Even on Tafamidis, ATTR-CM Patients Face High Mortality Over Time

Two out of every five patients with transthyretin amyloid cardiomyopathy (ATTR-CM) treated with tafamidis (Vyndamax and Vyndaqel; Pfizer) can be expected to die in less than 4 years, new real-world data suggest.

Despite the high mortality rate, researchers say the results should be interpreted favorably given that tafamidis was the first treatment approved for ATTR-CM just a few short years ago.   

“We went from a condition that was 100% fatal, untreatable, and no approved medications to now having a couple,” lead investigator Ahmad Masri, MD (Oregon Health & Science University, Portland), told TCTMD. “This is a very early real-world study done right around the time of approval and we’re already seeing there are signals where mortality looks better than what we have expected.”

The field is also hopeful that continued drug development will further improve outcomes for patients for ATTR-CM. “We want to push things to see how we can help these patients even more,” said Masri.

ATTR-CM is a progressive disease caused by the buildup of transthyretin in the heart muscle that eventually leads to heart failure. In the ATTR-ACT study, the transthyretin stabilizer tafamidis significantly reduced the risk of all-cause mortality compared with placebo, as well as reduced cardiovascular hospitalizations. Since then, US and European regulators have approved a second transthyretin stabilizer, acoramidis (Attruby and Beyonttra; BridgeBio), on the strength of the ATTRibute-CM trial. 

We’re already seeing there are signals where mortality looks better than what we have expected. Ahmad Masri

Julian Gillmore, MD, PhD (University College London/Royal Free Hospital, England), who led ATTRibute-CM, told TCTMD that the real-world data illustrate the ability of tafamidis to prolong survival and improve patient outcomes. Left untreated, the median survival time of patients with ATTR-CM varies, with those with hereditary ATTR-CM faring worse than those with wild-type.

However, these data also show that tafamidis “is not a panacea,” said Gillmore. Tafamidis slows the progression of transthyretin deposits in the heart but doesn’t cure the disease. “Tafamidis was a great drug when there were no options available,” he said, but added that researchers and clinicians still need better treatments.

Nowell Fine, MD (University of Calgary, Canada), who wrote an editorial accompanying the new paper, said there’s a “great thirst” among doctors to better understand long-term outcomes with tafamidis given that it was only just recently approved. He noted that even though there have been improvements in ATTR-CM prognosis, which are attributable to identifying patients earlier, the mortality rate seen here is still relatively high.

Change in Natural History of ATTR-CM

The study, published today in JACC: CardioOncology, reflects a contemporary ATTR-CM population, one that is changing as physicians are increasingly more aware of the disease and diagnoses are made using myocardial scintigraphy in conjunction with an evaluation of biomarkers. This has largely eliminated the need for biopsy.   

“There has been an evolution or change in the natural history of transthyretin amyloidosis,” said Masri. “We’re finding patients earlier and their characteristics are not exactly the same as the patients who were diagnosed 10 years prior.”

Tafamidis alone is not good enough. It’s better than nothing without a doubt, but there’s room for improvement. Julian Gillmore

Given the changes, investigators wanted to identify a more contemporary cohort of tafamidis-treated patients and follow them for several years to see how they fared. The observational study included 624 patients (mean age 76.9 years; 87.5% male) treated at five amyloidosis centers in the US. Just over 17% of patients were Black, more than one-third had NYHA functional class III/IV symptoms, and the median NT-proBNP level was 1,911 pg/mL. Overall, 17.5% had a genetic variant in transthyretin sequencing and were classified as variant ATTR-CM.

In terms of the disease, 48.1%, 25.5%, and 14.1% were in stages 1, 2, and 3, respectively, when using the prognostic National Amyloidosis Centre (NAC) system. With the Columbia staging system, which incorporates NYHA functional class and diuretic dose, 34.9%, 37.5%, and 9.1% were in stages 1, 2, and 3, respectively.

In general, patients were older but less sick than those in the randomized ATTR-ACT trial, said Masri. “We looked at the population that is coming after the clinical trials, but before the big surge in the diagnosis that is happening,” he said. “This was intentional as we needed enough follow-up for these patients—we sort of have an ‘intermediate’ population.”  

Over a median of 43.2 months, 38.6% of patients died and the probability of survival at 65 months was 54.1%. Overall, 39.3% of patients were hospitalized for cardiovascular reasons, with half of hospitalized patients returning more than once.

Age, male sex, Black race, variant ATTR-CM, Columbia stages II and III, and time from ATTR-CM diagnosis to starting tafamidis were all variables associated with worse survival. NYHA functional class was predictive of different survival over 65 months, with survival worsening across classes. Worsening survival was also seen across the NAC and Columbia stages. In a separate multivariate model, a cardiovascular hospitalization was associated with worse survival.

In a sensitivity analysis that restricted the cohort to patients who started tafamidis within 6 months of the ATTR-CM diagnosis, survival probability at 65 months (49.6%) was similar to the overall cohort.

More Options Great for Everybody

The mortality rate in this cohort is better than that observed in patients included in the ATTR-ACT open-label extension study where mortality at 58 months was 44.9% in those treated continuously with tafamidis. Still, Masri stressed that more works needs to be done to find ATTR-CM patients sooner.

“The fact that they’re older doesn’t mean you can’t prevent them for dying from cardiovascular reasons,” he said.

Both transthyretin stabilizers are exceptionally expensive, with tafamidis listed at $225,000 annually and acoramidis at $244,000, and many patients face high out-of-pocket costs. Masri said there have been no head-to-head studies comparing the two, so treatment decisions are based on a discussion with patients.

“More options for patients [are] great because whenever you’re stuck with one, sometimes it’s not for everybody,” he said. If a patient is treated with tafamidis and worsening, a switch may be warranted but it doesn’t necessarily mean the patient will improve or feel better. “This is a very complex condition,” said Masri. “The patient population themselves are heterogeneous. We know that a lot of patients progress on the current treatments that we have.”

In England, tafamidis wasn’t available for several years because the National Institute for Health and Care Excellence (NICE) recommended against its use given the high cost. The group reversed course in 2024, however, and it’s now approved for wild-type or hereditary ATTR-CM. Though the ability to prescribe the TTR stabilizer is helpful and a relief, Gillmore still aims to place his tafamidis-treated patients into a clinical trial testing antibody or gene editing therapy.

“Tafamidis alone is not good enough,” he said. “It’s better than nothing without a doubt, but there’s room for improvement.”

Several different avenues of treatment are in the works, including in vivo gene-editing therapy using CRISPR-Cas9 and the RNA interference therapeutic agent vutrisiran (Amvuttra; Alnylam) that inhibits the production of transthyretin. To TCTMD, Gillmore said there is also a good deal of excitement around research into the use of antibodies.

“All the drugs, whether it's a gene silencer, gene editor, or transthyretin stabilizer, they all are designed to stop amyloid formation or slow amyloid formation,” said Gillmore. “Obviously, they don’t address the amyloid clearance side of things, which is naturally very slow. Slower than the rate of formation, certainly in the absence of treatment.”

Antibody-based therapy, he said, is designed to accelerate the clearance of amyloid in the heart and potentially normalize cardiac structure and function.