ATTR-ACT - Tafamidis for transthyretin amyloid cardiomyopathy
Bottom line:
In patients with transthyretin amyloid cardiomyopathy (ATTR-CM), tafamidis 20-80 mg/d reduced the risk of death (NNT 8) & cardiovascular hospitalization (NNT 13) over 30 months.
Based on subgroup analyses, tafamidis may increase CV hospitalizations in patients with NYHA functional class 3 HF at baseline.
Tafamidis did not increase overall or any specific adverse effects.
Patients (n=441)
Included
18-90 y/o
ATTR, wild-type (ATTRwt) or due to a mutation (ATTRm), confirmed by cardiac or extra-cardiac biopsy
ATTR cardiomyopathy confirmed by
Echo - End-diastolic interventricular septal wall thickness >12 mm
Hx of heart failure (HF) with 1+ HF hospitalizations or clinical evidence of volume overload or NT-proBNP 600+ pg/mL
6-minute walk-test (6MWT) distance >100 m
Excluded
NYHA functional class 4
Cause of HF other than ATTR CM, light-chain amyloidosis
Receiving other proven/potential therapy for ATTR
Hx of liver or heart transplant
Diflunisal, doxycycline, tauroursodeoxycholate
eGFR <25; ALT/AST >2x ULN; Severe malnutrition (quantified as serum albumin [g/L] * BMI <600)
Use of calcium-channel blockers or digoxin
Baseline characteristics
74 y/o; male (90%); white (80%), black (14%)
ATTRwt (76%), ATTRm (24%)
NYHA functional class (FC): 1 (~8%), 2 (~59%), 3 (~33%)
Kansas City Cardiomyopathy Questionnaire (KCCQ) 66/100
6MWT distance 350 m
BP 115/70 mm Hg (supine & standing)
Echo: LVEF 48%, interventricular wall thickness ~16 mm
NT-proBNP median ~3000
Meds: RAAS inhibitor (27%), beta-blocker (29%), diuretic (66-70%), antithrombotic (40%)
Interventions & control
I: Tafamidis 20 or 80 mg PO once daily
If adverse effect, those randomized to 80 mg/d could be reduced to 40 mg/d
C: Matching placebo
Adherence: 97% from each group took at least 80% of their doses (assessed by pill count at follow-up visits)
Results @ 30 months
Primary outcome of death or CV hospitalization: Win ratio: 1.70 (95% confidence interval [CI] 1.26-2.29)
“Win ratio” calculated using the Finkelstein-Schoenfeld method
Non-parametric test that compares every patient from the intervention group to every patient in the control group in pairwise fashion;
First, pairs are compared based on whether each is alive or dead at last common follow-up (e.g. if patient A followed for 2 years, but patient B dropped out at 1 year, then both are compared at year 1);
Second, if both are alive or both dead, then there is a draw, & they are compared based on the rate of CV hospitalizations;
The win ratio is a tally of all of these comparisons, where higher scores are better. Because this is a ratio, a confidence interval that does not include 1.00 is statistically significant
Death: Tafamidis 29.5%, placebo 42.9% (NNT 8)
Hazard ratio (HR) 0.70 (95%CI 0.51-0.96)
No significant subgroup difference based on TTR genotype or NYHA FC
CV hospitalizations: 52.3% vs 60.5% (NNT 13, relative risk 0.68, 95%CI 0.56-0.81)
Rate per patient/year: 0.30 vs 0.46
Subgroup based on NYHA class: p<0.001 for interaction; INCREASE with tafamidis in NYHA FC 3
Subgroup based on TTR genotype: p=0.11 for interaction
6MWT distance vs placebo: +76 m
Quality of life (KCCQ) vs placebo: +13.6 points (range 0-100, higher scores are better)
No difference in overall, serious, or any individual adverse effects
Internal validity
Low risk of allocation, performance, detection & attrition bias
Computer-generated randomization stratified by TTR status (wild-type or mutant variant), baseline NYHA class
Allocation concealed: Allocation by using interactive web-response system
Blinding by use of matching placebo
Loss to follow-up <0.5% & modified intention-to-treat (mITT) analysis