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Association between Cumulative Pre-Transplant Amiodarone Dose and Post-Transplant Outcomes after Heart Transplantation
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The Journal of Heart and Lung Transplantation, Vol 38, No 4S, April 2019
alleles with MFI>500 compared to the carfilzomib-based desensitization protocol. Larger, prospective randomized studies are needed to confirm these results.
62 Mycophenolic Acid Area under the Curve Monitoring via Limited Sampling Strategy in Pediatric Heart Transplant Recipients S.A. Crow, S.H. Dahl and J.N. Johnson. Mayo Clinic, Rochester, MN. Purpose: The study aim was to investigate exposure to mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), after pediatric orthotopic heart transplantation (pOHT). Previous studies in pediatric kidney recipients demonstrated a relationship between MPA concentration and risk of rejection or hematologic side effects. The quantification of MPA in pOHT is not well established, and the relationship between a single-time-point-correlate and area under the curve (AUC) is lacking. We sought to assess the clinical individualization of MPA dosing after initiation of MPA AUC measurements in our patients. Methods: Between April 2017 and September 2018, 81 pOHT were performed, from which 22 AUCs in 14 patients were collected via a 3 point limited sampling strategy. Indication for MPA measurement, MMF dose, frequency of dosage adjustment, and time from transplant were examined via retrospective chart review. The first year post pOHT biopsies are for concern of rejection based on frequent echocardiograms, or per DSAs, monitored at transplant and months 3, 6, and 12 thereafter. Results: Median MPA AUC was 37.5 mg*h/L (range 14-216) at 61 days post-pOHT (range 11-4426). Median patient age was 10 years (range 46 days-16 years). Of 22 MPA AUCs collected, 12 warranted dosage adjustments for optimization. Within those, 9 patients’ AUCs were re-measured post adjustment with 8 attaining goal range 30-60 mg*h/L. Median MMF dose was 500 mg/m^2, or 18.8 mg/kg, both twice daily. Fifty percent of all AUCs were for-cause indications: high-risk Epstein-Barr Virus donor positive, recipient negative (n=4); high-risk Cytomegalovirus donor positive, recipient negative (n=2); recent infections requiring systemic antimicrobials (n=4); and diagnosis of post transplant lymphoproliferative disorder (n=1). All but one (90.9%) of the for-cause AUC analyses merited dose adjustments. Three patients had baseline nausea; one displayed a supratherapeutic AUC. One reported nausea abatement following MMF decrease whereas two spontaneously resolved. Five reports of leukopenia were found, three with AUCs above 60 mg*h/L. All leukocyte levels normalized following MMF dosage reduction. Conclusion: Patient specific tailoring of MMF via therapeutic drug monitoring of MPA AUC in pOHT may increase tolerability and diminish short and long term side effects of therapy. 63 Association between Cumulative Pre-Transplant Amiodarone Dose and Post-Transplant Outcomes after Heart Transplantation L.M. Lourenco,1 K. Lang,1 P. Simone,1 S. Patel,1 J. Powers,2 T. Riley,2 C. Murks,2 B. Smith,2 S. Kalantari,2 J. Raikhelkar,2 N. Sarswat,2 G. Kim,2 G. Sayer,2 and N. Uriel.2 1Pharmacy Services, University of Chicago
Medicine, Chicago, IL; and the 2Cardiology, University of Chicago Medicine, Chicago, IL. Purpose: Primary graft failure (PGF) is a growing concern following heart transplantation (HT) and is associated with early post-transplant mortality. Recent reports associate PGF with amiodarone therapy. This study aimed to investigate the effects of cumulative pre-HT amiodarone dosing on post-HT outcomes. Methods: Adult HT recipients from 1/1/2008 to 6/1/2018 who received amiodarone within 90 days prior to HT were retrospectively evaluated. Amiodarone dose was used as a continuous variable. We assessed the association of amiodarone dosing with the following outcomes: survival, ventilator days, length of stay, and the incidence of significant bradycardia requiring beta-agonist use or permanent pacemaker implantation. Results: 296 patients were transplanted and 108 patients received amiodarone as above and were included in this analysis. The overall 1-year survival was 78.2%. Pre-HT amiodarone dose was associated with an increased incidence of 1-year mortality (P=0.048), more days on the ventilator (P=0.002), significant bradycardia (P=0.003), and longer index HT hospital length of stay (P=0.002). Conclusion: Higher doses of amiodarone prior to HT are associated with worse outcomes, including higher mortality, length of stay, days on the ventilator, and significant bradycardia. Efforts should be made to minimize cumulative amiodarone dose in the three months preceding HT, particularly in patients with non-life-threatening indications such as supraventricular arrhythmias. 