Preventability of serious thromboembolic and bleeding events related to the use of oral anticoagulants: a prospective study.

AIMS: To determine the preventability of serious adverse drug reactions (ADRs) related to the use of direct oral anticoagulants (DOACs), and to explore contributing factors to preventable ADRs. Results were compared with vitamin K antagonists (VKAs). METHODS: We conducted a prospective observational study in the emergency departments of two teaching hospitals from July 2015 to January 2016. Patients admitted with a thrombotic or bleeding event while under DOAC or VKA were included. Four independent reviewers assessed causality, seriousness and preventability of ADRs using pilot-tested scales. For cases of serious and potentially preventable ADRs, we performed semi-structured interviews with general practitioners to identify contributing factors to ADRs. The primary outcome was the proportion of serious ADRs that were potentially preventable. RESULTS: The analysis included 46 DOAC and 43 VKA patients (median age 79 years). Gastrointestinal (n = 34) and intracranial (n = 16) bleedings were the most frequent ADRs. Results were that 53% of DOAC- and 61% of VKA-related serious ADRs were deemed potentially preventable. Prescribing issues and inadequate monitoring were frequent for DOAC and VKA respectively. We identified many causes of preventable ADRs that applied to all oral anticoagulants, such as pharmacodynamic drug interactions and lack of communication. CONCLUSIONS: More than half of serious ADRs were potentially preventable for both DOACs and VKAs. Interventions focusing on prescribing, patient education and continuity of care should help improve the use of DOACs in practice.

Rivaroxaban plasma levels in patients admitted for bleeding events: insights from a prospective study.

BACKGROUND: Serious bleeding events have been frequently described in patients taking direct oral anticoagulants (DOAC). In secondary analyses of phase 3 trials, DOAC plasma concentrations were shown to correlate with bleeding outcomes. This study aimed to describe rivaroxaban plasma levels in patients admitted to the emergency department (ED) for bleeding events. For each patient, risk factors for experiencing bleeding events were also investigated. METHODS: This analysis was part of an observational study conducted in the ED of two teaching hospitals. Plasma samples from 10 rivaroxaban-treated patients admitted for bleeding events were collected. Rivaroxaban plasma concentrations were determined by calibrated chromogenic anti-Xa assay. The measured rivaroxaban levels were then extrapolated at trough using a published population pharmacokinetic (PopPK) model, and compared to on-therapy ranges observed in large clinical trials. For each patient, clinical, medication and ABCB1 genotype data were collected. RESULTS: Rivaroxaban measurements varied from 5 to 358 ng/ml, with a post-intake delay ranging from 9 to 38 h. At trough, estimated plasma concentrations were between 12 and 251 ng/ml (median value 94 ng/ml). Four patients had higher-than-expected rivaroxaban levels. Inadequate dose regimen, excessive alcohol consumption and lack of treatment reassessment were observed in several patients. Half of patients were taking ≥1 drug with potential pharmacokinetics interactions (e.g. amiodarone, diltiazem), while half of patients were taking ≥1 drug increasing the risk of bleeding. All 3 patients with available genotyping data and higher-than-expected rivaroxaban levels were heterozygous or homozygous mutated for the ABCB1 1236C > T, 2677G > T, 3435 C > T and rs4148738 single nucleotide polymorphisms (SNP). CONCLUSIONS: Rivaroxaban patients admitted to the ED for bleeding events showed highly variable plasma concentrations. This analysis underlines the usefulness of rapid DOAC measurement and the value of PopPK models to estimate concentrations at trough in a context where the post-intake delay is unmanageable. Close patient follow-up, including renal function assessment and drug interactions review, is essential for bleeding risk minimization.

Appropriateness of prescribing dabigatran etexilate and rivaroxaban in patients with nonvalvular atrial fibrillation: a prospective study.

