Evaluating pharmacokinetic drug-drug interactions of direct oral anticoagulants in patients with renal dysfunction.

INTRODUCTION: Drug transporters, metabolic enzymes, and renal clearance play significant roles in the pharmacokinetics of direct oral anticoagulants (DOACs). Recommendations for DOAC drug-drug interactions (DDIs) by the product labeling are limited to selected CYP3A4 and P-glycoprotein inhibitors and lack considerations for concomitant renal dysfunction. AREAS COVERED: This review focuses on: 1) current recommendations for the management of pharmacokinetic DOAC DDIs and the evidence used to support them; 2) alterations in DOAC exposure in the setting of concomitant DDIs and mild, moderate, and severe renal impairment; 3) clinical outcomes associated with this combination; and 4) expert recommendations for the management of pharmacokinetic DOAC DDIs. English-language, full-text articles on apixaban, dabigatran, rivaroxaban, and edoxaban with a publication date up to 30 September 2021 were retrieved from PubMed. EXPERT OPINION: Given the lack of supporting clinical data, empiric dose adjustments based on pharmacokinetic data alone should be avoided. When a considerable increase in a DOAC exposure is anticipated, it may be advisable to use an alternative DOAC or anticoagulant from a different class. Future research on identification of DOAC therapeutic ranges and target patient populations is needed to inform clinical utility of DOAC level monitoring to guide the management of DDIs.

Effect of Replacing Vendor QTc Alerts with a Custom QTc Risk Alert in Inpatients.

OBJECTIVE: The aim of the study is to implement a customized QTc interval clinical decision support (CDS) alert strategy in our electronic health record for hospitalized patients and aimed at providers with the following objectives: minimize QTc prolongation, minimize exposure to QTc prolonging medications, and decrease overall QTc-related alerts. A strategy that was based on the validated QTc risk scoring tool and replacing medication knowledge vendor alerts with custom QTc prolongation alerts was implemented. METHODS: This is a retrospective quasi-experimental study with a pre-intervention period (August 2019 to October 2019) and post-intervention period (December 2019 to February 2020). The custom alert was implemented in November 2019. RESULTS: In the pre-implementation group, 361 (19.3%) patients developed QTc prolongation, and in the post-implementation group, 357 (19.6%) patients developed QTc prolongation (OR: 1.02, 95% CI: 0.87-1.20, p = 0.81). The odds ratio of an action taken post-implementation compared with pre-implementation was 18.90 (95% CI: 14.03-25.47, p <0. 001). There was also a decrease in total orders for QTc prolonging medications from 7,921 (5.5%) to 7,566 (5.3%) with an odds ratio of 0.96 (95% CI: 0.93-0.99, p = 0.01). CONCLUSION: We were able to decrease patient exposure to QTc prolonging medications while not increasing the rate of QTc prolongation as well as improving alert action rate. Additionally, there was a decrease in QTc prolonging medication orders which illustrates the benefit of using a validated risk score with a customized CDS approach compared with a traditional vendor-based strategy. Further research is needed to confirm if an approach implemented at our organization can reduce QTc prolongation rates.

Standard Versus Higher Intensity Anticoagulation for Patients With Mechanical Aortic Valve Replacement and Additional Risk Factors for Thromboembolism.

Current guidelines recommend targeting an international normalized ratio (INR) of 2.5 to 3.5 for patients with mechanical aortic valve replacement (AVR) and additional risk factors for thromboembolic events. Available literature supporting the higher intensity (INR) goal is lacking. We aimed to evaluate the association of standard and higher intensity anticoagulation on outcomes in this patient population. The Michigan Anticoagulation Quality Improvement Initiative database was used to identify patients with mechanical AVR and at least one additional risk factor. Patients were classified into 2 groups based on INR goal: standard-intensity (INR goal 2.5) or higher-intensity (INR goal 3.0). Cox-proportional hazard model was used to calculate adjusted hazard ratios. One hundred and forty-six patients were identified of whom 110 (75.3%) received standard-intensity anticoagulation and 36 (24.7%) received higher intensity anticoagulation. Standard-intensity patients were older and more likely to be on aspirin. Atrial fibrillation was the most common additional risk factor for inclusion. The primary outcome of thromboembolic events, bleeding, or all-cause death was 13.9 and 19.5/100-person-years in the standard-intensity and higher intensity groups, respectively (adjusted HR 2.58, 95% confidence interval 1.28 to 5.18). Higher-intensity anticoagulation was significantly associated with any bleeding (adjusted HR 2.52, 95% confidence interval 1.27 to 5.00) and there were few thromboembolic events across both groups (5 events total). These results challenge current guideline recommendations for anticoagulation management of mechanical AVR in patients with additional risk factors.

