ATTR-CM Trials Revisited: A Broader View of Treatment Benefit

Transthyretin amyloid cardiomyopathy (ATTR-CM) has shifted from a condition managed primarily through supportive care to one with multiple targeted pharmacotherapies. Four phase three randomized controlled trials—ATTR-ACT, APOLLO-B, ATTRibute-CM, and HELIOS-B—have each evaluated a disease-specific agent, but they varied in design, patient selection, and outcome metrics. That’s why a recent meta-analysis by Autherith et al. pooled data from these trials to assess treatment efficacy over time and across risk strata.

Here’s a brief look at what it found.

Patient Population Variability

Baseline clinical characteristics differed markedly among trials. ATTR-ACT included patients with higher NT-proBNP levels and more advanced renal dysfunction (mean eGFR 56 mL/min/1.73m²), while HELIOS-B enrolled patients with comparatively lower-risk profiles. These differences correlated with placebo group mortality rates at 30 months, which ranged from 17.4% to 42.4% across studies.

Despite this variability, the relative treatment effects were directionally consistent. The pooled analysis indicated that ATTR-specific agents reduced the hazard of all-cause mortality by 28% and the odds of cardiovascular events by 42% at extended follow-up.

Timing and Nature of Therapeutic Effects

At 12 months, ATTR-specific treatments were associated with smaller declines in NT-proBNP (geometric mean ratio 0.80), Kansas City Cardiomyopathy Questionnaire Overall Score (mean difference 4.7 points), and six-minute walk distance (12.9 meters, not statistically significant) compared to placebo. At 30 months, differences in all three measures increased: NT-proBNP ratio was 0.60, KCCQ score improved by 9.7 points, and six-minute walk distance improved by 46.8 meters.

No survival benefit was observed at 12 months (OR 1.00; 95% CI 0.69–1.44). This finding may reflect the typical disease trajectory of ATTR-CM, which progresses more slowly than some other forms of cardiac amyloidosis. Longer-term data from the ATTRibute-CM trial indicated divergence in event curves beginning around three months post-treatment, driven primarily by reduced cardiovascular hospitalizations.

Mechanistic Diversity Without Direct Comparison

The therapies included in the meta-analysis—tafamidis, acoramidis, patisiran, and vutrisiran—target different stages of the transthyretin amyloidogenic process. Tafamidis and acoramidis stabilize the tetrameric form of transthyretin, while patisiran and vutrisiran reduce its hepatic production. Although mechanistic complementarity is hypothesized, no trials to date have directly evaluated combination strategies. The concurrent use of tafamidis was allowed in three trials, but no subgroup analyses were powered to determine independent or additive effects.

Representation Limitations

Trial populations were demographically narrow: approximately 91% male, 85% White, and 85% with wild-type ATTR-CM. Observational registries using broader screening methods report higher representation of women and hereditary forms. The meta-analysis acknowledges that these demographic constraints limit the generalizability of findings to the wider patient population.

Clinical Relevance and Future Directions

The absolute event reductions associated with ATTR-specific treatment—2.5 deaths and 5.4 cardiovascular events prevented per 100 patient-years—are comparable to those observed in other cardiovascular pharmacotherapies. For reference, published analyses have estimated absolute risk reductions of 0.4 events per 100 patient-years for statins in primary prevention, and between 2.1 and 2.7 events for renin-angiotensin-acting agents in patients with heart failure with reduced ejection fraction.

Open questions remain regarding optimal treatment strategies. Future studies may evaluate the utility of combination therapy, the role of genetic or biomarker-based stratification, and the impact of newer therapeutic modalities such as gene-editing or amyloid-depleting antibodies. In the current framework, this meta-analysis provides a unified estimate of treatment effect across disparate trial populations, supporting the clinical use of amyloid-specific therapies in ATTR-CM over extended durations.

Reference:
Autherith M, Hauptmann L, Koschatko S, et al. Amyloid-specific medication in transthyretin amyloid cardiomyopathy: a systematic review and meta-analysis of cardiovascular outcome trials. J Card Fail. 2025;00:1-9. doi:10.1016/j.cardfail.2025.08.002