BACKGROUND: Direct oral anticoagulants have been developed to address some of the drawbacks of vitamin-K antagonists. However, special attention should be given when using these drugs, especially in patients with renal insufficiency, questionable compliance, and those at high risk of bleeding. OBJECTIVE: To evaluate the appropriateness of prescribing dabigatran etexilate (DE) and rivaroxaban in patients with nonvalvular atrial fibrillation (NVAF) in real-life clinical practice. METHODS: This was a prospective study that included patients presenting to a teaching hospital from April to mid-October 2013, who were taking rivaroxaban or DE for NVAF. Appropriateness of prescribing was evaluated using 9 of the 10 criteria of the Medication Appropriateness Index. The primary outcome measure was the prevalence of inappropriate prescribing. Secondary outcome measures included (a) categories of inappropriateness, (b) prevalence of adverse drug events, and (c) interventions made by a clinical pharmacist to optimize prescribing. RESULTS: A total of 69 patients were evaluated; 16 patients (23%) had 1 inappropriate criterion, and an additional 18 (26%) had more than 1 inappropriate criterion. The most frequent inappropriate criteria were inappropriate choice (28% of patients), wrong dosage (26%), and impractical modalities of administration (26%). An adverse event (AE) was found in 51% of patients (including 8 patients with transient ischemic attack/stroke). The clinical pharmacists performed 48 interventions, and 94% were accepted by the physician. CONCLUSIONS: Inappropriate use of DE and rivaroxaban in patients with NVAF is frequent and possibly leads to AEs. Reinforcing education of health care professionals and patients is needed. Collaboration with clinical pharmacists can contribute to better use.

Uninterrupted DOACs Approach for Catheter Ablation of Atrial Fibrillation: Do DOACs Levels Matter?

Most patients present for catheter ablation of atrial fibrillation (CAAF) with residual or full effect of vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs). In daily practice, it has been observed that the activated clotting time (ACT) was actually poorly sensitive to the effect of DOACs and that patients on DOACs required more unfractionated heparin (UFH) to achieve the ACT target of 300 s during the procedure, leading some authors to worry about potential overdosing. Conversely, we hypothesize that these higher doses of UFH are necessary to achieve adequate hemostasis during CAAF regardless of the residual effect of DOACs. During CAAF, thrombosis is promoted mainly by the presence of thrombogenic sheaths and catheters in the bloodstream. Preclinical data suggest that only high doses of DOACs are able to mitigate catheter-induced thrombin generation, whereas low dose UFH already do so. In addition, the effect of UFH seems to be lower in patients on DOACs, compared to patients on VKAs, explaining part of the differences observed in heparin requirements. Clinical studies could not identify increased bleeding risk in patients on DOACs compared to those on VKAs despite similar efficacy during CAAF procedures. Moreover, targeting a lower ACT was associated with an increased periprocedural thrombotic risk for both DOAC and VKA patients. Therefore, the low sensitivity of the ACT to the residual effect of DOACs should not be a major concern in its use in the interventional cardiology laboratory.

The Impact of Strong Inducers on Direct Oral Anticoagulant Levels.

PURPOSE: The concomitant use of direct oral anticoagulants (DOAC) and strong P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) inducers may lead to reduced DOAC levels and therapeutic failure. This study aimed to describe DOAC concentrations in patients receiving strong P-gp and CYP3A4 inducers, in relation to individual risk factors for high or low DOAC levels. METHODS: We retrospectively identified hospitalized patients simultaneously receiving a DOAC and carbamazepine, phenobarbital, phenytoin, or rifampicin between 2016 and 2021. Among them, patients who underwent DOAC measurement at steady state were included. DOAC peak or trough levels were compared with on-therapy ranges observed in pivotal trials. Individual risk factors for high or low DOAC levels were identified. RESULTS: We included 17 patients (median age 75 years), mainly receiving apixaban and carbamazepine. For 5 patients (29%), DOAC trough or peak level was below the expected range. Among the remaining 12 patients, 8 had at least one measurement in the lower quartile of the range. The median number of risk factors for drug accumulation was 0 (range 0-1) in patients with ≥1 measurement below the range and 2 (range 0-3) in other patients. DOAC measurement led to treatment adjustments in 9 patients (DOAC dose increase or switch). CONCLUSION: Our data suggest a significant risk of reduced DOAC levels in patients taking strong P-gp and CYP3A4 inducers, especially those without risk factors for drug accumulation. DOAC measurement could help manage this relevant drug-drug interaction.

Do computerized clinical decision support systems improve the prescribing of oral anticoagulants? A systematic review.

