her patient within each stratum in a pair-wise manner that proceededin a hierarchical fashion using all-cause mortalityfollowed by frequency of cardiovascular-relatedhospitalizations when patients could not be differentiated based on mortality.
This analysis demonstrated a significant reduction (p=0.0006) in all-cause mortality and frequency ofcardiovascular-related hospitalizations in the pooled VYNDAQEL 20-mg and 80-mg groups versus placebo(Table 2).
Table 2: Primary Analysis Using Finkelstein-Schoenfeld (F-S) Method of All-Cause Mortality and
Frequency of Cardiovascular-Related Hospitalizations
Primary Analysis Pooled
VYNDAQEL
N=264
Placebo
N=177
Number (%) of Subjects Alive* at Month 30 186 (70.5) 101 (57.1)
Mean Number of Cardiovascular-related Hospitalizations During
30 months (per patient per year) Among Those Alive at Month 30
0.297 0.455
p-value from F-S Method 0.0006
* Heart transplantation and cardiac mechanical assist device implantation are considered indicators of approaching end stage. As such, these subjectsare treated in the analysis as equivalent to death. Therefore, such subjects are not included in the count of “Number of Subjects Alive at Month 30”even if such subjects are alive based on 30 month vital status follow-up assessment.
Analysis of the individual components of the primary analysis (all-cause mortality and cardiovascular-relatedhospitalization) also demonstrated significant reductions for VYNDAQEL versus placebo.
The hazard ratio from the all-cause mortality Cox-proportional hazard model for pooled VYNDAQEL versusplacebo was 0.70 (95% confidence interval [CI] 0.51, 0.96), indicating a 30% relative reduction in the risk ofdeath relative to the placebo group (p=0.026). Approximately 80% of total deaths were cardiovascular-related in
both treatment groups. A Kaplan-Meier plot of time to event all-cause mortality is presented in Figure 1.
Figure 1: All-Cause Mortality*
*Heart transplants and cardiac mechanical assist devices treated as death. Hazard ratio from Cox proportional hazards model with treatment, TTRgenotype (variant and wild type), and NYHA baseline classification (NYHA Classes I and II combined and NYHA Class III) as factors.
There were significantly fewer cardiovascular-related hospitalizations with VYNDAQEL compared withplacebo with a reduction in risk of 32% corresponding to a Relative Risk Ratio of 0.68 (Table 3).
Table 3: Cardiovascular-Related Hospitalization Frequency
Pooled
VYNDAQEL
N=264
Placebo
N=177
Total (%) Number of Subjects with Cardiovascular-related
Hospitalizations
138 (52.3) 107 (60.5)
Cardiovascular-related Hospitalizations per Year* 0.48 0.70
Pooled VYNDAQEL vs Placebo Treatment Difference (Relative
Risk Ratio)*
0.68
p-value* <0.0001
*This analysis was based on a Poisson regression model with treatment, TTR genotype (variant and wild type), New York Heart Association
(NYHA). Baseline classification (NYHA Classes I and II combined and NYHA Class III), treatment-by-TTR genotype interaction, and The treatment effects of VYNDAQEL on functional capacity and health status were assessed by the 6-MinuteWalk Test (6MWT) and the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score,
respectively. A significant treatment effect favoring VYNDAQEL was first observed at Month 6 and remainedconsis |
