Difference in immunosuppressant dose requirement when transitioning to isavuconazole from other azoles in thoracic transplant recipients.

The triazole antifungal isavuconazole (ISAVU) is used for prevention and treatment of fungal infections in solid organ transplant (SOT). SOT recipients commonly need to transition from one azole to another due to breakthrough infection, toxicity, or other reasons. The purpose of our study was to evaluate the effect of ISAVU on immunosuppressant concentrations in thoracic transplant recipients when ISAVU was started de novo or transitioned from another azole. We conducted a single-center retrospective cohort study including 68 patients (51 lung, 14 heart, and 3 heart/lung transplant). Concentration to dosage ratios (C/D) of immunosuppressants were assessed at baseline, day 3, and weekly for 9 weeks. When starting ISAVU de novo, we observed a temporary doubling of tacrolimus exposure. Cyclosporine and sirolimus required dose decreases. Tacrolimus C/D increased by 110% at day 3 in patients started on ISAVU de novo then returned to baseline C/D ± 17% weeks 2-9 (n = 8). One cyclosporine patient started on ISAVU de novo had variable C/D, and C/D increased by 219% ± 72% in 2 sirolimus patients. When transitioning from other azoles, tacrolimus and cyclosporine required about twice the initial dose. After week 1, tacrolimus C/D decreased by 53% ± 6% in patients transitioned from posaconazole (n = 33), voriconazole (n = 14), or fluconazole (n = 2). Cyclosporine C/D decreased by 45% ± 16% in patients transitioning from other azoles (posaconazole [n = 2], voriconazole [n = 2], fluconazole [n = 1]). Sirolimus C/D decreased by 73% ± 13% in patients transitioned from posaconazole (n = 7). Aside from the initial loading phase, ISAVU had a lesser degree of interaction with immunosuppressants than other azoles in loading phase, ISAVU had a lesser degree of interaction with immunosuppressants than other azoles in adjustments for the 4-week period after initiating antifungal therapy with ISAVU or switching from another agent.

Sirolimus Long-Term Tolerability and Impact on Kidney Function in Lung Transplantation: A Single-Center Experience.

BACKGROUND: After lung transplant, 2 common complications are calcineurin inhibitor (CNI) induced nephrotoxicity and bronchiolitis obliterans syndrome. The objective of this study was to investigate the long-term effects of sirolimus conversion after lung transplantation. METHODS: This was a retrospective cohort study of patients who had undergone lung transplantation at a single center from June 2003 to December 2016. We compared patients converted to a sirolimus-based regimen to those maintained on our standard tacrolimus-based regimen. Kidney function, pulmonary function, and immunosuppression concentrations were compared between the groups. Additionally, indications, toxicity monitoring parameters, and discontinuation rates for sirolimus were collected. RESULTS: During the study period, 176 of the 205 patients who underwent lung transplants were converted to a sirolimus-containing regimen (86%). The most common reason for sirolimus initiation was impairment of kidney function or CNI-associated neurotoxicity. Sirolimus was initiated at a median of 150 days post-transplantation and continued for a medium time of 5.02 (2.27-7.85) years. Of those patients converted to sirolimus, 39 (22%) had sirolimus subsequently discontinued secondary to an adverse event. No difference in pulmonary function was found between the groups at 1- and 3-years post-transplantation. In the sirolimus group, the median estimated glomerular filtration rate improved by 8.6 mL/min/1.73 m2 at 3 months post-conversion (P < .001), which was maintained at both 1 and 3 years (P = .014 and .025, respectively). CONCLUSION: Sirolimus is a viable immunosuppressant option after lung transplant, which successfully allows for the reduction or withdrawal of the CNI, resulting in sustained improvement in kidney function.

Improved Time in Therapeutic Range with International Normalized Ratio Remote Monitoring for Patients with Left Ventricular Assist Devices.

Despite advances in therapy, bleeding and thromboembolic events are frequent complications in patients with left ventricular assist device (LVAD) support. Maintaining warfarin in therapeutic range has been shown to be more challenging in this patient population compared to other indications. Patients with LVADs on warfarin typically are within goal international normalized ratio (INR) range 36-57% of the time, compared to about 65% for other indications. The goal of this study was to evaluate if an INR remote monitoring system along with the implementation of a standardized warfarin management protocol improves warfarin time in therapeutic range (TTR) for patients with LVADs. This single-center, retrospective, observational study included 78 patients with LVADs that were followed at our academic center from January 2015 to October 2017. In October 2016, we updated our warfarin management protocol and implemented a remote monitoring system with patients' weekly INR results monitored. The primary objective of the study was to determine the difference between TTRs in remote monitoring versus standard monitoring. We found that the average TTR was significantly higher in the remote monitoring group compared to the standard monitoring cohort (61.1% vs. 40.0%, p < 0.005). However, bleeding, thrombotic incidence, and hospital readmission rates were similar between the two patient cohorts. Remote monitoring improved warfarin TTR significantly in this study and may have the potential to improve anticoagulation-related outcomes in patients with LVADs.

A multicenter case series documenting Medicare Part D plan denials of immunosuppressant drug coverage for organ transplant recipients.

