospitalization for any cause as a secondary endpoint with important quality of life implications. Other subjective quality of life measures can be used only if blinding is successful, but not as a composite outcome measure and only if blinding is successful (Green et al, 2000)
- The CED should state that Medicare coverage of TTVR will be terminated if mortality benefits are not proven by the CED data within an appropriate time frame. These data should be analyzed and made public annually so that if TTVR patients do not show clear benefits within the first year, CMS, physicians, and patients have additional information to help them determine if TTVR has benefits that outweigh the risks.
- Stratification by Age, Comorbidities, and Frailty
- Require stratification by age and comorbidities to assess how these factors influence outcomes and adverse events in the Medicare population (Rockwood et al., 2005). Incorporating a valid frailty index such as the Clinical Frailty Scale could improve risk assessment, by taking into account physical, cognitive, and functional vulnerabilities, especially for a high-risk subgroup.
- Long-Term Follow-Up
- Mandate studies to include multi-year follow-up data on mortality, rehospitalizations, and sustained quality-of-life improvements, given the high-risk profile of the target population (Kodali et al., 2022).
Additional Recommendation
When CED is used, it is essential that CMS have access to all the data collected and has staff able to appropriately analyze the data as quickly as possible. Given the uncertainty of TTVR benefits for mortality or hospitalization, data should be analyzed annually until the data are sufficient to draw conclusions about safety and effectiveness.
Conclusions
TTVR is a high-risk intervention with no evidence of benefit in terms of mortality compared to medical treatment and significant potential for harm. We urge CMS to proceed more cautiously because of the lack of benefit for mortality or hospitalization, and because the study did not evaluate whether there were any differences in risks or benefits associated with race, gender, or co-morbidities. CED seems premature for TTVR at this time, but if CMS decides to finalize CED, we strongly urge that the CED data be analyzed annually to enable CMS to ensure that only those procedures with clear and substantial benefit to Medicare beneficiaries are covered. As a nation, we must prioritize treatments that demonstrate a meaningful balance of safety, efficacy, and cost-effectiveness.
References
- Green, C. P., Porter, C. B., Bresnahan, D. R., & Spertus, J. A. (2000). Development and evaluation of the Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart failure. Journal of the American College of Cardiology, 35(5), 1245–1255. https://doi.org/10.1016/S0735-1097(00)00531-3
- Hahn, R. T., Makkar, R., Thourani, V. H., et al. (2024). Transcatheter Valve Replacement in Severe Tricuspid Regurgitation. The New England Journal of Medicine. https://doi.org/10.1056/NEJMoa2401918
- Kodali, S., Hahn, R. T., George, I., et al. (2022). Transfemoral Tricuspid Valve Replacement in Patients With Tricuspid Regurgitation: TRISCEND Study 30-Day Results. JACC Cardiovascular Interventions, 15(5), 471–480. https://doi.org/10.1016/j.jcin.2022.01.016
- Rockwood, K., Song, X., MacKnight, C., et al. (2005). A global clinical measure of fitness and frailty in elderly people. CMAJ, 173(5), 489–495. https://doi.org/10.1503/cmaj.050051
- Spertus, J. A., Jones, P. G., Sandhu, A. T., & Arnold, S. V. (2020). Interpreting the Kansas City Cardiomyopathy Questionnaire in Clinical Trials and Clinical Care: JACC State-of-the-Art Review. Journal of the American College of Cardiology, 76(20), 2379–2390. https://doi.org/10.1016/j.jacc.2020.09.542