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1.
Eur J Intern Med ; 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31955918

RESUMO

The association between preceding treatment with antiplatelet agents (APs), vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) and mortality after intracerebral hemorrhage (ICH) remains unclear. The aim of this multicenter, prospective cohort study was to assess the risk for death after ICH in consecutive patients who were on treatment with APs, VKAs, DOACs, or no antithrombotic agent. The primary outcome was in-hospital death by day 30. ICH volume at admission and volume expansion were centrally assessed. Out of 598 study patients, in-hospital death occurred in 21% of patients who were on treatment with APs, 25% with VKAs, 30% with DOACs, and 13% with no antithrombotics. Crude death rate was higher in patients on antithrombotics as compared to patients receiving no antithrombotic agent. At multivariate analysis, age (HR 1.07; 95% CI 1.04-1.10), previous stroke (HR 1.83; 95% CI 1.14-2.93), GCS ≤8 at admission (HR 6.06; 95% CI 3.16-9.74) and GCS 9-12 (HR 3.38; 95% CI 1.81-6.33) were independent predictors of death. Treatment with APs (HR 1.29; 95% CI 0.61-2.76), VKAs (HR 1.42; 95% CI 0.70-2.88) or DOACs (HR 1.28; 95% CI 0.61-2.73) were not predictors of death in the overall study population, in non-trauma associated ICH as well as when GCS was not included in the model. ICH volume and volume expansion were independent predictors of death. In conclusion, preceding treatment with antithrombotic is associated with the severity of ICH. Age, previous stroke and clinical severity at presentation were independent predictors of in-hospital death in patients with ICH.

2.
Lancet Haematol ; 7(1): e18-e27, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31699660

RESUMO

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.


Assuntos
Anticoagulantes/uso terapêutico , Rivaroxabana/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Fatores de Risco
3.
Thromb Haemost ; 120(1): 132-140, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31705521

RESUMO

The rapid determination of the presence of direct oral anticoagulants (DOACs) in a patient remains a major challenge in emergency medicine and for rapid medical treatment decisions. All DOACs are excreted into urine. A sensitive and specific point-of-care test has been developed to determine whether they are present in patient urine samples. This prospective multicenter study aimed to demonstrate at least 95% correct positive and negative predictive results for factor Xa and thrombin inhibitors in urine samples using DOAC Dipstick pads compared with liquid chromatography-tandem mass spectrometry (LC-MS/MS) (NCT03182829). Nine hundred and fourteen subjects were included and 880 were evaluated per protocol (factor Xa inhibitors apixaban, edoxaban, and rivaroxaban: n = 451, thrombin inhibitor dabigatran: n = 429) at 18 centers. The sensitivity, specificity, accuracy, and predictive values and agreement between methods for determination of factor Xa inhibitors were at least noninferior to 95% with a 0.5% margin and of thrombin inhibitor superior to 97.5%. These results were compared with LC-MS/MS results in the intention-to-analyze cohort (all p < 0.05). The receiver operating curve showed c-values of 0.989 (factor Xa inhibitors) and 0.995 (thrombin inhibitor). Visual evaluation of the factor Xa and thrombin inhibitor pads was not different between centers. Qualitative determination of both types of DOACs was accurate using the DOAC Dipstick compared with using LC-MS/MS. The high predictive values may impact laboratory and clinical decision-making processes.

