Warfarin Treatment Research Articles

Real-World Effectiveness and Safety of Apixaban versus Warfarin in Patients with Acute Venous Thromboembolism: Experience of a Large Tertiary Hospital in Saudi Arabia

PurposeThe main objective of this study was to evaluate the effectiveness and safety of apixaban versus warfarin in patients with venous thromboembolism (VTE) in a “real-world” setting.Patients and MethodsA retrospective cohort study was conducted using data from a large tertiary hospital in Saudi Arabia. Patients were included if they were adults (≥18 years), diagnosed with VTE, and treated with either apixaban or warfarin between January 2016 and September 2018. Patients who had received anticoagulation therapy within three months of the date of the index event were excluded. The effectiveness outcomes were incidence of VTE recurrence (ie, deep vein thrombosis DVT or pulmonary embolism [PE]), while the safety outcome was incidence of any major bleeding (MB) event within 90 days of follow-up.ResultsAmong the 492 patients included for study, 212 (43.1%) received apixaban and 280 (56.1%) received warfarin. The mean age of patients was 53.6±19.1 years and 62% of the cohort was female. Comparable rates of VTE recurrence were observed for apixaban and warfarin treatment groups during follow-up (adjusted odds ratio (AOR) =0.95; 95% CI 0.53–1.68), including DVT (AOR=1.06; 95% CI 0.52–2.17) and PE (AOR=0.78; 95% CI 0.31–1.96). However, apixaban was associated with significantly fewer MB events than warfarin (AOR=0.18; 95% CI 0.04–0.83).ConclusionThe use of apixaban for the treatment of Saudi patients with acute VTE is associated with a VTE recurrence rate comparable to that of warfarin, with significantly fewer MB events.

Warfarin Impairs the Bone Marrow Microenvironment and Hematopoiesis Via the Periostin/Integrin β3 Pathway

The coagulation system is a complex system comprised of various proteases and other factors which result in the formation of a blood clot, and proteases in general are known to regulate the mobilization of normal hematopoietic stem cells (HSC) from the bone marrow microenvironment (BMM). However, whether the proteases of the coagulation system are involved in the mobilization or maintenance of hematopoietic stem and progenitor cells (HSPC) is unknown.Hypothesizing that the proteases of the coagulation system play a role in the normal physiology of the BMM and that modulation of coagulation factors may have an effect on HSPC, we tested the effects of the anticoagulant warfarin, used in 1% of people worldwide for prophylactic or therapeutic anticoagulation. Indeed, treatment of wildtype mice with warfarin led to a decrease in myeloid cells in peripheral blood, decreased HSC function and mobilization from the BMM and an almost 8 fold reduction of functional HSC. Intrafemoral co-transplantation of warfarin-treated, ex-vivo expanded primary murine bone marrow stromal cells with untreated HSPC led to decreased engraftment of HSPC compared to co-transplantation of vehicle-treated stroma cells suggesting that warfarin may compromise bone marrow stroma. We have implicated periostin, a vitamin K dependent factor produced by bone marrow stroma - binding to integrin β3 and signaling via AKT in HSC - as being the cause of impairment of hematopoiesis during treatment with warfarin.In addition, warfarin treatment of NOD SCID interleukin-2 receptor gamma knockout (NSG) mice or intrafemoral cotransplantation of human warfarin-treated stroma cells and untreated human CD34+ HSC led to reduced engraftment of human CD45+ leukocytes. In corroboration of our murine data we showed that the total leukocyte and monocyte count, as well as the percentage of basophils and eosinophils were significantly reduced in 282 patients receiving warfarin and 89 patients receiving another vitamin K antagonist, fluindione, for anticoagulation compared to untreated healthy controls.In summary, warfarin or vitamin K antagonism treatment impairs HSC function in humans and mice via modification of the BMM and, specifically, by the impairment of the periostin/integrin β3 axis, which we, thereby, implicate also for the maintenance of normal HSC. [Display omitted] DisclosuresFontenay:Celgene: Research Funding.

