RESUMO
BACKGROUND: COVID-19 (coronavirus disease 2019) is associated with heightened risks of venous and arterial thrombosis and hospitalization due to respiratory failure. To assess whether prophylactic anticoagulation can safely reduce the frequency of venous and arterial thrombosis, hospitalization, and death in nonhospitalized patients with symptomatic COVID-19 and at least one thrombosis risk factor, we conducted the PREVENT-HD double-blind, placebo-controlled randomized trial (A Study of Rivaroxaban to Reduce the Risk of Major Venous and Arterial Thrombotic Events, Hospitalization and Death in Medically Ill Outpatients With Acute, Symptomatic COVID-19] Infection). METHODS: PREVENT-HD was conducted between August 2020 and April 2022 at 14 US integrated health care delivery networks. A virtual trial design used remote informed consent and clinical monitoring and facilitated data collection through electronic health record integration with a cloud-based research platform. Nonhospitalized patients with symptomatic COVID-19 and at least one thrombosis risk factor were enrolled and randomly assigned to either 10 mg of oral rivaroxaban or placebo daily for 35 days. The primary efficacy outcome was time to first occurrence of a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic arterial embolism, hospitalization, or death through day 35. The principal safety end point was International Society on Thrombosis and Hemostasis critical-site or fatal bleeding. The last study visit was on day 49. RESULTS: The study was terminated prematurely because of enrollment challenges and a lower-than-expected blinded pooled event rate. A total of 1284 patients underwent randomization with complete accrual of primary events through May 2022. No patients were lost to follow-up. The primary efficacy outcome occurred in 22 of 641 in the rivaroxaban group and 19 of 643 in the placebo group (3.4% versus 3.0%; hazard ratio, 1.16 [95% CI, 0.63-2.15]; P=0.63). No patient in either group experienced critical-site or fatal bleeding. One patient receiving rivaroxaban had a major bleed. CONCLUSIONS: The study was terminated prematurely after enrollment of 32% of planned accrual because of recruitment challenges and lower-than-expected event rate. Rivaroxaban prescribed for 35 days in nonhospitalized patients with symptomatic COVID-19 at risk for thrombosis did not appear to reduce a composite end point of venous and arterial thrombotic events, hospitalization, and death. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04508023.
Assuntos
COVID-19 , Trombose , Humanos , Rivaroxabana/efeitos adversos , Pacientes Ambulatoriais , Trombose/epidemiologia , Trombose/prevenção & controle , Hemorragia/induzido quimicamente , Hemorragia/tratamento farmacológico , Hospitalização , Anticoagulantes/efeitos adversosRESUMO
Antithrombotic agents reduce risk of thromboembolism in severely ill patients. Patients with coronavirus disease 2019 (COVID-19) may realize additional benefits from heparins. Optimal dosing and timing of these treatments and benefits of other antithrombotic agents remain unclear. In October 2021, ISTH assembled an international panel of content experts, patient representatives, and a methodologist to develop recommendations on anticoagulants and antiplatelet agents for patients with COVID-19 in different clinical settings. We used the American College of Cardiology Foundation/American Heart Association methodology to assess level of evidence (LOE) and class of recommendation (COR). Only recommendations with LOE A or B were included. Panelists agreed on 12 recommendations: three for non-hospitalized, five for non-critically ill hospitalized, three for critically ill hospitalized, and one for post-discharge patients. Two recommendations were based on high-quality evidence, the remainder on moderate-quality evidence. Among non-critically ill patients hospitalized for COVID-19, the panel gave a strong recommendation (a) for use of prophylactic dose of low molecular weight heparin or unfractionated heparin (LMWH/UFH) (COR 1); (b) for select patients in this group, use of therapeutic dose LMWH/UFH in preference to prophylactic dose (COR 1); but (c) against the addition of an antiplatelet agent (COR 3). Weak recommendations favored (a) sulodexide in non-hospitalized patients, (b) adding an antiplatelet agent to prophylactic LMWH/UFH in select critically ill, and (c) prophylactic rivaroxaban for select patients after discharge (all COR 2b). Recommendations in this guideline are based on high-/moderate-quality evidence available through March 2022. Focused updates will incorporate future evidence supporting changes to these recommendations.