BACKGROUND: Serious adverse drug reactions have been associated with the underuse or the misuse of oral anticoagulant therapy. We systematically reviewed the impact of computerized clinical decision support systems (CDSS) on the prescribing of oral anticoagulants and we described CDSS features associated with success or failure. METHODS: We searched Medline, Embase, CENTRAL, CINHAL, and PsycINFO for studies that compared CDSS for the initiation or monitoring of oral anticoagulants with routine care. Two reviewers performed study selection, data collection, and risk-of-bias assessment. Disagreements were resolved with a third reviewer. Potentially important CDSS features, identified from previous literature, were evaluated. RESULTS: Sixteen studies were included in our qualitative synthesis. Most trials were performed in primary care (n = 7) or hospitals (n = 6) and included atrial fibrillation (AF) patients (n = 9). Recommendations mainly focused on anticoagulation underuse (n = 11) and warfarin-drug interactions (n = 5). Most CDSS were integrated in electronic records or prescribing and provided support automatically at the time and location of decision-making. Significant improvements in practitioner performance were found in 9 out of 16 studies, while clinical outcomes were poorly reported. CDSS features seemed slightly more common in studies that demonstrated improvement. CONCLUSIONS: CDSS might positively impact the use of oral anticoagulants in AF patients at high risk of stroke. The scope of CDSS should now evolve to assist prescribers in selecting the most appropriate and tailored medication. Efforts should nevertheless be made to improve the relevance of notifications and to address implementation outcomes.

Medication Counselling in Older Patients Prior to Hospital Discharge: A Systematic Review.

BACKGROUND: Older patients are regularly exposed to multiple medication changes during a hospital stay and are more likely to experience problems understanding these changes. Medication counselling is often proposed as an important component of seamless care to ensure appropriate medication use after hospital discharge. OBJECTIVES: The purpose of this systematic review was to describe the components of medication counselling in older patients (aged ≥ 65 years) prior to hospital discharge and to review the effectiveness of such counselling on reported clinical outcomes. METHODS: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology (PROSPERO CRD42019116036), a systematic search of MEDLINE, EMBASE and CINAHL was conducted. The QualSyst Assessment Tool was used to assess bias. The impact of medication counselling on different outcomes was described and stratified by intervention content. RESULTS: Twenty-nine studies were included. Fifteen different components of medication counselling were identified. Discussing the dose and dosage of patients' medications (19/29; 65.5%), providing a paper-based medication list (19/29; 65.5%) and explaining the indications of the prescribed medications (17/29; 58.6%) were the most frequently encountered components during the counselling session. Twelve different clinical outcomes were investigated in the 29 studies. A positive effect of medication counselling on medication adherence and medication knowledge was found more frequently, compared to its impact on hard outcomes such as hospital readmissions and mortality. Yet, evidence remains inconclusive regarding clinical benefit, owing to study design heterogeneity and different intervention components. Statistically significant results were more frequently observed when counselling was provided as part of a comprehensive intervention before discharge. CONCLUSIONS: Substantial heterogeneity between the included studies was found for the components of medication counselling and the reported outcomes. Study findings suggest that medication counselling should be part of multifaceted interventions, but the evidence concerning clinical outcomes remains inconclusive.

Assessment of low plasma concentrations of apixaban in the periprocedural setting.

INTRODUCTION: Estimation of residual apixaban plasma concentrations may be requested in the management of emergencies. This study aims at assessing the performance of specific anti-Xa assays calibrated with apixaban on real-life samples with low apixaban plasma concentrations (<30 ng/mL) and on-treatment ranges, with and without interference of low-molecular-weight heparin (LMWH). METHODS: The performance of the STA® -Liquid Anti-Xa assay (STA® LAX) and the low and normal procedures of the Biophen® Direct Factor Xa Inhibitors (DiXaI) assay was tested on 134 blood samples, collected from patients on apixaban, wherefrom 74 patients received LMWH after apixaban cessation. The results were compared with the liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) measurements. RESULTS: The Biophen® DiXaI, Biophen® DiXaI LOW, and STA® LAX showed very good correlation with LC-MS/MS measurements in patients without LMWH administration (Spearman r .95, .99, and .98, respectively). Their limits of quantitation were defined at 48, 24, and 12 ng/mL, respectively. The Bland-Altman test measured mean bias (SD) at 5.6 (13.1), -2.5 (5.0), and -0.8 (6.1) ng/ml, respectively. The Spearman r of the Biophen® DiXaI decreased to 0.64 in presence of low apixaban concentrations. The Spearman r of the Biophen® DiXaI LOW and STA® LAX decreased to 0.39 and 0.26, respectively, in presence of LMWH. CONCLUSIONS: The accuracy of the low methodologies (Biophen® DiXaI LOW and STA® LAX) is slightly improved for low apixaban plasma concentrations, compared with the normal procedure of Biophen® DiXaI. The interference of LMWH on the low methodologies is measurable, however, less important than the previously reported interference of LMWH on rivaroxaban calibrated specific anti-Xa assays.