Differential Impact of Dietary Vitamin K (phylloquinone) on Coagulation Factor Activities and Clotting Times in Warfarin-Treated Rats

ObjectivesInvestigate the impact of variable vitamin K (VK) intakes on the coagulation activities of four VK-dependent factors and clotting times, in warfarin-treated rats. MethodsMale Wistar rats were randomly allocated to a AIN-93 based diet containing low (L: 80 mcg/kg/d), adequate (A: 750 mcg/kg/d) or enriched (E: 2000 mcg/kg/d) phylloquinone (K1) containing diet (n = 24/diet group). After one week, half the animals from each diet group were randomly allocated to receive 0.2 mg warfarin/kg/d through drinking water (W gp) or plain water (C gp), for 10 weeks. Coagulation activity (%) was assessed for factors II, VII, IX and X, and clotting times were based on prothrombin [PT (sec)] and activated thromboplastin times [APTT (sec)]. Measures were obtained at the end of the study and were conducted in the hospital clinical laboratory using standard procedures. Diet effects within C and W groups were investigated using one-way ANOVA and uncorrected Fisher post-hoc tests. ResultsWarfarin treatment resulted in significantly higher clotting times (PT and APTT) in all diet groups when compared to corresponding C groups (p < 0.05), the highest increase being observed in the L, followed by A and E groups, each diet being statistically different from each other (p < 0.01). Warfarin treatment also resulted in statistically significant decreases in activities of all coagulation factors although the impact of the diets varied according to factors: FVII and FX, between L and E groups only; FIX, between L and A, and L and E groups; FII, between all diet groups; (p < 0.05 in all cases). ConclusionsResults from this study confirm the impact of dietary VK on coagulation factor activities and resulting clotting times, and suggest that for a given dose of W, this impact will depend on VK intake levels. Currently, individuals undergoing warfarin treatment are advised to aim for stable daily VK intakes. Results from this study provide data supporting this recommendation. Funding SourcesThis study was funded by CIHR and MHI Foundation.

Characterization of dynamic changes in Matrix Gla Protein (MGP) gene expression as function of genetic risk alleles, osteoarthritis relevant stimuli, and the vitamin K inhibitor warfarin

We here aimed to characterize changes of Matrix Gla Protein (MGP) expression in relation to its recently identified OA risk allele rs1800801-T in OA cartilage, subchondral bone and human ex vivo osteochondral explants subjected to OA related stimuli. Given that MGP function depends on vitamin K bioavailability, we studied the effect of frequently prescribed vitamin K antagonist warfarin. Differential (allelic) mRNA expression of MGP was analyzed using RNA-sequencing data of human OA cartilage and subchondral bone. Human osteochondral explants were used to study exposures to interleukin one beta (IL-1β; inflammation), triiodothyronine (T3; Hypertrophy), warfarin, or 65% mechanical stress (65%MS) as function of rs1800801 genotypes. We confirmed that the MGP risk allele rs1800801-T was associated with lower expression and that MGP was significantly upregulated in lesioned as compared to preserved OA tissues, mainly in risk allele carriers, in both cartilage and subchondral bone. Moreover, MGP expression was downregulated in response to OA like triggers in cartilage and subchondral bone and this effect might be reduced in carriers of the rs1800801-T risk allele. Finally, warfarin treatment in cartilage increased COL10A1 and reduced SOX9 and MMP3 expression and in subchondral bone reduced COL1A1 and POSTN expression. Our data highlights that the genetic risk allele lowers MGP expression and upon OA relevant triggers may hamper adequate dynamic changes in MGP expression, mainly in cartilage. The determined direct negative effect of warfarin on human explant cultures functionally underscores the previously found association between vitamin K deficiency and OA.