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COVID-19 , Heparina de Baixo Peso Molecular , Assistência ao Convalescente , Anticoagulantes/efeitos adversos , Fibrinolíticos/efeitos adversos , Heparina/efeitos adversos , Humanos , Alta do Paciente , Inibidores da Agregação Plaquetária/efeitos adversos , RivaroxabanaRESUMO
BACKGROUND: Patients hospitalised with COVID-19 are at risk for thrombotic events after discharge; the role of extended thromboprophylaxis in this population is unknown. METHODS: In this open-label, multicentre, randomised trial conducted at 14 centres in Brazil, patients hospitalised with COVID-19 at increased risk for venous thromboembolism (International Medical Prevention Registry on Venous Thromboembolism [IMPROVE] venous thromboembolism [VTE] score of ≥4 or 2-3 with a D-dimer >500 ng/mL) were randomly assigned (1:1) to receive, at hospital discharge, rivaroxaban 10 mg/day or no anticoagulation for 35 days. The primary efficacy outcome in an intention-to-treat analysis was a composite of symptomatic or fatal venous thromboembolism, asymptomatic venous thromboembolism on bilateral lower-limb venous ultrasound and CT pulmonary angiogram, symptomatic arterial thromboembolism, and cardiovascular death at day 35. Adjudication was blinded. The primary safety outcome was major bleeding. The primary and safety analyses were carried out in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04662684. FINDINGS: From Oct 8, 2020, to June 29, 2021, 997 patients were screened. Of these patients, 677 did not meet eligibility criteria; the remaining 320 patients were enrolled and randomly assigned to receive rivaroxaban (n=160 [50%]) or no anticoagulation (n=160 [50%]). All patients received thromboprophylaxis with standard doses of heparin during hospitalisation. 165 (52%) patients were in the intensive care unit while hospitalised. 197 (62%) patients had an IMPROVE score of 2-3 and elevated D-dimer levels and 121 (38%) had a score of 4 or more. Two patients (one in each group) were lost to follow-up due to withdrawal of consent and not included in the intention-to-treat primary analysis. The primary efficacy outcome occurred in five (3%) of 159 patients assigned to rivaroxaban and 15 (9%) of 159 patients assigned to no anticoagulation (relative risk 0·33, 95% CI 0·12-0·90; p=0·0293). No major bleeding occurred in either study group. Allergic reactions occurred in two (1%) patients in the rivaroxaban group. INTERPRETATION: In patients at high risk discharged after hospitalisation due to COVID-19, thromboprophylaxis with rivaroxaban 10 mg/day for 35 days improved clinical outcomes compared with no extended thromboprophylaxis. FUNDING: Bayer.
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Assistência ao Convalescente , Coagulação Sanguínea/efeitos dos fármacos , COVID-19/complicações , Inibidores do Fator Xa/farmacologia , Inibidores do Fator Xa/uso terapêutico , Rivaroxabana/farmacologia , Rivaroxabana/uso terapêutico , Tromboembolia Venosa/prevenção & controle , Adulto , Idoso , Feminino , Heparina/administração & dosagem , Heparina/uso terapêutico , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Alta do Paciente , Resultado do Tratamento , Tratamento Farmacológico da COVID-19RESUMO
Background: Bronchiectasis is a chronic inflammation of the bronchi with recurrent infections and hemoptysis. The MAGELLAN study compared oral rivaroxaban, 10â mg once daily (QD), for 35 ± 4 days with subcutaneous enoxaparin 40â mg QD for 10 ± 4 days followed by placebo for 25 ± 4 days to prevent venous thromboembolism in patients hospitalized with an acute medical illness. MAGELLAN included a subset of patients with bronchiectasis. In a post hoc analysis, we evaluated the incidence and severity of pulmonary bleeding in patients with bronchiectasis who were hospitalized for an acute medical illness. This analysis included MAGELLAN patients diagnosed with bronchiectasis at baseline. Patients were evaluated by treatment group for International Society on Thrombosis and Haemostasis major bleeding, non-major clinically relevant (NMCR) bleeding, and the composite of the 2 (ie, clinically relevant bleeding). Results: Medically ill patients with bronchiectasis were randomized to rivaroxaban (n = 60) or enoxaparin/placebo (n = 61). There were 2 fatal pulmonary bleeds and 1 fatal gastrointestinal bleed in the rivaroxaban arm and no fatal or major bleeding in the enoxaparin/placebo arm. The incidence of major bleeding was 5% in the rivaroxaban arm. One NMCR bleed occurred in the rivaroxaban arm and 2 NMCR bleeds occurred in the enoxaparin/placebo arm. The incidence of clinically relevant bleeding was 6.7% versus 3.3% in the rivaroxaban and enoxaparin/placebo groups, respectively (relative risk = 2.06 [95% confidence interval: 0.351-12.046]). Conclusion: In-patients hospitalized with bronchiectasis and an acute medical illness, clinically relevant bleeding, including fatal pulmonary hemorrhage, occurs more frequently with extended rivaroxaban thromboprophylaxis than with enoxaparin followed by placebo.