64 Retrospective Nested Case Control Study of the Impact of Immunosuppression on Post Transplant Malignancy among Adult Heart Transplant Patients S.A. Crow, R.J. Bubik, N.L. Pereira, K.C. Mara, R.A. Dierkhising and S.S. Kushwaha. Mayo. Clinic, Rochester, MN. Purpose: Post-transplant malignancy is diagnosed in approximately 18% of heart transplant (HTx) recipients and is a leading long-term cause of death among these patients. The association between exposure to rabbit anti-thymocyte globulin (rATG), a polyclonal depleting antibody used for its immunomodulatory activity, and incidence of malignancy in HTx is unclear. Methods: This is a single-center, retrospective chart review of all HTx recipients who received rATG induction between October 1, 2008 and December 31, 2015. ICD-9 codes were used to identify HTx patients who were diagnosed with any malignancy post-transplant (cases). A nested, case-control study design was used to determine the relative risk of rATG exposure with the incidence of malignancy post-transplant. Cancer cases were matched to controls in a 1:2 method based on age, sex, Epstein Barr Virus donor/recipient status, and year of transplant. Secondary analyses amongst 1:2 matches examined the impact of maintenance immunosuppression exposure on cancer risk using a weighted equation composed of the drug dose, duration, and trough values when applicable. Results: Of the 126 patients included in the study, 25 developed malignancy. These 25 patient cases were matched to 50 control patients. The primary endpoint was to evaluate the association of rATG on the risk of malignancy. The median cumulative rATG dose in milligrams (mg) between groups was 365mg in cases and 465mg in controls (OR 0.94, 95% CI 0.79 - 1.11, p=0.46). The cumulative dose of rATG in mg/kg was 4.7 mg/kg in cases vs. 5.7 mg/kg in controls (OR 0.96, 95% CI 0.82 - 1.12, p=0.59). By both univariate and multivariate analyses, there were no statistically significant differences in malignancyassociated with the usage of or quantified exposure to tacrolimus, sirolimus, cyclosporine, or mycophenolate mofetil, although sirolimus showed antioncotic trends. Conclusion: The results of this study demonstrate current rATG dosing strategies may not singularly be associated with malignancy development as previous dosing strategies suggested. Additional investigations are needed to explore the multiple factors associated with posttransplant malignancy as well as the possible modulating effect of sirolimus.
The Journal of Heart and Lung Transplantation, Vol 38, No 4S, April 2019
alleles with MFI>500 compared to the carfilzomib-based desensitization protocol. Larger, prospective randomized studies are needed to confirm these results.
62 Mycophenolic Acid Area under the Curve Monitoring via Limited Sampling Strategy in Pediatric Heart Transplant Recipients S.A. Crow, S.H. Dahl and J.N. Johnson. Mayo Clinic, Rochester, MN. Purpose: The study aim was to investigate exposure to mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), after pediatric orthotopic heart transplantation (pOHT). Previous studies in pediatric kidney recipients demonstrated a relationship between MPA concentration and risk of rejection or hematologic side effects. The quantification of MPA in pOHT is not well established, and the relationship between a single-time-point-correlate and area under the curve (AUC) is lacking. We sought to assess the clinical individualization of MPA dosing after initiation of MPA AUC measurements in our patients. Methods: Between April 2017 and September 2018, 81 pOHT were performed, from which 22 AUCs in 14 patients were collected via a 3 point limited sampling strategy. Indication for MPA measurement, MMF dose, frequency of dosage adjustment, and time from transplant were examined via retrospective chart review. The first year post pOHT biopsies are for concern of rejection based on frequent echocardiograms, or per DSAs, monitored at transplant and months 3, 6, and 12 thereafter. Results: Median MPA AUC was 37.5 mg*h/L (range 14-216) at 61 days post-pOHT (range 11-4426). Median patient age was 10 years (range 46 days-16 years). Of 22 MPA AUCs collected, 12 warranted dosage adjustments for optimization. Within those, 9 patients’ AUCs were re-measured post adjustment with 8 attaining goal range 30-60 mg*h/L. Median MMF dose was 500 mg/m^2, or 18.8 mg/kg, both twice daily. Fifty percent of all AUCs were for-cause indications: high-risk Epstein-Barr Virus donor positive, recipient negative (n=4); high-risk Cytomegalovirus donor positive, recipient negative (n=2); recent infections requiring systemic antimicrobials (n=4); and diagnosis of post transplant lymphoproliferative disorder (n=1). All but one (90.9%) of the for-cause AUC analyses merited dose adjustments. Three patients had baseline nausea; one displayed a supratherapeutic AUC. One reported nausea abatement following MMF decrease whereas two spontaneously resolved. Five reports of leukopenia were found, three with AUCs above 60 mg*h/L. All leukocyte levels normalized following MMF dosage reduction. Conclusion: Patient specific tailoring of MMF via therapeutic drug monitoring of MPA AUC in pOHT may increase tolerability and diminish short and long term side effects of therapy. 