Real-world individual patient-level analysis for mavacamten in obstructive hypertrophic cardiomyopathy: multi-domain response, safety and cyp2c19 genotype effects
P Zwetsloot, A Van Hoogdalem, M Van Den Boogaard, S Stienen, A Achten, M G P J Cox, P J Van Rosendael, N Ajmone Marsan, R Nijveldt, C Knackstedt, A S J M Te Riele, A S Amin, A H Hirsch, M MichelsAbstract
Background
Mavacamten is the first approved cardiac myosin inhibitor for the treatment of symptomatic, obstructive HCM (oHCM). Its effect on an individual patient level is an important study subject. It is unknown how CYP2C19 genotype status and other variables affect individual dosing, safety and efficacy.
Purpose
This study aims to evaluate mavacamten in oHCM on an individual patient-level response on multiple domains in the real-world setting.
Methods
All Dutch patients prescribed mavacamten entered the Dutch Mavacamten Registry through the seven prescribing centers. Timepoints of interest were baseline, 12 weeks (12w) and the first moment a patient reaches its optimal dose (maintenance). CYP2C19 status was analysed in all patients. Individual response was measured on a symptom (≥1 NYHA class improvement), physiological (Valsalva LVOT gradient<30), and biomarker (NT-proBNP≥50% reduction) domain. Pre-defined responder variables of interest included age, genotype (G+/G-), history of hypertension, obesity (BMI≥30) and baseline NT-proBNP. Adverse events (composite endpoint and individual endpoints) were defined as a occurence of atrial fibrillation (AF), LVEF drop <50% and/or a temporary discontinuation of the drug.
Results
217 patients completed 12w of therapy and 177 patients reached maintenance phase. Median follow-up was 183 days. Mavacamten led to NYHA class improvement, LVOT gradient reduction and NT-proBNP reduction at 12w and maintenance. AF occurred in 16 patients, of which 15/16 in the first 12w. LVEF drops occurred in 15 patients. (Figure 1)
CYP2C19 status influenced optimal dose reached (faster metabolism results in higher dose needed, p=0.002). Slow metabolisers more often had an adverse event compared to the other groups (log-rank p=0.047). Efficacy measures (NYHA class improvement, LVOT gradient decrease, NT-proBNP decrease) were similar for different CYP2C19 statuses. (Figure 2)
In responder analyses mavacamten proved efficacious on the domain of symptoms (12w 53%, maintenance 73%), LVOT gradient (12w 44%, maintenance 95%) and biomarkers (12w 65%, maintenance 71%). 8%/14%/46%/32% responded on a total of 0/1/2/3 domains at 12w. When reaching maintenance, 3%/15%/42%/39% responded on either 0/1/2/3 domains respectively.
Only obesity significantly affected response domains, with obese patients less often reporting NYHA class improvements, compared to non-obese patients (p=0.01). LVOT gradient and NT-proBNP responses were similar for obese and non-obese patients. Other variables of interest did not influence symptom, physiological and biomarker response domains.
Conclusion
Mavacamten is a safe and effective therapy for oHCM in the real-world situation. CYP2C19 status affects mavacamten dosing and safety, while obesity affects symptom response. This new knowledge on CYP2C19 status, adverse event occurrence and individual response definitions can optimize future clinical mavacamten guidance.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.