Three-year outcomes of de novo tacrolimus extended-release tablets (LCPT) compared to twice-daily tacrolimus in adult heart transplantation.

BACKGROUND: Extended-release tacrolimus for prophylaxis of allograft rejection in heart transplant (HT) recipients is currently not FDA-approved. One such extended-release formulation of tacrolimus known as LCPT allows once-daily dosing and improves bioavailability compared to immediate-release (IR-) tacrolimus. We compared long-term efficacy and safety of LCPT to IR-tacrolimus applied de novo in adult OHT recipients. METHODS: 25 prospective recipients on LCPT at our center from 2017 to 2019 were matched 1:2 with historical control recipients treated with IR-tacrolimus based on age, gender, and baseline creatinine. The primary composite outcome of death, acute cellular rejection, and/or new graft dysfunction within 3 years following transplant was compared between groups using non-inferiority analysis. RESULTS: LCPT demonstrated non-inferiority to IR-tacrolimus, with a primary outcome risk reduction of 16% (90%CI, -37%, -1%, non-inferiority p = 0.002) up to 3 years following heart transplant. Up to 3-years post-transplant, 14 patients remained on once-daily LCPT and 10 patients were switched to IR-tacrolimus due to lack of insurance coverage. There were no significant differences in the rate of chronic kidney disease requiring dialysis, cytomegalovirus requiring treatment, cardiac allograft vasculopathy, and malignancy within 3 years following transplant. CONCLUSION: LCPT is non-inferior in efficacy to IR-tacrolimus in heart transplantation with a similar safety profile. Narrowly-constrained FDA labels specific to kidney transplant remain a barrier to consistent access to many immunosuppressant medications for recipients of non-kidney solid organs. We recommend the FDA consider developing facile pathways for expanding the approved label of extended-release tacrolimus formulations to heart transplant recipients.

Weight-based vs fixed dosing of darbepoetin alfa for anemia following kidney transplantation.

PURPOSE: Post-transplantation anemia (PTA) is common in kidney transplant recipients, with patients frequently treated with erythropoietin-stimulating agents such as darbepoetin alfa. The optimal dosing for darbepoetin alfa remains controversial. METHODS: This retrospective cohort study involved kidney transplant recipients who received darbepoetin alfa at 2 clinics. Patients were stratified into 2 groups: those who received a fixed dose of 200 µg and those who received a weight-based dose of 0.45 µg/kg. The dosing interval varied depending on clinical response, clinic visit timing, and frequency allowed by insurance. The primary outcome was achieving a hemoglobin concentration of at least 10 g/dL without blood transfusion by 12 weeks after darbepoetin alfa initiation. RESULTS: Of the 110 patients in the study, 45% received weight-based dosing and 55% received fixed dosing. Darbepoetin alfa was initiated significantly earlier after transplantation in the fixed-dose group (median of 14 vs 20 days; P = 0.003). The weight-based group received more doses of darbepoetin alfa (median of 4 vs 2 doses; P = 0.002) and had a significantly lower cumulative exposure to darbepoetin alfa (125 vs 590 µg; P < 0.001). The median time between doses was 9 days (interquartile range, 7-14 days) in the weight-based group and 12 days (7-32 days) in the fixed-dose group (P = 0.04). Patients in the weight-based group more frequently achieved the primary outcome (67.3% vs 47.5%; P = 0.059). There was no significant difference in secondary or safety outcomes between the groups. CONCLUSION: Weight-based and fixed dosing approaches for darbepoetin alfa were not different in the achievement of a hemoglobin concentration of at least 10 g/dL without blood transfusion at 12 weeks after darbepoetin alfa initiation, with significantly lower cumulative darbepoetin alfa utilization in the weight-based group. Weight-based dosing of darbepoetin alfa in PTA appears to be safe and effective, with the potential for significant patient and health-system cost savings.

Immunosuppression in Uterus Transplantation: Experience From the Dallas Uterus Transplant Study.