Assuntos
Bronquiectasia/complicações , Inibidores do Fator Xa/uso terapêutico , Hemorragia/induzido quimicamente , Rivaroxabana/efeitos adversos , Tromboembolia Venosa/complicações , Doença Aguda , Adulto , Bronquiectasia/tratamento farmacológico , Inibidores do Fator Xa/farmacologia , Feminino , Humanos , Incidência , Masculino , Fatores de Risco , Rivaroxabana/farmacologia , Tromboembolia Venosa/tratamento farmacológicoRESUMO
BACKGROUND: The devastating Coronavirus disease (COVID-19) pandemic is associated with a high prothrombotic state. It is unclear if the coagulation abnormalities occur because of the direct effect of SARS-CoV-2 or indirectly by the cytokine storm and endothelial damage or by a combination of mechanisms. There is a clear indication of in-hospital pharmacological thromboprophylaxis for every patient with COVID-19 after bleed risk assessment. However, there is much debate regarding the best dosage regimen, and there is no consensus on the role of extended thromboprophylaxis. DESIGN: This study aims to evaluate the safety and efficacy of rivaroxaban 10 mg once daily for 35 ± 4 days versus no intervention after hospital discharge in COVID-19 patients who were at increased risk for VTE and have received standard parenteral VTE prophylaxis during hospitalization. The composite efficacy endpoint is a combination of symptomatic VTE, VTE-related death, VTE detected by bilateral lower limbs venous duplex scan and computed tomography pulmonary angiogram on day 35 ± 4 posthospital discharge and symptomatic arterial thromboembolism (myocardial infarction, nonhemorrhagic stroke, major adverse limb events, and cardiovascular death) up to day 35 ± 4 posthospital discharge. The key safety outcome is the incidence of major bleeding according to ISTH criteria. SUMMARY: The MICHELLE trial is expected to provide high-quality evidence around the role of extended thromboprophylaxis in COVID-19 and will help guide medical decisions in clinical practice.1.
Assuntos
COVID-19/complicações , Inibidores do Fator Xa/administração & dosagem , Rivaroxabana/administração & dosagem , Trombose/prevenção & controle , Adulto , Brasil , Esquema de Medicação , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Estudos Prospectivos , Embolia Pulmonar/etiologia , Embolia Pulmonar/prevenção & controle , Rivaroxabana/efeitos adversos , Tromboembolia/etiologia , Tromboembolia/prevenção & controle , Trombose/etiologia , Trombose Venosa/etiologia , Trombose Venosa/prevenção & controleRESUMO
BACKGROUND: COVID-19 is associated with both venous and arterial thrombotic complications. While prophylactic anticoagulation is now widely recommended for hospitalized patients with COVID-19, the effectiveness and safety of thromboprophylaxis in outpatients with COVID-19 has not been established. STUDY DESIGN: PREVENT-HD is a double-blind, placebo-controlled, pragmatic, event-driven phase 3 trial to evaluate the efficacy and safety of rivaroxaban in symptomatic outpatients with laboratory-confirmed COVID-19 at risk for thrombotic events, hospitalization, and death. Several challenges posed by the pandemic have necessitated innovative approaches to clinical trial design, start-up, and conduct. Participants are randomized in a 1:1 ratio, stratified by time from COVID-19 confirmation, to either rivaroxaban 10 mg once daily or placebo for 35 days. The primary efficacy end point is a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality. The primary safety end point is fatal and critical site bleeding according to the International Society on Thrombosis and Haemostasis definition. Enrollment began in August 2020 and is expected to enroll approximately 4,000 participants to yield the required number of end point events. CONCLUSIONS: PREVENT-HD is a pragmatic trial evaluating the efficacy and safety of the direct oral anticoagulant rivaroxaban in the outpatient setting to reduce major venous and arterial thrombotic events, hospitalization, and mortality associated with COVID-19.
