Efficacy and safety of everolimus in heart transplant recipients: A meta-analysis

BACKGROUND: Long-term outcomes after heart transplantation remain limited by cardiac allograft vasculopathy (CAV) and calcineurin inhibitor (CNI)-related nephrotoxicity. Everolimus has emerged as a CNI-sparing strategy, yet its net clinical benefit remains debated. OBJECTIVES: To determine whether everolimus-based immunosuppression improves efficacy and safety compared with standard CNI-based therapy in heart transplant recipients. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials and comparative observational studies enrolling adult and/or pediatric heart transplant recipients. MEDLINE, EMBASE, and CENTRAL were searched from inception. The primary endpoint was the composite MATE-3 (acute rejection, CAV, or chronic kidney disease). Secondary outcomes included mortality, individual efficacy components, renal function, and the broader safety composite (MATE-6). Pooled effect estimates were generated using random-effects models. RESULTS: Sixty studies including 1786 heart transplant recipients (mean age ≈52 years) were analyzed. Everolimus-based regimens reduced cardiac allograft vasculopathy progression by intravascular ultrasound (RR ≈0.57) and improved renal function when combined with CNI minimization (mean eGFR increase ≈10-15 mL/min). The composite MATE-3 endpoint favored everolimus. All-cause mortality was neutral (RR ≈0.98). Acute rejection varied by protocol, with higher rates mainly in strategies involving abrupt or late CNI withdrawal. The safety composite (MATE-6) showed increased adverse events and treatment discontinuation with everolimus.Sixty studies were included. Everolimus-based regimens significantly reduced CAV progression by intravascular ultrasound and consistently preserved renal function when coupled with CNI minimization. The composite MATE-3 endpoint favored everolimus, driven by robust vascular and renal protection. Importantly, all-cause mortality was neutral, confirming that CNI reduction with everolimus does not compromise survival. Acute rejection demonstrated protocol-dependent variability, with excess risk observed primarily in strategies involving abrupt or late CNI withdrawal. The safety composite (MATE-6) revealed higher rates of drug discontinuation and adverse events, underscoring the need for careful monitoring. CONCLUSIONS: Everolimus-based immunosuppression provides meaningful vasculoprotection and renal preservation without increasing mortality. When used within structured CNI minimization protocols, it offers a strategy to improve long-term graft health after heart transplantation. Careful and individualized use is essential to balance efficacy and tolerability.