Glucose-regulated protein of 94 kDa contributes to the development of an aggressive phenotype in breast cancer cells.

Grp94 plays an essential role in protein assembly. We previously suggested that Grp94 overexpression is involved in tumor aggressiveness. However, the underlying mechanisms remain unknown. Since many tumors display high Grp94 levels, we investigated the effects of tumor microenvironment on the regulation of this chaperone expression. First, we found out that hypoxia did not change Grp94 expression in the human tumor cell lines MCF-7 (breast cancer) and HepG2 (liver cancer). Second, glucose deprivation significantly increased Grp94 protein levels. Subsequently, we focused in the putative role of Grp94 in the acquisition of an aggressive phenotype by cancer cells. Using a more aggressive cancer cell model (MDA-MB-231 breast tumor cells), we found out that Grp94 knockdown using siRNA decreased the invasive capacity of cancer cells. Moreover, cells with decreased Grp94 levels displayed an enhanced sensitivity of tumor cells to doxorubicin, a standard drug in the treatment of breast cancer. Taken together, our results suggest that the expression of Grp94 is linked to tumor aggressiveness. Therefore, targeting Grp94 could be an effective way to inhibit tumor growth improving chemotherapy outcome.

Implementing a screening tool to improve prescribing in hospitalized older patients: a pilot study.

Background The use of STOPP-START criteria during hospitalization reduced inappropriate medications in randomized controlled trials. Objective To evaluate whether the implementation of a screening tool (short version of STOPP-START criteria) in routine geriatric practice reduces potentially inappropriate medications (PIM) and potential prescribing omissions (PPO) at discharge. Methods We conducted a retrospective interrupted time series analysis. Four periods were selected between February and September 2013: (1) baseline situation; (2) screening tool made available to physicians; (3) 3 months later; (4) weekly meetings with junior doctors and a clinical pharmacist to review treatments according to the tool. The primary outcome was the proportion of patients with prescribing improvement from admission to discharge. Results We included 120 patients (median age 85 years). The prevalence of PIMs and PPOs on admission was 56% (67/120) and 51% (61/120) respectively. Hospitalization improved prescribing appropriateness in 49% of patients with PIMs (33/67) and 39% of patients with PPOs (24/61). The use of the screening tool by way of multidisciplinary meetings was a predictor of PIMs reduction at discharge. Conclusions The sole distribution of a screening tool in a geriatric unit did not reduce PIMs and PPOs. Multidisciplinary meetings to review treatments should be encouraged.

Effect of ABCB1 genetic polymorphisms on the transport of rivaroxaban in HEK293 recombinant cell lines.

Direct oral anticoagulants (DOAC) are substrates for the ABCB1 transporter (also called P-glycoprotein), an active efflux pump. ABCB1 polymorphisms have been previously reported to influence the pharmacokinetics of several drugs such as immunosuppressants and tyrosine kinase inhibitors. Recently, in vivo studies have suggested that genetic variants might contribute to the inter-individual variability in DOAC plasma concentrations. Therefore, we evaluated the in vitro effect of the most common coding ABCB1 single nucleotide polymorphisms (SNP), 1236 C > T-2677G > T-3435C > T, and the coding ABCB1 1199 G > A SNP on the transport activity towards rivaroxaban. HEK293 cells were transfected to overexpress the ABCB1 wild-type (1236C-2677G-3435C, 1199 G) or variant proteins (1236C-2677G-3435T, 1236T-2677T-3435T or 1199 A). ABCB1 expression decreased the intracellular accumulation of rivaroxaban, when compared to control cells. This confirms the involvement of ABCB1 in the active transport of rivaroxaban. However, the ABCB1 1236 C > T-2677G > T-3435C > T and 1199 G > A SNPs had no significant influence on the intracellular accumulation of rivaroxaban when compared to the wild-type protein. These results suggest that the ABCB1 coding SNPs investigated in the present study are unlikely to contribute to the inter-individual variability in rivaroxaban plasma concentrations.

