Pharmacokinetics of single-dose rivaroxaban under fed state in obese vs. non-obese subjects: An open-label controlled clinical trial (RIVOBESE-PK).

The evidence of rivaroxaban's pharmacokinetics in obese compared with non-obese populations remains inconclusive. We aimed to compare the pharmacokinetic profile of rivaroxaban between obese and non-obese populations under fed state. Participants who met the study's eligibility criteria were assigned into one of two groups: obese (body mass index ≥35 kg/m2) or non-obese (body mass index 18.5-24.9 kg/m2). A single dose of rivaroxaban 20 mg was orally administered to each participant. Nine blood samples over 48 h, and multiple urine samples over 18 h were collected and analyzed for rivaroxaban concentration using ultra-performance liquid chromatography coupled with tandem mass detector. Pharmacokinetic parameters were determined using WinNonlin software. Thirty-six participants were recruited into the study. No significant changes were observed between obese and non-obese participants in peak plasma concentration, time to reach peak plasma concentration, area under the plasma concentration-time curve over 48 h or to infinity, elimination rate constant, half-life, apparent volume of distribution, apparent clearance, and fraction of drug excreted unchanged in urine over 18 h. Rivaroxaban's exposure was similar between the obese and non-obese subjects, and there were no significant differences in other pharmacokinetic parameters between the two groups. These results suggest that dose adjustment for rivaroxaban is probably unwarranted in the obese population.

Trends in prescribing and outcomes in obese versus non-obese patients receiving rivaroxaban therapy: an observational study using real-world data.

PURPOSE: To investigate real-world prescribing trends and clinical outcomes based on body mass index (BMI) categorization in patients who received rivaroxaban therapy. METHODS: This was a retrospective cohort study involving all patients who received rivaroxaban therapy across all Hamad Medical Corporation (HMC) hospitals from 2015 to 2020. RESULTS: The number of patients initiated on rivaroxaban therapy significantly increased from 152 (3.3%) in 2015 to 1342 (28.9%) in 2020 (p <0.001). Within BMI categories, a similar increasing trend was observed in underweight, normal, and overweight patients, while from 2018 to 2020, there was a decreasing trend in rivaroxaban prescribing in all obese classes. The prevalence rate of all-cause mortality differed significantly between the BMI groups, with the highest mortality being among morbidly obese patients (BMI ≥ 40 kg/m2) (p< 0.001). On the other hand, no significant differences were found between the BMI groups in terms of bleeding, pulmonary embolism, deep vein thrombosis and stroke incidences. Multivariate logistic regression analyses showed that the likelihood of all-cause mortality was significantly higher in overweight and all categories of obese patients compared to underweight patients: overweight (OR: 5.3, 95% CI: 2.3-11.9, p< 0.001); obese class 1 (OR: 5.4, 95% CI: 2.3 - 12.2, p< 0.001); obese class 2 (OR: 6.5, 95% CI: 2.7 - 15.6, p< 0.001); and obese class 3 (OR: 3.7, 95% CI: 1.6 - 8.7, p = 0.003). CONCLUSIONS: Rivaroxaban prescribing has significantly increased over the years across general population, with a noticeable decline in obese population during the last few years (from 2018 onwards). Furthermore, an appreciable association was evident between all-cause mortality and BMI of these patients.

The impact of enteric coating of aspirin on aspirin responsiveness in patients with suspected or newly diagnosed ischemic stroke: prospective cohort study: results from the (ECASIS) study.