4.
Eur Heart J ; 41(4): 509-518, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31120118

RESUMO

AIMS: To investigate the efficacy and safety of early transition from hospital to ambulatory treatment in low-risk acute PE, using the oral factor Xa inhibitor rivaroxaban. METHODS AND RESULTS: We conducted a prospective multicentre single-arm investigator initiated and academically sponsored management trial in patients with acute low-risk PE (EudraCT Identifier 2013-001657-28). Eligibility criteria included absence of (i) haemodynamic instability, (ii) right ventricular dysfunction or intracardiac thrombi, and (iii) serious comorbidities. Up to two nights of hospital stay were permitted. Rivaroxaban was given at the approved dose for PE for ≥3 months. The primary outcome was symptomatic recurrent venous thromboembolism (VTE) or PE-related death within 3 months of enrolment. An interim analysis was planned after the first 525 patients, with prespecified early termination of the study if the null hypothesis could be rejected at the level of α = 0.004 (<6 primary outcome events). From May 2014 through June 2018, consecutive patients were enrolled in seven countries. Of the 525 patients included in the interim analysis, three (0.6%; one-sided upper 99.6% confidence interval 2.1%) suffered symptomatic non-fatal VTE recurrence, a number sufficiently low to fulfil the condition for early termination of the trial. Major bleeding occurred in 6 (1.2%) of the 519 patients comprising the safety population. There were two cancer-related deaths (0.4%). CONCLUSION: Early discharge and home treatment with rivaroxaban is effective and safe in carefully selected patients with acute low-risk PE. The results of the present trial support the selection of appropriate patients for ambulatory treatment of PE.

5.
Thromb Res ; 181 Suppl 1: S19-S22, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31477222

RESUMO

The recent approval of direct-acting oral anticoagulants (DOAC) for long-term anticoagulation in atrial fibrillation and venous thromboembolism resulted in a rapid implementation of these new drugs into daily care. Although DOAC dosing is similar for women and men and, overall, results in comparable outcomes, sex specific issues need to be considered. This review will discuss DOAC topics specifically related to women's health, including the risks and benefits of DOAC treatment for women, the issue of abnormal uterine bleeding from DOAC and the risk and management of DOAC exposure in pregnancy.

6.
Lancet Haematol ; 6(10): e500-e509, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31420317

RESUMO

BACKGROUND: Rivaroxaban has been shown to be efficacious for treatment of venous thromboembolism in adults, and has a reduced risk of bleeding compared with standard anticoagulants. We aimed to develop paediatric rivaroxaban regimens for the treatment of venous thromboembolism in children and adolescents. METHODS: In this phase 2 programme, we did three studies to evaluate rivaroxaban treatment in children younger than 6 months, aged 6 months to 5 years, and aged 6-17 years. Our studies used a multicentre, single-arm design at 54 sites in Australia, Europe, Israel, Japan, and north America. We included children with objectively confirmed venous thromboembolism previously treated with low-molecular weight heparin, fondaparinux, or a vitamin K antagonist for at least 2 months or, in children who had catheter-related venous thromboembolism for at least 6 weeks. We administered rivaroxaban orally in a bodyweight-adjusted 20 mg-equivalent dose, based on physiologically-based pharmacokinetic modelling predictions and EINSTEIN-Jr phase 1 data in young adults, in either a once-daily (tablets; for those aged 6-17 years), twice-daily (in suspension; for those aged 6 months to 11 years), or three times-daily (in suspension; for those younger than 6 months) dosing regimen for 30 days (or 7 days for those younger than 6 months). The primary aim was to define rivaroxaban treatment regimens that match the target adult exposure range. The principal safety outcome was major bleeding and clinically relevant non-major bleeding. Analyses were per-protocol. The predefined efficacy outcomes were symptomatic recurrent venous thromboembolism, asymptomatic deterioration on repeat imaging at the end of the study treatment period. These trials are registered at ClinicalTrials.gov, numbers NCT02564718, NCT02309411, and NCT02234843. FINDINGS: Between Feb 11, 2013, and Dec 20, 2017, we enrolled 93 children (ten children younger than 6 months; 15 children aged 6 months to 1 year; 25 children aged 2-5 years; 32 children aged 6-11 years; and 11 children aged 12-17 years) into our study. 89 (96%) children completed study treatment (30 days of treatment, or 7 days in those younger than 6 months), and 93 (100%) children received at least one dose of study treatment and were evaluable for the primary endpoints. None of the children had a major bleed, and four (4%, 95% CI 1·2-10·6) of these children had a clinically relevant non-major bleed (three children aged 12-17 years with menorrhagia and one child aged 6-11 years with gingival bleeding). We found no symptomatic recurrent venous thromboembolism in any patients (0%, 0·0-3·9). 24 (32%) of 75 patients with repeat imaging had their thrombotic burden resolved, 43 (57%) patients improved, and eight (11%) patients were unchanged. No patient deteriorated. We confirmed therapeutic rivaroxaban exposures with once-daily dosing in children with bodyweights of at least 30 kg and with twice-daily dosing in children with bodyweights of at least 20 kg and less than 30 kg. Children with low bodyweights (<20 kg, particularly <12 kg) showed low exposures so, for future studies, rivaroxaban dosages were revised for these weight categories, to match the target adult exposure range. 61 (66%) of 93 children had adverse events during the study. Pyrexia was the most common adverse event (ten [11%] events), and anaemia and neutropenia or febrile neutropenia were the most frequent grade 3 or worse events (four [4%] events each). No children died or were discontinued from rivaroxaban because of adverse events. INTERPRETATION: Treatment with bodyweight-adjusted rivaroxaban appears to be safe in children. The treatment regimens that we confirmed in children with bodyweights of at least 20 kg and the revised treatment regimens that we predicted in those with bodyweights less than 20 kg will be evaluated in the EINSTEIN-Jr phase 3 trial in children with acute venous thromboembolism. FUNDING: Bayer AG, Janssen Research and Development.


