Translating Patisiran’s 6-Minute Walk Test Gains into Real-Life Impact in ATTR-CM

Preserving physical function in patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is critical, as progressive myocardial infiltration leads not only to heart failure symptoms but also to declining mobility and loss of independence. The APOLLO-B trial introduced patisiran as a therapeutic option for preserving patient function, and over the course of the 12-month, randomized, double-blind, placebo-controlled phase 3 study, patisiran demonstrated a 15-meter treatment benefit in six-minute walk test (6MWT) distance compared with placebo.

While the 6MWT is a commonly used endpoint to quantify functional capacity in heart failure trials, its practical significance in the day-to-day lives of patients with ATTR-CM has remained less well defined. A recently published post hoc analysis of the APOLLO-B trial published in JACC Advances addressed this gap by examining whether gains in 6MWT performance correlate with improvement in a patient’s ability to perform daily activities and maintain quality of life.

APOLLO-B enrolled 360 patients with ATTR-CM, with a median age of 76 years. Approximately 80 percent of patients had wild-type ATTR. Participants were randomized to receive either patisiran or placebo. To contextualize 6MWT outcomes, investigators anchored changes in walk distance to the Kansas City Cardiomyopathy Questionnaire–Overall Summary (KCCQ-OS), a validated patient-reported measure of health status.

The study estimated that a change of 6.9 to 7.8 meters in 6MWT represents the minimal clinically important difference (MCID) for patients with ATTR-CM. By that standard, patisiran’s 15-meter improvement was approximately double the MCID, indicating a benefit that is likely to be perceived as meaningful by patients.

More than just preserving walking distance, the study modeled how improvements in 6MWT are associated with performance in activities of daily living (ADLs). Using patient-reported responses from the Physical Limitation domain of the KCCQ, researchers found that a 15-meter gain was linked to lower odds of functional deterioration across several key areas. For example, patients with this level of walking preservation were about 11 to 16 percent less likely to report worsening ability to walk one block, climb stairs, hurry or jog, dress themselves, or carry groceries. These are not trivial endpoints; they define whether a patient can live independently or if they depend on others for everyday needs.

Figures from the trial support this interpretation. By the end of the 12-month period, 32 percent of patisiran-treated patients had improved their 6MWT distance by at least 15 meters, compared to 21 percent of patients in the placebo group. Declines of 30 meters or more were more prevalent among those on placebo (45 percent placebo versus 34 percent patisiran). Similar patterns were observed in the KCCQ-OS scores. Improvements of five points or more were seen in 34 percent of the patisiran group compared to 24 percent in the placebo group, while larger deteriorations were more frequent in the latter. These findings suggest that patisiran not only delays decline but enables recovery of function for a substantial subset of patients.

The significance of these improvements with patisiran becomes even clearer when compared to clinical deterioration following an outpatient worsening heart failure event. Previous studies in ATTR-CM populations have shown that such events lead to an average annual decline of 10.7 meters in 6MWT distance. This degree of functional loss is associated with increased all-cause mortality and recurrent cardiovascular events.

It is worth noting, however, that this analysis was conducted post hoc and is considered hypothesis-generating. While the association between 6MWT and daily functioning was robust, the study relied on patient-reported outcomes rather than direct observation of ADL performance. Additionally, the trial only included participants capable of walking at least 150 meters at baseline, which may limit the applicability of findings to patients with more advanced limitations. Despite these considerations, the consistent trends across multiple measures suggest that the observed benefits are not incidental.

It is also important to note that, as of the study's publication, patisiran is not approved for the treatment of ATTR-CM in the United States. It is, however, approved in Brazil and available in France for patients who have not responded to tafamidis 61 milligrams.

For clinicians, these results offer a practical reframing of therapeutic impact in ATTR-CM. The 6MWT is not just a clinical trial benchmark. It reflects a patient’s ability to manage stairs, walk to the corner store, or maintain independence without assistance. When improvements on the 6MWT are validated against tools like the Kansas City Cardiomyopathy Questionnaire (KCCQ), they help translate trial data into outcomes that matter in daily life. Ultimately, findings from this post hoc analysis broaden our understanding of what constitutes meaningful progress in ATTR-CM.

Reference

Berk JL, Lairez O, Schwartzmann P, et al. Benefits of Patisiran on Functional Capacity in ATTR Cardiac Amyloidosis: Post Hoc Analysis of APOLLO-B. JACC Adv. Published online June 23, 2025.