Target INR Research Articles

The efficacy of low-dose warfarin initiation (3 mg versus 5 mg) in newly diagnosed venous thromboembolism patients among a population with a high prevalence of warfarin-sensitive haplotype of the VKORC1 gene: a randomized controlled trial

ABSTRACT Objectives The fact that a lower warfarin maintenance dose is required by Asian populations is well-known. Currently, the American College of Chest Physicians recommends commencing warfarin at a dose between 5 and 10 mg for venous thromboembolism (VTE). However, the optimal initiating dose in Asians is unknown. This study aimed to evaluate the efficacy of a 3 mg versus a 5 mg of warfarin initiating dose and a corresponding nomogram in patients with VTE. Methods Eligible patients were randomized to receive 3 mg or 5 mg per day warfarin for the first 2 days of treatment. The subsequent dose was adjusted according to the warfarin nomogram. The primary outcome was the number of patients who achieved an INR 2.0–3.0 within 8 days. Results Fifty-six patients were enrolled. There was no significant difference in baseline characteristics between the groups. Seventeen (60.7%) patients in the 3-mg group and 22 (78.6%) patients in the 5-mg group achieved a therapeutic INR within 8 days (p = 0.146). However, there were significantly more patients in the 5-mg group who achieved the target INR on day 5 (53.6% vs 25.0%, p = 0.029). Furthermore, VKORC1-1639G > A was associated with an increased likelihood to achieve the target INR within 5 days (OR 3.81, 95%CI 1.19–12.16, p = 0.021). Conclusions The efficacy of a 3 mg warfarin starting dose with subsequent dose adjustment was similar to that of 5 mg on day 8 after warfarin initiation. However, a 5 mg initiating dose resulted in more patients who achieved therapeutic INR on day 5.

Comparison of 3-factor versus 4-factor prothrombin complex concentrate for emergent warfarin reversal: a systematic review and meta-analysis

BackgroundPatients requiring emergent warfarin reversal (EWR) have been prescribed three-factor prothrombin complex concentrate (PCC3) and four-factor prothrombin complex concentrate (PCC4) to reverse the anticoagulant effects of warfarin. There is no existing systematic review and meta-analysis of studies directly comparing PCC3 and PCC4.MethodsThe primary objective of this systematic review and meta-analysis was to determine the effectiveness of achieving study defined target INR goal after PCC3 or PCC4 administration. Secondary objectives were to determine the difference in safety endpoints, thromboembolic events (TE), and survival during the patients’ hospital stay. Random-effects meta-analysis models were used to estimate the odds ratios (OR), and heterogeneity associated with the outcomes. The Newcastle-Ottawa Scale was used to assess study quality, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed.ResultsTen full-text manuscripts and five abstracts provided data for the primary and secondary outcomes. Patients requiring EWR had more than three times the odds of reversal to goal INR when they were given PCC4 compared to PCC3 (OR = 3.61, 95% CI: 1.97–6.60, p < 0.001). There was no meaningful clinical association or statistically significant result between PCC4 and PCC3 groups in TE (OR = 1.56, 95% CI: 0.83–2.91, p = 0.17), or survival during hospital stay (OR = 1.34, 95% CI: 0.81–2.23, p = 0.25).ConclusionPCC4 is more effective than PCC3 in meeting specific predefined INR goals and has similar safety profiles in patients requiring emergent reversal of the anticoagulant effects of warfarin.

Étude comparative en soins primaires du taux d'INR dans la cible thérapeutique chez des patients traités par warfarine ou fluindione pour une fibrillation atriale. L’étude FLOWER (FLuindione Or WarfarinE – Result INR)