Assuntos
Anticoagulantes/uso terapêutico , Rivaroxabana/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Adolescente , Anemia/etiologia , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacocinética , Peso Corporal , Criança , Pré-Escolar , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Fator Xa/análise , Feminino , Meia-Vida , Hemorragia/etiologia , Humanos , Lactente , Masculino , Neutropenia/etiologia , Tempo de Protrombina , Rivaroxabana/efeitos adversos , Rivaroxabana/farmacocinética , Resultado do Tratamento , Tromboembolia Venosa/patologia
7.
Dtsch Arztebl Int ; 116(23-24): 420-421, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31366437
9.
Thromb J ; 17: 7, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31169831

RESUMO

Background: Real-world data on non-vitamin K oral anticoagulants (NOACs) are essential in determining whether evidence from randomised controlled clinical trials translate into meaningful clinical benefits for patients in everyday practice. RIVER (RIVaroxaban Evaluation in Real life setting) is an ongoing international, prospective registry of patients with newly diagnosed non-valvular atrial fibrillation (NVAF) and at least one investigator-determined risk factor for stroke who received rivaroxaban as an initial treatment for the prevention of thromboembolic stroke. The aim of this paper is to describe the design of the RIVER registry and baseline characteristics of patients with newly diagnosed NVAF who received rivaroxaban as an initial treatment. Methods and results: Between January 2014 and June 2017, RIVER investigators recruited 5072 patients at 309 centres in 17 countries. The aim was to enroll consecutive patients at sites where rivaroxaban was already routinely prescribed for stroke prevention. Each patient is being followed up prospectively for a minimum of 2-years. The registry will capture data on the rate and nature of all thromboembolic events (stroke / systemic embolism), bleeding complications, all-cause mortality and other major cardiovascular events as they occur. Data quality is assured through a combination of remote electronic monitoring and onsite monitoring (including source data verification in 10% of cases). Patients were mostly enrolled by cardiologists (n = 3776, 74.6%), by internal medicine specialists 14.2% (n = 718) and by primary care/general practice physicians 8.2% (n = 417). The mean (SD) age of the population was 69.5 (11.0) years, 44.3% were women. Mean (SD) CHADS2 score was 1.9 (1.2) and CHA2DS2-VASc scores was 3.2 (1.6). Almost all patients (98.5%) were prescribed with once daily dose of rivaroxaban, most commonly 20 mg (76.5%) and 15 mg (20.0%) as their initial treatment; 17.9% of patients received concomitant antiplatelet therapy. Most patients enrolled in RIVER met the recommended threshold for AC therapy (86.6% for 2012 ESC Guidelines, and 79.8% of patients according to 2016 ESC Guidelines). Conclusions: The RIVER prospective registry will expand our knowledge of how rivaroxaban is prescribed in everyday practice and whether evidence from clinical trials can be translated to the broader cross-section of patients in the real world. Trial registration: Unique identifier: NCT02444221. Registerd 14 May 2015; Retrospectively Registered.