Assuntos
COVID-19/complicações , Inibidores do Fator Xa/uso terapêutico , Hospitalização , Pacientes Ambulatoriais , Rivaroxabana/uso terapêutico , Trombose/prevenção & controle , Adulto , COVID-19/mortalidade , Causas de Morte , Método Duplo-Cego , Extremidades/irrigação sanguínea , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Hemorragia/mortalidade , Mortalidade Hospitalar , Humanos , Isquemia/etiologia , AVC Isquêmico/etiologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Placebos/uso terapêutico , Rivaroxabana/efeitos adversos , Trombose/mortalidade , Tromboembolia Venosa/mortalidade , Tromboembolia Venosa/prevenção & controleRESUMO
Venous thromboembolism (VTE) is the leading preventable cause of death in hospitalized patients and data consistently show that acutely ill medical patients remain at increased risk for VTE-related morbidity and mortality in the post-hospital discharge period. Prescribing extended thromboprophylaxis for up to 45 days following an acute hospitalization in key patient subgroups that include more than one-quarter of hospitalized medically-ill patients represents a paradigm shift in the way hospital-based physicians think about VTE prevention. Advances in the field of primary thromboprophylaxis in acutely-ill medical patients using validated VTE and bleeding risk assessment models have established key patient subgroups at high risk of VTE and low risk of bleeding that may benefit from both in-hospital and extended thromboprophylaxis. The direct oral anticoagulants betrixaban and rivaroxaban are now U.S. Food and Drug Administration-approved for in-hospital and extended thromboprophylaxis in medically ill patients and provide net clinical benefit in these key subgroups. Coronavirus disease-2019 may predispose patients to VTE due to excessive inflammation, platelet activation, endothelial dysfunction, and hemostasis. The optimum preventive strategy for these patients requires further investigation. This article aims to review the latest concepts in predicting and preventing VTE and discuss the new era of extended thromboprophylaxis in hospitalized medically ill patients.
Assuntos
Anticoagulantes/uso terapêutico , COVID-19/terapia , Duração da Terapia , Hospitalização , Embolia Pulmonar/prevenção & controle , Tromboembolia Venosa/prevenção & controle , Trombose Venosa/prevenção & controle , Benzamidas/uso terapêutico , COVID-19/sangue , COVID-19/complicações , Cuidados Críticos , Sistemas de Apoio a Decisões Clínicas , Humanos , Informática Médica , Alta do Paciente , Embolia Pulmonar/etiologia , Piridinas/uso terapêutico , Medição de Risco , Rivaroxabana/uso terapêutico , SARS-CoV-2 , Tromboembolia Venosa/etiologia , Trombose Venosa/etiologiaRESUMO
BACKGROUND: We aimed to identify the prevalence and predictors of venous thromboembolism (VTE) or mortality in hospitalized coronavirus disease 2019 (COVID-19) patients. METHODS: A retrospective cohort study of hospitalized adult patients admitted to an integrated health care network in the New York metropolitan region between March 1, 2020 and April 27, 2020. The final analysis included 9,407 patients with an overall VTE rate of 2.9% (2.4% in the medical ward and 4.9% in the intensive care unit [ICU]) and a VTE or mortality rate of 26.1%. Most patients received prophylactic-dose thromboprophylaxis. Multivariable analysis showed significantly reduced VTE or mortality with Black race, history of hypertension, angiotensin converting enzyme/angiotensin receptor blocker use, and initial prophylactic anticoagulation. It also showed significantly increased VTE or mortality with age 60 years or greater, Charlson Comorbidity Index (CCI) of 3 or greater, patients on Medicare, history of heart failure, history of cerebrovascular disease, body mass index greater than 35, steroid use, antirheumatologic medication use, hydroxychloroquine use, maximum D-dimer four times or greater than the upper limit of normal (ULN), ICU level of care, increasing creatinine, and decreasing platelet counts. CONCLUSION: In our large cohort of hospitalized COVID-19 patients, the overall in-hospital VTE rate was 2.9% (4.9% in the ICU) and a VTE or mortality rate of 26.1%. Key predictors of VTE or mortality included advanced age, increasing CCI, history of cardiovascular disease, ICU level of care, and elevated maximum D-dimer with a cutoff at least four times the ULN. Use of prophylactic-dose anticoagulation but not treatment-dose anticoagulation was associated with reduced VTE or mortality.