BACKGROUND: Uterus transplantation is a temporary transplant allowing women with absolute uterine factor infertility to experience pregnancy and childbirth. The degree of immunosuppression (IS) required to prevent rejection while minimizing toxicity to the recipient and fetus remains an area of investigation. METHODS: In this article, we describe immunosuppressive therapy, rejection episodes, infections, and adverse events in 14 uterus transplant recipients. Induction consisted of antithymocyte globulin and methylprednisolone. Ten recipients (71%) received no steroids postoperatively, and 4 (29%) had steroids tapered off at 42 d. All received oral tacrolimus, either immediate release (n = 2, 14%) or extended release (n = 12, 86%). Mycophenolate was used in 4 cases (29%), de novo azathioprine in 9 (64%), and de novo everolimus in 1 (7%). RESULTS: Sixteen clinically silent, treatment-responsive rejection episodes occurred in 10 recipients. Five recipients (36%) experienced acute kidney injury. In 3 recipients, IS was discontinued due to renal dysfunction. Eleven infection episodes were noted in 7 recipients. No babies had congenital abnormalities. CONCLUSIONS: Our experience demonstrates that safe IS regimens can be used for uterus transplant recipients before and during pregnancy.

Early outcomes of kidney transplant recipients from donors with severe SARS-CoV-2 pneumonia: A report of 5 cases.

BACKGROUND: Transplanting kidneys from donors with a recent history of severe SARS-CoV-2 pneumonia is uncommon due to concerns about the risk of viral transmission and the quality of kidneys from these donors. To date, there are no conclusive data on viral transmission from extrapulmonary solid organ transplants. Given the prevalence of SARS-CoV-2 infections in potential donors, shortage of kidneys available for transplantation, and low risk of viral transmission, we developed a clinical protocol for accepting kidneys from donors with recent severe SARS-CoV-2 pneumonia who demonstrate preserved kidney function. MATERIALS AND METHODS: We collected data on early outcomes of 5 kidney transplant recipients from 4 deceased donors hospitalized for severe SARS-CoV-2 infection. RESULTS: Donor creatinine ranged from 0.51 to 0.60 mg/dL and kidney donor profile index (KDPI) from 14 to 52%. Three of the five kidneys were from donation after circulatory death. All recipients were fully vaccinated, and 4/5 received post-exposure prophylactic monoclonal antibody treatment. While 3 recipients had delayed graft function, all had excellent graft function at 3 or 4 weeks post-operatively. None of the recipients displayed signs or symptoms of SARS-CoV-2 infection post-transplant. CONCLUSION: Our findings suggest that kidney grafts from donors with a recent history of severe SARS-CoV-2 infection but with preserved kidney function can be safely used and have good early outcomes.

Comparison of Patiromer to Sodium Polystyrene Sulfonate in Acute Hyperkalemia.

Background: Patiromer and sodium polystyrene sulfonate (SPS) are cation-exchangers approved for the treatment of chronic hyperkalemia. Data regarding their efficacy acutely is lacking. Despite this, both drugs are frequently used in the emergent setting. Objective: The purpose of this study was to compare the potassium reduction of patiromer to SPS within 6 to 24 hours following a single dose. Methods: This retrospective quality improvement project included hyperkalemic patients receiving 1 dose of patiromer or SPS and had a second potassium level drawn in 6 to 24 hours. Doses of 8.4 g of patiromer and 15 g of SPS were considered "low dose" while 16.8 g of patiromer and 30 g of SPS were considered "high dose." The presence of a dose-response relationship was assessed through a linear regression analysis. Results: Mean (SD) potassium reduction was higher in SPS than patiromer [0.76 (0.63) mEq/L vs 0.32 (0.65) mEq/L, (P = .001)]. A dose response relationship was not demonstrated in low versus high dose groups [-0.21 (0.14), P = .13] and CKD, ESRD, and renal transplant patients when compared to patients with normal renal function [0.11 (0.17), P = .51, -0.07 (0.19), P = -0.07 (0.19), P = .73, and -0.10 (0.22), P = .65]. Conclusions: This study suggests a clinically significant reduction in potassium with SPS compared to patiromer. Although SPS was successful in demonstrating this outcome, due to well-documented adverse reactions in the literature and a time to onset of 6 hours, it cannot be recommended for use in acute hyperkalemia either.

Angiotensin II: A Multimodal Approach to Vasoplegia in a Cardiac Setting.

Patients experiencing vasoplegia, a type of distributive shock, have limited options when conventional vasopressors are not appropriate or sufficient. This is especially true for patients with cardiac dysfunction, whether after heart transplant or ventricular assist device (VAD) implantation. Angiotensin II has been used in various clinical settings for distributive shock; however, its role in patients after orthotopic heart transplant or VAD implantation is not well studied. We present two cases where angiotensin II played a vital role in correcting vasoplegia for critical cardiac patients.

De novo tacrolimus extended-release tablets (LCPT) versus twice-daily tacrolimus in adult heart transplantation: Results of a single-center non-inferiority matched control trial.