IntroductionThe aim of our study was to compare the time spent within the target INR or Time in Therapeutic Range (TTR) of patients treated with fluindione to that of patients treated with warfarin for non-valvular atrial fibrillation (NVAF) and followed in general practice, with the hypothesis of a better TTR with warfarin, which is the VKA most commonly prescribed in France. MethodLiberal nurses and general practitioners working in the Auvergne region recruited patients treated with fluindione or warfarin for NVAF. Patients' INRs (International Normalized Ratios) were recorded by medical analysis laboratories for 6 months. The primary endpoint was TTR, the secondary endpoint the number of hemorrhagic and/or thromboembolic events. ResultsOf the 342 participants with a mean age of 75.3 ± 9.8 years, 239 (70%) were treated with fluindione and 103 (30%) with warfarin. The mean number of INRs achieved per patient was 9.2 ± 4.0 in the fluindione group and 9.3 ± 4.0 in the warfarin group (p=0.73). The median TTR of fluindione was 81.9% [63.5; 94.1] and that of warfarin was 81.3% [65.6; 92.6] (p=0.98). Twenty-eight of 263 patients reported hemorrhage (10.6%) and 4 reported thromboembolic events (0.8%), with no significant difference between the groups. ConclusionThe TTRs of patients treated for NVAF with fluindione versus warfarin do not differ significantly over an observation period of 6 consecutive months in a patient population comparable to that of the publications in this field. However, these TTRs are significantly higher than those reported in the literature, with no difference between the two treatments.The TTRs of patients treated for VANF with fluindione versus warfarin do not differ significantly over a 6-month observation period in a patient population comparable to that of the publications in this indication.

WITHDRAWN: Low-Dose Versus Standard Warfarin After Mechanical Mitral Valve Replacement

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Investigation of Education Requirements of Individuals Using Warfarin and Achievement of Target INR Value

Thromboembolic diseases are important causes of morbidity and mortality. Oral anticoagulants for preventing or treating thromboembolic diseases reduce blood clotting and prevent fibrin deposition, thrombus development, and growth. This study aimed to investigate the educational needs and the rate of reaching the target INR level of individuals using warfarin for heart diseases. The population of this cross-sectional study was attempted to reach the entire population by not choosing a sample due to heart diseases between August –September 2019 in the cardiology outpatient clinic of a public hospital operating in Istanbul. However, due to the voluntary basis and incorrect registration of the questionnaires, 157 participants formed the sample. Data were analyzed using the SPSS 25.0 program. 75.1% of the individuals stated that they were informed about the use of warfarin, and 66.8% of those who received the information stated that they received the information from their physician. In addition, 75.7% stated that they took warfarin regularly, 81.7% had regular INR control, 52.1% knew the target INR value, 68.9% knew the complications. It was found to be 47.6. A statistically significant difference was found between individuals who reached the target INR level and those who did not, according to their information acquisition status (p &lt;0.05). The low rate of individuals reaching the target INR level draws attention. For this reason, it is thought that the knowledge level of patients who are starting treatment with warfarin should be increased, and new generation oral anticoagulant drugs can be used as an anticoagulant treatment instead of warfarin in patients whose target INR cannot be achieved despite sufficient training.

Concordance of experienced-based maintenance warfarin dosing vs. algorithm-based dosing

IntroductionWarfarin maintenance dosing algorithms improve the time in therapeutic International Normalized Ratio (INR) range (TTR), a surrogate marker for clinical outcomes. Despite demonstrated benefit, many anticoagulation providers utilize experience-based dosing instead. This study assessed rates of concordance between experience-based and algorithm-based warfarin dosing at a single anticoagulation clinic. MethodsWithin University of Utah Health Thrombosis Service, patients on a maintenance dose of warfarin with an INR goal of 2.0–3.0 or 2.5–3.5 and who had INR results during November 2019 were included. Experienced-based approaches for out-of-range INRs were compared to a validated dosing algorithm to determine algorithm concordance rates as well as likelihood that algorithm concordance would return the INR into therapeutic range. ResultsDuring the one-month study period, there were 1120 out-of-range INRs in 770 patients included in this analysis. Providers’ decisions were 50.5% algorithm-concordant for dosing adjustments and 59.2% concordant for follow-up intervals. Algorithm-concordant dosing practices resulted in a significantly higher likelihood of returning the subsequent INR to the target range (odds ratio [OR] 1.33, 95% confidence interval [CI] 1.05–1.68), whereas algorithm-concordant follow-up intervals did not significantly impact return of INR to therapeutic range (OR 0.79, 95% CI 0.62–1.00). Baseline deviation from INR goal was determined to be significantly different between concordant and discordant study groups. Controlling for the deviation magnitude attenuated the significance of dosing concordance rates on return to INR target range (adjusted OR 1.16, 95% CI 0.91–1.48), while impact of follow-up concordance remained not statistically significant (adjusted OR 0.84, 95% CI 0.66–1.07). No provider characteristics were associated with the likelihood of return to INR goal. ConclusionExperience-based dosing was concordant with a validated dosing algorithm only half the time. Algorithm-concordant dosing increased the likelihood of returning the next INR to therapeutic range, though controlling for deviation magnitude attenuated the statistical significance of dosing concordance with return to INR goal rates. These findings support further research regarding implementing strategies that promote the use of a validated dosing algorithm among experienced anticoagulation providers.

