A Comparison Of Single Versus Dual Treatment With Stabilizers And Silencers In Transthyretin Amyloid Cardiomyopathy

Introduction

Treatment for transthyretin amyloid cardiomyopathy (ATTR-CM) with TTR stabilization or gene silencing depends on presence of pathogenic variant and phenotype (cardiomyopathy v neuropathy). There are limited data on efficacy of dual treatment with TTR stabilizer and silencer.

Hypothesis

We hypothesize dual treatment with stabilizers and silencers will confer no added benefit compared to single agent treatment.

Methods

Patients seen at our center with a diagnosis of ATTR-CM treated with either stabilizer (Tafamidis, Diflunisal), silencer (Patisiran, Vutisiran), or both (stabilizer and silencer) for >6 months were included. Mortality data was collected through 5 years from diagnosis. Characteristics for single v dual treatment groups were compared using chi-squared or Fisher's exact tests, or t-tests or Wilcoxon tests. Kaplan-Meier curves and Cox proportional hazard regression models were used to assess relationships with mortality.

Results

Of 183 patients, 144 (79%) were on single agent, including 132 (72%) on stabilizer, and 13 (7%) on silencer and 38 (21%) were on dual treatment with stabilizer and silencer. Patients on dual treatment were younger (70.1 [8.3] v 76.1 [9.0] yrs), more likely hereditary (79.0% v 43.9%), had higher eGFR, lower NT-proBNP, and less likely on loop diuretic (39.5 v 69.9%) at baseline, all p<0.05. There was no difference in sex, race, or NAC stage by groups at baseline (Table). K-M curves showed significantly superior survival with dual treatment (log-rank p-value 0.009, Figure). In univariate Cox analysis, dual treatment significantly reduced risk of death (HR 0.363, 95% CI 0.164-0.801, p<0.05); however, in multivariate model including age, dual treatment was no longer statistically significant (HR 0.468, 95% CI 0.21-1.07 p=0.07), though age was significantly associated with risk of death (HR 1.04, 95% CI 1.004-1.07, p=0.025).

Conclusion

In a large ATTR-CM cohort, we found that dual treatment with stabilizers and silencers was not associated with reduction in risk of death when adjusted for age. While larger scale studies are needed, given the expense of current FDA approved treatments, our findings suggest that dual treatment is unlikely to be cost effective or of incremental clinical benefit. Future studies are needed to determine optimal treatment, stabilizer or silencer, for the various phenotypes associated with ATTR-CM.