Anti-factor IIa (FIIa) heparin assay for patients on direct factor Xa (FXa) inhibitors.

BACKGROUND: Direct factor Xa (FXa) inhibitors are increasingly prescribed for outpatients, and those transitioning to unfractionated heparin (UFH) for hospital admission are monitored via an anti-FXa assay. Because of assay interference, UFH results would often be critically elevated, confounding dosing. OBJECTIVES: An anti-factor IIa (FIIa) UFH assay was evaluated for clinical use. METHODS: The BIOPHEN ANTI-IIa (Aniara Diagnostica) assay and anti-FXa INNOVANCE Heparin assay (Siemens Healthcare Diagnostics Products GmbH) were compared on the Siemens BCS XP system. Samples included UFH controls and calibrators and specimens from patients transitioning from apixaban or rivaroxaban to UFH. Method comparison, linearity, recovery, precision, and interference by direct FXa inhibitors were evaluated. The effect of the BIOPHEN ANTI-IIa assay on the rate of critically high UFH results was retrospectively reviewed 4 months after implementation. RESULTS: Accuracy studies using 0.24 and 0.50 IU/mL UFH yielded means and standard deviations of 0.26 ± 0.01 and 0.58 ± 0.01 IU/mL, respectively. Within-run and between-run coefficients of variation were 4.6% and 15.5% for the low control, and 1.8% and 10.6% for the high control. The method comparison slope was 0.9965 (r2  = 0.9468). The linear range was 0.1 to 1.3 IU/mL. The assay measured UFH in the presence of 192 ng/mL apixaban or 158 ng/mL rivaroxaban. Introduction of the assay for clinical use reduced the monthly percentage of critically high results from 9.4% to 3.8% for admitted heparinized patients who recently discontinued apixaban or rivaroxaban. CONCLUSIONS: The BIOPHEN ANTI-IIa assay is suitable for patients transitioning off apixaban or rivaroxaban.

The real world use of combined P-glycoprotein and moderate CYP3A4 inhibitors with rivaroxaban or apixaban increases bleeding.

The use of direct oral anticoagulants for stroke prevention in atrial fibrillation continues to rise. Certain populations may be at higher risk for increased drug exposure and adverse events. Pharmacokinetic studies suggest increased exposure of rivaroxaban and apixaban with combined P-gp and moderate CYP3A4 inhibitors but the clinical relevance of this is unknown. This retrospective cohort study included patients receiving rivaroxaban or apixaban from January 1, 2012 to December 31, 2016 with a moderate inhibitor (amiodarone, dronedarone, diltiazem, verapamil) for at least 3 months in the drug-drug interaction (DDI) group. Propensity matching was used to identify similar control patients without the presence of the DDI. The primary outcome was a time to event analysis of any bleeding episode as defined by the International Society of Thrombosis and Hemostasis. After propensity matching, 213 patients with similar baseline characteristics were included in each group. The mean CHA2DS2-VASc score was 3.0 and median duration of follow-up was 1.45 years. The primary outcome occurred in 26.4% of patients in the DDI group and 18.4% in the control group (hazard ratio 1.8, 95% confidence interval [CI] 1.19 to 2.73; p-value = 0.006). There was no difference in bleeding rates based on type of inhibitor. Use of a combined P-gp and moderate CYP3A4 inhibitor with rivaroxaban or apixaban increased bleeding risk compared to patients without the DDI in this real world, retrospective study. Analysis in a larger patient population is needed to confirm these findings.