Management of Recurrent Deep Vein Thrombosis in a Transgender Woman

Background: Transgender people using hormone treatment require lifelong medical care. Although cross-sex hormone treatment (CSHT) is usually considered safe, serious adverse events may occur. Here we report a case of deep vein thrombosis associated with estradiol treatment in an otherwise healthy young transgender woman. Case Presentation: A 21-year-old transgender woman using CSHT applied to our outpatient clinic with the complaint of painful swelling in her left leg. She was diagnosed with deep vein thrombosis (DVT) in the same leg one year earlier when she was admitted to the emergency room of another hospital with similar symptoms, and was given warfarin treatment for 3 months which has improved the symptoms. Three months after cessation of warfarin, symptoms re-occurred, but she was only able to apply to our clinic after another 3 months due to COVID-19 pandemic. Physical examination was unremarkable except asymmetrical swelling in the left leg. She has been receiving oral estradiol 6 mg/day and spironolactone 200 mg/day for 2 years. She denied taking estradiol in higher doses than recommended. She did not have any predisposing factors for DVT including obesity, immobilization and smoking. She had no prior history of venous thromboembolic events (VTE). Family history was also negative for thrombophilia except her uncle was diagnosed with ischemic cerebrovascular event at the age of 60. Lower extremity venous doppler ultrasonography revealed a thrombus in the left popliteal vein that caused total obstruction of blood flow to the distal. Plasma levels of d-dimer and fibrinogen were 0.35 mg/L and 262 mg/dL, respectively. Serum levels of sex hormones were estradiol: 204 pg/mL, total testosterone: 22.4 ng/dL, FSH: 0.22 mIU/mL, LH: 1.5 mIU/mL. Thrombophilia panel revealed a homozygous mutation in MTHFR (1296), and heterozygous mutations in both Factor V Leiden and plasma activator inhibitor (4G/5G). She was given enoxaparin in addition to warfarin until INR was elevated up to desired levels. Oral estradiol treatment was switched to transdermal route. Life-long anticoagulant treatment was suggested since the thrombotic event was triggered by estradiol treatment which will be continued. Conclusions: Limited data are available on incidence and management of VTE associated with estradiol treatment in male-to-female individuals. As in general population, routine screening for thrombophilia is not recommended in transgender women prior to the initiation of CSHT if no personal or family history of VTE is present. Even in the absence of predisposing factors, life-long anticoagulant therapy may be considered since the VTE-provoking estradiol treatment will be continued. Switching the route of estradiol treatment from oral to transdermal may be beneficial.

Off‐target effects of oral anticoagulants – vascular effects of vitamin K antagonist and non‐vitamin K antagonist oral anticoagulant dabigatran etexilate

IntroductionVitamin K antagonists (VKA) and non‐vitamin K oral antagonist anticoagulants (NOAC) are used in the clinic to reduce risk of thrombosis. However, they also exhibit vascular off‐target effects. The aim of this study is to compare VKA and NOAC on atherosclerosis progression and calcification in an experimental setup. Material and methodsFemale Apoe−/− mice (age 12 weeks) were fed Western‐type diet as control or supplemented with dabigatran etexilate or warfarin for 6 or 18 weeks. Vascular calcification was measured in whole aortic arches using µCT and [18F]‐NaF. Atherosclerotic burden was assessed by (immuno)histochemistry. Additionally, in vitro effects of warfarin, thrombin, and dabigatran on primary vascular smooth muscle cells (VSMC) were assessed. ResultsShort‐term treatment with warfarin promoted formation of atherosclerotic lesions with a pro‐inflammatory phenotype, and more rapid plaque progression compared with control and dabigatran. In contrast, dabigatran significantly reduced plaque progression compared with control. Long‐term warfarin treatment significantly increased both presence and activity of plaque calcification compared with control and dabigatran. Calcification induced by warfarin treatment was accompanied by increased presence of uncarboxylated matrix Gla protein. In vitro, both warfarin and thrombin significantly increased VSMC oxidative stress and extracellular vesicle release, which was prevented by dabigatran. ConclusionWarfarin aggravates atherosclerotic disease activity, increasing plaque inflammation, active calcification, and plaque progression. Dabigatran lacks undesired vascular side effects and reveals beneficial effects on atherosclerosis progression and calcification. The choice of anticoagulation impacts atherosclerotic disease by differential off target effect. Future clinical studies should test whether this beneficial effect also applies to patients.

Warfarin Induces Calcification of the Aortic Valve Through Extracellular Signal-regulated Kinase 1/2 and β-catenin Signaling