BACKGROUND AND PURPOSE: Uncertainty remains regarding the impact of enteric-coated aspirin (EC-ASA) on secondary prevention of ischemic stroke compared to plain aspirin (P-ASA). Hence, this study was designed to investigate the effect of EC formulation on ASA response via evaluating thromboxane B2 (TXB2) levels in patients with suspected or newly diagnosed stroke. METHODS: A prospective cohort study on suspected or newly diagnosed ischemic stroke patients who are aspirin-naive was conducted. Patients were received either EC aspirin or plain aspirin for at least 3 days. The primary outcome was the proportion of aspirin non-responsiveness between two groups (level of residual serum TXB2 associated with elevated thrombotic risk (< 99.0% inhibition or TXB2 > 3.1 ng/ml) within 72 h after three daily aspirin doses, while secondary outcomes were the incidence of early gastrointestinal tract (GIT) bleeding with the various aspirin preparations. (Trial registration: Clinicaltrials.gov NCT04330872 registered on 02 April 2020). RESULTS: Of 42 patients, ischemic strokes were confirmed in both P-ASA (81%) and EC-ASA (67%) arms. ASA non-responsiveness showed no significant difference between the two formulations (P-ASA vs. EC-ASA; 28.6% vs 23.8%; P = 0.726). Univariate and multivariate logistic regression analysis showed that patients treated with EC-ASA were more likely to have a lower rate of non-responders compared to P-ASA (unadjusted OR 0.78; 95% CI 0.20, 3.11); with the risk highest in type 2 diabetic patients with HBA1c > 6.5% (adjusted OR 6; 95% CI 1.02, 35.27; P = 0.047). No incidence of GIT bleeding observed throughout the study. CONCLUSION: A significant proportion of ASA non-responsiveness was recorded regardless of ASA formulation administered. The increased risk of ASA non-responsiveness in diabetic patients needs further exploration by larger prospective studies.

Perceptions and attitudes toward participation in clinical research in the Eastern Mediterranean Region: A systematic review.

INTRODUCTION: Successful recruitment of participants into clinical research has always been challenging and is affected by many factors. This systematic review aimed to explore the perceptions and attitudes as well as identify the factors affecting the participation in clinical research among the Eastern Mediterranean Regional Office countries' population. METHODS: A systematic search of the literature was conducted to explore attitudes or perceptions of the general public or patients towards participation in clinical research. PubMed, Pro-Quest Central, World Health Organizations Index Medicus for the Eastern Mediterranean Region, and Google Scholar were searched. Studies were considered eligible for inclusion if they presented primary data and were conducted in one of the Eastern Mediterranean Regional Office countries. A data extraction sheet was used to record the following: year, country, aim, population, sample size, study design, data collection, and setting. The identified factors from the included studies were categorized into motivators and barriers. RESULTS: In total, 23 original research articles were identified that addressed perceptions or attitudes towards clinical research participation. Six main motivators and barriers of research participation among patients, the general public, and patient family members were identified. The most common cited motivators included personal benefits to the individual, altruism and the desire to help others, the research process, the influence of the physician, family encouragement, and religion. Concerns regarding safety, confidentiality, and other factors in addition to the research process, lack of trust in healthcare providers or healthcare system, lack of interest in research and no perceived personal benefit, religious concerns, and family/cultural concerns were the most cited barriers to participation. CONCLUSION: The identified motivators and barriers are essential to tackle during clinical research planning among the population of Eastern Mediterranean Regional Office countries. Further research is needed to assess the attitudes and perceptions of individuals approached to participate in trials.

Treatment Failure of Cerebral Venous Thrombosis With Rivaroxaban: A Case Report and Narrative Review.

Direct oral anticoagulants (DOACs) are approved for the treatment and prevention of venous thromboembolism (VTE), with multiple advantages they offer over the older available anticoagulant drugs. Cerebral vein thrombosis (CVT) is an uncommon type of stroke that is usually associated with intracerebral hemorrhage (ICH), for which early anticoagulation is still recommended to prevent thrombus expansion, to facilitate recanalization, and to prevent the development of deep vein thrombosis (DVT) and pulmonary embolism (PE). DOACs' use for the treatment of CVT is an area of clinical equipoise, and hence it is still not recommended especially in the acute phase. This case report presents a patient who was on a therapeutic dose of rivaroxaban after an episode of CVT. He developed another CVT that was evident on an intracranial CT (CT) venogram. This was considered a therapeutic failure of DOACs, specifically rivaroxaban, in preventing the recurrence of CVT. Such observation might add to the existing yet scarce body of evidence regarding the use of DOACs in the anticoagulation management of CVT.

Thrombocytopenia Associated With Teicoplanin Use: A Retrospective Observational Study.