Assuntos
COVID-19/complicações , Tromboembolia Venosa/etiologia , Adulto , Fatores Etários , Idoso , Coagulação Sanguínea , COVID-19/sangue , COVID-19/diagnóstico , COVID-19/mortalidade , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2/isolamento & purificação , Tromboembolia Venosa/sangue , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/mortalidade , Adulto JovemRESUMO
Patients with renal impairment are at higher risk of thrombosis and bleeding than those with normal renal function. The optimal rivaroxaban dose for thromboprophylaxis in acutely ill medical patients with renal impairment is unknown. MARINER and MAGELLAN were multicenter, randomized clinical trials of rivaroxaban in acutely ill medical patients. Efficacy and safety outcomes in patients with renal impairment in MARINER (7.5 mg once daily) were compared with those in patients with normal renal function in MARINER (10 mg once daily) and in a subpopulation of MAGELLAN that excluded patients at high risk for bleeding at baseline (10 mg once daily). Compared with enoxaparin/placebo in the MAGELLAN subpopulation, the relative risk (RR) of symptomatic venous thromboembolism (VTE) and VTE-related death with rivaroxaban 10 mg in patients with renal impairment (RR = 0.62; 95% confidence interval [CI] 0.27-1.44) was similar to that in those with normal renal function (RR = 0.78; 95% CI 0.44-1.40), while in MARINER, the 7.5 mg dose did not reduce the risk in patients with renal impairment (hazard ratio = 1.00; 95% CI 0.52-1.92). Major bleeding with rivaroxaban 10 mg once daily was higher in patients with renal impairment than in those with normal renal function in MAGELLAN (1.54% vs. 0.98%) and in the MAGELLAN subpopulation (0.94% vs. 0.61%). At a dose of 10 mg once daily, rivaroxaban is effective for thromboprophylaxis in acutely ill medical patients with impaired or normal renal function. The safety of this regimen is enhanced without loss of efficacy by excluding patients at high risk for bleeding, but not by using a reduced-dose strategy. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00571649 for the MAGELLAN trial, NCT02111564 for the MARINER trial.
Assuntos
Nefropatias/sangue , Nefropatias/complicações , Rivaroxabana/uso terapêutico , Trombose/prevenção & controle , Doença Aguda , Idoso , Anticoagulantes , Método Duplo-Cego , Enoxaparina/uso terapêutico , Feminino , Hemorragia , Humanos , Incidência , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Resultado do Tratamento , Tromboembolia Venosa/tratamento farmacológicoRESUMO
Acutely ill medical patients are at risk of venous thromboembolism (VTE) and VTE-related mortality during hospitalization and posthospital discharge, but widespread adoption of extended thromboprophylaxis has not occurred. We analyzed a subpopulation within the MAGELLAN study of extended thromboprophylaxis with rivaroxaban to reevaluate the benefit risk profile. We identified 5 risk factors for major and fatal bleeding after a clinical analysis of the MAGELLAN study and analyzed efficacy and safety with these patients excluded (n = 1551). Risk factors included: active cancer, dual antiplatelet therapy at baseline, bronchiectasis/pulmonary cavitation, gastroduodenal ulcer, or bleeding within 3 months before randomization. We evaluated efficacy, safety, and benefit risk using clinically comparable endpoints in the subpopulation. At day 10, rivaroxaban was noninferior to enoxaparin (relative risk [RR] = 0.82, 95% confidence interval [CI] = 0.58-1.15) and at day 35 rivaroxaban was significantly better than enoxaparin/placebo (RR = 0.68, 95% CI = 0.53-0.88) in reducing VTE and VTE-related death. Major bleeding was reduced at day 10 (RR = 2.18, 95% CI = 1.07-4.44 vs 1.19, 95% CI = 0.54-2.65) and at day 35 (2.87, 95% CI = 1.60-5.15 vs 1.48, 95% CI = 0.77-2.84) for MAGELLAN versus this subpopulation, respectively. The benefit risk profile was favorable in this subpopulation treated for 35 days, with the number needed to treat ranging from 55 to 481 and number needed to harm from 455 to 1067 for all pairwise evaluations. Five exclusionary criteria defined a subpopulation of acutely ill medical patients with a positive benefit risk profile for in-hospital and extended thromboprophylaxis with rivaroxaban.
