Effect of anti-fibrotic therapy on regression of myocardial fibrosis after TAVI: 'As-treated' analysis of the Reduce-MFA DZHK 25-trial

Background Myocardial fibrosis (MF) represents a key player in transition to heart failure in aortic stenosis (AS), and patients with high baseline MF are at increased risk to die within 12 months after TAVI. Purpose The objective of this early clinical trial was to assess the impact of anti-fibrotic medication on MF-regression after TAVI in patients with high baseline MF. Key secondary objectives included reverse LV remodeling and symptomatic improvement. Methods Reduce-MFA represents a prospective, randomized, parallel group, multi-center early clinical trial with blinded outcome assessment. At baseline and 12 months, MF was assessed by cardiac MRI (CMR) via quantification of the extracellular volume fraction (ECV%)-derived LV matrix volume. Only patients with a prognostically relevant baseline MF (ECV% ≥25.9%) were randomized into 3 parallel groups. Antifibrotic treatment was administered for 12 months. Due to asymmetric withdrawals and treatment crossovers, the intention-to-treat-analysis of the primary endpoint remained inconclusive. Therefore, an as-treated analysis according to the “treatment-received” principle was performed, with patients pertaining to the treatment arms as follows: A: TAVI alone (n=52), B: + Spironolactone (n=34), and C: + Spironolactone + low-dose Dihydralazine (n=34). Changes of ECV%-derived LV matrix volume, measures of heart failure (6MWT, KCCQ) and cardiac hospitalisations were evaluated. Results The study cohort comprised 120 patients (46% women; mean age 81 years) characterised by preserved EF and renal function, but a high heart failure burden. Whereas the decrease of LV cellular volume (i.e. cellular hypertrophy) was similar in all groups (comparison A vs. B+C: P=0.87), the regression of LV matrix volume (i.e. extracellular matrix) was significantly greater under antifibrotic treatment (Arm B: -16.0%; Arm C: -15.7%) as compared to TAVI alone (Arm A: -2.6%) (P=0.046). Regarding the primary endpoint (hierarchical composite of all-cause mortality and regression of LV matrix volume), a win ratio of 1.64 (95% CI 1.0.-2.67; P=0.049) could be achieved. Furthermore, improvement in quality of life was greater under anti-fibrotic medication (KCCQ: +6 points in Arm A, +12 points in Arm B, and +23 points in Arm C at 12 months; P=0.01). The secondary clinical benefit endpoint, a hierarchical composite consisting of CV mortality, cardiac hospitalisations, improvement in KCCQ, and improvement in 6 MWT, demonstrated a win ratio of 1.60 (95% CI 1.05-2.42; P=0.03) for antifibrotic treatment, indicating a clinically meaningful benefit. Conclusions In TAVI-patients with preserved EF and high baseline MF burden, the early administration of antifibrotic medication including spironolactone and dihydralazine shows clinically meaningful effects on LV matrix volume regression as a surrogate for diffuse MF, and on clinical endpoints including quality of life.