Primary analysis determined by the Finkelstein-Schoenfeld method, a hierarchical combination of both the components, prioritises all-cause mortality²

*Heart transplantation, heart and liver transplantation, and implantation of a mechanical cardiac-assist device were treated as death for the purposes of this analysis.²

 

ATTR-CM: transthyretin amyloid cardiomyopathy; CV: cardiovascular; MOA: mechanism of action; MOD: mechanism of disease.

Objective: ATTR-ACT was designed to determine the efficacy and safety of tafamidis in patients with hereditary and wildtype transthyretin amyloid cardiomyopathy.²
 

Study design: ATTR-ACT was a phase 3, multicenter, international, parallel-design, placebo-controlled, double-blind, randomized trial. Patients were randomly assigned to receive 80 mg of tafamidis, 20 mg of tafamidis, or matching placebo once daily in ratio of a 2:1:2.²
 

*Heart transplantation, heart and liver transplantation, and implantation of a mechanical cardiac-assist device were treated as death for the purposes of this analysis.²

ATTR-CM: transthyretin amyloid cardiomyopathy; CV: cardiovascular; HR: hazard ratio; MOA: mechanism of action; MOD: mechanism of disease; NNT: number needed to treat.

The KCCQ-OS changes from baseline, along with distance walked during the 6MWT, were key secondary endpoints in ATTR-ACT. Changes from baseline at Month 30 on the KCCQ-OS domain scores were exploratory endpoints in ATTR-ACT; no adjustment was made for multiplicity. Scores range from 0 to 100, with higher scores reflecting a better health status.²

*The 6-minute walk test (6MWT) evaluates patients' functional capacity by measuring their distance walked in 6 minutes.^2
†The KCCQ-OS score assesses patients' quality of life using the following domains: total symptoms (symptom frequency, symptom burden), physical limitation, quality of life, and social limitation. Scores range from 0 to 100, with higher scores reflecting better health status.⁴ Vital status at month 30 was assessed for all enrolled patients.²

ATTR-CM: transthyretin amyloid cardiomyopathy; KCCQ-OS: Kansas City Cardiomyopathy Questionnaire-Overall Summary; MOA: mechanism of action; MOD: mechanism of disease.

Greater reductions in all-cause mortality* were achieved in patients who were initially on 80 mg and then transitioned to 61 mg versus those initially on 20 mg

• All patients treated in ATTR-ACT²
• ATTR-ACT plus all patients treated in the LTE, including patients on placebo in ATTR-ACT who were re-randomised to tafamidis meglumine 20 mg or 80 mg²
• All of the patients above, following their transition to tafamidis meglumine 61 mg, while continuing to be compared based on their initial tafamidis meglumine dose in ATTR-ACT or LTE²

In ATTR-ACT, patients with ATTR-CM were randomised (2:1:2) to tafamidis meglumine 80 mg, tafamidis meglumine 20 mg or placebo once daily (qd) for 30 months. Upon completion of ATTR-ACT, patients could enroll in the ongoing LTE study. Patients receiving tafamidis meglumine in ATTR-ACT continued to receive the same dose, while those in the placebo group were re-randomised (2:1) to 80 mg or 20 mg tafamidis meglumine. As of July 2018, the LTE protocol was amended to transition all patients to tafamidis free acid 61 mg, a new single-capsule formulation bioequivalent to the tafamidis meglumine 80 mg used in ATTR-ACT. Patients were treated with tafamidis meglumine 80 mg or 20 mg (up to the protocol amendment) for a median of 39 months. The median follow-up for ATTR-ACT and the LTE in this analysis was 51 months.

ATTR-ACT was not powered for dose response on the clinical endpoints. The patients in the LTE were assigned for treatment with tafamidis meglumine 80 mg or tafamidis meglumine 20 mg in a 2:1 randomisation.²

The unadjusted row was based on the prespecified Cox proportional hazards model with treatment, New York Heart Association (NYHA) baseline classification and genotype in the model. The single-covariate-adjusted rows were generated by adding age, NT-proBNP (log transformed) and 6MWT distance separately as covariates to the prespecified model. The all-covariate-adjusted row was generated by adding all covariates to the prespecified model.²

*Heart transplantation, combined heart and liver transplantation and cardiac mechanical assist device implantation were treated as equivalent to death in this analysis.²

6MWT: 6-minute walk test; ATTR-CM: transthyretin amyloid cardiomyopathy; CI: confidence interval; MOA: mechanism of action; MOD: mechanism of disease; NT-proBNP: N-terminal pro-B-type natriuretic peptide.

