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Effect of everolimus introduction on cardiac allograft vasculopathy--results of a randomized, multicenter trial
Satish Arora1, Thor Ueland, Bertil Wennerblom
1Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
Insights
Everolimus conversion did not affect cardiac allograft vasculopathy (CAV) progression in heart transplant recipients. However, azathioprine combined with everolimus attenuated CAV, unlike mycophenolate mofetil, suggesting drug interactions influence outcomes.
Area of Science:
- Cardiology
- Immunology
- Transplantation Medicine
Background:
- Cardiac allograft vasculopathy (CAV) is a major long-term complication after heart transplantation (HTx).
- Everolimus is known to reduce CAV progression in de novo HTx recipients.
- The effect of everolimus on established CAV in maintenance HTx recipients remains unclear.
Purpose of the Study:
- To investigate the influence of everolimus on the progression of established CAV in maintenance heart transplant recipients.
- To compare the effects of everolimus combined with reduced calcineurin inhibitor (CNI) versus standard CNI therapy.
- To assess the impact of background immunosuppressive agents (azathioprine or mycophenolate mofetil) on everolimus efficacy in CAV.
Main Methods:
- A substudy of the Nordic Certican Trial in Heart and lung Transplantation involving 111 maintenance HTx recipients.
- Patients were randomized to everolimus plus reduced CNI or standard CNI therapy.
- Intravascular ultrasound examinations at baseline and 12 months assessed CAV progression.
Main Results:
- No significant difference in CAV progression was observed between everolimus and standard CNI groups overall.
- In patients receiving azathioprine (AZA), everolimus attenuated CAV progression and reduced inflammatory markers.
- In patients receiving mycophenolate mofetil (MMF), everolimus accelerated CAV progression and increased inflammatory markers.
Conclusions:
- Conversion to everolimus with reduced CNI does not alter CAV progression in maintenance HTx recipients.
- Background immunosuppressive therapy significantly modulates everolimus's effect on CAV.
- Everolimus combined with AZA shows beneficial effects, while combined with MMF it appears detrimental, possibly due to unknown interactions.
Background:
Everolimus reduces the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant (HTx) recipients, but the influence on established CAV is unknown.
Methods:
In this Nordic Certican Trial in Heart and lung Transplantation substudy, 111 maintenance HTx recipients (time post-HTx 5.8 ± 4.3 years) randomized to everolimus+reduced calcineurin inhibitor (CNI) or standard CNI had matching (intravascular ultrasound) examinations at baseline and 12 months allowing accurate assessment of CAV progression.
Results:
No significant difference in CAV progression was evident between the treatment groups (P = 0.30). When considering patients receiving concomitant azathioprine (AZA) therapy (n = 39), CAV progression was attenuated with everolimus versus standard CNI (Δmaximal intimal thickness 0.00 ± 0.04 and 0.04 ± 0.04 mm, Δpercent atheroma volume 0.2% ± 3.0% and 2.6% ± 2.5%, and Δtotal atheroma volume 0.25 ± 14.1 and 19.8 ± 20.4 mm(3), respectively [P < 0.05]). When considering patients receiving mycophenolate mofetil (MMF), accelerated CAV progression occurred with everolimus versus standard CNI (Δmaximal intimal thickness 0.06 ± 0.12 vs. 0.02 ± 0.06 mm and Δpercent atheroma volume 4.0% ± 6.3% vs. 1.4% ± 3.1%, respectively; P < 0.05). The levels of C-reactive protein and vascular cell adhesion molecule-1 declined significantly with AZA+everolimus, whereas MMF+everolimus patients demonstrated a significant increase in levels of C-reactive protein, vascular cell adhesion molecule-1, and von Willebrand factor.
Conclusions:
Conversion to everolimus and reduced CNI does not influence CAV progression among maintenance HTx recipients. However, background immunosuppressive therapy is important as AZA+everolimus patients demonstrated attenuated CAV progression and a decline in inflammatory markers, whereas the opposite pattern was seen with everolimus+MMF. The different effect of everolimus when combined with AZA versus MMF could potentially reflect hitherto unknown interactions.
