Efficacy of new medical therapies in patients with heart failure, reduced ejection fraction and chronic kidney disease already receiving neurohormonal inhibitors: a network meta-analysis

Aims: We assessed the efficacy of the drugs developed after neurohormonal inhibitors (NEUi) in patients with heart failure with reduced ejection fraction (HFrEF) and concomitant chronic kidney disease (CKD). Methods and results: The literature was systematically searched for phase 3 randomized controlled trials (RCTs) involving ≥90% patients with left ventricular ejection fraction <45%, of whom <30% were acutely decompensated, and with published information about the subgroup of estimated glomerular filtration rate <60 mL/min/1.73m2. Six RCTs were included in a study-level network meta-analysis evaluating the effect of NEUi, ivabradine, angiotensin receptor-neprilysin inhibitor (ARNI), sodium-glucose cotransporter-2 inhibitors (SGLT2i), vericiguat, and omecamtiv mecarbil (OM) on a composite outcome of cardiovascular death or hospitalization for heart failure. In a fixed-effects model, SGLT2i (HR 0.78, 95%CrI 0.69-0.89), ARNI (HR 0.79, 95%CrI 0.69-0.90), and ivabradine (HR 0.82, 95%CrI 0.69-0.98) decreased the risk of the composite outcome vs. NEUi, whereas OM did not (HR 0.98, 95%CrI 0.89-1.10). A trend for improved outcome was also found for vericiguat (HR 0.90, 95%CrI 0.80-1.00). In indirect comparisons, both SLGT2i (HR 0.80, 95%CrI 0.68-0.94) and ARNI (HR 0.80, 95%CrI 0.68-0.95) reduced the risk vs. OM; furthermore, there was a trend for a greater benefit of SGLT2i vs. vericiguat (HR 0.88, 95%CrI 0.73-1.00) and ivabradine vs. OM (HR 0.84, 95%CrI 0.68-1.00). Results were comparable in a random-effects model and in sensitivity analyses. SUCRA scores were 81.8%, 80.8%, 68.9%, 44.2%, 16.6%, and 7.8% for SGLT2i, ARNI, ivabradine, vericiguat, OM, and NEUi, respectively. Conclusion: Expanding pharmacotherapy beyond NEUi improves outcomes in HFrEF with CKD.