Assuntos
Anticoagulantes/uso terapêutico , Inibidores do Fator Xa/uso terapêutico , Rivaroxabana/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Administração Oral , Idoso , Anticoagulantes/farmacologia , Método Duplo-Cego , Inibidores do Fator Xa/farmacologia , Feminino , Humanos , Pessoa de Meia-Idade , Fatores de Risco , Rivaroxabana/farmacologiaRESUMO
INTRODUCTION: Limited data exist on direct-acting oral anticoagulants in morbidly obese patients with venous thromboembolism (VTE). We compared clinical and health/economic outcomes with rivaroxaban versus warfarin for VTE treatment in morbidly obese patients. MATERIALS AND METHODS: This retrospective 1:1 propensity score matched cohort study analyzed data from 2 US claims databases. VTE patients initiating rivaroxaban or warfarin were identified who had diagnosis codes for morbid obesity (ICD-9:278.01,V85.4; ICD-10:E66.01,E66.2,Z68.4) 12â¯months pre- or 3â¯months post-initiation and followed ≥3â¯months. Intent-to-treat (ITT) and on-treatment (OT) analyses were conducted using conditional logistic regression and generalized linear models to compare recurrent VTE and major bleeding risks, healthcare resource utilization (HRU), and per patient per year (PPPY) costs. RESULTS: In total, 2890 matched pairs of morbidly obese VTE patients initiating rivaroxaban or warfarin were identified. Risks of recurrent VTE (ITT: OR: 0.99; 95% CI: 0.85-1.14) and major bleeding (OT: OR: 0.75; 95% CI: 0.47-1.19) were similar for cohorts. Anti-Factor Xa laboratory measurement was performed on <1% of rivaroxaban cohort. Hospitalizations (OR: 0.86; 95% CI: 0.77-0.96) and outpatient visits (OR: 0.23; 95% CI: 0.10-0.56), were lower with rivaroxaban versus warfarin (ITT analysis). Average total medical costs PPPY were $2829 lower with rivaroxaban versus warfarin ($34,824 vs $37,653), mainly driven by hospitalization costs. Total healthcare costs (including pharmacy) were similar ($43,034 vs $44,565). CONCLUSIONS: Morbidly obese VTE patients receiving rivaroxaban had similar risks of recurrent VTE and major bleeding versus warfarin. Rivaroxaban treatment yielded significantly less HRU and total medical costs, with similar total healthcare costs between groups.
Assuntos
Anticoagulantes/uso terapêutico , Obesidade Mórbida/complicações , Rivaroxabana/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Varfarina/uso terapêutico , Adulto , Idoso , Anticoagulantes/efeitos adversos , Anticoagulantes/economia , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/economia , Inibidores do Fator Xa/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/tratamento farmacológico , Obesidade Mórbida/economia , Estudos Retrospectivos , Rivaroxabana/efeitos adversos , Rivaroxabana/economia , Resultado do Tratamento , Tromboembolia Venosa/complicações , Tromboembolia Venosa/economia , Varfarina/efeitos adversos , Varfarina/economiaRESUMO
This study evaluates three warfarin dosing algorithms (Kimmel, Dawson, High Dose ≥ 2.5 mg) for hospitalized older adults. A random selection of 250 patients with overshoots (INR ≥ 5 after 48 h of hospitalization) and 250 patients without overshoots were accessed from a database of 12,107 inpatients ≥ 65 years treated with chronic warfarin during hospitalization between January 1, 2014 and June 30, 2016. Algorithms were retrospectively applied to patients 2 days prior to overshoots in the overshoot group, and 2 days prior to the maximum INR reached after 48 h of hospitalization in the non-overshoot group. Patients were categorized as overdosed or not overdosed and compared using descriptive statistics. Logistic regression modeling determined predictors for overshoots. There was no significant difference between overdose and non-overdose groups for progressing to overshoots by the Kimmel (51.0% vs. 48.7%, p = 0.67) or Dawson (48.5 vs. 57.9%, p = 0.19) algorithms. The Low Dose Group (≤ 2.5 mg) was significantly more likely to experience an overshoot than the High Dose Group (56.6% vs. 45.5%, p = 0.04). The Low Dose Group was more likely to be older (81.4% vs. 71.1%, p = 0.02), female (63.5% vs. 49.8%, p = 0.02), weigh less (71.3 ± 21.9 vs. 79 ± 23.1, p = 0.002), and be prescribed amiodarone (16.6% vs. 8.1%, p = 0.01). While none of the algorithms predicted overshoots in logistic regression modeling, weight over 70 kg and black race remained protective. The High Dose Algorithm revealed that providers appropriately gave lower doses to patients at highest risk for warfarin sensitivity. Future studies are needed to investigate tools for inpatient warfarin dosing in older adults.