BackgroundRecent clinical evidence suggests an association between warfarin use and calcification of the aortic valve. We sought to determine the effect of warfarin on aortic valve interstitial cell (AVIC) osteogenic protein expression and the signaling pathways by which this effect is mediated. MethodsHuman AVICs were isolated from normal aortic valves of patients undergoing cardiac transplantation, whereas diseased AVICs were isolated from patients undergoing aortic valve replacement for aortic stenosis. AVICs were treated with various anticoagulants, and osteogenic protein expression was evaluated using immunoblotting. Phosphorylation of lipoprotein receptor-related protein 6 (LRP6) and extracellular signal-regulated kinase 1/2 (ERK1/2) was evaluated after treatment with warfarin. AVICs were pretreated with LRP6 inhibitor dkk1 and ERK1/2 inhibitor PD98059 followed by treatment with warfarin, and osteogenic protein expression was evaluated. ResultsWarfarin, but not heparin or dabigatran, significantly increased Runx-2 and Osx expression in both normal and diseased human AVICs. Upregulation of β-catenin protein expression and nuclear translocation occurred in diseased AVICs but not normal AVICs after warfarin treatment. Warfarin induced phosphorylation of LRP6 in diseased AVICs only and phosphorylation of ERK1/2 in both normal and diseased AVICs. LRP6 inhibition attenuated warfarin-induced Runx-2 expression in diseased AVICs. ERK1/2 inhibition attenuated warfarin-induced Runx-2 expression in both normal and diseased AVICs. ConclusionsWarfarin induces osteogenic activity in normal and diseased isolated human AVICs. This effect is mediated by ERK1/2 in both diseased and normal AVICs, but in diseased AVICs β-catenin signaling also plays a role. These results implicate the role of warfarin in aortic valve calcification and highlight potential mechanisms for warfarin-induced aortic stenosis.

The effect of reinforcing an educational programme using telephone follow-up on health-related quality of life of individuals using warfarin: A randomised controlled trial.

To evaluate the effect of reinforcing an educational programme through telephone follow-up on health-related quality of life and anxiety and depression symptoms in individuals starting warfarin therapy. Educational interventions have improved quality of life in individuals using warfarin. Few studies have examined the addition of telephone follow-up to enhance educational interventions. Randomised controlled trial in outpatient setting. Hospitalised adults starting warfarin therapy who agreed to participate received an educational programme about the warfarin treatment. At discharge, they were randomised to receive either five telephone follow-up calls (intervention) or no telephone calls (controls). Both groups were evaluated for health-related quality of life (using Duke Anticoagulation Satisfaction Scale) and symptoms of anxiety and depression (using Hospital Anxiety and Depression Scale) at three and six months post-discharge. Groups were compared at each time by independent-samples t test, and over time by repeated-measures analysis of variance, with time (three and six months), groups (intervention and control) and an interaction between time and group as factors. Level of significance was set at 0.05. The Consolidated Standards of Reporting Trials was used for reporting. Fifty-two individuals (26 per group) completed the study. There were no statistical differences between groups in health-related quality of life, anxiety and depression symptoms, at both times post-discharge. Participants who received follow-up telephone calls reported better positive psychological impact (a subscale of quality of life) than controls. Reinforcing an educational programme with telephone follow-ups did not have an overall effect on health-related quality of life of individuals using warfarin but promoted positive psychological impact. The low cost of reinforcing educational programmes with telephone calls and the improvement in positive psychological aspects indicate that this type of intervention is still a promising intervention that could be further investigated and improved.

Oral Health-Related Quality of Life in Anticoagulated Patients with Warfarin Treatment: A Cross-Sectional Study.

To evaluate factors associated with oral health-related quality of life (OHRQoL) in patients under oral anticoagulant therapy with warfarin, a cross-sectional study was conducted. Validated questionnaires assessed self-reported periodontal disease, demographic variables, and OHRQoL using the short version of the Oral Health Impact Profile (OHIP-14) instrument. After calibration (Kappa > 0.60), an examiner evaluated patients’ experience with dental caries and the need for dental prostheses. Statistical analysis involved proportions and measures of central tendency. Negative binomial regression models were used to estimate the rate ratios (RR) and the corresponding 95% confidence interval (CI). The sample consisted of 158 individuals, with a mean age of 58.8 years (SD = 12.1), of which 62.7% of the participants were women. The OHIP-14 mean was 10.62 (SD = 10.92). A higher OHIP-14 total score (worse OHRQoL) was associated with ethnic group, age, periodontal disease self-report, dental caries, and oral health self-report. Demographic and clinical factors can negatively influence the perception of anticoagulated patients on OHRQoL.

Randomized, placebo-controlled trial of orally administered vitamin K1 for warfarin-associated coagulopathy in Chinese patients with mechanical heart valves.