BACKGROUND: Contradictory studies reporting vast heterogeneity in the teicoplanin-induced thrombocytopenia (TIT) incidence exist. OBJECTIVE: To identify the incidence of TIT associated with teicoplanin dosing range (6-12 mg/kg/dose) and the risk factors of TIT. METHODS: This retrospective observational study included adult patients who received teicoplanin for ≥3 consecutive days over a period of 3.5 years. Thrombocytopenia was defined as a platelet count of <100 × 103/µL coupled with at least a 25% drop from the baseline count. The TIT incidence was assessed using the adverse drug reaction probability scale (Naranjo scale). RESULTS: Data from 482 patients who received teicoplanin and met the predefined inclusion criteria were included in the analyses. The cohort presented a mean age of 53.5 ± 19 years, where 72.4% were male, and 49.2% exhibited normal baseline renal function. Teicoplanin was most commonly used for bacteremia (n = 134), and the most common isolated pathogen being Staphylococcus aureus (n = 221). The TIT incidence was 4.6% (the possible and probable category using the Naranjo scale; 22/482). The median time to first platelet count dropped to <100 × 103/µL after teicoplanin initiation was 5 (interquartile range [IQR], 3-10) days and 8 (IQR, 5-14) days till the maximum platelet count dropped. None of the tested patient variables were found to be independently associated with an increased risk of thrombocytopenia. CONCLUSION AND RELEVANCE: The overall TIT incidence was low across our study cohort, including critically ill patients. Our study results may aid in the optimal monitoring of such serious teicoplanin-induced adverse effects.

Comparative effectiveness and safety of direct oral anticoagulants compared to warfarin in morbidly obese patients with acute venous thromboembolism: systematic review and a meta-analysis.

Direct oral anticoagulant (DOAC) agents are becoming the anticoagulation strategy of choice. However, their use in the treatment of acute venous thromboembolism (VTE) in morbidly obese patients (bodyweight of > 120 kg or BMI > 40 kg/m2) guarded. This is due to the scarce data supporting their use in this population. As a result, the International Society on Thrombosis and Haemostasis recommended against their use in this cohort of patients. New data emerged supporting the use of DOACs in these patients. Hence, we aimed to systematically review the literature exploring the efficacy and safety of these agents compared to warfarin in VTE treatment in morbidly obese patients. A systematic review of PubMed and EMBASE since inception until 01/04/2020. Subsequently, a non-inferiority (NI of 1.75) meta-analysis utilizing the random-effects model. Five observational studies (6585 patients) were included in our meta-analysis. DOAC analogs were non-inferior compared to warfarin in reducing the primary efficacy outcome of VTE recurrence (OR 1.07, 95% CI 0.93-1.23) and the primary safety outcome (major bleeding events) (OR 0.80, 95% CI 0.54-1.17). Our meta-analysis comprising real-world observational data concludes that the use of DOAC analogs in morbidly obese patients (bodyweight of > 120 kg or BMI > 40 kg/m2) is non-inferior with regards to efficacy and safety compared to warfarin. This finding helps to resolve the uncertainty associated with the use of DOACs in this cohort. Additionally, it invites for a confirmatory non-inferiority randomized controlled trial testing DOAC vs. Warfarin in this group of patients.

The experience of Hamad General Hospital collaborative anticoagulation clinic in Qatar during the COVID-19 pandemic.

Hamad General Hospital Anticoagulation Clinic is one of the largest collaborative-practice clinics of its type in Qatar. The patients being followed at this clinic are typically complex and vulnerable. During the coronavirus disease 2019 pandemic, measures were implemented at the clinic to minimize the exposure of patients and healthcare providers to the acute respiratory syndrome coronavirus-2 and to promote social distancing. These measures included extending INR-recall period, transitioning to direct oral anticoagulant drugs whenever feasible, home visits to elderly and immunocompromised patients for INR testing, establishing an anticoagulation hotline, and relocation of warfarin dispensing from the main pharmacy to the anticoagulation clinic. In addition, the clinic shifted its multidisciplinary team meetings onto an online platform using Microsoft Teams. Telehealth consultations were extensively utilized to closely follow up with the patients and ensure that anticoagulation efficacy and safety remained optimal. The aim of this paper is to share our experience and describe the measures adopted by the clinic as part of the Hamad Medical Corporation response to the emerging situation.

