Comparison of standard versus low-dose valganciclovir regimens for cytomegalovirus prophylaxis in high-risk liver transplant recipients.

PURPOSE: The purpose of this study was to compare the safety and efficacy of two valganciclovir (VGCV) institutional dosing protocols for cytomegalovirus (CMV) prophylaxis in liver transplant (LT) recipients with CMV serotype donor +/recipient- (D+/R-). METHODS: This was a single-center review of CMV D+/R- adult LT recipients who received VGCV 450 mg/day for 90 days (low-dose) or VGCV 900 mg/day for 180 days (standard-dose). The primary outcome was incidence of CMV disease at 1 year. Secondary outcomes included rates of CMV syndrome, end-organ disease, breakthrough infection, and resistance. Neutropenia, early discontinuation of VGCV, growth colony stimulating factors use (G-CSF), biopsy-proven rejection (BPAR), graft loss, and death at 1 year were analyzed. RESULTS: Ninety-six CMV D+/R- LT recipients were included. Although no difference in CMV disease was observed (low-dose 26% vs. standard-dose 23%, p = 0.71), 75% of CMV infections in the low-dose group presented with end-organ disease. Ganciclovir (GCV) resistance was observed only in the low-dose group (n = 2). Significantly more patients in the standard-dose group developed neutropenia (low-dose 10% vs 60% standard-dose, p < 0.001). In the standard-dose group, 29% required early discontinuation of VGCV (vs. 5% in the low-dose group, p < 0.001), and 20% were treated with G-CSF. Both cohorts had similar rates of BPAR, graft loss, and death at 1 year. CONCLUSIONS: VGCV 900 mg/day for 180 days had higher rates of hematologic adverse effects resulting in frequent treatment interruptions. However, the occurrence of two cases of GCV-resistant CMV disease raises concerns about routinely using low-dose VGCV prophylaxis.

Use of direct-acting oral anticoagulants in solid organ transplantation: A systematic review.

The use of direct-acting oral anticoagulants (DOACs) has increased secondary to the mounting evidence for comparable efficacy and potentially superior safety to vitamin K antagonists (VKAs) in the general population. However, insufficient data regarding DOAC use in solid organ transplant (SOT) recipients and numerous pharmacokinetic and pharmacodynamic considerations limit their use in this highly selected patient population. A systematic review of recent clinical evidence on the safety and efficacy of DOACs compared to VKAs in SOT recipients was conducted. Additional considerations including transplant-specific strategies for DOAC reversal and common pharmacokinetic/pharmacodynamic concerns were also reviewed. Although current evidence is limited to single-center retrospective analyses, DOACs, especially apixaban, appear to be a safe and effective alternative to VKAs for SOT recipients with stable graft function and without drug-drug interactions. Reliable data on DOAC reversal at the time of transplant surgery are lacking, and clinicians should consider idarucizumab, andexanet alfa, and other non-specific reversal agents on an individual patient basis. There is no evidence supporting deviations from the Food and Drug Administration labeling recommendations for DOAC dosing in the setting of drug-drug interactions, obesity, and renal function, especially in patients on hemodialysis.

Safety and efficacy of direct-acting oral anticoagulants versus warfarin in kidney transplant recipients: a retrospective single-center cohort study.

Despite the increased use, comparative safety and efficacy of direct-acting oral anticoagulants (DOACs) against warfarin have not been well studied in kidney transplant recipients. In this single-center retrospective study, we evaluated 197 adult kidney transplant recipients on DOAC or warfarin between January 1, 2011, and June 30, 2018. The primary outcome was incidence of major bleeding defined as a hemoglobin decrease ≥2 g/dl, blood transfusion ≥2 units, or symptomatic bleeding in a critical area or organ. Patients were initiated on anticoagulation therapy at a median of 6.5 years post-transplant and followed for a median of 12.3 months. The rates of major bleeding were 7.2% per year with DOACs vs. 11.4% per year with warfarin (Mantel-Cox P = 0.15). No difference was found in composite bleeding, clinically relevant nonmajor bleeding, or thromboembolic events between the groups. There was a lower incidence of major bleeding with apixaban compared to all other anticoagulants (6.7% vs. 19.0%, P = 0.027). After controlling for potential confounders, DOAC use was not associated with an increased risk of major bleeding (HR 0.73, 95% CI 0.27-1.95). Further research is warranted to definitively determine whether DOACs are effective and safe alternatives to warfarin for anticoagulation in kidney transplant recipients.

Successful use of carbamazepine in a patient with drug rash with eosinophilia and systemic symptoms.

