Clinical versus fixed warfarin dosing and the impact on quality of anticoagulation (The ClinFix trial).

Different dosing strategies exist to initiate warfarin, most commonly fixed warfarin dosing (FWD), clinical warfarin dosing (CWD), and genetic-guided warfarin dosing (GWD). Landmark trials have shown GWD to be superior when compared to FWD in the EU-PACT trial or CWD in the GIFT trial. COAG trial did not show differences between GWD and CWD. We aim to compare the anticoagulation quality outcomes of CWD and FWD. This is a prospective cohort study with a retrospective comparator. Recruited subjects in the CWD (prospective) arm were initiated on warfarin according to the clinical dosing component of the algorithm published in www.warfarindosing.org. The primary efficacy outcome was the percentage time in the therapeutic range (PTTR) from day 3 to 6 till day 28 to 35. The study enrolled 122 and 123 patients in the CWD and FWD, respectively. The PTTR did not differ statistically between CWD and FWD (62.2 ± 26.2% vs. 58 ± 25.4%, p = 0.2). There was also no difference between both arms in the percentage of visits with extreme subtherapeutic international normalized ratio (INR) (<1.5; 15 ± 18.3% vs. 16.8 ± 19.1%, p = 0.44) or extreme supratherapeutic INR (>4; 7.7 ± 14.7% vs. 7.5 ± 12.4%, p = 0.92). We conclude that CWD did not improve the anticoagulation quality parameters compared to the FWD method.

Comparative Effectiveness and Safety of Direct Oral Anticoagulants Compared with Warfarin in Patients with Low Bodyweight who have Atrial Fibrillation: A Systematic Review and Meta-analysis.

INTRODUCTION: oral anticoagulant (DOAC) agents are becoming the anticoagulation strategy of choice for most clinical risks for which they are indicated. However, residual uncertainty remains regarding their use in preventing stroke in patients with low bodyweight [< 60 kg or body mass index (BMI) < 18 kg/m2]. We have carried out pooled systematic analyses of published studies to determine the efficacy and safety of these agents compared with warfarin in stroke prevention in patients with low bodyweight. METHODS: We carried out a comprehensive search of electronic databases from inception to June 2023 for eligible studies reporting on the efficacy and safety of direct oral anticoagulants versus warfarin in patients with atrial fibrillation who had low bodyweight. These include PubMed, EMBASE, the Cochrane Database of Systematic Reviews, the Science Citation Index, and the Database of Abstracts of Reviews of Effectiveness. Using the random effects model, derived pooled odd ratios (with their corresponding confidence intervals) of mortality outcomes in patient cohorts exposed to direct oral anticoagulants versus warfarin in patients with atrial fibrillation who had low bodyweight. RESULTS: Nine studies (n = 159,514 patients) were included in our meta-analysis. DOAC analogs were associated with lower stroke recurrence compared with warfarin [odds ratio (OR) 0.66, 95% confidence interval (CI) 0.49-0.9]; however, there was no significant difference in the composite outcome (OR 0.81, 95% CI 0.59-1.09) and mortality (OR 0.82, 95% CI 0.48-1.41). Additionally, DOAC analogs showed a significant reduction in major bleeding events by 30% compared with warfarin (OR 0.70, 95% CI 0.62-0.80). CONCLUSION: In this pooled meta-analytical synthesis of studies comprising both real-world and randomized controlled data, the use of DOAC analogs in patients with atrial fibrillation and low bodyweight (< 60 kg or BMI < 18 kg/m2) was associated with a significant reduction in risks of stroke and major bleeding compared with patient cohorts stabilized on warfarin-based therapy. There was uncertainty regarding the composite outcome and mortality point estimate between these two anticoagulation strategies. This finding helps to resolve the uncertainty associated with the use of DOACs in this cohort. Additionally, it suggests the need for confirmatory non-inferiority randomized controlled trials evaluating DOACs versus warfarin in this cohort of patients.

