Earlier diagnosis, new therapies boost ATTR-CM survival rates: Review
More recent clinical trials also show less advanced disease in patients
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People with transthyretin amyloid cardiomyopathy (ATTR-CM) enrolled in more recent clinical trials show less advanced disease and improved survival compared with those in earlier studies, likely reflecting early diagnosis and advances in treatment.
That’s according to a systematic review of 58 published studies covering 13 ATTR-CM clinical trials conducted between 2008 and 2022.
“Given the changes in patient characteristics over time, differences or comparisons in outcomes across trials should be interpreted with caution,” researchers wrote. “With the increase in ATTR-CM awareness, patients are increasingly receiving diagnoses earlier in the disease course; thus, it is important to consider the relevance of clinical outcomes when designing future trials to assess treatment benefit accurately and to inform optimal patient care.”
The study, “Evolution of patient characteristics and outcomes in ATTR-CM clinical trials: A systematic review,” was published in Progress in Cardiovascular Diseases.
ATTR-CM has often been underdiagnosed, identified at later stages
In ATTR-CM, misfolded transthyretin proteins form toxic clumps, known as amyloid fibrils, in the heart. These deposits stiffen the heart muscle, making it harder to pump blood and ultimately leading to heart failure. Although primarily a heart condition, it can also affect other organs, including the kidneys.
ATTR-CM may be caused by inherited mutations in the gene encoding transthyretin (hereditary ATTR-CM) or develop with age in the absence of mutations (wild-type ATTR-CM).
Historically, ATTR-CM has often been underdiagnosed or identified at advanced stages due to nonspecific symptoms overlapping with those of other heart conditions and the need for invasive diagnostic procedures such as heart biopsies.
However, increased awareness, advances in noninvasive imaging, and the availability of disease-modifying therapies have enabled earlier diagnosis, broadening the range of patients enrolled in clinical trials.
“Given these shifts, it is crucial to understand how [initial] characteristics and outcomes of patients in ATTR-CM trials have evolved,” the researchers wrote.
More recent trials showed less severe disease at study start
To this end, a team of U.S. researchers conducted a systematic review of published studies up to September 2024 that reported on clinical trials involving people with ATTR-CM.
From an initial pool of more than 800 published reports, 58 studies covering 13 clinical trials conducted between 2008 and 2022 in people with hereditary and wild-type ATTR-CM were included in the final analysis.
There were five placebo-controlled trials, five single-arm studies (in which all participants received the same treatment), and three long-term extension studies. All but one study enrolled people with hereditary and wild-type ATTR-CM.
Placebo-controlled trials included four Phase 3 studies, each supporting the approval of a different ATTR-CM therapy. ATTR-ACT (NCT01994889) tested Vyndamax (tafamidis), the first approved therapy for ATTR-CM. APOLLO-B (NCT03997383) evaluated Onpattro (patisiran), ATTRibute-CM (NCT03860935) tested Attruby (acoramidis), and HELIOS-B (NCT04153149) evaluated Amvuttra (vutrisiran). The remaining placebo-controlled trial was a Phase 2 study testing Attruby.
Across studies, eligibility criteria were largely consistent, generally requiring a confirmed ATTR-CM diagnosis, evidence of heart involvement, and a history of heart failure. However, diagnostic approaches changed over time. Earlier trials often required invasive heart biopsies, whereas more recent studies allowed noninvasive imaging.
Participant characteristics such as age, sex, and ethnicity were broadly similar across trials, with most participants being male (67% to 97%). However, patients enrolled in more recent trials showed less severe disease at study start compared with those in earlier studies.
This was reflected by a smaller proportion of participants classified as New York Heart Association class III, indicating more severe symptoms and greater limitations in physical activity, in trials conducted after Vyndamax’s U.S. approval in 2019. In addition, trial participants showed lower levels of NT-proBNP and troponin, markers of heart stress and damage, over time, as well as better kidney function.
Survival outcomes also improved over time in placebo groups
Changes in treatment patterns were also observed. Rates of use of heart failure medications, such as diuretics, were higher at enrollment in newer trials, reaching 92% in APOLLO-B and 80% in HELIOS-B, compared with 68% in the earlier ATTR-ACT study.
Because all three Phase 3 trials conducted after Vyndamax approval allowed its use as concomitant or as a drop-in treatment, some participants in the placebo group were already receiving Vyndamax at the start of the trial, while others initiated treatment during the study.
Survival outcomes also improved over time in placebo groups. Following Vyndamax’s approval in 2019, subsequent trials reported fewer deaths from any cause at both 12 and 30 months compared with ATTR-ACT.
At 12 months, mortality decreased from 9% in ATTR-ACT to 6.9% in ATTRibute-CM, 5.6% in APOLLO-B, and as low as 4.3% in HELIOS-B. At 30 months (about 2.5 years), mortality declined from 42.9% in ATTR-ACT to 25.7% in ATTRibute-CM to as low as 17.4% in HELIOS-B.
Overall, the findings suggest that “patients enrolled in more recent clinical trials” show initial characteristics “consistent with less severe disease than those enrolled in earlier clinical trials,” the researchers wrote. This likely reflects earlier diagnosis driven by “advancements in diagnostic techniques” and “the availability of disease-modifying treatments.”
“Because trial populations evolve and change over time, direct comparisons between patient groups from different clinical trials over time may not be appropriate, particularly in the absence of head-to-head trials,” the team concluded.
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