Extended-release tacrolimus for prophylaxis of allograft rejection in orthotopic heart transplant (OHT) recipients is currently not FDA-approved. One such extended-release formulation of tacrolimus known as LCPT allows once-daily dosing and improves bioavailability compared to immediate-release tacrolimus (IR-tacrolimus). We compared the efficacy and safety of LCPT to IR-tacrolimus applied de novo in adult OHT recipients. Twenty-five prospective recipients on LCPT at our center from 2017 to 2019 were matched 1:2 with historical control recipients treated with IR-tacrolimus based on age, gender, and baseline creatinine. The primary composite outcome of death, acute cellular rejection, and/or new graft dysfunction within 1 year was compared using non-inferiority analysis. LCPT demonstrated non-inferiority to IR-tacrolimus, with a primary outcome risk reduction of 20% (90% CI: -40%, -.5%; non-inferiority P = .001). Tacrolimus trough levels peaked at 2-3 months and were higher in LCPT (median 14.5 vs. 12.7 ng/ml; P = .03) with similar dose levels (LCPT vs. IR-tacrolimus: .08 vs. .09 mg/kg/day; P = .33). Cardiovascular-related readmissions were reduced by 62% (P = .046) in LCPT patients. The complication rate per transplant admission and all-cause readmission rate did not differ significantly. These results suggest that LCPT is non-inferior in efficacy to IR-tacrolimus with a similar safety profile and improved bioavailability in OHT.

Impact of risk-stratified mycophenolate dosing in heart transplantation.

Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid, is a highly effective immunosuppressive agent in heart transplant therapy. While the FDA approved dose is 1500 mg twice daily, dosing is often reduced due to dose-dependent adverse effects. However, empiric MMF dose reductions may lead to sub-therapeutic dosing and impair clinical outcomes. Our single center protocolized a risk-stratified approach based on age and weight to dose 500 mg twice daily or 1000 mg twice daily to patients after heart transplantation. This retrospective single-center study analyzed 140 consecutive heart transplant patients who were initiated on our risk-stratified MMF protocol post-transplant. The analysis revealed that the composite rate of biopsy-proven rejection, graft loss, or mortality at 1-year post-transplantation was similar between the two groups. Incidence of neutropenia, thrombocytopenia, infection, cardiac allograft vasculopathy, or acute kidney injury by 1-year also showed similar results between the two groups. Risk-stratification of MMF dosing appears to be a safe and effective strategy after heart transplantation.

Impact of antimicrobial selection for prophylaxis of left ventricular assist device surgical infections.

BACKGROUND: Surgical site infections (SSIs) after left ventricular assist device (LVAD) implantation are associated with high mortality, while surgical prophylaxis is variable. METHODS: This retrospective study included adult patients who underwent LVAD implantation at a single center. We compared outcomes in patients who received narrow antimicrobial prophylaxis (cefazolin, vancomycin, or both) to those who received broad antimicrobial prophylaxis (any antimicrobial combination targeting gram-positive and gram-negative organisms not included in the narrow group) at 30-day and 1-year postimplantation. Cox-proportional hazards models and log-rank tests were used for survival analysis. RESULTS: Among the 39 and 65 patients comprising narrow and broad groups respectively, there was no difference in rate of SSI at 30 days (6.2% vs. 12.8%, p = .290) and 1 year (16.9% vs. 25.6%, p = .435). Comparing narrow to broad prophylaxis, the risk of mortality (hazard ratio [HR] = 0.44, 95% confidence interval [CI] = 0.15-1.35, logrank p = .14), and composite of mortality and infection was reduced (HR = 0.92, 95% CI = 0.45-1.88, logrank p = .83), but did not reach statistical significance. Most culture positive infections were due to gram-positive bacteria (70%) and the most common organisms were the Staphylococcus spp (47%). There were no significant differences in the rate of SSI at 1-year (p = 1.00) and mortality (p = .33) by device type. CONCLUSIONS: The rates of infection and all-cause mortality were not different between patients who received narrow or broad prophylaxis. This highlights an opportunity for institutions to narrow their surgical infection prophylaxis protocols to primarily cover gram-positive organisms.

A retrospective analysis of the safety and efficacy of apixaban use after lung transplant.

