Impact of induction immunosuppression on patient survival in heart transplant recipients treated with tacrolimus and mycophenolic acid in the current allocation era

Abstract

Background:The practice of induction therapy with either rabbit anti-thymocyte globulin (r-ATG) or interleukin-2 receptor antagonists (IL-2RA) is common among heart transplant recipients. However, its benefits in the setting of contemporary maintenance immunosuppression with tacrolimus/mycophenolic acid (TAC/MPA) are unknown. Methods:We compared post-transplant mortality among three induction therapy strategies (r-ATG vs IL2-RA vs no induction) in a retrospective cohort analysis of heart transplant recipients maintained on TAC/MPA in the Organ Procurement Transplant Network (OPTN) database between the years 2006 and 2015. We used a multivariable model adjusting for clinically important co-morbidities, and a propensity score analysis using the inverse probability weighted (IPW) method in the final analysis. Results:In multivariable IPW analysis, r-ATG (HR = 1.23; 95% CI = 1.05-1.46, P = 0.01) remained significantly associated with a higher mortality. There was a trend toward having a higher mortality in the IL2-RA (HR = 1.11; 95% CI = 1.00-1.24, P = 0.06) group. Subgroup analyses failed to show a patient survival benefit in using either r-ATG or IL2-RA among any of the subgroups analyzed. Conclusion:In this contemporary cohort of heart transplant recipients receiving TAC/MPA, neither r-ATG nor IL2-RA were associated with a survival benefit. On the contrary, adjusted analyses showed a significantly higher mortality in the r-ATG group and a trend toward higher mortality in the IL2-RA group. While caution is needed in interpreting treatment effects in an observational cohort, these data call into question the benefit of induction therapy as a common practice and highlight the need for more studies. K E Y W O R D Sheart transplant, interleukin-2 receptor antagonist, mycophenolic acid, patient survival, rabbit anti-thymocyte globulin, tacrolimus

Rabbit Antithymocyte Globulin Induction in Heart Transplant Recipients at High Risk for Rejection

“… 7 , 11 Moreover, reports from 2018 and 2019 suggest increased mortality with the use of LDA induction with rATG. 12 , 13 Of interest will be the results of an ongoing pilot randomized study of LDA induction with rATG in heart transplantation (NCT03292861). 19 Thus, as of May 2020, conflicting data supporting its use and its high cost explain why LDA induction is not universally adopted.…”

“… 7 However, LDAs are not universally used because of conflicting reports of efficacy. 11 - 13 Further limiting their use is the concern for increased adverse effects related to infection. 6 , 7 , 13 Finally, older studies that reported benefits from LDA induction included antiquated immunosuppression regimens, raising the question of whether LDA induction is beneficial when combined with newer immunosuppressive agents.…”

“… 11 - 13 Further limiting their use is the concern for increased adverse effects related to infection. 6 , 7 , 13 Finally, older studies that reported benefits from LDA induction included antiquated immunosuppression regimens, raising the question of whether LDA induction is beneficial when combined with newer immunosuppressive agents. 5 , 7 Thus, the net benefit of LDA induction in high immunologic risk patients receiving contemporary immunosuppression requires further investigation.…”

Current status and outcomes in heart transplantation: a narrative review

“…In gen- eral, only 46% of recipients receive induction therapy preoperatively, as it does not seem to affect survival post-HTx [100]. More acute rejection episodes were observed in recipients who received induction therapy using rabbit antithymocyte globulin (ATG) or IL2RA therapy (20.2% vs. 19%, respectively) compared to those who did not receive any induction (16.8%) prior to HTx [101]. Similar findings were also reported in the ISHLT registry report of 2019, with no difference in treated rejection episodes observed between recipients who received ATG as opposed to IL2RA therapy [3].…”

Nationwide Variability in the Use of Induction Immunosuppression for Adult Heart Transplantation

“…While the studies included in these meta-analyses have a high degree of bias, it is still important to consider the potential different efficacies of the available induction agents. Amin et al investigated the survival of 12,103 OHT recipients from 2006 to 2015 and reported an increase in mortality associated with induction therapy, without identifying any benefits in reductions rejection rates (20). Similarly, a retrospective analysis by Whitson et al (21) of 17,857 OHT recipients from 1987 to 2012 failed to show an overall survival benefit from induction therapy.…”