63 Association between Cumulative Pre-Transplant Amiodarone Dose and Post-Transplant Outcomes after Heart Transplantation L.M. Lourenco,1 K. Lang,1 P. Simone,1 S. Patel,1 J. Powers,2 T. Riley,2 C. Murks,2 B. Smith,2 S. Kalantari,2 J. Raikhelkar,2 N. Sarswat,2 G. Kim,2 G. Sayer,2 and N. Uriel.2 1Pharmacy Services, University of Chicago
Medicine, Chicago, IL; and the 2Cardiology, University of Chicago Medicine, Chicago, IL. Purpose: Primary graft failure (PGF) is a growing concern following heart transplantation (HT) and is associated with early post-transplant mortality. Recent reports associate PGF with amiodarone therapy. This study aimed to investigate the effects of cumulative pre-HT amiodarone dosing on post-HT outcomes. Methods: Adult HT recipients from 1/1/2008 to 6/1/2018 who received amiodarone within 90 days prior to HT were retrospectively evaluated. Amiodarone dose was used as a continuous variable. We assessed the association of amiodarone dosing with the following outcomes: survival, ventilator days, length of stay, and the incidence of significant bradycardia requiring beta-agonist use or permanent pacemaker implantation. Results: 296 patients were transplanted and 108 patients received amiodarone as above and were included in this analysis. The overall 1-year survival was 78.2%. Pre-HT amiodarone dose was associated with an increased incidence of 1-year mortality (P=0.048), more days on the ventilator (P=0.002), significant bradycardia (P=0.003), and longer index HT hospital length of stay (P=0.002). Conclusion: Higher doses of amiodarone prior to HT are associated with worse outcomes, including higher mortality, length of stay, days on the ventilator, and significant bradycardia. Efforts should be made to minimize cumulative amiodarone dose in the three months preceding HT, particularly in patients with non-life-threatening indications such as supraventricular arrhythmias. 64 Retrospective Nested Case Control Study of the Impact of Immunosuppression on Post Transplant Malignancy among Adult Heart Transplant Patients S.A. Crow, R.J. Bubik, N.L. Pereira, K.C. Mara, R.A. Dierkhising and S.S. Kushwaha. Mayo. Clinic, Rochester, MN. Purpose: Post-transplant malignancy is diagnosed in approximately 18% of heart transplant (HTx) recipients and is a leading long-term cause of death among these patients. The association between exposure to rabbit anti-thymocyte globulin (rATG), a polyclonal depleting antibody used for its immunomodulatory activity, and incidence of malignancy in HTx is unclear. Methods: This is a single-center, retrospective chart review of all HTx recipients who received rATG induction between October 1, 2008 and December 31, 2015. ICD-9 codes were used to identify HTx patients who were diagnosed with any malignancy post-transplant (cases). A nested, case-control study design was used to determine the relative risk of rATG exposure with the incidence of malignancy post-transplant. Cancer cases were matched to controls in a 1:2 method based on age, sex, Epstein Barr Virus donor/recipient status, and year of transplant. Secondary analyses amongst 1:2 matches examined the impact of maintenance immunosuppression exposure on cancer risk using a weighted equation composed of the drug dose, duration, and trough values when applicable. Results: Of the 126 patients included in the study, 25 developed malignancy. These 25 patient cases were matched to 50 control patients. The primary endpoint was to evaluate the association of rATG on the risk of malignancy. The median cumulative rATG dose in milligrams (mg) between groups was 365mg in cases and 465mg in controls (OR 0.94, 95% CI 0.79 - 1.11, p=0.46). The cumulative dose of rATG in mg/kg was 4.7 mg/kg in cases vs. 5.7 mg/kg in controls (OR 0.96, 95% CI 0.82 - 1.12, p=0.59). By both univariate and multivariate analyses, there were no statistically significant differences in malignancyassociated with the usage of or quantified exposure to tacrolimus, sirolimus, cyclosporine, or mycophenolate mofetil, although sirolimus showed antioncotic trends. Conclusion: The results of this study demonstrate current rATG dosing strategies may not singularly be associated with malignancy development as previous dosing strategies suggested. Additional investigations are needed to explore the multiple factors associated with posttransplant malignancy as well as the possible modulating effect of sirolimus.