10.
J Clin Oncol ; 37(20): 1713-1720, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31116676

RESUMO

PURPOSE: Pulmonary embolism is incidentally diagnosed in up to 5% of patients with cancer on routine imaging scans. The clinical relevance and optimal therapy for incidental pulmonary embolism, particularly distal clots, is unclear. The aim of the current study was to assess current treatment strategies and the long-term clinical outcomes of incidentally detected pulmonary embolism in patients with cancer. PATIENTS AND METHODS: We conducted an international, prospective, observational cohort study between October 22, 2012, and December 31, 2017. Unselected adults with active cancer and a recent diagnosis of incidental pulmonary embolism were eligible. Outcomes were recurrent venous thromboembolism, major bleeding, and all-cause mortality during 12 months of follow-up. Outcome events were centrally adjudicated. RESULTS: A total of 695 patients were included. Mean age was 66 years and 58% of patients were male. Most frequent cancer types were colorectal (21%) and lung cancer (15%). Anticoagulant therapy was initiated in 675 patients (97%), of whom 600 (89%) were treated with low-molecular-weight heparin. Recurrent venous thromboembolism occurred in 41 patients (12-month cumulative incidence, 6.0%; 95% CI, 4.4% to 8.1%), major bleeding in 39 patients (12-month cumulative incidence, 5.7%; 95% CI, 4.1% to 7.7%), and 283 patients died (12-month cumulative incidence, 43%; 95% CI, 39% to 46%). The 12-month incidence of recurrent venous thromboembolism was 6.4% in those with subsegmental pulmonary embolism compared with 6.0% in those with more proximal pulmonary embolism (subdistribution hazard ratio, 1.1; 95% CI, 0.37 to 2.9; P = .93). CONCLUSION: In patients with cancer with incidental pulmonary embolism, risk of recurrent venous thromboembolism is significant despite anticoagulant treatment. Patients with subsegmental pulmonary embolism seemed to have a risk of recurrent venous thromboembolism comparable to that of patients with more proximal clots.

11.
Diabetes Obes Metab ; 21(9): 2107-2114, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31099460

RESUMO

AIMS: To assess the effectiveness and safety of rivaroxaban versus warfarin for the prevention of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in patients with type 2 diabetes (T2D) and non-valvular atrial fibrillation (NVAF). MATERIALS AND METHODS: Using MarketScan data from January 2012 to December 2017, we identified oral anticoagulant-naïve patients with NVAF and comorbid T2D and ≥12 months of insurance coverage prior to rivaroxaban or warfarin initiation. Differences in baseline covariates between cohorts were adjusted for using inverse probability of treatment weights based on propensity scores (absolute standardized differences <0.1 achieved for all covariates after adjustment). Patients were followed until a MACE, MALE or major bleeding event, oral anticoagulant discontinuation/switch, insurance disenrolment or end of data availability. Hazard ratios (HRs) and 95% confidence intervals (CIs) comparing the cohorts were calculated using Cox regression. RESULTS: We identified 10 700 rivaroxaban users (24.1% received a reduced dose) and 13 946 warfarin users. The median (25%, 75% range) age was 70 (62, 79) years, CHA2DS2-VASc score was 4 (3, 5) and duration of available follow-up was 1.4 (0.6, 2.7) years. Eleven percent of patients had peripheral artery disease, 5.1% had coronary artery disease, and 5.1% had a prior MALE, at baseline. Rivaroxaban was associated with a 25% (95% CI 4-41) reduced risk of MACE and a 63% (95% CI 35-79) reduced risk of MALE compared to warfarin. Major bleeding risk did not significantly differ between cohorts (HR 0.95). CONCLUSIONS: Among patients with NVAF and T2D treated in routine practice, rivaroxaban was associated with lower risks of both MACE and MALE versus warfarin, with no significant difference in major bleeding.