Greater reductions in all-cause mortality* were achieved in patients who were initially on 80 mg and then transitioned to 61 mg versus those initially on 20 mg

• All patients treated in ATTR-ACT²
• ATTR-ACT plus all patients treated in the LTE, including patients on placebo in ATTR-ACT who were re-randomised to tafamidis meglumine 20 mg or 80 mg²
• All of the patients above, following their transition to tafamidis meglumine 61 mg, while continuing to be compared based on their initial tafamidis meglumine dose in ATTR-ACT or LTE²

In ATTR-ACT, patients with ATTR-CM were randomised (2:1:2) to tafamidis meglumine 80 mg, tafamidis meglumine 20 mg or placebo once daily (qd) for 30 months. Upon completion of ATTR-ACT, patients could enroll in the ongoing LTE study. Patients receiving tafamidis meglumine in ATTR-ACT continued to receive the same dose, while those in the placebo group were re-randomised (2:1) to 80 mg or 20 mg tafamidis meglumine. As of July 2018, the LTE protocol was amended to transition all patients to tafamidis free acid 61 mg, a new single-capsule formulation bioequivalent to the tafamidis meglumine 80 mg used in ATTR-ACT. Patients were treated with tafamidis meglumine 80 mg or 20 mg (up to the protocol amendment) for a median of 39 months. The median follow-up for ATTR-ACT and the LTE in this analysis was 51 months.

ATTR-ACT was not powered for dose response on the clinical endpoints. The patients in the LTE were assigned for treatment with tafamidis meglumine 80 mg or tafamidis meglumine 20 mg in a 2:1 randomisation.²

The unadjusted row was based on the prespecified Cox proportional hazards model with treatment, New York Heart Association (NYHA) baseline classification and genotype in the model. The single-covariate-adjusted rows were generated by adding age, NT-proBNP (log transformed) and 6MWT distance separately as covariates to the prespecified model. The all-covariate-adjusted row was generated by adding all covariates to the prespecified model.²

*Heart transplantation, combined heart and liver transplantation and cardiac mechanical assist device implantation were treated as equivalent to death in this analysis.²

6MWT: 6-minute walk test; ATTR-CM: transthyretin amyloid cardiomyopathy; CI: confidence interval; MOA: mechanism of action; MOD: mechanism of disease; NT-proBNP: N-terminal pro-B-type natriuretic peptide.

• The safety data reflects the exposure of 176 patients with ATTR-CM to tafamidis meglumine 80 mg (administered as 4 × 20 mg) daily in a 30-month, placebo-controlled trial in patients diagnosed with ATTR-CM¹

• VYNDAMAX™ may decrease serum concentrations of total thyroxine, without an accompanying change in thyroid-stimulating hormone (TSH). No corresponding clinical findings consistent with thyroid dysfunction have been observed¹

• Patients with moderate hepatic impairment (Child-Pugh Score of 7 to 9) showed decreased systemic exposure (approximately 40%) and increased clearance (approximately 68%) of tafamidis compared to healthy subjects. No clinically significant differences in the pharmacokinetics of tafamidis were observed in patients with mild hepatic impairment (Child Pugh Score of 5 to 6) compared to healthy subjects. The effect of severe hepatic impairment on tafamidis is unknown.¹

• Tafamidis inhibits breast cancer resistant protein (BCRP) in humans. Coadministration of tafamidis and drugs that are BCRP substrates may increase exposure of substrates of this transporter (e.g., methotrexate, rosuvastatin, imatinib). Dose adjustment may be needed for these substrates.¹

*VYNDAMAX™ 61 mg (tafamidis) is bioequivalent to 80 mg of tafamidis meglumine.2 Tafamidis and tafamidis meglumine are not interchangeable on a per-mg basis.^!
 

ATTR-CM: transthyretin amyloid cardiomyopathy; MOA: mechanism of action; MOD: mechanism of disease.