Correlation between CYP2C9 gene polymorphism and warfarin dose in Chinese Han population with coronary heart disease.

This study aimed to explore the correlation between CYP2C9 gene polymorphism and warfarin dose in Chinese Han patients with coronary heart disease. The selection was made to the analysis of blood coagulation test of Chinese Han ethnic group, 200 cases of coronary heart disease patients as target group, the patients were satisfied taking warfarin INR target (in the range of 2.0 ~ 3.0), the other to select 200 cases proved by physical examination health as health group. The warfarin dose and the clinical laboratory INR after warfarin administration were taken, and the DNA of the patients was extracted and tested. The CYP2C9 genotype and allele frequency of patients in the standard group were observed, and the basic information and gene test results of the healthy group and the standard group were compared. Patients in the standard group were grouped according to the CYP2C9 and VKORC1 genotype, and the warfarin dosage was compared respectively. The number of cases of anticoagulant overdose in patients with different genotypes in the target group at the initial stage of warfarin treatment was compared. Results showed that CYP2C9*1/*2, *2/*2, *2/*3, *3/*3 genotypes were not found by detecting CYP2C9 genotype and allele frequency in the standard group. There were no significant differences in genotype and allele frequency between the standard group and the healthy group (P BBB 0 0.05). The mean daily dose of the CYP2C9*1/*3 genotype was lower than the mean daily dose of warfarin required by the CYP2C9*1/*1 genotype, and the difference was statistically significant (P < 0.05). There were significant differences in the incidence of anticoagulation overdose at the initial stage of treatment among different CYP2C9 genotypes (P < 0.05), and the incidence of an anticoagulation overdose in group *1/*3 was significantly higher than that in group *1/*1. In general, There was a correlation between CYP2C9 gene polymorphism and warfarin dose in Chinese Han population with coronary heart disease. Compared with the wilD-type (*1/*1) enzyme, the metabolic ability of warfarin in mutant CYP2C9 enzyme (mainly *1/*3 in Chinese population) decreases, and the patients were sensitive to warfarin treatment, and the dose required decreases.

778 Acute clinical valve thrombosis after transcatheter mitral valve-in-valve replacement

Abstract Aims Transcatheter heart valve (THV) thrombosis is a frequent and potentially life-threatening complication of transcatheter mitral valve replacement (TMVR), occurring in approximately 12% of patients (mainly within the first 3 months after the procedure). The majority of THV thromboses is non-obstructive and subclinical, and remains undetected until a routine echocardiogram is performed. Methods A 65 years old male was suffering from post-ischaemic dilated cardiomyopathy and severe left ventricle systolic dysfunction (LVEF 28%), secondary to a previous STEMI in 2010 treated with primary PCI on proximal LAD; after the STEMI he developed a left ventricle aneurysm and a subsequent severe secondary mitral regurgitation. In late 2020 he underwent a surgical valve replacement with a biologic valve (Perimount Magna Mitral Ease n. 27), alongside a left ventricle reshaping (Dor procedure). After a few months, the patient developed worsening dyspnoea and severe exercise intolerance; a transesophageal echocardiogram (TEE) showed an extensive valve degeneration with diffuse leaflet thickening determining severe valve stenosis and regurgitation. The patient was then admitted to the Cardiology department. A coronary angiography was performed, showing good result of previous PCI and excluding other critical stenoses. The patient then underwent a transcatheter valve-in-valve replacement with a Sapien S3 n. 29 in mitral position. The patient was already in chronic therapy with acetilsalicilic acid (ASA), and after the procedure anticoagulant therapy with Warfarin was started. In the post-procedural period the patient developed an acute worsening of the LVEF with severe hypotension, likely due to after-load mismatch; hence, supportive inotropic therapy with Adrenalin and Enoximone was required. A TEE performed 7 days after the procedure showed absence of diastolic excursion of posterior and lateral cusps and leaflet thickening with a 4 mm thrombotic apposition on the ventricular side, determining severe valve stenosis with markedly increased transvalvular gradients (peak gradient 20 mmHg, mean gradient 11 mmHg). A CT scan of the heart confirmed the valve thrombosis on the inferior and lateral leaflets. Results Unfractioned heparin (UFH) was then added to ASA and Warfarin (INR target of 3.0). After 11 days of aggressive antithrombotic therapy a new TEE was performed, showing marked reduction in transvalvular gradients (peak gradient 10 mmHg, mean gradient 5 mmHg) due to partial dissolution of the thrombotic formation. Warfarin was then stopped, and after switching from UFH to Enoxaparin the patient was discharged asymptomatic and in good general conditions, with indication of follow-up with TEE at 1 month. Conclusions Valve-in-valve TMVR is a relatively new and still infrequent procedure, therefore few evidences about its complications are currently available. Thrombosis on these valves is not rare (12%), but usually develops on the atrial side of the leaflets; interestingly, in this patient the thrombosis was on the ventricular side, likely due to an acute reduction in flow velocity caused by the after-load mismatch and the subsequent cardiogenic shock.