12.
Thromb J ; 17: 6, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31011294

RESUMO

Background: Clinical practice shows that venous thromboembolism (VTE) presents a substantial burden in medical patients, and awareness and advocacy for its primary and secondary prevention remains inadequate. Specific patient populations, such as those with cancer and the critically ill, show elevated risk for VTE, bleeding or both, and significant gaps in VTE prophylaxis and treatment exist in these groups. Objective: To present novel insights and consolidated evidence collected from experts, clinical practice guidelines and original studies on the unmet needs in thromboprophylaxis, and on the treatment of VTE in two high-risk patient groups: patients with cancer and the critically ill. Methodology: To identify specific unmet needs in the management of VTE, a methodology was designed and implemented that assessed gaps in prophylaxis and treatment of VTE through interviews with 44 experts in the field of thrombosis and haemostasis, and through a review of current guidelines and seminal studies to substantiate the insights provided by the experts. The research findings were then analysed, discussed and consolidated by a multidisciplinary group of experts. Results: The gap analysis methodology identified shortcomings in the VTE risk assessment tools, patient stratification approaches for prophylaxis, and the suboptimal use of anticoagulants for primary prophylaxis and treatment. Conclusions: Specifically, patients with cancer need better VTE risk assessment tools to tailor primary thromboprophylaxis to tumour types and disease stages, and the potential for drug-drug interactions needs to be considered. In critically ill patients, unfractionated heparin is not advised as a first-line treatment option, and the strength of evidence is increasing for direct oral anticoagulants as a treatment option over low-molecular-weight heparins.

13.
Res Pract Thromb Haemost ; 3(2): 207-216, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31011705

RESUMO

Background: Exposure to vitamin K antagonists (VKA) has been suggested to accelerate progression of chronic kidney disease (CKD) but robust clinical data are currently lacking. Methods: We retrospectively evaluated the impact of VKA exposure on kidney function in patients with atrial fibrillation (AF) and CKD stage 3/4. Patients were prospectively followed within a primary care electronic database (median follow-up of 1.45 years). The kidney function trajectory over time, defined as the annualized change in estimated glomerular filtration rate (eGFR), was analyzed with linear mixed-effects regression including propensity score adjustment. Results: 14 432 patients (median age 78 years, median CHA 2 DS 2-VASc score 4 points) contributed 97 792 eGFR measurements (mean 6.8 measurements/patient; range: 1-197). Mean baseline eGFR was 50.3 mL/min/1.73 m2; and declined by 1.10 mL/min/1.73 m2/year (95% CI: 0.91-1.28, P < 0.0001). In 7409 patients with VKA exposure, CKD progression was significantly faster compared to patients without VKA exposure (5-year absolute eGFR loss from baseline: 6.0 mL/min/1.73 m2 vs 4.5 mL/min/1.73 m2, for an absolute 5-year excess eGFR decline with VKA exposure of 1.5 mL/min/1.73 m2 (95% CI: 0.4-2.7, P = 0.002). These results prevailed upon adjusting for CHA 2 DS 2-VASc score and other potential imbalances in prognostic variables, and in several sensitivity analyses. In the group without documented VKA exposure, 1775 VKA patients (24%) and 1012 patients (14%) developed a 30% decline in eGFR during follow-up (P < 0.0001). Conclusions: In patients with AF and CKD, VKA use is associated with accelerated eGFR decline. Within the limitations of a retrospective analysis, this finding supports the "VKA-renal-calcification hypothesis." However, although statistically significant, the excess loss in eGFR over 5 years with VKA was modest.