Warfarin-associated coagulopathy commonly occurs in patients undergoing treatment with this anticoagulant. This trial aimed to determine the efficacy of using low-dose orally administered vitamin K1 to lower international normalized ratio (INR) values into the target range in a cohort of Chinese patients with mechanical heart valves. This was a double-blind, placebo-controlled, randomized trial. Chinese patients with mechanical heart valves who were undergoing warfarin treatment and who had INR values from 4.0 to 10.0 without bleeding were the subjects of this study. These patients were randomized into two treatment groups and were orally administered either vitamin K1 (2.5mg) or placebo. Warfarin was discontinued in both groups until INR values were ≤ 2.5. INR values on the day following treatment were the primary study outcome, with INR values on the following days and adverse clinical events over a 3-month follow-up serving as secondary study outcomes. In total, 80 patients were enrolled in the present study, and 40 patients each were assigned to the placebo and vitamin K1 treatment groups. Patients administered vitamin K1 exhibited a quick reduction in INR values relative to patients administered placebo (29 of 40 [72.5%] vs. 0 of 44 [0%] patients exhibiting INR values from 1.5-2.5 on the day following treatment, respectively, p = 0.000). Lower bleeding incidence was observed among patients administered vitamin K1 relative to those administered placebo during follow-up (4 [10%] vs. 12 [30%] patients, respectively, p = 0.045). There were no instances of thromboembolic complications or warfarin resistance in either group. Low-dose oral vitamin K1 can be effectively administered to Chinese patients with mechanical heart valves taking warfarin to rapidly reduce elevated INR values.

Associations of Gene Polymorphism in Kazakhstani Patients with Implanted LVAD

Purpose Heart failure is one of the main problem in the health care system. The best option of the treatment is heart transplantation (HT). Left ventricular assist device (LVAD) implantation is the best option of alternative treatment instead of HT. Outcome of the LVAD treatment is usually followed with side effects of bleeding and thrombosis. To reduce side effects patients are prescribed with antithrombotic therapy warfarin, which can be followed with side effects because of incorrect individual dosage. Warfarin dosage can be identified according to the results of genetic polymorphisms CYP2C9 and VKORC1. The study is aimed to identify genetic associations of SNP polymorphisms rs1799853, 1057910, rs9923231. Methods Venous blood samples were recruited from 98 patients with implanted LVAD at the National Research Center for Cardiac Surgery. Heart failure patients contained 92 males and 6 females (52.7±10.95 years old) with implanted LVAD devices. The control group contains ninety-five (n=95) conditionally healthy individuals. Warfarin treatment was prescribed after LVAD implantation monthly (after 1st month, 3rd, 6th, 9th and after 1 year etc). SNP polymorphisms were genotyped in case and control groups by real-time polymerase chain reaction with TaqMan probes. Results Genotyping test results were not statistically significant. Case and control groups did not have mutant type of genotypes TT (rs1799853) and CC (rs1057910). Genotype frequency of CC genotype rs1799853 was slightly higher in the case group (92.9% vs.92.6%, p = 1.000). The second SNP rs1057910 had higher frequency of AA genotypes in case group (92.9% vs. 86.3%, p = 0.161). Mutant genotype TT of rs9923231 was slightly higher in the control group (37.9% vs.36.7%, p = 0.718). Monthly clinical dosage of warfarin was compared between three genotypes of rs9923231. Warfarin dosage was significantly associated between three genotypes (p Conclusion Research need to include other polymorphisms for deeper research about individual warfarin dosage and their associations with side effects.

Rivaroxaban versus low-molecular weight heparin plus warfarin prevents portal vein system thrombosis after splenectomy and pericardial devascularization: A randomized clinical trial.

This study aimed to evaluate the safety and efficacy of rivaroxaban in preventing portal vein system thrombosis (PVST) in patients with liver cirrhosis after splenectomy and pericardial devascularization. 70 cirrhotic patients undergoing splenectomy and pericardial devascularization were randomly assigned to rivaroxaban treatment (n=35) or low-molecular weight heparin (LMWH) plus warfarin treatment (n=35) for 30 days in this randomized controlled trial. The primary endpoint is the PVST formation. Ultrasound doctors and radiologists were blinded to the randomization results. Both groups received routine outpatient inspection every month and were followed for one year. 17 patients (48.6 %) in rivaroxaban group developed PVST, compared with 27 patients (77.1 %) in LMWH plus warfarin group (P=0.025). The incidence of PVST during the first year postoperation was significantly lower in rivaroxaban group than in LMWH plus warfarin group (F=7.901, P=0.006). The intra-group comparisons versus baseline showed the liver function improved from POD 21 to POM 1, and coagulation function improved from POM 2, in rivaroxaban group. In contrast, the liver function improved from POM 1 to POM 2, and coagulation function improved from POM 4, in LMWH plus warfarin group. The prophylactic use of rivaroxaban significantly decreases the incidence of PVST after splenectomy and pericardial devascularization in cirrhotic patients compared to LMWH plus warfarin treatment. Besides, rivaroxaban treatment was safe and effective and associated with better liver and coagulation functions improvement than LMWH plus warfarin treatment.