C78. Prosthetic valve thrombosis in uncontrolled internormalized ratio ended up with disaster on prosthetic valve surgary : a barrier of anticoagulant management in rural area

Abstract Background Mechanical prosthetic valve thrombosis (PVT) is a life-threatening complication that requires immediate intervention. With current prosthetic devices and aggressive prophylactic anticoagulation, the incidence of PVT remains low. It needs monitoring of international normalized ratio (INR), which is somewhat difficult to do in rural areas such as West Aceh due to geography. This report details the case of a woman with PVT who developed heart failure after a period of suboptimal anticoagulation. Case Summary We described a 51-year-old woman who had undergone coronary artery bypass graft and mitral valve replacement procedure in 2017. Her physical examination showed the decrease of the prosthetic click sound and lung congestion. From her blood examination, the INR was subtherapeutic. A thrombus was detected on the prosthetic mitral valve by transoesophageal echocardiography. She had history of uncontrolled INR because the patient do not routinely checked her blood to control the optimal dose of anticoagulant. The patient underwent reoperation for mechanical valve thrombosis but unfortunately in the end the patient died at the procedure. Discussion In patients undergoing mechanical heart valve replacement, time in therapeutic range of targeted INR should be ≥ 70 % otherwise it will increase in risk of thromboembolic events. However, in developing countries which have remote areas, repeated examination of the use of warfarin in obtaining the INR target is still a major challenge. Conversely, serious risks can occur if this is not achieved and might be ended up with disaster toward the patient.

C78. Prosthetic valve thrombosis in uncontrolled internormalized ratio ended up with disaster on prosthetic valve surgary : a barrier of anticoagulant management in rural area

Abstract Background Mechanical prosthetic valve thrombosis (PVT) is a life-threatening complication that requires immediate intervention. With current prosthetic devices and aggressive prophylactic anticoagulation, the incidence of PVT remains low. It needs monitoring of international normalized ratio (INR), which is somewhat difficult to do in rural areas such as West Aceh due to geography. This report details the case of a woman with PVT who developed heart failure after a period of suboptimal anticoagulation. Case Summary We described a 51-year-old woman who had undergone coronary artery bypass graft and mitral valve replacement procedure in 2017. Her physical examination showed the decrease of the prosthetic click sound and lung congestion. From her blood examination, the INR was subtherapeutic. A thrombus was detected on the prosthetic mitral valve by transoesophageal echocardiography. She had history of uncontrolled INR because the patient do not routinely checked her blood to control the optimal dose of anticoagulant. The patient underwent reoperation for mechanical valve thrombosis but unfortunately in the end the patient died at the procedure. Discussion In patients undergoing mechanical heart valve replacement, time in therapeutic range of targeted INR should be ≥ 70 % otherwise it will increase in risk of thromboembolic events. However, in developing countries which have remote areas, repeated examination of the use of warfarin in obtaining the INR target is still a major challenge. Conversely, serious risks can occur if this is not achieved and might be ended up with disaster toward the patient.

