This was an exploratory, retrospective, observational cohort study (NCT05139680) using structured secondary anonymized data from electronic medical records at MedStar Health. Patients with mixed-phenotype ATTRv-CM receiving tafamidis 61 mg orally once daily for at least 6 months were identified. The study data were extracted and evaluated from three assessment windows. The pre-treatment assessment was 6–12 months prior to the date of tafamidis treatment initiation (index date). The tafamidis initiation assessment window was from 3 months before to 3 months after the start of tafamidis treatment (baseline). The post-treatment assessment window was 6–12 months after tafamidis initiation (Fig. 1).

Study design overview. CMTNS2, Charcot-Marie-Tooth Neuropathy Score v2; mBMI, modified body mass index; MRC, Medical Research Council; NIS-CS, Neuropathy Impairment Score–Composite Score; NIS-LL, Neuropathy Impairment Score–Lower Limbs; PND, Polyneuropathy Disability instrument

This study was approved by the MedStar Health Research Institute Institutional Review Board (IRB) (IRB ID: STUDY00006170) and granted a waiver from informed consent. The study followed Good Pharmacoepidemiology Practices guidelines and the principles of the Declaration of Helsinki.

Patients included in this study were at least 18 years of age, diagnosed with hereditary mixed-phenotype ATTRv-CM, and treated with tafamidis (61 mg capsule, orally once daily) for ≥ 6 months (with a ± 3-month window), with at least one neurologic assessment pre- and post-tafamidis treatment. Polyneuropathy was diagnosed on the basis of clinical evidence of neuropathy and electrophysiological diagnostics. Patients were excluded from the study if they had a history of organ transplant or wild-type TTR genotype; were non-ambulatory; had prior treatment with any disease-modifying therapy (investigational or approved) alone or in combination, except tafamidis; or had peripheral neuropathy attributed to causes other than ATTR amyloidosis (e.g., diabetes mellitus, B12 deficiency, HIV infection).

Tafamidis treatment was characterized as follows: Time to treatment initiation was calculated as the time from ATTRv-CM diagnosis to tafamidis initiation. Treatment duration was calculated as the time from tafamidis treatment initiation to the end of treatment or last visit.

The primary study endpoint was neurologic disease progression, as assessed by the Neuropathy Impairment Score–Composite Score (NIS-CS), the Neuropathy Impairment Score–Lower Limbs (NIS-LL), the Polyneuropathy Disability (PND) score, the Medical Research Council (MRC) Scale for Muscle Strength, and the Charcot-Marie-Tooth Neuropathy Score v2 (CMTNS2).

The NIS-CS assesses motor strength, muscle stretch reflexes, and sensation to arrive at a composite score ranging from 0 (normal) to 244 (total impairment). The NIS-LL assesses motor strength, muscle stretch reflexes, and sensation in the lower body, with a score ranging from 0 (normal) to 88 (total impairment). The PND assesses walking capacity, classifying patients in stages from 0 (no impairment) to IV (confined to a wheelchair or bedridden). The MRC measures muscle strength on a scale of 0–5, with higher scores signaling greater strength. The CMTNS2 classifies patients as having mild, moderate, or severe impairment according to the summed scores for nine components, with higher scores indicating greater impairment.

The secondary study endpoint was mBMI, an indicator of overall health status. mBMI is calculated as the product of BMI in kg/m2 and serum albumin in g/L to compensate for peripheral edema.

Patient demographics, clinical characteristics, and comorbidities in the pre-treatment baseline period were collected. They included but were not limited to sex, age, race, and TTR genotype.

Continuous and categorical variables were reported descriptively using summary statistics. Descriptive analysis for continuous outcomes included mean, standard deviation (SD), median, range, and interquartile range (IQR). Frequencies and percentages were reported for categorical and ordinal outcomes. Primary and secondary outcomes were collected at multiple time points. Measures were reported in the pre-treatment baseline period (at least 6 months and up to 12 months before tafamidis initiation), at tafamidis initiation (±3 months), and in the post-treatment period (at least 6 months after tafamidis initiation with a ± 3-month window). In practice, the final data collected for neurological assessments and mBMI reflected pre- and post-treatment time periods only. Pre- and post-treatment comparisons were not conducted for all neurologic function scales where data were missing. Pre- and post-treatment scores for the MRC, PND, NIS muscle weakness subscale, and mBMI were reported. All analyses were conducted using SAS version 9.4 software (SAS Institute, Inc., Cary, NC).