Comparative Study between Rivaroxaban and Warfarin inTreatment of Patients with Recurrent Deep Venous Thrombosis

AbstractBackground: Venous Thrombo-Embolism (VTE) manifestsas Deep Venous Thrombosis (DVT) and/or Pulmonary Em-bolism (PE). Per 1000 persons in the general population, theannual incidence is 1 to 2 cases. For decades, the gold standard of anti-thrombotic therapy has been based on heparins and Vitamin K Antagonists (VKAs), their narrow therapeutic range and multiple interactions led to the development of New Oral Anticoagulants (NOACs) beginning in 2003. Two types of new anticoagulants have been developed: Direct factor Xa inhibitors (Rivaroxaban) and direct factor IIa (thrombin) inhibitors.Aim of Study: The aim of this study was to comparerivaroxaban versus warfarin in treatment of recurrent DVTas regard efficacy, safety and complications.Patients and Methods: This was a prospective studyconducted on 30 patients suffering from recurrent deep venousthrombosis. The studied cases were divided into two groups,Group A treated by rivaroxaban, while group B treated bywarfarin over a period of 6 months. All cases were subjectedto full history taking, complete general and local examination,routine laboratory investigations and Duplex Scanning.Results: No statistically significant differences amongrivaroxaban and warfarin groups as regards presence of riskfactors, DVT extension, duplex results and incidence ofcomplications, while there was significant difference as regardsduration till symptoms relief.Conclusion: Rivaroxaban seems to have same efficacyas warfarin with advantage being earlier in symptoms relief/days, recanalization and patient compliance. In addition,warfarin users need to be monitored regularly.

Variants in CDHR3, CACNAC1, and LTA Genes Predisposing Sensitivity and Response to Warfarin in Patients with Cardiovascular Disease.

IntroductionWarfarin has been in use for more than 60 years; however, it has serious side effects including major bleeding. The high interpatient variability in the required dose impacts the sensitivity and responsiveness to warfarin in different patients. This study aims to assess the influence of CDHR3, CACNAC1, and LTA gene polymorphisms on the variability of warfarin dose requirements and susceptibility to coronary heart disease in the Jordanian population.MethodsThis study was conducted in the anti-coagulation clinic in Queen Alia Heart Institute in Amman, with 212 patients in total. Three SNPs were genotyped within CDHR3 (rs10270308), CACNAC1 (rs216013), and LTA (rs1041981) genes.ResultsOur findings revealed that patients with LTA polymorphism are more prone to warfarin sensitivity than others. Furthermore, carriers of the LTA polymorphism needed a lower initial dose of warfarin and are associated with less variation in doses required to achieve target INR.ConclusionThe current study could help in understanding the role of genetic variability in warfarin dosing and matching patients to different treatment options. Clinical applications of these findings for warfarin treatment may also contribute to improving the efficacy and safety of warfarin treatment in Jordanian patients with cardiovascular disease.

The Complex Relationship between C4b-Binding Protein, Warfarin, and Antiphospholipid Antibodies

Low levels of total C4b-binding protein (C4BPt), a circulating inhibitor of the classical/lectin complement pathways, were observed in patients with antiphospholipid antibodies (aPLs) and during warfarin treatment. To investigate the associations between aPL and C4BPt in patients with persistently positive (++) aPL, with/without clinical manifestations and systemic lupus erythematosus (SLE), and in controls. Furthermore, we explored the impact of anticoagulation on C4BPt and in relation to complement activation. In a cross-sectional design we investigated defined subgroups: primary (p) antiphospholipid syndrome (APS, N = 67), aPL++ individuals without clinical manifestations (aPL carriers, N = 15), SLE-aPL++ (N = 118, among them, secondary [s] APS, N = 56), aPL negative (-) SLE (SLE-aPL-, N = 291), and 322 controls. Clinical characteristics, including treatment, were tabulated. C4BPt was determined with a magnetic bead method. Complement proteins (C1q, C2, C3, C4, C3a, C3dg, sC5b-9, factor I [FI]) were measured. A mediation analysis was performed to decompose the total effect of aPL++ on C4BPt into the direct and indirect effects of aPL++ through warfarin. Overall, C4BPt is 20% decreased in aPL++ patients, regardless of SLE, APS, clinical manifestations, and aPL profile. C4BPt levels associate positively with complement proteins C1q, C2, C3, and C4, and negatively with complement activation product C3dg. In the SLE group, warfarin treatment contributes to approximately half of the C4BPt reduction (9%) CONCLUSION: Both aPLs and warfarin are associated with C4BPt reduction. Complement activation in aPL++ patients may partly be explained by impaired inhibition through depressed C4BPt levels. Further studies are needed to understand the clinical implications.