Abstract 11868: A Reduced Anticoagulation Strategy Among Patients Supported With Ventricular Assist Device is Not Associated With Increased Mortality

Introduction: Patients with left ventricular assist device (VAD) are typically treated with aspirin and warfarin. However, some patients are unable to tolerate full anticoagulation (AC). There is limited information available regarding intermediate-term outcomes in patients on reduced or no anticoagulation. Methods: Patients who underwent VAD implantation at California Pacific Medical Center from January 2015 to January 2020 were studied retrospectively. Patients received aspirin 81 mg daily and warfarin with a target INR of 2-3, and anticoagulation was gradually de-intensified or withdrawn in response to recurrent mucosal bleeding. Pre-implantation characteristics, thrombolytic events (hemolysis, pump thrombosis requiring exchange, TIA, or ischemic CVA), and survival post-implant were compared among patients treated with full AC vs. reduced or no AC. We performed nonparametric survival analysis to obtain Kaplan-Meier survival estimates as of 9/15/2020. Cox proportional hazards regression was used to adjust for confounders measured at baseline. Results: 91 patients underwent VAD implant (80 HeartMate 3 and 11 HeartMate II). The median age was 65, and the majority of patients (79%) were treated as destination therapy. Reduced AC was used in 43 patients (47%), including no anticoagulation (12 patients), aspirin monotherapy (2 patients), warfarin monotherapy (16), warfarin monotherapy with a reduced INR target (10), and aspirin plus warfarin with a reduced INR target (3). During a median follow-up of 22 months, 15 thrombotic events were observed (12 in the reduced AC group and 3 in the full AC group, P=0.19). Two patients underwent pump exchange. 67% of thrombotic events and both pump exchanges occurred in HMII recipients. Survival was similar in both groups (Figure). Conclusions: The use of a reduced or no anticoagulation strategy after VAD implant is not uncommon and is associated with acceptable outcomes, particularly among HeartMate 3 recipients.

The Immediate Effect of COVID-19 Vaccination on Anticoagulation Control in Patients Using Vitamin K Antagonists

Background: In January 2021, the Dutch vaccination programme against SARS-CoV-2 was started. Clinical studies have shown that systemic reactions occur in up to 50% of vaccine recipients. Therefore, COVID-19 vaccination could affect anticoagulation control, potentially leading to an increased risk of thrombotic events and bleeding complications.Aims: To investigate whether the BNT162b2 vaccine affects anticoagulation control in outpatients using Vitamin K antagonists (VKAs).Methods: A case-crossover study was performed in a cohort of outpatient VKA users from four Dutch anticoagulation clinics who received a BNT162b2 vaccine. INR results and VKA dosages before the first vaccination, the reference period, were compared with those after the first and second vaccination.Results: A total of 3148 outpatient VKA users were included, with a mean age (standard deviation (SD)) of 86.7 (8.7) years, of whom 43.8% were male, 67.0% used acenocoumarol and 33.0% phenprocoumon. We observed a decrease of 8.9% of INRs within range in the standard intensity group (target INR 2.0-3.0). There was both an increased risk of supratherapeutic [OR=1.34 (95% CI 1.08-1.67)] and subtherapeutic levels [OR=1.40 (95% CI 1.08-1.83)] after first vaccination. In the high-intensity group (target INR 2.5-3.5), the risk of a supratherapeutic INR was 2.3 times higher after first vaccination [OR=2.29 (95% CI 1.22-4.28)] and 3.3 times higher after second vaccination [OR 3.25 (95% CI 1.06-9.97).Conclusion: BNT162b2 was associated with an immediate negative effect on anticoagulation control in patients treated with vitamin K antagonists, so it is advisable to monitor the INR short after vaccination, even in stable patients. [Display omitted] DisclosuresKruip: Daiichi Sankyo: Research Funding; Bayer: Honoraria, Research Funding.

