Everolimus-based immunosuppression in heart transplantation reduces cardiac allograft vasculopathy progression and preserves renal function: a systematic review and meta-analysis

Background Late mortality after heart transplantation is predominantly driven by cardiac allograft vasculopathy (CAV) and chronic kidney disease. Calcineurin inhibitor (CNI) toxicity contributes substantially to long-term renal dysfunction. Everolimus, a proliferation signal inhibitor, has emerged as a potential strategy to attenuate CAV while minimising nephrotoxicity; however, its global risk–benefit profile remains debated. Purpose To evaluate the efficacy and safety of everolimus-based immunosuppression compared with conventional CNI-based regimens in heart transplant recipients. Methods A systematic review and meta-analysis were conducted according to PRISMA guidelines. Randomised controlled trials and comparative observational studies enrolling adult heart transplant recipients receiving everolimus versus standard CNI therapy were included. Primary outcomes were all-cause mortality, treated acute rejection and CAV progression. Secondary outcomes included renal function,and treatment discontinuation. Pooled risk ratios (RR) or mean differences (MD) with 95% confidence intervals (CI) were calculated using random-effects models. Heterogeneity was assessed with the I² statistic. Results 15 studies comprising 1,723 patients were included. Everolimus significantly reduced CAV progression compared with CNI-based therapy (RR 0.72; 95% CI 0.58–0.90; I² = 21%). Renal function was significantly better preserved in the everolimus group (MD +8.41 mL/min/1.73m²; 95% CI 4.12–12.70; I² = 34%). There was no significant difference in all-cause mortality (RR 0.94; 95% CI 0.68–1.30; I² = 0%) or treated acute rejection (RR 1.08; 95% CI 0.85–1.37; I² = 17%). Rates of infection (RR 1.05; 95% CI 0.89–1.24) and malignancy (RR 0.88; 95% CI 0.54–1.43) were comparable between groups. However, treatment discontinuation due to adverse events was significantly higher with everolimus (RR 1.67; 95% CI 1.29–2.17; I² = 12%), primarily related to wound-healing complications and peripheral edema. Conclusions Everolimus-based immunosuppression significantly attenuates CAV progression and preserves renal function without increasing mortality or rejection risk in heart transplant recipients. Despite higher discontinuation rates, its favourable impact on two major determinants of late graft failure supports a precision-based approach to patient selection. These findings provide quantitative evidence to refine long-term immunosuppressive strategies in advanced heart failure and transplantation.