Clinical outcomes among hemodialysis patients with atrial fibrillation: a Korean nationwide population-based study.

BackgroundThe number of patients requiring dialysis is increasing worldwide, and the atrial fibrillation and atrial flutter (AF) prevalence among hemodialysis (HD) patients is higher than in the general population. There have been no studies of Korean AF patients undergoing HD that investigated how AF affects outcomes, such as all-cause mortality, hospitalization, and stroke events. We conducted a large-scale retrospective cohort study with data from the National Health Insurance System to determine how AF affects these outcomes.MethodsIn 2013, the Health Insurance Review and Assessment service, a Korean national health insurance scheme, collected data from 21,839 HD patients to evaluate the adequacy of dialysis centers. All-cause mortality, hospitalization, and stroke events were compared between patients with and without AF. Sub-analyses compared these outcomes between AF patients receiving warfarin and those not receiving warfarin.ResultsCox regression analysis found that AF was a significant risk factor for death from any cause (hazard ratio [HR], 1.356; 95% confidence interval [CI], 1.222–1.506; p < 0.001), hospitalization (HR, 1.323; 95% CI, 1.225–1.430; p < 0.001), and hemorrhagic stroke (HR, 1.500; 95% CI, 1.050–2.141; p = 0.026). AF was not significantly associated with an increased risk of ischemic stroke. The use of warfarin was significantly associated with hemorrhagic stroke incidence (HR, 1.593; 95% CI, 1.075–2.360; p = 0.020), while there was no significant correlation between warfarin treatment and all-cause mortality, hospitalization, and ischemic stroke.ConclusionThis cohort study of Korean dialysis patients showed that AF was a risk factor for multiple outcomes among HD patients.

Anticoagulation Quality of Warfarin and the Role of Physician-Pharmacist Collaborative Clinics in the Treatment of Patients Receiving Warfarin: A Retrospective, Observational, Single-Center Study.

Background: The management of patients receiving warfarin is complicated. This study evaluated the anticoagulation quality of warfarin, explored potential predictors associated with poor anticoagulation quality, and elucidated the role of clinical pharmacists in the management of warfarin treatment. Methods: We retrospectively collected data on patients who either initially received warfarin or returned to warfarin after withdrawal between January 1, 2015 and January 1, 2020. The primary outcome was time in therapeutic range (TTR), and a TTR of ≥60% was considered as good anticoagulation quality. The secondary outcomes included thromboembolic and bleeding events during the follow-up. We assessed the TTR of each participant and investigated the potential predictors of poor anticoagulation quality (TTR < 60%) using logistic regression analysis. Additionally, we compared the warfarin anticoagulant quality and the incidence of clinical adverse events between atrial fibrillation patients in physician–pharmacist collaborative clinics (PPCCs) and general clinics. Results: Totally, 378 patients were included. The mean TTR of patients was 42.6 ± 29.8%, with only 32% of patients having achieved good anticoagulation quality. During a mean follow-up period of 192 ± 92 days, we found no significant differences in the incidences of thromboembolic events (5.0% vs. 5.1%, p = 0.967) and bleeding events (1.7% vs. 4.7%, p = 0.241) between patients with good and those with poor anticoagulation quality. The presence of PPCCs (odds ratio [OR]: 0.47, 95% confidence interval [CI]: 0.25–0.90, p = 0.022) was an independent protective factor of poor anticoagulation quality, while the presence of more than four comorbidities (OR: 1.98, 95% CI: 1.22–3.24, p = 0.006) and an average interval of international normalized ratio monitoring of >30 days (OR: 1.74, 95% CI: 1.10–2.76, p = 0.019) were independent risk factors of poor anticoagulation quality. Compared with atrial fibrillation patients in general clinics, patients in PPCCs were found to have a significantly increased mean TTR level (48.4% ± 25.7% vs. 38.0% ± 27.6%, p = 0.014). Conclusion: The anticoagulation quality of warfarin was relatively low at our institution. The presence of more than four comorbidities and an average interval of international normalized ratio monitoring of >30 days independently contributed to poor anticoagulation quality. Meanwhile, the use of PPCC model improved the anticoagulation quality of warfarin.