An optimized dRVVT-based assay to estimate the intensity of anticoagulation in patients treated with direct oral anticoagulants.

BACKGROUND: The dilute Russell's viper venom time (dRVVT) has been suggested for the assessment of the intensity of anticoagulation of all direct oral anticoagulants (DOACs). This study aimed to compare the performance of an optimized liquid-stable dRVVT-based DOAC assay (DRVV-DOAC) on clinical samples before and after mixing these with normal pooled plasma (NPP). METHODS: Forty-one apixaban, 25 dabigatran, 56 rivaroxaban and 49 vitamin K antagonists (VKAs) plasma samples were included for retrospective analysis. Plasma DOAC concentrations were determined by liquid chromatography coupled with tandem mass-spectrometry. INR was determined for all VKA samples. DRVV-DOAC was performed with an original ready-to-use reagent (Haematex Research™) where plasma samples were tested neat and in a 1:1 mix with NPP. RESULTS: Plasma concentrations ranged from 1 to 406ng/ml for apixaban, 0 to 386ng/ml for dabigatran and 0 to 719ng/ml for rivaroxaban. INR ranged from 2.2 to 6.1. DRVV-DOAC correlated well with plasma concentrations (r2=0.70, 0.94, 0.63 (non-mixed procedure) and 0.77, 0.97, 0.86 (mixed procedure) for apixaban, dabigatran and rivaroxaban, respectively). DRVV-DOAC measurements in the normal range ruled out dabigatran and rivaroxaban concentrations above 30 and 50ng/ml, but performance was lower for apixaban. DRVV-DOAC was sensitive to VKA samples but poorly reflected INR values. When VKA samples were mixed with NPP, DRVV-DOAC measurements decreased to values close to baseline clotting time. CONCLUSIONS: DRVV-DOAC is a quick method which showed increased sensitivity compared with other phospholipid-rich dRVVT reagents already investigated. Mixing samples with NPP improved the specificity but reduced sensitivity, especially for apixaban.

Does the Russell Viper Venom time test provide a rapid estimation of the intensity of oral anticoagulation? A cohort study.

BACKGROUND: Dilute Russell Viper Venom Time (DRVV-T) might be useful in urgent settings for screening patients on Non-VKA Oral Anticoagulants (NOACs). AIM: To compare the accuracy of DRVV-T with gold standard assays for the assessment of pharmacodynamics of dabigatran, rivaroxaban and vitamin K antagonist (VKA) in plasma samples from patients. METHODS: Sixty rivaroxaban, 48 dabigatran and 50 VKA samples from patients were included. DRVV-T was performed in all groups using STA®-Staclot®DRVV-Screen and -Confirm. For NOACs, PT and aPTT were performed using different reagents while plasma drug concentrations were measured by liquid mass-spectrometry (LC-MS/MS). For VKA, INR was performed using RecombiPlasTin 2G®. RESULTS: For NOACs, correlations between calibrated STA®-Staclot®DRVV-Confirm and LC-MS/MS (rs=0.88 and 0.97 for rivaroxaban and dabigatran, respectively) were higher than the ones obtained with STA®-Staclot®DRVV-Screen (rs=0.87 and 0.91), PT (rs=0.83 to 0.86) or aPTT (rs=0.84 to 0.89). Bland Altman analyses showed that calibrated DRVV-T methods tend to overestimate plasma concentrations of NOACs. ROC curves revealed that cut-off to exclude supra-therapeutic levels at Ctrough (i.e. 200ng/mL) are different for dabigatran and rivaroxaban. Neither STA®-Staclot®DRVV-Screen nor -Confirm correlated sufficiently with the intensity of VKA therapy (rs=0.35 and 0.52). CONCLUSIONS: STA®-Staclot®DRVV-Confirm provides a rapid estimation of the intensity of anticoagulation with rivaroxaban or dabigatran without specific calibrators. At Ctrough, thresholds for rivaroxaban and dabigatran can be used to identify supra-therapeutic plasma level. However, this test cannot differentiate the nature of the NOACs. The development of a point-of-care device optimising this method would be of particular interest in emergency situations.