Impact of a Guideline for the Management of Antimicrobial/Warfarin Interactions in the Inpatient Setting and Across Transition of Care.

BACKGROUND: Drug-drug interactions (DDIs) with warfarin and antimicrobial agents are a common cause of international normalized ratio (INR) instability, which can affect the risk for bleeding and thrombotic events. OBJECTIVE: The purpose of this study was to assess the impact of a comprehensive guideline for the management of warfarin-antimicrobial DDIs across transitions of care. The guideline emphasizes improving identification of significant antimicrobial-warfarin DDIs during hospitalization, empirical warfarin dose modification based on DDI and baseline INR, patient education, documentation of the DDI, communication with outpatient providers regarding the DDI and anticipated antimicrobial stop date, and warfarin dose adjustment on discontinuation of antimicrobial. METHODS: This retrospective, single-center, quasiexperimental, pre-post study compared end points 3 months before and after guideline implementation. The primary outcome was time within therapeutic range (TTR). RESULTS: The study included 78 preguideline and 31 postguideline patients; baseline characteristics were similar between groups. Implementation of the guideline resulted in greater in-hospital TTR (72% vs 50%, P = 0.04) and improved TTR across transition of care (70% vs 46%, P = 0.01). Documentation of DDI in the pharmacy anticoagulation discharge summary significantly improved in the postguideline group (40% vs 14%, P = 0.02) and numerically improved within the daily pharmacy progress notes (94% vs 82%, P = 0.13). The implementation of the guideline was associated with a nonsignificant, numerical reduction in bleeding events compared with the preguideline group (0 vs 4 events, P = 0.11). CONCLUSION: This single-center approach to optimize the comprehensive management of significant antimicrobial-warfarin DDIs resulted in improved communication with outpatient providers and improved INR TTR.

Effects of Total Dose Infusion of Iron Intravenously in Patients With Acute Heart Failure and Anemia (Hemoglobin < 13 g/dl).

Iron deficiency is common in heart failure (HF), and intravenous (IV) iron therapy has been associated with improved clinical status in ambulatory patients with HF. There are limited data to support the safety and efficacy of IV iron administration in patients with acute HF. This was a retrospective cohort study of patients admitted to the University of Michigan Health System for HF with low iron studies during admission. Patients were grouped based on the receipt of IV iron therapy. Study outcomes included change in hemoglobin, 30-day readmission, and adverse events. Forty-four patients who received IV iron and 128 control patients were identified. The mean dose of IV iron received was 1,057 (±336) mg. IV iron resulted in a significantly greater increase in hemoglobin over time (p = 0.0001). The mean change in hemoglobin in the iron and control groups was 0.74 g/dl and 0.01 g/dl at day 7 and 2.61 g/dl and 0.23 g/dl at day 28, respectively. Thirty-day readmission rates were 30% and 22% for patients in the iron and control groups, respectively (p = 0.2787). In conclusion, total dose infusion IV iron is well tolerated and associated with significant improvement in hemoglobin in acute HF.

Emerging Therapies for Acute and Chronic Heart Failure: Hope or Hype?

Although the period from 1953 to 2001 resulted in the approval of more than 30 medications currently used to treat heart failure (HF), few novel drugs have been approved in the last decade. However, the investigational pipeline for HF medications once again appears promising. In patients with chronic heart failure with reduced ejection fraction (HFrEF), ivabradine and valsartan/sucubitril (LCZ696) were recently approved by the US Food and Drug Administration. Both agents have been shown to reduce the risk of cardiovascular death and HF hospitalization. In the treatment of acute HF, serelaxin and ularitide are the farthest along in development. Both agents have demonstrated favorable effects on surrogate end points and preliminary data suggest a possible mortality benefit with serelaxin. Consequently, phase 3 trials are ongoing to evaluate the effect of serelaxin and ularitide on clinical outcomes. Given the poor history of recent investigational acute HF drugs that have advanced to phase 3/4 studies, enthusiasm for both serelaxin and ularitide must be tempered until these trials are completed.