Comparative Effectiveness and Safety of Direct Oral Anticoagulants in Low Body Weight Patients with Atrial Fibrillation: A Systematic Review and Meta-analysis.

INTRODUCTION: Direct oral anticoagulant (DOAC) agents are established as the anticoagulation strategy of choice for a variety of clinical risks. Despite this, uncertainty still exists with regard to their efficacy and safety for the prevention of stroke and systemic embolism in some patient populations; most notably those with low body weight (LBW) (<60 kg or body mass index [BMI] <18 kg/m2). Currently, there is a paucity of trial and non-trial data to support a prescriptive recommendation for their use in these patient cohorts. We have carried out a pooled systematic review of the most up to date published data of patients stabilized on various DOAC analogs with the view to ascertaining the exact matrices of their efficacy and safety in these cohorts of patients. METHODS: We initially carried out a comprehensive search of databases from inception to June 2023 for eligible studies exploring the efficacy and safety of various analogs of direct oral anticoagulants in patients with atrial fibrillation who had low body weight. Databases accessed include PubMed, EMBASE, the Science Citation Index, the Cochrane Database of Systematic Reviews, and the Database of Abstracts of Reviews of Effectiveness. We carried out a weighted comparison of derived pooled odd ratios (with their corresponding confidence intervals) of mortality outcomes between various DOACs using the random effects model. RESULTS: Thirteen studies (n = 165,205 patients) were included in our meta-analysis. DOAC analogs were associated with increased stroke-related events, composite outcome, and mortality in low body weight patients compared to non-low body weight patients (odds ratio [OR] 1.50, 95% confidence interval [CI] 1.17-1.92), (OR 1.55, 95% CI 1.29-1.86), (OR 2.92, 95% CI 1.87-4.58), respectively. There was no significant difference in the safety outcome (major bleeding events) between the DOAC analogs (OR 1.19, 95% CI 0.93-1.52). DISCUSSION: In this meta-analytical review comprising both real-world and randomized controlled studies, the use of DOAC analogs in low body weight patients (body weight of <60 kg or BMI<18 kg/m2) with atrial fibrillation was associated with increased risks of stroke-related events, composite outcomes, and mortality compared to non-low body weight cohorts patients. At the same time, there was no significant difference in terms of major bleeding events. This finding has provided the first resolution of pervading uncertainty surrounding the use of DOAC analogs in these patient cohorts and suggests the need for follow-up confirmatory systematic studies in this group of patients.

Seroconversion and safety of Covid-19 vaccines in pa-tients with chronic liver disease and liver transplant: A systematic review.

BACKGROUND AND AIMS: As part of the COVID-19 control strategy, a growing number of vaccine portfolios evolved and got fast-tracked through regulatory agencies, with a limited examination of their efficacy and safety in vulnerable populations, such as patients with chronic conditions and immunocompromised states. Patients with chronic liver disease (CLD), and cohorts post liver transplant (LT) in particular, were underrepresented in the determinant trials of vaccine development, hence the paucity of data on their efficacy and safety in published literature. This systematic review aims to examine the available evidence and ascertain the effectiveness and safety of Covid-19 vaccination in patients with CLD and those with LT. METHODS: A systematic review of PubMed (Medline), Google Scholar, Cochrane Library, and ScienceDirect from inception until 1st March 2022 was conducted. We included observational studies and assessed vaccine efficacy regarding seroconversion or immunological rate, whereas serious or significant adverse effects have been considered safety outcomes when reported. RESULTS: Studies comprised 45275 patients, performed in 11 different countries. Seroconversion or immunological rate after Covid-19 vaccination was mostly the primary endpoint, whereas other endpoints like covid-19 related adverse effects were also reported. Twenty-four of the final analyzed studies are prospective cohort studies, while four are retrospective cohort studies. Twenty-one studies included patients who underwent LT and received the Covid vaccine; nine included patients who had CLD due to various etiologies. The median age range of all included patients varied from 43-69 years. All patients with LT who received at least two doses of Covid vaccine had a seroconversion rate of around 60%. Patients with CLD had a seroconversion rate of about 92% post two doses of Covid vaccination. The average seroconversion rate in post-transplant recipients was around 45% after two doses of the significant Covid vaccines: Pfizer, AstraZeneca, Moderna, and Jansen. Only two studies have reported a higher seroconversion rate of 75% and 73% after the third dose of Covid vaccine. No significant adverse effects were reported in all studies; the most commonly reported negative effect was local injection site pain. CONCLUSION: The present systematic review, comprising real-world observational data studies, concludes that Covid-19 vaccination was associated with 92% and 60% seroconversion rates in patients with CLD and LT, respectively. No significant side effects were reported in all studies. This finding helps to resolve the uncertainty associated with Covid-19 vaccination in this cohort of patients.