Avoidability of drug-induced liver injury (DILI) in an elderly hospital cohort with cases assessed for causality by the updated RUCAM score.

BACKGROUND: Drug-induced liver injury (DILI) represents an increasing morbidity in the general population, but more so in the elderly cohort of patients. Despite this, the concept of its prevention through prospective analysis has largely remained unexamined. We evaluated the utility of recently validated adverse drug reactions (ADR) avoidability tool in a cohort of elderly patients with DILI. METHODS: We examined 38 DILI-drug pairs from n=38 patients in a prospective cohort of patients presenting with adverse drug reactions to a Weill Cornell-affiliated tertiary hospital between February 2019 and January 2020. DILI outcomes were adjudicated by the updated Roussel Uclaf Causality Assessment Method (RUCAM). Two clinical pharmacologists and two general physicians utilized the Liverpool adverse drug reactions avoidability tool (LAAT) and the modified Hallas tools to rate the preventability of DILI-drug pairs. Inter-rater, exact agreement proportions, as well as intraclass correlation coefficients were generated and expressed as ordinal outcomes. RESULTS: The cases examined for the determination of DILI avoidability had probability likelihood of "probable" or "highly probable" by the updated RUCAM scale. Examination of the 38 DILI-drug pairs (n= 38 patients) resulted in a total of 152 ordinal outcome decisions. We found about 32.3% (50/152) and 34.2% (52/152) of DILI-drug pairs were rated as "avoidable" ("probable" or "definite") by the LAAT and the modified Hallas tools respectively. The overall median Krippendorf's kappa with the LAAT was 0.61 (SE 0.12, CI 0.36, 0.85) and for modified Hallas tool was 0.53 (SE 0.18; CI 0.16, 0.89). The inter-rater correlation coefficient (ICC) for the LAAT and modified Hallas were 0.50 [0.32, 0.65] and 0.63 [0.48, 0.76] respectively. Exact pairwise agreement was present in 30/38 (IQR 29.5, 34.5), and 28/38 (IQR 27.5-35.5) of DILI-ADR pairs using the LAAT and modified Hallas tools respectively. CONCLUSION: We found a significant proportion of drug-induced liver injury adjudicated by the updated RUCAM scale in elderly hospitalized cohort of patients were avoidable with significant implication for therapeutic commissioning as well as cost effectiveness interventions in this cohort of patients.

An investigation into the impact of enteric coated of aspirin in patients with newly diagnosed ischemic stroke (ECASIS).

INTRODUCTION: Uncertainty remains regarding the impact of enteric-coated (EC) aspirin as it relates to the reduction of cardiovascular risk. We hypothesize that EC formulation based on a previous report may blunt aspirin response as evidenced by reduced Thromboxane A2 (TXA 2) levels in diabetic patients. Thus, it was imperative to ascertain and validate the effect of the EC formulation of Aspirin on the Thromboxane B2 (TXB2) level. METHODS/DESIGN: An open-label consecutive randomized interventional controlled trial. Patients with newly diagnosed ischemic stroke who are just about to start Aspirin were assessed for eligibility and inclusion in our trial. Consecutive patients (admitted to the stroke unit of Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar) will be randomized to receive either EC aspirin or plain Aspirin. They will be required to continue taking them throughout the study (3 days). Demographics and laboratory records of the study participants will be abstracted from online records. Further study variables will be obtained manually in designated case record forms (CRF). The primary outcomes are the incidence of aspirin non-responders (level of residual serum TXB2 associated with elevated thrombotic risk (<99.0% inhibition or TXB2 >3.1 ng/mL) within 72 h after three daily aspirin doses). Whereas secondary outcomes are the incidence of GIT bleeding of various preparations of Aspirin. The study was approved by MRC and IRB of Hamad Medical Corporation (MRC number: 01-18-156). DISCUSSION: This trial will determine potential differences in the efficacy of EC Aspirin and plain Aspirin on the Thromboxane B2 level. Additionally, it will ascertain the tolerability and safety of both formulations of Aspirin in patients with newly diagnosed ischemic stroke. These results will either support the current notion of no difference between the two formulations. However, if a difference is found, this will invite for future trials exploring clinical outcomes occurrence between various formulations. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT04330872 registered on April 2, 2020.