Efficacy and Safety of Tinzaparin in CAT Patients with Hematological Malignancy

IntroductionIn patients with hematological cancers, the high risk of bleeding raises serious concerns when anticoagulant therapy is initiated for treatment of acute venous thromboembolism (VTE). In the CATCH trial, we showed that tinzaparin is associated with a significantly lower risk of clinically relevant bleeding (CRB) and clinically relevant non-major bleeding (CRNMB) compared with warfarin therapy in patients with a solid tumor or hematological cancer. Hence, we performed a post-hoc analysis to assess the risk of recurrent VTE (rVTE) and bleeding in the hematological cancer patient subgroup. Risk factors associated with rVTE and bleeding were also explored.MethodsCATCH (ClinicalTrials.govNCT01130025; Lee A et al. JAMA 2015) was a Phase III, multinational, randomized, active-controlled, open-label trial. Patients with solid tumors or hematological malignancies were randomized to receive therapeutic dosing of tinzaparin (175 IU/kg OD) vs warfarin (INR target 2.0 - 3.0) for treatment of acute VTE. Treatment was given for up to 6 months but was withheld during periods of severe thrombocytopenia (platelet count < 50 x 10 9/L). The primary efficacy outcome was the composite of symptomatic deep vein thrombosis (DVT), symptomatic nonfatal pulmonary embolism (PE), fatal PE, incidental proximal DVT and incidental proximal PE. All thrombosis and bleeding outcomes, including rPE, rDVT, major bleeding (MB), CRB, and CRNMB were objectively documented and centrally adjudicated in a treatment-blinded fashion. Patients with myeloma, lymphoma or leukemia were included in this sub-group analysis. Treatment effect was assessed by means of a cox-regression with time to first event as outcome and deaths not due to fatal PE as a competing risk factor. The cumulative incidence functions and the corresponding 95% CIs were estimated.Results94 of 900 subjects (10.4%) in CATCH had a hematological cancer. Of these patients, 44 and 50 received tinzaparin and warfarin, respectively. The most common hematological cancer was lymphoma (59.6%), followed by myeloma (30.9%), chronic leukemia (5.3%) and acute leukemia (4.3%). rVTE occurred in fewer patients assigned to tinzaparin versus warfarin (2.4% vs 6.4%) but this difference was not statistically significant (HR 0.36; 95%CI 0.04-3.14). All recurrent thrombotic events were PE; no rDVT occurred. Also, trends for less bleeding with tinzaparin were noted for MB (tinzaparin 0.0% versus warfarin 5.0%), CRB (tinzaparin 10.4% vs warfarin 23.5%; HR 0.53; 95%CI 0.15-1.83) and CRNMB (tinzaparin 10.4% vs warfarin 19.5%; HR 0.69; 95%CI 0.19-2.51). 3 patients in each treatment arm had a fatal bleeding event and there was no difference in overall mortality (tinzaparin 22.7% vs warfarin 22.0%). There were no risk factors associated with rVTE identified. Factors associated with CRB in patients with hematological cancer included the use of antiplatelet agents (HR 7.63; 95%CI 1.17-49.6; p=0.033) and renal insufficiency (HR 12.4; 95%CI 2.15-72.0; p=0.005).ConclusionIn this post-hoc subgroup analysis of patients with hematological cancers who received anticoagulation for acute VTE, tinzaparin may be a more effective and safer alternative to warfarin. Randomized controlled trials are warranted to test this hypothesis in this challenging population with a high risk of bleeding. [Display omitted] DisclosuresLee: Leo Pharma: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Servier: Consultancy, Honoraria. Bauersachs: Bayer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; LEO Pharma: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Janus: LEO Pharma: Current Employment. Leeder: LEO Pharma: Current Employment. Thoning: LEO Pharma: Current Employment. Khorana: Anthos: Consultancy, Honoraria; Halozyme: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria.

Comprehensive Multi-Parameter Characterisation of Circulating Extracellular Vesicles from Rivaroxaban-Treated VTE Patients Reveals Reduced Inflammation and Ameliorated Endothelial Dysfunction