Warfarin-Rifampin-Gene (WARIF-G) Interaction: A Retrospective, Genetic, Case-Control Study.

Warfarin is extensively metabolized by cytochrome P450 2C9 (CYP2C9). Concomitant use with the potent CYP2C9 inducer, rifampin, requires close monitoring and dosage adjustments. Although, in theory, warfarin dose increase should overcome this interaction, most reported cases over the last 50 years have not responded even to high warfarin doses, but some have responded to modest doses. To investigate the genetic polymorphisms' impact on this unexplained interpatient variability, we performed genotyping of CYP2C9, VKORC1, and CYP4F2 for warfarin and rifampin concomitant receivers from 2016 to 2022 at Hamad Medical Corporation, Doha, Qatar. We identified and included 36 patients: 22 responders and 14 nonresponders. Warfarin-responders were significantly more likely to have one or more warfarin-sensitizing CYP2C9/VKORC1 alleles than nonresponders (odds ratio = 23.2, 95% confidence interval = 3.2-195.6; P = 0.0001). The mean genetic-based pre-interaction calculated dose was significantly lower for responders than for nonresponders (P < 0.001); and was negatively correlated with warfarin sensitivity index (WSI) (r = -0.58; P = 0.0002). The median percentage time in therapeutic range and mean WSI were significantly higher in the warfarin-sensitizing CYP2C9/VKORC1 alleles carriers than noncarriers (P = 0.017 and 0.0004, respectively). Whereas the warfarin-sensitizing CYP2C9/VKORC1 genotypes were associated with modest on-rifampin warfarin dose requirements, the noncarriers would have required more than double these doses to respond. Warfarin-sensitizing CYP2C9/VKORC1 genotypes and low genetic-based warfarin calculated doses were associated with higher warfarin sensitivity and better anticoagulation quality in patients receiving rifampin concomitantly.

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.

Colchicine use might be associated with lower mortality in COVID-19 patients: A meta-analysis.

BACKGROUND: Colchicine was recently repurposed for the management of coronavirus disease 2019 (COVID-19). This rapid review and meta-analysis aimed to assess colchicine's impact on mortality outcomes in COVID-19 patients. MATERIALS AND METHODS: We systematically searched PubMed, EMBASE, Google Scholar since their inception till 25/03/2021 for observational or controlled studies that reported mortality as an outcome. The mortality odd ratios were generated with their corresponding 95% confidence intervals utilizing the random-effects model. RESULTS: Nine studies comprising 5522 patients met our inclusion criteria. Our meta-analysis revealed significantly lower mortality in the colchicine group (OR 0.35, 95% CI 0.25-0.48, I2 0%) compared with controls. A subgroup analysis limited to hospitalized patients (OR 0.35, 95% CI 0.25-0.50, I2 0%) revealed similarly lower mortality in the colchicine group. CONCLUSIONS: This meta-analysis suggests a mortality benefit with colchicine when used in the treatment of COVID-19 patients. The majority of included studies were observational; thus, the findings of this review need to be further supported by the results of ongoing trials.

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.

Osmolar-gap in the setting of metformin-associated lactic acidosis: Case report and a literature review highlighting an apparently unusual association.

