With targeted treatment using both medical therapy for transthyretin-associated cardiac amyloidosis (ATTR-CA) and valve replacement for aortic stenosis (AS), patients with the dual pathology can fare quite well, according to registry data from the AS-Amyloidosis Consortium.
With a twofold approach to care, these patients are just as likely to survive as those with isolated AS who undergo valve replacement, the researchers report in a paper published recently in the European Heart Journal. Each treatment individually added to the survival benefit, and those who got both benefited the most.
“This is quite compelling evidence that we should not withhold ATTR-specific treatment from these patients, as has been done by many centers, [some of which] contributed to this registry,” lead author Christian Nitsche, MD, PhD (Medical University of Vienna, Austria), told TCTMD. The reason for this, he explained, is because without trial data on the topic, reimbursement has been challenging. As reported by TCTMD, the hefty prices for the ATTR drugs have drawn notice again and again as they each enter the market.
There is much overlap between the two populations with ATTR-CA or AS—an estimated 10% of patients who present with the valve disorder also have ATTR, a progressive disease caused by the buildup of protein deposits in the myocardium that eventually leads to heart failure.
This quite compelling evidence that we should not withhold ATTR-specific treatment from these patients.Christian Nitsche
“Back in 2021, we showed that actually TAVI is not futile in these patients,” said Nitsche, noting that individuals with structural disease had been excluded from the major ATTR drug trials. “The remaining open question was whether this specific patient population would benefit from additional ATTR-specific treatment” on top of valve replacement, he added.
Ahmad Masri, MD (Oregon Health & Science University, Portland), agreed that in dual AS and amyloidosis, it’s been established for some time that “you should fix their valves.” Yet even with valve replacement, these patients “continue to have significant heart failure admissions,” so it’s not surprising to see a benefit with ATTR drugs, Masri commented to TCTMD.
The onus is on the interventional cardiology and imaging communities to recognize these amyloidosis cases within the larger population with aortic stenosis, Masri emphasized.
“It is really important that our interventional colleagues understand that even though the focus may be sometimes fixing the aortic valve, the patients will not do well unless they get the right diagnosis. I think these two things coexist frequently enough that probably [screening] should become standard for those at risk,” he said, though he noted that certainly not every AS patient should be screened for cardiac amyloidosis.
AS-Amyloidosis Consortium
Nitsche and colleagues looked at 226 patients (mean age 85 years; 80.4% male) with both moderate/severe AS and ATTR-CA who enrolled in the registry across 16 specialist referral centers in 10 countries from September 2014 to December 2023. Among them, AS was severe in 86.7% and moderate in 13.3% based on transthoracic echocardiography. ATTR-CA, 99.1% of which was wild-type, was diagnosed via myocardial uptake on bone scintigraphy and/or positive endomyocardial biopsy in the absence of monoclonal proteins.
Comorbidities were common: 78.8% had hypertension, 57.3% atrial fibrillation, 50.4% chronic kidney disease, and 25.2% diabetes.
Treatment of AS included transcatheter aortic valve intervention in 71.7%, conservative management in 23.5%, surgical aortic valve replacement in 3.5%, and balloon angioplasty in 1.3%. ATTR-specific medications—nearly all tafamidis (Vyndamax and Vyndaqel; Pfizer)—were prescribed to 32.3%, with 30.5% of the cohort ultimately receiving drug therapy; these patients tended to be younger and have lower EuroSCORE II values. They also were more likely to have moderate (versus severe) AS but also had thicker intraventricular septa and more severely impaired LV function.
Reasons for not receiving ATTR-specific medications included the lack of availability before market authorization (31.2%), absence of local reimbursement (21.0%), lack of data suggesting benefit in the AS population (12.7%), Grade 1 cardiac uptake (12.7%), and severe comorbidities (6.4%). However, use of the drugs rose over time, from no patients in 2014-2017 to a quarter of patients in 2018-2020 and 53.1% in 2021-2023 (P < 0.001).
Median time from ATTR-CA diagnosis to receipt of medical therapy was 126 days overall, decreasing from 225 days in 2018-2020 to 76 days in 2021-2023 (P < 0.001).
During a mean follow-up of 3.6 years, half of patients died, with 80% of the deaths being cardiovascular. Around a quarter were hospitalized for heart failure.
Use of medical therapy for ATTR was independently linked to lower mortality, both all-cause (weighted HR 0.40; 95% CI 0.24-0.68) and cardiovascular (weighted HR 0.47; 95% CI 0.27-0.83), but had no apparent impact on heart failure hospitalization. Aortic valve replacement was linked to better survival both overall (HR 0.60; 95% CI 0.39-0.93) and specifically in patients with severe AS (HR 0.42; 95% CI 0.26-0.70).
Prognosis was best among patients who received ATTR-specific medical therapy as well as aortic valve replacement—with results comparable to controls with isolated AS who underwent AVR (adjusted HR 1.11; 95% CI 0.81-1.51).
Even though the focus may be sometimes fixing the aortic valve, the patients will not do well unless they get the right diagnosis.Ahmad Masri
Clinicians treating AS should be alert to the possibility that their patients may also have ATTR-CA, Nitsche noted. “There are multiple screening opportunities or modalities that you can use in order to estimate the pretest probability of concomitant amyloids,” one of which is the RAISE score, which he and others proposed in 2021. Clues include a history of carpal tunnel syndrome, spinal stenosis, proteinuria, and other symptoms signaling amyloidosis.
“The bottom line is you should just be aware that this condition is more prevalent than previously thought and is still overlooked by clinicians,” said Nitsche.
Even with their known overlap, the mechanistic link between the two diseases isn’t yet clear, both Nitsche and Ahmad said. It may be that the aortic stenosis primes the left ventricle for amyloid deposition, or that each condition simply grows more prevalent as patients age. Beyond what’s driving the dual pathology, there’s much left to learn about who to treat, when to start, and which ATTR-specific agent to prescribe, Nitsche stressed.
Importantly, too, this analysis “reiterates the very high mortality in this condition,” Masri added. “That’s why we need to study it more.”