Why the ATTRibute-CM Trial is a Game-Changer in ATTR-CM

CardioNerds Academy Fellow Anna Radakrishnan, MD, MBA, of The Mount Sinai Hospital, spoke with Daniel Judge, MD, of Medical University of South Carolina, who detailed the ATTRibute-CM trial, which assessed the use of acoramidis, a high-affinity transthyretin stabilizer, which shows tremendous promise in treating patients with transthyretin amyloid cardiomyopathy.

Transcript:

Ana Radakrishnan:  Hello. My name is Ana Radakrishnan. I’m a third-year resident and future cardiology fellow at The Mount Sinai Hospital in New York City and a CardioNerds Academy fellow. Today we’ll be discussing the very exciting new data from the ATTRibute-CM Trial and its new insights into the treatment of TTR [transthyretin] cardiac amyloidosis. These data are hot off the press and presented recently at the 2025 American College of Cardiology annual meeting.

Today, I have the great pleasure of introducing Dr. Daniel Judge, Edwin W. and Teresa H. Rogers Endowed Chair for Cardiovascular Research, director of the Cardiovascular Genetics Program, and the fellowship director for Cardiovascular Disease at the Medical University of South Carolina. He received his medical degree at the University of Pennsylvania and did his postgraduate training in internal medicine, cardiology, and advanced heart failure and transplant cardiology at Johns Hopkins. Dr. Judge is a teacher, a mentor, a clinician, and an absolute leader in the field of cardiac amyloidosis; and we are just so thrilled to be chatting with him today.

Welcome, Dr. Judge.

Dr. Daniel Judge: Thanks so much for having me back on CardioNerds, Ana. Nice to see you again.

Ana Radakrishnan:          Likewise. And thank you for being here again. To start us off and set the stage, could you provide an overview of the ATTRibute-CM trial and its significance in the treatment landscape for a transthyretin amyloid cardiomyopathy?

Dr. Daniel Judge: Yes, absolutely. The study was the phase 3 trial for acoramidis, and it was something that was really desperately needed. We had only one therapy for ATTR [transthyretin amyloid] cardiomyopathy prior to that, and that’s tafamidis. We’ll certainly get into that, but this was the phase 3 study. It randomized 632 people in a 2:1 ratio to acoramidis versus placebo. Sometimes if you’re looking at the raw numbers, you’ll have to take that into account in terms of the 2:1 randomization.

It’s probably the last placebo-controlled trial for TTR amyloid that we’ll ever see. We saw that tafamidis was coming along. When we started, it was just hot off the presses, again for new FDA approval in the US, but it was not available for most of the rest of the world. So we said for the first year, you can’t take tafamidis. After that, if the patient had access, if the investigator or their primary cardiologist then prescribed it, they were able to take it. But it was prohibited for the first year.

Of course, the trial was successful. We had a complex Finkelstein-Schoenfeld method for analyzing the data, and that’s a win ratio, so that every patient is really compared to everyone else in the clinical trial to see who does better. We were successful with an overall win ratio of 1.8, largely very much in favor of acoramidis versus placebo.

Ana Radakrishnan: That’s awesome. Thank you for setting the stage. We know from the ATTRACT trial that tafamidis led to a 30% reduction in all-cause mortality and a 32% reduction in cardiovascular-related hospitalizations compared to placebo in patients with transthyretin amyloid cardiomyopathy.

Given that tafamidis use was permitted during the ATTRibute-CM trial, how did your team—and you mentioned this a little bit, but we’d love to hear a little bit more about it. But how did you and your team address the potential confounding effects of concomitant tafamidis use on the primary efficacy analysis? You mentioned a really interesting methodology, the Finkelstein-Schoenfeld test and the sensitivity analyses that were conducted, but could you walk us through that a little bit more in depth?

Dr. Daniel Judge: Yes. That’s a great question because tafamidis is a good drug. It works. Because it was allowed—even though it was not allowed for the first year, it was allowed afterwards—it led to some questions, just as you’re asking. Did it have any impact on the study outcomes?

The first number to think about is how many people took tafamidis? Of course, the timing and the duration of exposure to tafamidis are going to vary across the board of patients, and also with some stratification. But when we think about stratification—meaning people in the US had access for the entire study—people in the United Kingdom did not have access to tafamidis, and they were the largest enrolling site, with Julian Gillmore and Marianna Fontana leading that site. So we had to take that into account.

Only 17.5% of people overall, participants, were on tafamidis, and it was biased against us. So 14.9, just about 15% of the acoramidis patients had some exposure to tafamidis versus 22.8% in the placebo group. If tafamidis was having an effect, we’d see it in that placebo group.

Well, you mentioned the primary analysis being this Finkelstein-Schoenfeld method, and that’s a hierarchical win ratio. We start with the first hierarchy or first stratum, and that’s all-cause mortality. If you die during the study, you’re worse off than if you’re alive. If you die sooner, you’re worse than if you’re living or die later in the study. That’s the first overall comparison. That was a small percentage of participants who met their win ratio on that basis.

CV [cardiovascular] hospitalizations were next, and we did the overall burden of CV hospitalization, not the time to first event. If you’re hospitalized twice, it’s worse than if you’re hospitalized once. If you’re not hospitalized, of course, that’s better. But we were able later to show in a more traditional analysis, a Kaplan-Meier analysis, that time to first event was also less, particularly for those two hard end points.

Now, the third stratum was change in NT-proBNP [N-terminal pro-brain natriuretic peptide], and we all know that’s something that bounces around a bit. We said it has to be a 500-point difference for it to count as a win ratio for comparison in the primary analysis. Then the fourth was change in [the] 6-minute walk test distance. All of them led to some contribution to the outcome, but the predominant, in fact overall, more than half of the ties were broken in the first two strata, the hard end points.

Well, back to the tafamidis question. We used two different methods to say, “Did tafamidis have a role?” The first was to say, “Anybody who took tafamidis, let’s just cross them off altogether.” The second way to do it was to say, “Any event that happened after someone started tafamidis, we’ll just censor it right there.” If they were hospitalized three or four times and then they got tafamidis, anything after that would not be counted, but anything prior to that would be counted. In both of those different methods, we were able to see no change at all in the outcome, the primary outcome, the Finkelstein-Schoenfeld method, showing great improvement of outcomes with acoramidis versus placebo.