-
1.
Risk Factors for Severe Bleeding Complications in Vitreoretinal Surgery and the Role of Antiplatelet or Anticoagulant Agents.
Lauermann, P, Klingelhöfer, A, Mielke, D, van Oterendorp, C, Hoerauf, H, Striebe, NA, Storch, MW, Pfeiffer, S, Koscielny, J, Sucker, C, et al
Ophthalmology. Retina. 2021;(8):e23-e29
Abstract
PURPOSE To evaluate the influences and risk factors for severe bleeding complications during vitreoretinal surgery and to investigate the role of antiplatelet and anticoagulant agents. DESIGN Prospective trial. PARTICIPANTS Patients undergoing vitreoretinal surgery. METHODS The procedures included were pars plana vitrectomy and scleral buckling. We developed a uniform classification to grade the bleeding severity. Bleeding was graded on an ordinal scale ranging from 0 to 5. Immediately after surgery and 1 day later, the incidence and the severity of bleeding events was documented on a standardized form. A grade of 3 or more was defined as severe bleeding. Furthermore, the influence of known systemic disorders before surgery, the type of anesthesia, type of surgical procedure, intraoperative blood pressure, and the use or change of antiplatelet or anticoagulant agents on intraoperative bleeding was analyzed. MAIN OUTCOME MEASURES Incidence and risk factors for severe intraoperative bleeding events. RESULTS Data from 374 eyes undergoing vitreoretinal procedures were included in our study (mean age, 67.6 ± 12.9 years). A severe intraoperative bleeding event was observed in 15 eyes (4%). We found that concomitant diseases such as diabetes mellitus and carotid artery stenosis, the presence of diabetic retinopathy, younger age, and scleral buckling combined with a transscleral puncture were associated significantly with severe bleeding events. By contrast, use of antiplatelet or anticoagulant agents, or both, had no significant influence on severe intraoperative bleeding events. CONCLUSIONS Although external manipulations during buckling surgery (e.g., drainage of subretinal fluid) and concomitant diseases such as diabetes mellitus and carotid artery stenosis influences the risk of severe intraoperative bleeding events, we did not detect an increased risk related to coexisting antiplatelet or anticoagulant medication use, or both.
-
2.
Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial.
Male, C, Lensing, AWA, Palumbo, JS, Kumar, R, Nurmeev, I, Hege, K, Bonnet, D, Connor, P, Hooimeijer, HL, Torres, M, et al
The Lancet. Haematology. 2020;(1):e18-e27
-
-
Free full text
-
Abstract
BACKGROUND Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. METHODS In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children <2 years of age with catheter-related venous thromboembolism). The primary efficacy outcome, symptomatic recurrent venous thromboembolism (assessed by intention-to-treat), and the principal safety outcome, major or clinically relevant non-major bleeding (assessed in participants who received ≥1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. FINDINGS From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0·40, 95% CI 0·11-1·41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0·012). Major or clinically relevant non-major bleeding in participants who received ≥1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1·58, 95% CI 0·51-6·27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths. INTERPRETATION In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants. FUNDING Bayer AG and Janssen Research & Development.
-
3.
Educational Impact on Apixaban Adherence in Atrial Fibrillation (the AEGEAN STUDY): A Randomized Clinical Trial.