14.
Dtsch Arztebl Int ; 116(3): 31-38, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30832760

RESUMO

BACKGROUND: The risk of venous thromboembolism (VTE) is 4 to 7 times higher in cancer patients than in the normal population. Moreover, cancer patients who take anticoagulants suffer more frequently from hemorrhagic complications and VTE recurrences. Patients often find low-molecular-weight heparin (LMWH) treatment unpleasant; approximately 20% stop taking LMWH during the first six months of treatment. METHODS: Based on a non-systematic literature search, an interdisciplinary group of specialists (hematology, oncology, hemostaseology, and angiology) developed a set of recommendations concerning the treatment of tumor-related thrombosis with non-vitamin K antagonist oral anticoagulants (NOAC). RESULTS: Patient-, tumor-, and tumor-treatment-related factors and clinical situations were identified that should be considered in therapeutic decision-making in the indi- vidual case. NOAC may be an alternative that lessens the rate of VTE recurrence (though at the cost of more hemorrhagic complications), without lessening mortality. Moreover, many factors need to be considered that can limit the utility of NOAC treatment or even make it impossible. CONCLUSION: It seems likely that, in future, the treatment of tumor-related VTE will often not involve a single decision to use either NOAC or LWMH, but rather a switching of treatment in either of two directions: from LWMH to NOAC in stable phases of the underlying malignant disease, conferring better quality of life to suitable patients; or from NOAC to LWMH, e.g., in patients suffering from emesis or thrombocytopenia, to whom the greater clinical experience with LWMH, parenteral application, or stepwise dose titration can confer benefits.


Assuntos
Anticoagulantes/uso terapêutico , Neoplasias/complicações , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/etiologia , Administração Oral , Anticoagulantes/administração & dosagem , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos
16.
N Engl J Med ; 380(14): 1326-1335, 2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30730782

RESUMO

BACKGROUND: Andexanet alfa is a modified recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors. METHODS: We evaluated 352 patients who had acute major bleeding within 18 hours after administration of a factor Xa inhibitor. The patients received a bolus of andexanet, followed by a 2-hour infusion. The coprimary outcomes were the percent change in anti-factor Xa activity after andexanet treatment and the percentage of patients with excellent or good hemostatic efficacy at 12 hours after the end of the infusion, with hemostatic efficacy adjudicated on the basis of prespecified criteria. Efficacy was assessed in the subgroup of patients with confirmed major bleeding and baseline anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.25 IU per milliliter for those receiving enoxaparin). RESULTS: Patients had a mean age of 77 years, and most had substantial cardiovascular disease. Bleeding was predominantly intracranial (in 227 patients [64%]) or gastrointestinal (in 90 patients [26%]). In patients who had received apixaban, the median anti-factor Xa activity decreased from 149.7 ng per milliliter at baseline to 11.1 ng per milliliter after the andexanet bolus (92% reduction; 95% confidence interval [CI], 91 to 93); in patients who had received rivaroxaban, the median value decreased from 211.8 ng per milliliter to 14.2 ng per milliliter (92% reduction; 95% CI, 88 to 94). Excellent or good hemostasis occurred in 204 of 249 patients (82%) who could be evaluated. Within 30 days, death occurred in 49 patients (14%) and a thrombotic event in 34 (10%). Reduction in anti-factor Xa activity was not predictive of hemostatic efficacy overall but was modestly predictive in patients with intracranial hemorrhage. CONCLUSIONS: In patients with acute major bleeding associated with the use of a factor Xa inhibitor, treatment with andexanet markedly reduced anti-factor Xa activity, and 82% of patients had excellent or good hemostatic efficacy at 12 hours, as adjudicated according to prespecified criteria. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327.).