Direct acting oral anticoagulants (DOACs) have become the mainstay of treatment for patients requiring anticoagulation for atrial arrhythmias and venous thromboembolism (VTE) but safety and efficacy has not been established in lung transplantation. This is a retrospective review of 28 adult lung transplant patients who were prescribed apixaban for stroke prevention in atrial arrhythmias or treatment of VTE between October 15, 2015 and December 31, 2018. The primary outcome was a composite of efficacy and safety measured by recurrence or breakthrough of stroke or thromboembolism and bleeding events. Seven patients were treated for atrial arrhythmias and 21 treated for VTE. Fifteen patients received CYP3A4 or P-gp inhibitors at initiation of anticoagulation, and 4 of these patients received strong CYP3A4 inhibitors. During the follow-up period, one breakthrough DVT and one clinically relevant non-major bleed were observed. These data suggest that apixaban may be safe to use for lung transplant patients, and larger studies are warranted to assess long-term outcomes as well as safety and efficacy of alternative DOACs.

The dynamic treatment of SARS-CoV-2 disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or novel coronavirus disease 2019 (COVID-19) emerged from China in December 2019 and progressed to become a global pandemic. Our understanding of its pathophysiology and potential management was initially extrapolated from previous epidemics of coronaviruses like SARS and MERS. SARS-CoV-2 is asymptomatic or minimally symptomatic in more than 80% of patients and requires no additional management; however, the remaining patients progress to pneumonia and hypoxemia with ranging severity, including a smaller group that requires intensive care unit admission. To date, there are no approved treatments for SARS-CoV-2, and current management is focused on supplemental oxygen and supportive care. The antiviral medication remdesivir recently received emergency use authorization by the US Food and Drug Administration for patients with severe disease. Multiple clinical trials evaluating different treatment modalities such as antivirals, immunomodulators, convalescent plasma, and monoclonal antibodies, among others, are still ongoing. We believe that patients present with clinical phenotypes that correlate with the spectrum of disease. Each phenotype may benefit from one or multiple interventions. We discuss treatments under evaluation in clinical trials and their potential application based on clinical phenotype presentation.

Rational Heart Transplant From a Hepatitis C Donor: New Antiviral Weapons Conquer the Trojan Horse.

BACKGROUND: Donors with hepatitis C (HCV) viremia are rarely used for orthotopic heart transplantation (HT) owing to post-transplantation risks. New highly effective HCV antivirals may alter the landscape. METHODS: An adult patient unsuitable for bridging mechanical support therapy accepted a heart transplant offer from a donor with HCV viremia. On daily logarithmic rise in HCV viral load and adequate titers to ensure successful genotyping, once daily sofosbuvir (400 mg)-velpatasvir (100 mg) (Epclusa; Gilead) was initiated empirically pending HCV genotype (genotype 3a confirmed after initiation of therapy). RESULTS: We report the kinetics of acute hepatitis C viremia and therapeutic response to treatment with a new pangenotypic antiviral agent after donor-derived acute HCV infection transmitted incidentally with successful cardiac transplantation to an HCV-negative recipient. Prompt resolution of viremia was noted by the 1st week of a 12 week course of antiviral therapy. Sustained virologic remission continued beyond 12 weeks after completion of HCV therapy (SVR-12). CONCLUSIONS: The availability of effective pangenotypic therapy for HCV may expand donor availability. The feasibility of early versus late treatment of HCV remains to be determined through formalized protocols. We hypothesize pharmacoeconomics to be the greatest limitation to widespread availability of this promising tool.

Impact of the Pharmacy Practice Model Initiative on Clinical Pharmacy Specialist Practice.

This paper describes the goals of the American Society of Health-System Pharmacists' Pharmacy Practice Model Initiative (PPMI) and its recommendations for health-system pharmacy practice transformation to meet future patient care needs and elevate the role of pharmacists as patient care providers. PPMI envisions a future in which pharmacists have greater responsibility for medication-related outcomes and technicians assume greater responsibility for product-related activities. Although the PPMI recommendations have elevated the level of practice in many settings, they also potentially affect existing clinical pharmacists, in general, and clinical pharmacy specialists, in particular. Moreover, although more consistent patient care can be achieved with an expanded team of pharmacist providers, the role of clinical pharmacy specialists must not be diminished, especially in the care of complex patients and populations. Specialist practitioners with advanced training and credentials must be available to model and train pharmacists in generalist positions, residents, and students. Indeed, specialist practitioners are often the innovators and practice leaders. Negotiation between hospitals and pharmacy schools is needed to ensure a continuing role for academic clinical pharmacists and their contributions as educators and researchers. Lessons can be applied from disciplines such as nursing and medicine, which have developed new models of care involving effective collaboration between generalists and specialists. Several different pharmacy practice models have been described to meet the PPMI goals, based on available personnel and local goals. Studies measuring the impact of these new practice models are needed.

