6ER-008 Aficamten and mavacamten: when side effects affect efficacy

<h3>Background and Importance</h3> Coats et al.¹ demonstrated the clinical relevance of increased peak oxygen consumption (pkVO2) in hypertrophic obstructive cardiomyopathy by finding a significant correlation between pkVO2 increases and reduced death and transplantation. This highlights the importance of mavacamten and aficamten, which primarily raise pkVO2. However, left ventricular ejection fraction (LVEF), also affected by these drugs, is a significant covariate in Coats et al.’s regression and must be considered. <h3>Aim and Objectives</h3> To evaluate, using the centred prognostic index (CPI) from Coats et al.’s equation, the impact of pkVO2 increase from mavacamten and aficamten, first without considering the variation in LVEF, and then taking this variation into account. <h3>Material and Methods</h3> Retrospective analysis conducted in June 2024. Pivotal clinical trials of mavacamten (EXPLORER-HCM)² and aficamten (SEQUOIA-HCM)³ were reviewed, collecting the increase in pkVO2 and mean change in LVEF. Using the hazard ratios from Coats et al.’s equation, coefficients for pkVO2 and LVEF were calculated. Assuming that the rest of the parameters in the equation (demographic and clinical) remained constant, the CPI was first calculated based on the pkVO2 increase alone. A second calculation was then performed, incorporating both the pkVO2 increase and the LVEF change reported in the trials. <h3>Results</h3> The pkVO2 increase was 1.5 ml/kg/min with mavacamten and 1.7 ml/kg/min with aficamten. Both trials showed reductions in LVEF: −4.0 percentage points for mavacamten and −4.8 points for aficamten. The coefficients in Coats et al.’s equation were −0.198 for pkVO2 and −17.32 for LVEF. When only the pkVO2 increase was considered (assuming other parameters constant), the CPI was −0.30 for mavacamten and −0.34 for aficamten, indicating a favourable prognosis. However, when both the LVEF reduction and pkVO2 increase were considered, the CPI was 68.99 for mavacamten and 82.80 for aficamten, indicating a worse prognosis when adjusted for these covariates. <h3>Conclusion and Relevance</h3> According to Coats et al.’s equation, the pkVO2 increase is initially associated with a better prognosis when other variables are held constant. However, when the reduction in LVEF is also taken into account, the prognosis worsens. It cannot be concluded from this data that the use of these drugs reduces death or transplantation risk. <h3>References and/or Acknowledgements</h3> https://pubmed.ncbi.nlm.nih.gov/26374874/ https://pubmed.ncbi.nlm.nih.gov/32871100/ https://pubmed.ncbi.nlm.nih.gov/38739079/ <h3>Conflict of Interest</h3> No conflict of interest