Montalescot, G, Brotons, C, Cosyns, B, Crijns, HJ, D'Angelo, A, Drouet, L, Eberli, F, Lane, DA, Besse, B, Chan, A, et al
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2020;(1):61-71
-
-
Free full text
-
Abstract
INTRODUCTION Adherence to non-vitamin-K oral anticoagulants (NOACs) may be lower than to vitamin K antagonists because NOACs do not require routine monitoring. OBJECTIVE We assessed the impact of an educational program on adherence and persistence with apixaban in patients with non-valvular atrial fibrillation (NVAF). METHODS Patients with NVAF eligible for NOACs with one or more stroke risk factor (prior stroke/transient ischemic attack, age ≥ 75 years, hypertension, diabetes, or symptomatic heart failure) were randomized (1:1) to standard of care (SOC) or SOC with additional educational (information booklet, reminder tools, virtual clinic access). The primary outcome was adherence to apixaban (2.5 or 5 mg twice daily) at 24 weeks. Patients receiving the educational program were re-randomized (1:1) to continue the program for 24 further weeks or to switch to secondary SOC. Implementation adherence and persistence were reassessed at 48 weeks. RESULTS In total, 1162 patients were randomized (SOC, 583; educational program, 579). Mean implementation adherence ± standard deviation (SD) at 24 weeks was 91.6% ± 17.1 for SOC and 91.9% ± 16.1 for the educational program arm; results did not differ significantly between groups at any time-point. At 48 weeks, implementation adherence was 90.4% ± 18.0, 90.1% ± 18.6, and 89.3% ± 18.1 for continued educational program, SOC, and secondary SOC, respectively; and corresponding persistence was 86.1% (95% confidence interval [CI] 81.3-89.7), 85.2% (95% CI 81.5-88.2), and 87.8% (95% CI 83.4-91.1). Serious adverse events were similar across groups. CONCLUSION High implementation adherence and persistence with apixaban were observed in patients with NVAF receiving apixaban. The educational program did not show additional benefits. CLINICAL TRIAL REGISTRATION This study is registered at ClinicalTrials.gov [NCT01884350].
-
4.
XALIA-LEA: An observational study of venous thromboembolism treatment with rivaroxaban and standard anticoagulation in the Asia-Pacific, Eastern Europe, the Middle East, Africa and Latin America.
Kreutz, R, Mantovani, LG, Haas, S, Monje, D, Schneider, J, Bugge, JP, Gebel, M, Tamm, M, Ageno, W, Turpie, AGG
Thrombosis research. 2019;:125-132
Abstract
INTRODUCTION The prospective, non-interventional XALIA study investigated the safety and effectiveness of rivaroxaban and standard anticoagulation for the treatment of deep vein thrombosis (DVT). XALIA-LEA was conducted in regions not included in XALIA (Latin America, Eastern Europe, the Middle East, Africa, and the Asia-Pacific), and enrolled patients with isolated pulmonary embolism (PE). MATERIALS AND METHODS Adult patients with acute venous thromboembolism (VTE) indicated for ≥3 months' anticoagulant treatment were eligible; treatment strategies were at the physician's discretion. Patients receiving rivaroxaban or standard anticoagulation (unfractionated or low-molecular weight heparin/fondaparinux alone or overlapping with and followed by a vitamin K antagonist [VKA]) were included in the safety analysis. "Early switchers" to rivaroxaban (i.e. after receiving heparin/fondaparinux for >2-14 days and/or a VKA for 1-14 days) were not included in the safety analysis set. RESULTS Of the 1972 eligible patients, 1285 received rivaroxaban, 402 received standard anticoagulation, and 285 were early switchers. Most patients who received rivaroxaban were appropriately selected, received the correct dosing schedule, reported few adverse effects. Outcomes were similar to previously published results, with rivaroxaban associated with a low rate of major bleeding (1.6%), recurrent VTE (1.4%) and all-cause mortality (2.3%). Including early switchers, relatively fewer patients with index isolated PE received rivaroxaban (14.4%) versus standard anticoagulation therapy (20.9%). Some regional variations and differences in outcomes by VTE subtype were apparent with standard anticoagulation treatment. CONCLUSION XALIA-LEA reaffirms the safety and effectiveness of rivaroxaban for VTE treatment for countries not included in XALIA.
-
5.
Determinants of the Quality of Warfarin Control after Venous Thromboembolism and Validation of the SAMe-TT2-R2 Score: An Analysis of Hokusai-VTE.