Drug rash with eosinophilia and systemic symptoms (DRESS) is a serious adverse drug reaction with a high mortality rate. Discontinuation of the causative agent is the primary treatment. History of DRESS may put patients at higher risk of future episodes; however, cross-reactivity between various medications is not well established. An 18-year-old African American male with a history of bipolar I disorder with psychotic features was admitted for mania on his home dose of divalproex. After 1 week, olanzapine was added for refractory symptoms, but due to elevated creatinine phosphokinase (CPK), it was subsequently discontinued, and he was started on lorazepam and lithium. One week later, the patient was transferred to the intensive care unit with elevated CPK, fever, thrombocytopenia, elevated serum creatinine, hypotension, diarrhea, mild rigidity, bilateral inducible ankle clonus, and a rash. All medications were discontinued except for lorazepam. The skin pathology report was consistent with a drug eruption, and he was started on prednisone. Given continued symptoms of mania, carbamazepine was initiated. After clinical and laboratory improvement, the patient was discharged on hospital day 59 with instructions to continue carbamazepine and lorazepam. A MEDLINE search revealed no published case reports of the successful use of carbamazepine in a patient with a history of DRESS. Information regarding cross-reactivity between medications is limited primarily to aromatic antiepileptics. In our case report, carbamazepine was successfully used in a patient with a recent episode of DRESS during olanzapine, lithium, and valproate use.

Impact of direct-acting antivirals for hepatitis C virus therapy on tacrolimus dosing in liver transplant recipients.

INTRODUCTION: Direct-acting antivirals (DAAs) have transformed hepatitis C virus (HCV) management post-liver transplant. As HCV clears during DAA treatment, hepatic metabolism improves, resulting in decreased tacrolimus concentrations that may require dose adjustment. The purpose of this study was to determine appropriate management of immunosuppression in liver transplant recipients during and following treatment of HCV. METHODS: This study was a single-center retrospective analysis of 71 liver transplant recipients who were treated for HCV with DAAs. The primary outcome was change in dose-normalized tacrolimus concentrations from the start of DAA treatment to 12 weeks following therapy. RESULTS: The mean change in log-transformed dose-normalized tacrolimus concentrations was a reduction of 0.43 ng/mL/mg (95% CI; 0.26-0.60, P < 0.0001). The greatest decrease occurred in the first 4 weeks of treatment, after which levels stabilized. The overall mean tacrolimus concentration was 4.8 ng/mL (±2.5). Two patients (3%) developed acute cellular rejection and two patients (3%) had graft loss and died. CONCLUSION: From the start of treatment to 12 weeks post-DAA therapy, liver transplant recipients experienced a significant decrease in dose-normalized tacrolimus concentrations. In conclusion, close monitoring of tacrolimus concentrations is warranted during and following treatment with DAAs, as dose increases may be indicated in order to maintain therapeutic concentrations to prevent graft rejection.

Clinical Management of Bleeding Risk With Antidepressants.

OBJECTIVE: This nonsystematic review describes risk of bleeding in treatment with serotonin reuptake inhibitors (SRIs) and provide recommendations for the management of patients at risk of bleeding. DATA SOURCES: Articles were identified by English-language MEDLINE search published prior to June 2018 using the terms SRI, serotonin and noradrenaline reuptake inhibitors, OR antidepressive agents, AND hemorrhage OR stroke. STUDY SELECTION AND DATA EXTRACTION: Meta-analyses were utilized to identify information regarding risk of bleeding with antidepressants. Individual studies were included if they had information regarding bleeding risk with specific SRIs, timing of risk, or risk with medications of interest. DATA SYNTHESIS: SRIs increase risk of bleeding by 1.16- to 2.36-fold. The risk is synergistic between SRIs and nonsteroidal anti-inflammatory drugs (NSAIDs; odds ratio [OR] range between studies 3.17-10.9). Acid-reducing medications may mitigate risk of gastrointestinal bleeds in chronic NSAIDs and SRI users (OR range between studies 0.98-1.1). Antidepressants with low or no affinity for the serotonin transporter, such as bupropion or mirtazapine, may be appropriate alternatives for patients at risk of bleeding. Relevance to Patient Care and Clinical Practice: This review includes data regarding bleeding risk for specific antidepressants, concomitant medications, and risk related to duration of SRI use. Considerations and evidence-based recommendations are provided for management of SRI users at high bleeding risk. CONCLUSIONS: Clinicians must be aware of the risk of bleeding with SRI use, especially for patients taking NSAIDs. Patient education is prudent for those prescribed NSAIDs and SRIs concurrently.