The association between warfarin treatment and serum undercarboxylated‒osteocalcin levels in hemodialysis patients

The association between warfarin treatment and serum undercarboxylated‒osteocalcin levels in hemodialysis patients

Which is the best for the warfarin monitoring: Following up by fixed or variable physician?

Objective:Warfarin therapy has some difficulties in terms of close monitoring and dosage. This study aims to evaluate the effect of same-fixed versus different-variable physician-based monitoring of warfarin therapy on treatment quality and clinical end-points.Methods:A total of 625 consecutive patients requiring warfarin treatment were enrolled at seven centers. INR values of the patients measured at each visit and registered to hospital database were recorded. Time in therapeutic range (TTR) was calculated using linear interpolation method (Rosendaal’s method). A TTR value of ≥65% was considered as effective warfarin treatment. If a patient was evaluated by the same-fixed physician at each INR visit, was categorized into the same-physician (SP) group. In contrast, if a patient was evaluated by different-variable physicians at each INR visit, was categorized into variable physician (VP) group. Enrolled patients were followed up for bleeding and embolic events.Results:One hundred and fifty-six patients (24.9%) were followed by SP group, 469 (75.1%) patients were followed by VP group. Median TTR value of the VP group was lower than that of SP group (56.2% vs. 65.1%, respectively, p=0.009). During median 25.5 months (9–36) of follow-up, minor bleeding, major bleeding and cerebral embolic event rates were higher in VP group compared to SP group (p<0.001, p=0.023, p<0.001, respectively). In multivariate analysis, INR monitoring by VP group was found to be an independent predictor of increased risk of bleeding events (OR 2.55, 95% CI 1.64–3.96, p<0.001) and embolism (OR 3.42, 95% CI 1.66–7.04, p=0.001).Conclusion:INR monitoring by same physician was associated with better TTR and lower rates of adverse events during follow-up. Hence, it is worth encouraging an SP-based outpatient follow-up system at least for where warfarin therapy is the only choice.

High Dose Ivermectin for the Early Treatment of COVID-19 (COVIER Study): A Randomised, Double-Blind, Multicentre, Phase II, Dose-Finding, Proof of Concept Clinical Trial

Background: High concentrations of ivermectin demonstrated antiviral activity against SARS-CoV-2 in vitro. Aim of this study was to assess safety and efficacy of high-dose ivermectin in reducing viral load in individuals with initial SARS-CoV-2 infection. Methods: Randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial performed in outpatients in Italy. Participants: adults recently diagnosed with asymptomatic/oligosymptomatic SARS-CoV-2 infection, providing informed consent. Exclusion criteria: pregnant or lactating women; CNS diseases; participants under dialysis; severe medical condition with prognosis Findings. From 31th July, 2020 to 26th May, 2021, 32 participants were randomized to arm A, 29 to arm B and 32 to arm C. The recruitment was stopped on 10th June, because of a dramatic drop of cases. Eighty-nine participants were included in the safety analysis set, the change in viral load was calculated on 87 participants. No SADR were registered. The mean log10 viral load reduction was 2.9 in arm C (SD 1.6), 2.5 (2.2) in arm B and 2.0 (2.1) in arm A, with no significant differences (p=0.099 and 0.122 for C versus A and B versus A, respectively). Interpretation: High- dose ivermectin demonstrated safe, but did not prove efficacy to reduce viral load.Trial Registration: The protocol was registered with ClinicalTrials.gov , NCT04438850. Funding: The trial was partly funded by the Italian Ministry of Health.Declaration of Interest: None to declare. Ethical Approval: This study was approved by the national Ethics Committee of INMI – Spallanzani in Rome that is competent for all COVID-19 trials in Italy (resolution 139/2020 of 28th May, 2020), and by the Italian drug agency AIFA (resolution 136BIS/2020 of 18th May, 2020).