Medicare Part D plans make coverage decisions according to FDA-labeled indications and off-label uses endorsed by two CMS-recognized compendia. Patients who rely on Medicare Part D for immunosuppressive drug coverage are at risk for denied coverage when these medications are prescribed off-label. The purpose of this multicenter collaboration was to assemble a case series documenting situations where immunosuppressive therapies prescribed for transplant patients were denied by Medicare Part D prescription drug plans. This case series documents 66 instances in 39 patients where immunosuppressive drug claims were denied coverage due to off-label use not endorsed by the compendia. Patients were recipients of lung (n = 28, 72%), heart (n = 7, 18%), or liver (n = 4, 10%) transplants. Denied claims were for mycophenolate mofetil (n = 22, 33%), azathioprine (n = 18, 27%), sirolimus (n = 15, 23%), mycophenolate sodium (n = 5, 8%), everolimus (n = 5, 8%), and belatacept (n = 1, 1%). Most denials were upheld across all the levels of attempted appeal, including those escalated to a Medicare Administrative Law Judge. This case series demonstrates a critical flaw in the construct of the Medicare Prescription Drug Benefit. The currently referenced compendia are not up to date and do not reflect best practices in organ transplantation.

Outcomes of heart transplantation from hepatitis C virus-positive donors.

BACKGROUND: National data demonstrate that increasing opportunities exist for organ donation among hepatitis C virus (HCV)-infected individuals. METHODS: We developed a clinical practice protocol for the acceptance of HCV+ organs for HCV- patients who underwent heart transplantation (HT) and retrospectively reviewed the outcomes at our institution. Inclusion criteria were as follows: all adult patients listed for HT. Exclusion criteria were as follows: pre-existing HIV or active hepatitis B viremia in the recipient/donor. RESULTS: We transplanted 21 patients from HCV+ donors. Nineteen were viremic donors, and 2 were non-viremic donors. The recipients included 18 patients who underwent HT alone, and 3 patients who underwent combined heart-kidney transplants. There was no HCV transmission from the non-viremic donors (n = 2). All 19 recipients of the viremic donors developed HCV infection (100% transmission). The median age of the viremic donors was 34 years (interquartile range 30-46), and 84.2% were considered US Public Health Service-increased risk. Induction immunosuppression consisted of anti-thymocyte globulin (7/21), basiliximab (7/21), or none (8/21). Maintenance immunosuppression comprised tacrolimus, mycophenolate mofetil, and prednisone. Post-operative Week 2 HCV viral load was not related to induction. Direct anti-viral agent (DAA) therapy for a 12-week course consisted of glecaprevir/pibrentasvir (14/19, 74%), sofosbuvir/velpatasvir (2/19, 11%), elbasvir/grazoprevir (2/19, 11%), and ledipasvir/sofosbuvir (1/19, 5%). All the patients on DAA therapy cleared viremia. The sustained virological response rate at 12 weeks in 18 evaluable patients was 100%. CONCLUSIONS: We report successful single-center experience using HCV+ organs for HT into HCV- recipients. We believe that there is utility in using such organs to expand the current donor pool. Further long-term follow-up is needed.

Safety and Efficacy of High-Dose Unfractionated Heparin for Prevention of Venous Thromboembolism in Overweight and Obese Patients.

STUDY OBJECTIVE: To determine the safety and efficacy of high-dose subcutaneous unfractionated heparin (UFH) for prevention of venous thromboembolism (VTE) in overweight and obese patients. DESIGN: Single-center retrospective observational cohort study. SETTING: Large academic tertiary care medical center. PATIENTS: A total of 1335 adults who weighed more than 100 kg on admission and received either subcutaneous UFH 7500 units every 8 hours (751 patients [high-dose group]) or 5000 units every 8 hours (584 patients [low-dose group]) for VTE prophylaxis during their hospitalization between January 1, 2013, and August 31, 2014. MEASUREMENTS AND MAIN RESULTS: The incidences of VTE and bleeding complications were assessed in each group. Each group was further divided into four groups based on their body mass index (BMI): overweight (BMI 25-29.9 kg/m(2) ), obese class I (BMI 30-34.9 kg/m(2) ), obese class II (BMI 35-39.9 kg/m(2) ), and obese class III (BMI ≥ 40 kg/m(2) ). The incidence of VTE was similar for patients in the high-dose group versus those in the low-dose group for all BMI categories. Bleeding complications were significantly higher for patients in the high-dose group. The proportion of patients with at least a 2-g/dl hemoglobin drop from admission was higher in patients in the high-dose groups in obese classes II and III: obese class II, 46 (30%) of 152 patients in the high-dose group versus 30 (18%) of 171 patients in the low-dose group (p<0.01); obese class III, 109 (25%) of 432 patients in the high-dose group versus 31 (12%) of 249 patients in the low-dose group (p<0.01). In addition, the proportion of patients who received at least 2 units of packed red blood cell transfusion was significantly higher in patients in the high-dose group who were in obese class III: 47 (11%) of 432 in the high-dose group versus 13 (5%) of 249 in the low-dose group (p<0.01). CONCLUSION: Administering a higher dose of heparin to patients weighing more than 100 kg may not impart additional efficacy in reducing the incidence of VTE. However, it may increase the risk for bleeding.