An investigation into the avoidability of adverse drug reactions using the LAAT and modified Hallas tools.

An adverse drug reactions avoidability tool called the Liverpool ADR avoidability assessment tool (LAAT) was recently developed (for research purposes), and subsequently validated with mixed interrater reliability (IRR). We investigated the comparative IRR of this tool in an inpatient cohort to ascertain its practical application in this setting.The patient population was comprised of 44 ADR drug pairs drawn from an observational prospective cohort of patents with ADR attending a Weill Cornell Medicine-affiliated tertiary medical Centre in Doha Qatar (Hamad General Hospital). Using the LAAT, and modified Hallas tools, 4 independent raters (2 Clinical Pharmacologists, and 2 General Physicians) assessed and scored the 44 ADR-drug pairs. Agreement proportions between the rating pairs were evaluated as well individual/overall kappa statistics and intraclass correlation coefficients. We evaluated the weight of each of the 7 questions on the LAAT tool to ascertain its determinative role.Across 44 ADR-drug pairs, the overall median Fleiss kappa using the LAAT, and modified Hallas tools were 0.67 (interquartile range (IQR) 0.55, 0.76), 0.36 (IQR, 0.23-0.71) respectively. The overall percentage pairwise agreement with the LAAT and modified Hallas tools were 78.5%, and 62.2% respectively. Exact pairwise agreement occurred in 37 out of 44 (range 0.71-1), and 27 of 44 (0.53-0.77) ADR-drug pairs using the LAAT and modified Hallas tools respectively. Using the LAAT tool, the overall intraclass correlation coefficient was 0.68 (CI 0.55, 0.79), and 0.37 (CI 0.22, 0.53) with the modified Hallas tool.We report a higher proportion of "possible" and "definite" avoidability outcomes of adverse drug reactions compared with the modified Hallas, or that reported by developers of the LAAT tool. Although initially developed for research purposes, our report has suggested for the first time a potential applicability of this tool in clinical environment as well.

Blood glucose control for patients with acute coronary syndromes in Qatar.

BACKGROUND: Blood glucose is known to be elevated in patients presenting with acute coronary syndromes. However a gap in knowledge exists regarding effective management strategies once admitted to acute care units. It is also unknown what factors (if any) predict elevated glucose values during initial presentation. OBJECTIVES: OBJECTIVES of the study were to characterize blood glucose control in patients admitted to the cardiac care unit (CCU) in Qatar and to determine predictive factors associated with high glucose levels (>10 mmol/l) on admission to the CCU. SETTING: All data for this study were obtained from the CCU at Heart Hospital in Doha, Qatar. METHOD: A retrospective chart review was completed for patients admitted to the CCU in Qatar from October 1st, 2012 to March 31st, 2013, of which 283 were included. Baseline characteristics (age, gender, nationality, medical history, smoking status, type of acute coronary syndrome), capillary and lab blood glucose measurements, and use of insulin were extracted. Time spent in glucose ranges of <4, 4 to <8, 8 to <10, and >10 mmol/1 was calculated manually. Univariate and multivariate logistic regression were performed to assess factors associated with high glucose on admission. The primary analysis was completed with capillary data and a sensitivity analysis was completed using laboratory data. MAIN OUTCOME MEASURE: Blood glucose values measured on admission and throughout length of stay in the CCU. RESULTS: Capillary blood glucose data showed majority of time was spent in the range of >10 mmol/l (41.95%), followed by 4-8 mmol/l (35.44%), then 8-10 mmol/l (21.45%), and finally <4 mmol/l (1.16%). As a sensitivity analysis, laboratory data showed very similar findings. Diabetes, hypertension, and non-smoker status predicted glucose values >10 mmol/l on admission (p < 0.05) in a univariate analysis but only diabetes remained significant in a multivariate model (OR 23.3; 95% CI, 11.5-47.3). CONCLUSION: Diabetes predicts high glucose values on hospital admission for patients with ACS and patients are not being adequately controlled throughout CCU stay.