Assuntos
Coagulantes/uso terapêutico , Inibidores do Fator Xa/efeitos adversos , Fator Xa/uso terapêutico , Hemorragia/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/tratamento farmacológico , Inibidores do Fator Xa/metabolismo , Inibidores do Fator Xa/uso terapêutico , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/tratamento farmacológico , Hemorragia/induzido quimicamente , Humanos , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/tratamento farmacológico , Masculino , Curva ROC
17.
Thromb Haemost ; 119(4): 675-684, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30731492

RESUMO

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.


Assuntos
Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Tromboembolia Venosa/tratamento farmacológico , Vitamina K/antagonistas & inibidores , Varfarina/uso terapêutico , Adulto , Fibrilação Atrial/sangue , Coagulação Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Feminino , Hemorragia/tratamento farmacológico , Humanos , Coeficiente Internacional Normatizado , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Recidiva , Projetos de Pesquisa , Medição de Risco , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
18.
Int J Cardiol ; 282: 47-52, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30777405

RESUMO

BACKGROUND: Chronic kidney disease (CKD), commonly described by estimated glomerular filtration rate (eGFR), is a frequent comorbidity in patients with atrial fibrillation (AF) and associated with thromboembolic and bleeding complications. Instead of single eGFR measurements, kidney function decline over time may better predict clinical outcomes but this has not been studied so far. METHODS: Patients with AF and stage 3/4 CKD were prospectively followed within a primary care electronic database from the United Kingdom (IMS-THIN). The associations between the longitudinal eGFR trajectory of these patients and stroke/systemic embolism, major bleeding, first hospitalization-for-any-cause, and death-from-any-cause were estimated with joint models of longitudinal and time-to-event data. RESULTS: 18,240 patients were included (median age 80.4 years, median CHA2DS2-VASc score 4). In 133,676 eGFR measurements (mean: 6 per patient) median "baseline" eGFR was 49 ml/min/1.73m2 [41-55] and mean eGFR decline was 0.54 ml/min/1.73m2/year (95%CI: 0.47-0.62). During follow-up (median 3.2 years; 50,841 patient-years at risk), 5-year cumulative incidence estimates were 9%, 3%, 32% and 76% for stroke/systemic embolism, major bleeding, hospitalization and death, respectively. In joint modeling, an accelerated decline in kidney function strongly predicted for a higher risk of major bleeding (hazard ratio [HR] 1.09 per ml/min/1.73m2/year increase in eGFR decline), hospitalization (HR 1.06), and death-from-any-cause (HR 1.11; all p < 0.05), but not for stroke/systemic embolism (HR 0.97; p = 0.239). CONCLUSIONS: Declining kidney function is a critical determinant of unfavourable outcomes in patients with AF and CKD. Longitudinal kidney function trajectories may enable a much more individualized prediction of adverse outcomes in this vulnerable patient population.


Assuntos
Fibrilação Atrial/mortalidade , Hemorragia/mortalidade , Hospitalização/tendências , Rim/fisiologia , Insuficiência Renal Crônica/mortalidade , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/diagnóstico , Feminino , Hemorragia/diagnóstico , Hemorragia/fisiopatologia , Humanos , Estudos Longitudinais , Masculino , Mortalidade/tendências , Valor Preditivo dos Testes , Estudos Prospectivos , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/fisiopatologia
19.
J Thromb Haemost ; 17(3): 499-506, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30657628

