Descriptive analysis evaluating the use of direct oral anticoagulation therapy in heart and lung transplant recipients.

BACKGROUND: Direct oral anticoagulants (DOACs) are widely utilized following cardiothoracic transplantation with limited guidance regarding drug-drug interactions (DDIs), periprocedural management, and DOAC-specific monitoring. METHODS: We performed a single-center, retrospective, descriptive analysis of adult cardiothoracic transplant recipients initiated on DOAC therapy between May 2016 and July 2021. The primary endpoint for this analysis was the percentage of patients dosed per package labeling. Secondary endpoints included DOAC prescribing in the context of DDIs, renal dysfunction, and periprocedural management, as well as thromboembolism and major bleeding at 12 months. RESULTS: A total of 125 patients were included in this analysis with a median age of 62 years. At initiation, 63.2% of patients were dosed according to package labeling. The most common reason for non-labeled dosing was concomitant azole antifungal therapy. DOAC therapy was held for 82 procedures with no reported thrombotic events and one major bleed in the setting of AKI. Hemodialysis-dependence was associated with a reduced risk of thrombosis (0 vs. 10 events per 100 PY, p = .002) and an increased risk of major bleeding (23 vs. 8 events per 100 PY, p = .006). Additionally, DOAC-specific anti-xa guided dosing was associated with a reduced risk of major bleeding (0 vs. 13 events per 100 PY, p < .001). CONCLUSION: Our findings show that deviation from package labeling is common following cardiothoracic transplantation and its association with clinical outcomes warrants further study.

Orladeyo (Berotralstat): A Novel Oral Therapy for the Prevention of Hereditary Angioedema.

OBJECTIVE: The purpose of this article is to review the available trials that led to the Food and Drug Administration (FDA) approval of berotralstat, an oral kallikrein inhibitor, for the prevention of hereditary angioedema (HAE) attacks. DATA SOURCES: PubMed and ClincalTrials.gov were searched using key term berotralstat to identify phase III clinical trials related to the FDA approval of berotralstat from April 2018 to May 2021. STUDY SELECTION AND DATA EXTRACTION: Trials selected were those that influenced the FDA approval of berotralstat or provided novel information regarding the safety and efficacy of this therapy in the treatment of HAE. DATA SYNTHESIS: Both APeX-2 and ApeX-J found clinically significant benefit with berotralstat 150 mg daily for reduction in HAE attacks when compared with placebo (1.31 vs 2.35, P < 0.001, and 1.11 vs 2.18, P < 0.001, attacks in the APeX-2 and APeX-J trials, respectively). APeX-2 also showed a statistically significant benefit for berotralstat 110 mg daily (1.65 vs 2.35 attacks [1.65 attacks, P = 0.024]). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: An advantage berotralstat has over the other approved therapies is that it is administered orally, which may garner patient preference because of ease of administration. Berotralstat has also shown a potential benefit in reducing the need for standard-of-care treatment for HAE attacks, which has not been studied with alternative agents. CONCLUSIONS: Berotralstat 150 mg daily has been proven safe and effective in clinical studies and appears to be a viable oral alternative to parenteral medications currently used in HAE prophylaxis.

Early therapeutic monitoring of ß-lactams and associated therapy outcomes in critically ill patients.

BACKGROUND: In the ICU, early and appropriate antimicrobial therapy is important to lower infection-related mortality. OBJECTIVES: Assess whether achieving early ß-lactam free concentration above the MIC 100% of the time (fT>MIC) is associated with positive outcomes in the ICU. METHODS: This retrospective study was conducted in ICU patients admitted to UF Health Shands Hospital between 2016 and 2018. Adult patients who received ß-lactam therapy and had drug concentration measured were included. Data collected included demographics, ß-lactam regimens and concentrations, sources of infection, cultures and susceptibilities, mortality, length of stay, resistance acquisition for 30 days and clinical outcome at end of therapy. Multiple regression and time-to-event (TTE) analyses were performed. RESULTS: Two-hundred and six patients were included. Clinical cure occurred in 71%, microbial eradication occurred in 58% and new resistance to the ß-lactam received developed in 8% of patients. Hospital and 30 day mortalities were 17% and 14%, respectively. fT>MIC and fT>4×MIC were associated with clinical cure (P = 0.0303), microbial eradication (P = 0.0476) and suppression of resistance (P = 0.0043). Delay in measuring ß-lactam concentration was associated with clinical failure (P = 0.0072), longer ICU stay (P < 0.0001) and higher mortality (P = 0.0387). In the TTE analysis, patients with 100% fT>MIC had a significantly shorter ICU stay (P = 0.0297). Patients who had clinical cure and microbial eradication had drug concentrations measured earlier (P = 0.0025 and 0.0254, respectively). CONCLUSIONS: This study highlights the importance of early measurement of ß-lactam concentration and confirms the association between fT>MIC and clinical cure, microbial eradication and emergence of resistance.