Barco, S, Granziera, S, Coppens, M, Douxfils, J, Nijkeuter, M, Riva, N, Vanassche, T, Zhang, G, Lin, M, Kamphuisen, PW, et al
Thrombosis and haemostasis. 2019;(4):675-684
Abstract
BACKGROUND Time in therapeutic range (TTR) measures the quality of vitamin K antagonist (VKA) anticoagulation. In patients with atrial fibrillation, the dichotomized SAMe-TT2-R2 score (≥2 vs. < 2 points) can predict if adequate TTR is unlikely to be achieved. AIMS We validated the SAMe-TT2-R2 score in patients with venous thromboembolism (VTE) randomized to the warfarin arm of the Hokusai-VTE trial. PATIENTS AND METHODS A total of 3,874 patients were included in the primary analysis (day 31-180 from randomization). The efficacy and safety outcomes were symptomatic recurrent VTE and major or clinically relevant non-major bleeding. RESULTS The rates of recurrent VTE and bleeding events were higher in patients with a TTR below the median (< 66% vs. ≥66%) resulting in an absolute risk difference (ARD) of +0.5% (95% confidence interval: 0%, +1.1%) and +2.2% (0.9%, +3.5%), respectively. Patients with high SAMe-TT2-R2 score were 76% of total and had lower median TTR (64.7% vs. 70.7%). The SAMe-TT2-R2 score exhibited low negative (0.59) and positive (0.52) predictive value (TTR threshold 66%), and poor discrimination (c-statistic, 0.58). ARD between patients with high and low score was 0% (-0.6%, +0.7%) for recurrence and +1.3% (-0.1%, +2.7%) for bleeding. Results were confirmed in sensitivity analyses focusing on the whole study period (day 1-365). CONCLUSION In VTE patients, the SAMe-TT2-R2 score showed unsatisfactory discrimination and predictive value for individual TTR and did not correlate well with clinical outcomes. The choice of starting a patient on VKA cannot be based on this parameter and its routine use after VTE may not translate into clinical usefulness.
-
6.
Characteristics in Non-Vitamin K Antagonist Oral Anticoagulant-Related Intracerebral Hemorrhage.
Gerner, ST, Kuramatsu, JB, Sembill, JA, Sprügel, MI, Hagen, M, Knappe, RU, Endres, M, Haeusler, KG, Sobesky, J, Schurig, J, et al
Stroke. 2019;(6):1392-1402
Abstract
Background and Purpose- Given inconclusive studies, it is debated whether clinical and imaging characteristics, as well as functional outcome, differ among patients with intracerebral hemorrhage (ICH) related to vitamin K antagonists (VKA) versus non-vitamin K antagonist (NOAC)-related ICH. Notably, clinical characteristics according to different NOAC agents and dosages are not established. Methods- Multicenter observational cohort study integrating individual patient data of 1328 patients with oral anticoagulation-associated ICH, including 190 NOAC-related ICH patients, recruited from 2011 to 2015 at 19 tertiary centers across Germany. Imaging, clinical characteristics, and 3-months modified Rankin Scale (mRS) outcomes were compared in NOAC- versus VKA-related ICH patients. Propensity score matching was conducted to adjust for clinically relevant differences in baseline parameters. Subgroup analyses were performed regarding NOAC agent, dosing and present clinically relevant anticoagulatory activity (last intake <12h/24h or NOAC level >30 ng/mL). Results- Despite older age in NOAC patients, there were no relevant differences in clinical and hematoma characteristics between NOAC- and VKA-related ICH regarding baseline hematoma volume (median [interquartile range]: NOAC, 14.7 [5.1-42.3] mL versus VKA, 16.4 [5.8-40.6] mL; P=0.33), rate of hematoma expansion (NOAC, 49/146 [33.6%] versus VKA, 235/688 [34.2%]; P=0.89), and the proportion of patients with unfavorable outcome at 3 months (mRS, 4-6: NOAC 126/179 [70.4%] versus VKA 473/682 [69.4%]; P=0.79). Subgroup analyses revealed that NOAC patients with clinically relevant anticoagulatory effect had higher rates of intraventricular hemorrhage (n/N [%]: present 52/109 [47.7%] versus absent 9/35 [25.7%]; P=0.022) and hematoma expansion (present 35/90 [38.9%] versus absent 5/30 [16.7%]; P=0.040), whereas type of NOAC agent or different NOAC-dosing regimens did not result in relevant differences in imaging characteristics or outcome. Conclusions- If effectively anticoagulated, there are no differences in hematoma characteristics and functional outcome among patients with NOAC- or VKA-related ICH. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT03093233.