RATIONALE: Metformin-associated lactic acidosis (MALA) is a rare adverse effect that has significant morbidity and mortality. MALA is a high anion gap (AG), nonosmolar acidosis. Associated osmolar-gap (OG) is rarely reported, so finding an OG may make the diagnosis of MALA challenging. PATIENT CONCERNS: Forty-five years' old type II diabetic patient on metformin presented to emergency with a two-day history of vomiting, watery diarrhea, and mild abdominal discomfort. On examinations, he looked dehydrated. Investigation revealed acute kidney injury (AKI) with a high lactic acid (LA) level of 24 mmol/L, pH of 6.8, AG of 40, and an OG of 20 mOsm/kg DIAGNOSES:: The presence of an OG made the diagnosis challenging; the history was negative for alcohol, osmolar substance, or illicit drug ingestion or use. The toxicology screen was negative. After ruling out plausible causes of AG and OG, MALA was deemed the likely reason for his presentation likely precipitated by dehydration and AKI. INTERVENTIONS: He underwent two sessions of hemodialysis, afterward managed with fluid hydration. OUTCOMES: On day 3, he was in the polyuric phase suggestive of acute tubular necrosis. His serum creatinine improved afterward with improved acidosis; after 8 days, he was discharged in stable condition. LESSONS: MALA is a rare side effect of metformin therapy. Acute kidney injury is a known precipitant of MALA. In our review, we highlight the association of MALA and the presence of an OG. We believe that treating physicians should be aware of this relationship to avoid delaying or overlooking such an important diagnosis.

The efficacy of colchicine in the management of coronavirus disease 2019: A protocol for systematic review and meta-analysis.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-COV2) infection is a recently emerged viral infection causing predominantly mild upper respiratory symptoms. However, in some instances, it might result in acute respiratory distress syndrome (ARDS) that poses a significant mortality risk. ARDS is postulated to be mediated by a surge of pro-inflammatory cytokines and chemokines, leading to a dysregulated hyper inflammatory response. Colchicine being an anti-inflammatory agent, might mitigate this dysregulated response. Thus, in the absence of therapeutic options available to manage coronavirus disease 2019 (COVID-19), it is imperative to ascertain the effect of colchicine on improving outcomes in COVID-19 patients. METHOD: We will perform a systematic review including a search of the following databases: PubMed, EMBASE, MEDLINE, Clinicaltrials.gov, Cochrane library, and google scholar since inception. We will include randomized controlled trials exploring the effect of colchicine on the efficacy and safety outcomes of COVID-19 patients. Subsequently, we will perform a meta-analysis utilizing the random-effects to ascertain the effect of colchicine on reducing COVID-19 related mortality (primary endpoint) and other efficacy and safety outcomes. RESULTS: Our review results are anticipated in early 2021 (based on the completion of several ongoing randomized controlled trial). Our review results will be published in a peer-reviewed journal. CONCLUSION: This systematic review and meta-analysis, is exploring the effect of colchicine on the efficacy and safety outcomes of COVID-19 patients. If colchicine proved to be effective, it would be a significant milestone in the management of COVID-19, a disease with limited available therapeutic options. PROSPERO REGISTRATION NUMBER: CRD42020191086.

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.

Inhaled Tranexamic Acid for Non-Massive Haemoptysis in a Rivaroxaban-Receiving Patient Not Responding to the Oral Form.

Haemoptysis is the expectoration of blood originating from the respiratory tract and occurs secondary to infection, malignancy, bronchiectasis or vascular disease. Its severity varies from minimal blood-streaked sputum to life-threatening haemorrhage. Therefore, prompt evaluation of the cause of the haemoptysis and its severity, and timely management are crucial. Although there is still no effective therapy for haemoptysis apart from treating the cause, inhaled tranexamic acid (TXA) might have a potential role in controlling non-massive haemoptysis. Here, we present a case of non-massive haemoptysis in a COPD patient with bronchiectasis on rivaroxaban for atrial fibrillation who responded to inhaled TXA following a failed trial of the oral formulation. LEARNING POINTS: Haemoptysis is the expectoration of blood and has several causes including bronchitis, bronchiectasis and bronchial neoplasms; severity ranges from simple blood-streaking of sputum to massive blood without sputum.Early recognition of haemoptysis, identification of the cause, and controlling it are crucial, especially in patients on anti-coagulation medicine.Inhaled tranexamic acid has shown benefit in controlling bleeding in patients with non-massive haemoptysis.

