Dual Pathology No Longer a Dead End: Tafamidis and AVR Improve Survival in Aortic Stenosis with Cardiac Transthyretin Amyloidosis

Highlights

– In a 16‑center transatlantic registry of 226 patients with dual AS and ATTR‑CA, ATTR‑specific therapy (99% tafamidis) was associated with a 60% lower adjusted risk of all‑cause mortality (weighted HR 0.40) and a 53% lower risk of cardiovascular death (weighted HR 0.47).

– AVR (predominantly TAVR) improved survival overall and in the severe AS subgroup; patients receiving both AVR and ATTR therapy had the most favorable prognosis, approximating outcomes of matched patients with lone AS who underwent AVR.

– ATTR therapy did not reduce heart‑failure hospitalizations (HHF) in this cohort, underscoring persistent heart failure morbidity despite survival gains.

Structured Graphical Abstract

Background: disease burden and clinical context

Aortic stenosis (AS) and transthyretin cardiac amyloidosis (ATTR‑CA) both increase in prevalence with age and are now frequently encountered together in older adults. ATTR‑CA—caused by misfolding of transthyretin with myocardial deposition—produces restrictive cardiomyopathy, conduction disease, and progressive heart failure. When present alongside AS, ATTR‑CA complicates diagnosis, symptom attribution, procedural risk assessment, and prognosis.

Historically, the presence of cardiac amyloidosis has been considered a high‑risk feature when evaluating patients for aortic valve replacement (AVR), and uncertainty existed whether AVR would alter natural history. Separately, transthyretin stabilizers such as tafamidis demonstrated a survival and functional benefit in randomized trials of ATTR‑CA, but data on their effectiveness in patients with concomitant AS have been limited. This registry addresses whether ATTR‑specific therapy modifies prognosis in patients with dual AS and ATTR‑CA and how it interacts with AVR.

Study design

This international, multicenter, transatlantic registry (AS‑Amyloidosis Consortium; ClinicalTrials.gov NCT06129331) enrolled patients with both clinically significant AS (moderate or severe by transthoracic echo) and ATTR‑CA (diagnosed by positive myocardial bone scintigraphy uptake and/or endomyocardial biopsy in the absence of monoclonal protein). The cohort comprised 226 patients from 16 centers across 10 countries; mean age 85 ± 6 years and 80.4% male.

Valve management varied: transcatheter AVR (TAVR) in 71.7%, surgical AVR in 3.5%, balloon valvuloplasty in 1.3%, and conservative therapy in 23.5%. ATTR‑specific therapy was prescribed to 73 patients (32.3%) and eventually taken by 69 (30.5%) — 99% received tafamidis. Outcomes included all‑cause mortality, cardiovascular mortality, and hospitalization for heart failure (HHF). A control cohort of patients with lone AS undergoing AVR, matched for EuroSCORE II, was used for outcome comparison.

Key findings

The registry follow‑up averaged 3.6 ± 1.7 years. Overall, 112 patients (49.6%) died during follow‑up, with cardiovascular death accounting for 79.5% (89 deaths). HHF occurred in 58 patients (25.7%).

ATTR‑specific therapy and survival

ATTR‑specific therapy was associated with a substantial reduction in risk of death in adjusted analyses. After weighting, treatment correlated with a lower all‑cause mortality (weighted hazard ratio [HR] 0.40; 95% confidence interval [CI] 0.24–0.68) and lower cardiovascular mortality (weighted HR 0.47; 95% CI 0.27–0.83). These effects were observed despite treated patients being, on average, younger and having lower surgical risk but with more pronounced myocardial disease (greater septal thickness and worse LV function) and a higher proportion of moderate AS.

Interpretation: Tafamidis (the agent used almost exclusively in this cohort) likely reduced progressive amyloid cardiomyopathy–related mortality, translating into meaningful survival benefit even in the presence of valvular disease.

AVR and outcomes

AVR was independently associated with improved survival in the whole cohort (HR 0.60; 95% CI 0.39–0.93) and strongly so in patients with severe AS (HR 0.42; 95% CI 0.26–0.70). This supports the paradigm that relief of valvular outflow obstruction benefits patients even when myocardial infiltrative disease is present.

Weighted Kaplan-Meier curves for all-cause mortality stratified by ATTR-treatment prescription. ATTR-Rx was associated with lower mortality hazard for both the population with general availability of ATTR-medication (A) and the overall population (B)

Kaplan-Meier curves for time-dependent co-variates stratified by performance of aortic valve replacement. Aortic valve replacement was associated with lower mortality hazard for both the overall cohort (A) and the severe aortic stenosis cohort (B)

Combined therapy: additive benefit

Patients treated with both AVR and ATTR therapy experienced the most favorable prognosis. Importantly, outcomes in this subgroup approximated those of a control cohort of patients with lone AS undergoing AVR who were matched by surgical risk (EuroSCORE II). In practical terms, receipt of both disease‑targeting therapy (tafamidis) and valve correction offset much of the excess mortality historically attributed to the combination of AS and ATTR‑CA.