-
7.
A simple, sensitive, and high-throughput LC-APCI-MS/MS method for simultaneous determination of vitamin K1, vitamin K1 2,3-epoxide in human plasma and its application to a clinical pharmacodynamic study of warfarin.
Hu, K, Li, Y, Ding, R, Zhai, Y, Chen, L, Qian, W, Yang, J
Journal of pharmaceutical and biomedical analysis. 2018;:82-91
Abstract
Warfarin exerts its anticoagulation activity by blocking the vitamin K-epoxide cycle. A quantitative understanding of how warfarin and related genes interact with the vitamin K-epoxide cycle and the associated change of coagulation activity in the human body may help study the pharmacodynamics of warfarin. The plasma concentration of vitamin K1 (VK1) and vitamin K1 2,3-epoxide (VK1O) could reflect the status of vitamin K-epoxide cycle. However, their determination is a challenging task due to their extremely low concentrations in human plasma and the severe interferences caused by co-extracted lipids. In this study, we developed an LC-APCI-MS/MS method for the simultaneous determination of VK1 and VK1O in human plasma using stable deuterium-labeled vitamin K1 (vitamin K1-d7) as the internal standard (IS). Plasma samples were prepared through protein denaturation followed by one-step liquid extraction with cyclohexane. Chromatographic separation of analytes from isobaric interferences and endogenous ion suppressor was performed on a Synergi Hydro-RP column (150 mm × 4.6 mm, 4 μm) under the reversed-phase condition with isocratic elution. The selective reaction monitoring (SRM) transitions were chosen as m/z = 451.5→187.3 for VK1, m/z = 467.5→161.2 for VK1O, and m/z = 458.6→194.3 for IS in APCI positive mode. The assay was linear in the range of 100-10,000 pg/mL for the two analytes and achieved considerable extraction recoveries (87.8-93.3%, 91.0-96.9%, and 92.0% for VK1, VK1O, and IS, respectively), negligible matrix effects (93.6-96.0%, 96.3-100.1%, and 95.5%), and high selectivity with a small sample volume requirement (0.2 mL) and short run time (15 min). The validated method was successfully applied in a clinical pharmacodynamic study of warfarin, and the clotting activity was found to be negatively correlated with the plasma concentration ratio of VK1O to VK1.
-
8.
Management and outcome of major bleeding in patients receiving vitamin K antagonists for venous thromboembolism.
Moustafa, F, Stehouwer, A, Kamphuisen, P, Sahuquillo, JC, Sampériz, Á, Alfonso, M, Pace, F, Suriñach, JM, Blanco-Molina, Á, Mismetti, P, et al
Thrombosis research. 2018;:74-80
Abstract
BACKGROUND The optimal management of major bleeding in patients receiving vitamin K antagonists (VKA) for venous thromboembolism (VTE) is unclear. METHODS We used the RIETE (Registro Informatizado Enfermedad TromboEmbólica) registry to assess the management and 30-day outcomes after major bleeding in patients receiving VKA for VTE. RESULTS From January 2013 to December 2017, 267 of 18,416 patients (1.4%) receiving long-term VKA for VTE had a major bleeding (in the gastrointestinal tract 78, intracranial 72, hematoma 50, genitourinary 20, other 47). Overall, 151 patients (57%) received blood transfusion; 110 (41%) vitamin K; 37 (14%) fresh frozen plasma; 29 (11%) pro-haemostatic agents and 20 (7.5%) a vena cava filter. During the first 30 days, 59 patients (22%) died (41 died of bleeding) and 13 (4.9%) had a thrombosis. On multivariable analysis, patients with intracranial bleeding (hazard ratio [HR]: 4.58; 95%CI: 2.40-8.72) and those with renal insufficiency at baseline (HR: 2.73; 95%CI: 1.45-5.15) had an increased mortality risk, whereas those receiving vitamin K had a lower risk (HR: 0.47; 0.24-0.92). On the other hand, patients receiving fresh frozen plasma were at increased risk for thrombotic events (HR: 4.22; 95%CI: 1.25-14.3). CONCLUSIONS Major bleeding in VTE patients receiving VKA carries a high mortality rate. Intracranial bleeding and renal insufficiency increased the risk. Fresh frozen plasma seems to increase this risk for recurrent VTE.