Venous Thromboembolism (VTE) remains a significant cause of morbidity and mortality worldwide. Rivaroxaban, a direct oral factor Xa inhibitor, mediates anti-inflammatory and cardiovascular-protective effects besides its well-established anticoagulant properties, however, these remain poorly characterized. Extracellular vesicles (EVs) are important circulating messengers regulating a myriad of biological and pathological processes and may be highly relevant to the pathophysiology of VTE as they reflect alterations in platelet and endothelial biology. However, the effects of Rivaroxaban on circulating pro-inflammatory EVs in VTE patients remain unknown. We hypothesized that rivaroxaban's anti-inflammatory properties are reflected upon differential molecular profiles of circulating EVs.Single-episode VTE patients anticoagulated with 20 mg Rivaroxaban or warfarin at a target INR of 2.0-3.0, respectively, who had commenced therapy no sooner than 3 months previously were recruited following informed written consent at the Mater Misericordiae University Hospital, Dublin, Ireland. Patient data including age, sex, BMI, prevalent risk factors and comorbidities were collected. Patients on warfarin therapy had a time in therapeutic range of at least 55% and an INR in target range at time of blood sampling. Exclusion criteria included known pro-inflammatory conditions, active malignancy, recurrent VTE, antiphospholipid syndrome, bleeding or platelet function disorders, use of anti-platelet drugs, and thrombocytopenia.To address the hypothesis, we firstly used a combination of Nanoparticle Tracking Analysis (NTA) and flow cytometry to comprehensively characterise differences in the concentration and size of small (0-200 nm) and large (200-1000 nm) circulating EVs, respectively. Statistical analysis revealed a trend towards reduced levels of circulating small and large EVs in Rivaroxaban-treated VTE patients compared with matched warfarin controls. Moreover, small and large EVs measured in the patients plasma correlated strongly and highly significantly (r=0.804, p<0.0001), indicating a concomitant decrease in both populations. As circulating EVs are considered pro-coagulant and pro-inflammatory, these results may point towards an ameliorated baseline pro-inflammatory state of VTE patients anticoagulated with Rivaroxaban. To further uncover Rivaroxaban-mediated alterations, we next compared proteomic profiles of circulating EVs. We robustly quantified over 300 vesicular proteins. Statistical analysis of the protein expression level using a student's t-test with a false discovery rate of 5% and a minimal fold change of 0.1 identified differential protein expression of a tightly regulated cluster of proteins involved in negative feedback regulation of inflammatory and coagulation pathways in Rivaroxaban-treated patients, which may in part contribute to the superior outcomes of Rivaroxaban-treated patients seen in recent clinical trials. Furthermore, we recently established that Rivaroxaban potentially ameliorates endothelial dysfunction in a cohort of non-valvular atrial fibrillation patients. Therefore, we aimed to also assess circulating markers of endothelial activation (Intercellular Adhesion Molecule 1 [ICAM-1] and Tissue Factor Pathway Inhibitor [TFPI]). Intriguingly, Rivaroxaban-treated patients exhibited an increase in plasma TFPI levels with a simultaneous decrease in soluble ICAM-1, potentially pointing towards ameliorated endothelial dysfunction in Rivaroxaban-treated VTE patients relative to warfarin.Collectively, we established that EV proteomic signatures are powerful biological sensors of Rivaroxaban's anti-inflammatory potential. Moreover, Rivaroxaban therapy may ameliorate endothelial dysfunction relative to warfarin. These findings are of translational relevance towards characterizing the anti-inflammatory and cardiovascular-protective mechanisms associated with Rivaroxaban therapy. DisclosuresKevane: Leo Pharma: Research Funding. Murphy: Bayer Pharma: Research Funding. Ni Ainle: Daiichi-Sankyo: Research Funding; Actelion: Research Funding; Leo Pharma: Research Funding; Bayer Pharma: Research Funding. Maguire: Bayer Pharma: Research Funding; Actelion: Research Funding.

Direct Oral Anticoagulants for Stroke Prevention in Patients with Atrial Fibrillation and Bioprosthetic Heart Valves

Direct Oral Anticoagulants for Stroke Prevention in Patients with Atrial Fibrillation and Bioprosthetic Heart Valves

Fixed-dose prothrombin complex concentrate for emergent warfarin reversal among patients with intracranial hemorrhage.