RESUMO

Essentials In 2016 the SSC proposed definitions for effective hemostasis in management of major bleeding. To validate these definitions, we studied the use in three large anticoagulant-reversal studies. Method agreement analysis and interobserver reliability showed at least acceptable agreement. Recommendations were made, advising use of the definition in hemostatic effectiveness studies. SUMMARY: Introduction In 2016 the Scientific and Standardization Subcommittee (SSC) on Control of Anticoagulation of the International Society on Thrombosis and Haemostasis (ISTH) proposed criteria to evaluate the effectiveness of anticoagulant reversal in major bleeding management. Testing and validation of these criteria are required. Objective To investigate the method agreement, interobserver reliability and applicability of the ISTH proposed definitions for hemostatic effectiveness. Methods Patient data from three anticoagulant-antidote studies were used for hemostatic effectiveness assessment using the ISTH-proposed definitions and clinical opinion. For every patient a case document was produced. For each cohort, four adjudicators were asked to assess the hemostatic effectiveness independently on a case-by-case basis. Agreement between the two methods of hemostatic effectiveness assessment was calculated using Cohen's kappa (κ), with a calculated sample size of at least 73 cases. Results The full dataset consisted of 116 cases, resulting in 464 assessments. Method agreement in outcome was observed in 364 of 464 assessments (78.5%), resulting in κ of 0.634 (95% CI: 0.575-0.694), or "substantial agreement." Interobserver reliability analysis of the proposed definitions computed an overall agreement of 54.2% with κ of 0.312 ("fair agreement"). Discussion Method agreement analysis shows that the conclusions drawn using the ISTH definitions have "substantial agreement" with clinical opinion. Interobserver reliability analysis demonstrated acceptable agreement. In-depth analysis provided minor opportunities for further improvement and correct application of the definition. The definition is recommended to be used in all future studies evaluating hemostatic effectiveness, taking the suggested recommendations into account.

20.
Eur J Haematol ; 102(2): 143-149, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30328143

RESUMO

OBJECTIVES: To assess the association between rivaroxaban and warfarin and major bleeding risk in unprovoked venous thromboembolism (VTE) patients. METHODS: Using US MarketScan claims from 1/2012-12/2016, we identified patients who had ≥1 primary hospitalization/emergency department visit diagnosis code for an unprovoked VTE, newly initiated on rivaroxaban or warfarin within 30 days after the VTE and ≥12 months of insurance coverage prior to the VTE. Differences in baseline covariates were adjusted using inverse-probability-of-treatment weights based on propensity scores (residual absolute standardized differences <0.1 achieved for all covariates). Endpoints included any major, gastrointestinal, genitourinary, intracranial, and other bleeds. Patients were followed for up to 12 months or until endpoint occurrence, index oral anticoagulant discontinuation/switch, insurance disenrollment or end of follow-up. RESULTS: We identified 10 489 rivaroxaban and 26 364 warfarin patients with an unprovoked VTE. Upon Cox regression, rivaroxaban reduced patients' hazard of major bleeding by 27% (95% confidence interval [CI] = 8%-42%), gastrointestinal bleeding by 38% (95% CI = 14%-55%), and intracranial hemorrhage by 81% (95% CI = 41%-99%) vs warfarin. No subtype of major bleeding occurred statistically more often in rivaroxaban vs warfarin-treated patients. CONCLUSIONS: Rivaroxaban was associated with a reduced risk of overall, gastrointestinal, and intracranial major bleeding vs warfarin in unprovoked VTE. No bleeding subtype was significantly more frequent in rivaroxaban patients.


Assuntos
Anticoagulantes/efeitos adversos , Inibidores do Fator Xa/efeitos adversos , Hemorragia/epidemiologia , Hemorragia/etiologia , Rivaroxabana/efeitos adversos , Tromboembolia Venosa/complicações , Tromboembolia Venosa/epidemiologia , Varfarina/efeitos adversos , Idoso , Anticoagulantes/uso terapêutico , Estudos de Coortes , Comorbidade , Inibidores do Fator Xa/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vigilância da População , Modelos de Riscos Proporcionais , Medição de Risco , Fatores de Risco , Rivaroxabana/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Varfarina/uso terapêutico
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