-
9.
Haemodialysis with Tinzaparin Versus Dialysate Citrate as Anticoagulation.
Mahmood, D, Stegmayr, BG
Blood purification. 2018;(3):257-263
Abstract
Anticoagulation with citrate-containing haemodialysate (cHD) is an alternative to tinzaparin haemodialysate (tHD). The study investigated whether cHD would differ when changed from tHD. The same 18 patients were their own controls followed up with cHD for 5 months. LDL-cholesterol decreased at the end of a cHD session (p = 0.01). Neutrophils (p = 0.013) and monocytes (p = 0.007) dropped more during a cHD session. During the follow-up period of cHD, approximately 50% needed additional tinzaparin. Before the cHD session could start, there was a lower total cholesterol at 2 weeks (p = 0.014) and LDL-cholesterol at 1 month (p = 0.011) versus an increase of LDL at 5 months (p = 0.02). Only patients without additional tinzaparin had a reduction of -C-reactive protein (CRP) at 2 months of cHD (p < 0.05) but not later. Solely cHD seems possible only in half of the patients. A greater reduction in granulocytes and monocytes during cHD indicates a more extensive blood membrane interaction, while CRP may be lower.
-
10.
Simple citrate anticoagulation protocol for low flux haemodialysis.
Lim, EK, Seow, YT, Chen, SE, Yang, G, Liaw, ME, Isaac, S
BMC nephrology. 2018;(1):16
Abstract
BACKGROUND For patients unable to receive heparin anticoagulation during haemodialysis, saline flushes to reduce circuit clotting are often the norm. Regional citrate anticoagulation (RCA) although effective is not used by many centres including in Singapore. We wanted to demonstrate the superiority and safety of a simple regional citrate anticoagulation regime, compared to saline flushes, for heparin-free low flux haemodialysis. METHODS This is a prospective, open label, cross over study on 25 sequential haemodialysis sessions for inpatients receiving heparin-free haemodialysis. Patients were allocated either to regional citrate anticoagulation or standard heparin free haemodialysis and subsequently cross over to the alternate method. RCA was carried out using a protocol derived from previous studies. Assessment of anticoagulation was performed using visual inspection of clot formation in dialysis circuits and post-filter ionized calcium (iCa2+) using point-of-care Ionized calcium device at stipulated intervals. Intravenous Calcium gluconate replacement was given to patients receiving citrate adjusting the rate according to pre-filter iCa2+. Laboratory analyses of electrolytes were also assessed at the start and end of the RCA sessions. RESULTS There were no clots in the RCA arm, with 79% (n = 19) in the saline flush arm having some clot, including 1 clotted circuit. Post-filter iCa2+ at various time points were within acceptable range. Electrolyte readings in the RCA group were all within normal limits except for 4 cases of total Calcium:iCa2+ ratio > 2.5. CONCLUSION RCA is confirmed to be superior to saline flushes for circuit patency. We have a simple and safe protocol that can be followed for low flux haemodialysis. The study was approved by Singapore National Health Group domain-specific ethnical committee. NHG DSRB reference number 2014/01037. TRIAL REGISTRATION Trial registration number: ISRCTN69952745 (registration date 8/11/17).