Expanding the role of pharmacists and pharmacy students in the promotion of organ donation awareness.

The gap between supply and demand for available organs has resulted in numerous deaths of patients on the transplant waiting list each year. Given the substantial public health impact of the organ shortage crisis, efforts have been focused on the use of educational interventions aimed both at the public and health care professionals to spread awareness of the disparity in organ supply and demand and ultimately improve organ donation rates. Transplant pharmacists are fundamental members of transplant multidisciplinary teams and are expected to promote organ and tissue awareness in an effort to decrease the morbidity and mortality of patients on the transplant waiting list. The role of pharmacists and pharmacy students in the promotion of organ donation awareness is expanding.

Rates and determinants of ventriculostomy-related infections during a hospital transition to use of antibiotic-coated external ventricular drains.

OBJECT: The authors evaluated the rates of ventriculostomy-related infections (VRIs) after antibiotic-coated extraventricular drains (ac-EVDs) were introduced as the standard of care. METHODS: A retrospective chart review was conducted of adult patients admitted to NewYork-Presbyterian Hospital neurological intensive care unit in whom an EVD was placed between February 2007 and November 2009, excluding individuals receiving EVDs due to an infection of a primary device. Three time periods were defined depending on type of EVD in use: Period 1, conventional EVDs; Period 2, either ac-EVDs or conventional EVDs; and Period 3, ac-EVDs. Definite/probable VRIs that occurred during the 3 periods were evaluated and established as determinants of VRIs by using a Cox proportional hazards model. Prolonged systemic antibiotics were given for the duration of EVD placement in each of the 3 periods per institutional policy. RESULTS: Data from 141 individuals were evaluated; mean patient age was 53.8 ± 17.2 years and 54% were female. There were 2 definite and 19 probable VRIs. The incidence of definite/probable VRI (per 1000 person-catheter days) decreased from Period 1 to 3 (24.5, 16.2, and 4.4 in Periods 1, 2, and 3, respectively; p < 0.0001). Patients with VRIs were more likely to be female than male (23.7% vs 3.1%, p < 0.003) and have had an EVD in place for a longer duration, although there was no significant difference among the 3 periods (7.9 ± 6.7 [Period 1], 8.1 ± 7.1 [Period 2], and 8.6 ± 5.8 [Period 3] mean days; p = 0.87, ANOVA). Analysis of effect modification in a stepwise model showed that period, age, and age and female interaction were significant predictors of VRIs. The period was the strongest predictor of VRI (p = 0.0075). After adjustment for age and age and sex interaction, the survival rate was 53% at the end of Period 2 and 91% at the end of Period 3. CONCLUSIONS: Rates of VRIs have decreased with the addition of ac-EVDs to the routine use of prolonged systemic antibiotics at the authors' institution.

Risk evaluation and mitigation strategies: a focus on belatacept.

OBJECTIVE: To review the elements and components of the risk evaluation and mitigation strategies (REMS) for the costimulation blocker belatacept and associated implications for health care providers working with transplant recipients. DATA SOURCES AND EXTRACTION: The MEDLINE and EMBASE databases (January 1990 to March 2012) were searched by using risk evaluation and mitigation strategies, REMS, belatacept, and organ transplant as search terms (individual organs were also searched). Retrieved articles were supplemented with analysis of information obtained from the Federal Register, the Food and Drug Administration, and the manufacturer of belatacept. DATA SYNTHESIS: REMS are risk-management strategies implemented to ensure that a product's benefits outweigh its known safety risks. Although belatacept offers a novel strategy in maintenance immunosuppression and was associated with superior renal function compared with cyclosporine in phase 2 and 3 trials, belatacept is also associated with increased risk of posttransplant lymphoproliferative disorder and central nervous system infections. The Food and Drug Administration required development of a REMS program as part of belatacept's approval process to ensure safe and appropriate use of the medication and optimization of its risk-benefit profile. CONCLUSION: Elements of the belatacept REMS include a medication guide that must be dispensed with each infusion and a communication plan. In the management of a complex population of patients, it is essential that those who care for transplant recipients, and patients, recognize the implications of potential and known risks of belatacept. The REMS program aims to facilitate careful selection and education of patients and vigilant monitoring.