Heart‑failure hospitalizations

ATTR‑specific therapy was not associated with a statistically significant reduction in HHF in this registry. This suggests that while survival improved, symptomatic heart failure and morbidity remained common—likely reflecting advanced myocardial remodeling and diastolic dysfunction that are less reversible, or the competing risk of nonfatal decompensations in a longer‑surviving population.

Safety and other observations

The registry did not report new safety signals for tafamidis in this cohort. Procedural details mirrored contemporary practice, with TAVR being the dominant AVR approach in this elderly population. The nonrandomized design and clinical heterogeneity across centers were important contextual features.

Expert commentary and interpretation

Biological plausibility: Tafamidis stabilizes transthyretin tetramers, retarding amyloid formation and deposition. In the ATTR‑ACT randomized trial, tafamidis reduced all‑cause mortality and cardiovascular hospitalizations among patients with transthyretin cardiomyopathy. The present registry extends these therapeutic principles to a real‑world, older cohort in whom valvular disease coexists.

Clinical implications:

Screening for ATTR‑CA in older patients with AS (particularly men >75 years with increased wall thickness, low flow states, conduction disease, or discordance between symptoms and valve metrics) should be strongly considered because detection changes prognosis and management options.
AVR—most commonly TAVR in this age group—should not be reflexively withheld on the basis of coexistent ATTR‑CA; AVR provided a survival benefit even with amyloid present and appears additive to ATTR‑directed therapy.
Initiating tafamidis in eligible patients with confirmed ATTR‑CA may confer survival benefit; the greatest gains were seen when combined with AVR where indicated.

Limitations and cautions

Key limitations temper the conclusions. This was an observational, nonrandomized registry with treatment selection influenced by age, comorbidity, perceived prognosis, access to therapy, and center practices. Treated patients differed from untreated ones in important ways (younger, lower EuroSCORE II, more moderate AS), so residual confounding and confounding by indication are possible despite weighted analyses. The majority of ATTR therapy in this registry was tafamidis, which supports class inference but limits generalizability to other agents. Data on quality of life, functional capacity (e.g., 6‑minute walk), and cost‑effectiveness were not reported here but remain clinically relevant.

Practical takeaways for clinicians

1. Consider systematic screening for ATTR‑CA in older patients with AS who display increased wall thickness, low flow low gradient physiology, carpal tunnel or neuropathy history, or discordant symptoms.

2. Do not withhold AVR solely because of ATTR‑CA. Evaluate patients in a multidisciplinary heart team that includes cardiology, imaging, geriatrics, and, where available, an amyloidosis specialist.

3. When ATTR‑CA is confirmed, discuss the option of transthyretin stabilizer therapy (most commonly tafamidis where approved and accessible) with patients who meet eligibility criteria. Anticipate survival benefit but counsel that reduction in heart‑failure hospitalizations is not guaranteed, especially in those with advanced myocardial disease.

4. Address access, cost, and practical considerations: tafamidis is costly and availability varies by region; engage with payers and patient support services early.

Research and policy priorities

The registry findings generate testable hypotheses that merit prospective study. Priority questions include:

Randomized trials of tafamidis (or other ATTR therapies) specifically in patients with concomitant AS and ATTR‑CA, including earlier versus later initiation relative to AVR.
Prospective studies of timing and sequencing of AVR and ATTR therapy to optimize functional outcomes and HHF reduction.
Quality‑of‑life and cost‑effectiveness analyses in health systems with variable drug access to inform resource allocation and guideline development.
Biomarker and imaging studies to identify patients most likely to benefit from combined therapy and to track disease modification.

Conclusion

The AS‑Amyloidosis Consortium registry demonstrates that ATTR‑specific therapy (predominantly tafamidis) and AVR independently confer survival benefit in patients with dual pathology of AS and ATTR‑CA. Combined therapy produced the most favorable outcomes, approximating those of patients with lone AS undergoing AVR. While observational data cannot replace randomized evidence, these findings support active identification of ATTR‑CA in older patients with AS and a therapeutic approach that combines targeted medical therapy with valve correction when appropriate. Further prospective and randomized research is needed to refine timing, patient selection, and strategies to reduce heart‑failure morbidity.

Funding and clinicaltrials.gov

The registry is registered as NCT06129331. Funding sources and detailed site contributions are reported in the primary reference.

References

1. Nitsche C, Dobner S, Rosenblum HR, et al; AS‑Amyloidosis Consortium. Cardiac transthyretin amyloidosis treatment improves outcomes after aortic valve replacement for severe stenosis. Eur Heart J. 2025 Nov 21;46(44):4795–4806. doi:10.1093/eurheartj/ehaf362 IF: 35.6 Q1 B1. PMID: 40452225 IF: 35.6 Q1 B1; PMCID: PMC12634099 IF: 35.6 Q1 B1.

2. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379(11):1007–1016. doi:10.1056/NEJMoa1805685 .

3. Vahanian A, Beyersdorf F, Praz F, et al. 2021 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2022;43(7):561–632. (Guideline document on selection and timing for AVR.)

4. Kazi DS, Trompeter S, Stuart B, et al. Cost‑effectiveness of tafamidis therapy for transthyretin amyloid cardiomyopathy. JAMA Cardiol. 2020;5(7):739–748. (Discusses economic considerations relevant to therapy access.)