Prevalence of Venous Thromboembolism in Critically Ill COVID-19 Patients: Systematic Review and Meta-Analysis.

Background: Recent studies revealed a high prevalence of venous thromboembolism (VTE) events in coronavirus disease 2019 (COVID-19) patients, especially in those who are critically ill. Available studies report varying prevalence rates. Hence, the exact prevalence remains uncertain. Moreover, there is an ongoing debate regarding the appropriate dosage of thromboprophylaxis. Methods: We performed a systematic review and proportion meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched PubMed and EMBASE for studies exploring the prevalence of VTE in critically ill COVID-19 patients till 25/07/2020. We pooled the proportion of VTE. Additionally, in a subgroup analysis, we pooled VTE events detected by systematic screening. Finally, in an exploratory analysis, we compared the odds of VTE in patients on prophylactic compared with therapeutic anticoagulation. Results: The review comprised 24 studies and over 2,500 patients. The pooled proportion of VTE prevalence was 0.31 [95% confidence interval (CI) 0.24, 0.39; I 2 94%], of VTE utilizing systematic screening was 0.48 (95% CI 0.33, 0.63; I 2 91%), of deep venous thrombosis was 0.23 (95% CI 0.14, 0.32; I 2 96%), and of pulmonary embolism was 0.14 (95% CI 0.09, 0.20; I 2 90%). Exploratory analysis of few studies, utilizing systematic screening, VTE risk increased significantly with prophylactic, compared with therapeutic anticoagulation [odds ratio (OR) 5.45; 95% CI 1.90, 15.57; I 2 0%]. Discussion: Our review revealed a high prevalence of VTE in critically ill COVID-19 patients. Almost 50% of patients had VTE detected by systematic screening. Higher thromboprophylaxis dosages may reduce VTE burden in this patient's cohort compared with standard prophylactic anticoagulation; however, this is to be ascertained by ongoing randomized controlled trials.

Efficacy of sodium-glucose co-transporter 2 inhibitors in patients with type II diabetes: A protocol for systematic review of randomised controlled clinical trials utilising a generalised pairwise modelling methodology.

BACKGROUND: Recent systematic reviews have evaluated the efficacy of sodium-glucose co-transporter 2 inhibitors (SGLT2) inhibitors (SGLT2I) in improving glycaemic control and mortality in patients with type II diabetes mellitus. None have incorporated the most recent study or utilized the generalized pairwise modeling methodology network meta-analysis (NMA), as well as a novel bias risk assessment approach. METHODS: We propose to conduct literature search of all randomized controlled clinical trials published in English language evaluating the efficacy of (SGLT2I) versus placebo or usual standard of care from the inception of following databases to September 30, 2019: Controlled Clinical Trials Cochrane Controlled Trials Register (CCTR), Cochrane Database of Systematic Reviews (CDSR), EMBASE, Database of Abstracts of Reviews of Effectiveness (DARE), PubMed. Two reviewers will independently search these databases to identify studies that satisfy pre-specified eligibility criteria. Study bias risk assessment amongst other methodology quality evaluation of the studies will be carried out using a novel risk bias assessment tool. RESULTS: We anticipate that the result of this review will provide additional insight into the ranking of the efficacy of various (SGLT2I) in type II diabetic patients especially as it relates to mortality, glycemic control, and body weight reduction. CONCLUSION: The result of this review will be useful informing therapeutic decisions by policy makers with regards to commissioning of diabetic care.Prospero registration number: CRD42019139708.