Four-factor prothrombin complex concentrate (4PCC) is the preferred reversal agent for warfarin reversal, although the ideal dose is unknown. Fixed-dose 4PCC offers simplified dosing compared to standard-dosing algorithms with potentially lower risks of thromboembolic complications given lower doses are typically utilized. Retrospective, observational, multicentered, pre- post- study of patients who received 4PCC for warfarin reversal among four hospitals within the same regional health system. Standard-dose patients received variable doses ranging from 25 to 50 units/kg based on total body weight and initial INR and fixed-dose patients received 2000 units. The primary outcome was achievement of a target INR ≤ 1.4 on the first post-4PCC INR result. After exclusions, 48 and 42 patients were analyzed in the standard-dose and fixed-dose groups, respectively. There was no difference in the ability to achieve a target INR of ≤1.4 (82.6% vs 81.5%, p = 0.14). Both groups received the same median dose of 2000 units, although fixed-dose patients actually received a higher weight-based dose than standard-dose patients (27 units/kg vs 24.5 units/kg). A fixed-dose 4PCC regimen of 2000 units among patients with ICH was as effective as standard-dose 4PCC for INR reversal among patients with ICH. However, fixed-doses of 2000 units at times exceeded standard 4PCC doses which may be contradictory to the goals of fixed-dose 4PCC for warfarin reversal.

Frequency of Achieving Target INR in Patient on Warfarin for Atrial Fibrillation

Background: Warfarin has long been established as the oral anticoagulant of choice. The benefits of warfarin depend on maintaining the International Normalized Ratio (INR). It has been shown that the optimal INR target range is 2-3 for AF patients. Very less number of patients had been reported to achieve and remain in that target INR range. The prevalence of AF in the general population is about 1.6% in women and 2.4% in men and is generally lower in Asian countries Aim: To determine the frequency of achieving target INR in patient on warfarin for atrial fibrillation. Methodology: This is cross sectional study conducted at national institute of cardio vascular disease, Karachi from 31st May 2016 30th November 2016.The sample size of the study were 111, and nonprobability convenience sampling technique was used. Results: Among study population 61 (54.9%) were male and 50(45%) female patients. Mean duration of atrial fibrillation was 3.44±0.97 years. The mean duration of warfarin taken was 11.34±3.96 months. INR (2-3) target achieved in 72(64.9%) patients. Significant association of achieved INR target was observed with duration of atrial fibrillation, duration of warfarin, hypertension, stroke, and Left ventricular dysfunction. Conclusion: Target of INR was achieved in 64.9% patients when these patients were given warfarin doses of 5.0 to 7.5 mg/day. Keywords: Achieving Target INR, Warfarin, Atrial Fibrillation.

O24 Malignancy in antiphospholipid syndrome: a catastrophe

O24 Malignancy in antiphospholipid syndrome: a catastrophe

O16 A diagnosis of BehÇet’s Disease with secondary antiphospholipid syndrome

O16 A diagnosis of BehÇet’s Disease with secondary antiphospholipid syndrome

Efficacy and safety of low intensity vitamin K antagonists in Western and East-Asian patients with left-sided mechanical heart valves.

The optimal INR target in patients with mechanical heart valves is unclear. Higher INR targets are often used in Western compared with East Asian countries. The objective of this systematic review and meta-analysis was to summarize the evidence for the efficacy and safety of lower versus higher INR targets in Western and East Asian left-sided mechanical heart valve patients. We searched Western databases including Cochrane CENTRAL, Medline, and Embase as well as Chinese databases including SinoMed, CNKI, and Wanfang Data in addition to grey literature for Randomized Controlled Trials (RCTs) and observational studies. We pooled risk ratios (RRs) using random-effects model. Low and high INR targets were defined by the individual studies. We identified nine RCTs, including six Western (n = 5496) and three East Asian (n = 209) trials, and 17 observational studies, including two Western (n = 3199) and 15 East Asian (n = 5485) studies. In the RCTs, lower compared with higher targets were associated with similar rates of thromboembolism (2.4 vs. 2.3%; RR: 1.14, 95% CI 0.82, 1.60, I2 = 0%) and lower rates of both total bleeding (21.9 vs. 40.9%, RR: 0.46, 95% CI 0.28, 0.78, I2 = 88%) and major bleeding. RCT data showed no statistical heterogeneity by region. These effects were consistent in the observational data. We downgraded the quality of evidence due to serious risk of bias and imprecision. In patients with left-sided contemporary mechanical heart valves, low quality evidence suggests lower INR targets are associated with similar rates of thromboembolism and moderate quality evidence suggests lower rates of bleeding.