Assuntos
Algoritmos , Varfarina/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Amiodarona/administração & dosagem , Cálculos da Dosagem de Medicamento , Feminino , Hospitalização , Humanos , Coeficiente Internacional Normatizado , Masculino , Estudos RetrospectivosRESUMO
BACKGROUND: There are limited data regarding clinical outcomes and healthcare resource utilization of direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) who are morbidly obese (body mass index >40 kg/m2 or body weight >120 kg). METHODS: Using data from 2 US healthcare claims databases, we identified patients initiating rivaroxaban or warfarin who had ≥1 medical claim with an AF diagnosis, a diagnostic code for morbid obesity (ICD-9: 278.01, V85.4%; ICD-10: E66.01%, E66.2%, Z68.4%), and a minimum continuous enrollment of 12 months before and 3 months after treatment initiation. Patients were excluded if they had mitral stenosis, a mechanical heart valve procedure, an organ/tissue transplant, or an oral anticoagulant prescription prior to the index date. Rivaroxaban and warfarin patients were 1:1 propensity score matched. Conditional logistic regression was used to compare ischemic stroke/systemic embolism and major bleeding risk. Generalized linear models were used to compare healthcare resource utilization and costs. RESULTS: A total of 3563 matched pairs of morbidly obese AF patients treated with rivaroxaban or warfarin were identified. The majority (81.4%) of patients in the rivaroxaban cohort were receiving the 20 mg dose. The rivaroxaban and warfarin cohorts were well balanced after propensity score matching. The risks of ischemic stroke/systemic embolism and major bleeding were similar for rivaroxaban and warfarin users (stroke/systemic embolism: 1.5% vs 1.7%; odds ratio [OR]: 0.88; 95% confidence interval [CI]: 0.60, 1.28; P = .5028; major bleeding: 2.2% vs 2.7%; OR: 0.80; 95% CI: 0.59, 1.08; P = .1447). Total healthcare costs including medication costs per patient per year (PPPY) were significantly lower with rivaroxaban versus warfarin ($48,552 vs $52,418; P = .0025), which was primarily driven by lower hospitalization rate (50.2% vs 54.1%; P = .0008), shorter length of stay (7.5 vs 9.1 days; P = .0010), and less outpatient service utilization (86 vs 115 visits PPPY; P < .0001). CONCLUSIONS: Morbidly obese AF patients treated with rivaroxaban had comparable risk of ischemic stroke/systemic embolism and major bleeding as those treated with warfarin, but lower healthcare resource utilization and costs.
Assuntos
Fibrilação Atrial/tratamento farmacológico , Custos de Medicamentos , Obesidade Mórbida/complicações , Rivaroxabana/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Varfarina/uso terapêutico , Anticoagulantes/economia , Anticoagulantes/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/epidemiologia , Inibidores do Fator Xa/economia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Morbidade/tendências , Obesidade Mórbida/epidemiologia , Estudos Retrospectivos , Rivaroxabana/economia , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Taxa de Sobrevida/tendências , Estados Unidos/epidemiologia , Varfarina/economiaRESUMO
BACKGROUND: Patients who are hospitalized for medical illness remain at risk for venous thromboembolism after discharge, but the role of extended thromboprophylaxis in the treatment of such patients is a subject of controversy. METHODS: In this randomized, double-blind trial, medically ill patients who were at increased risk for venous thromboembolism on the basis of a modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) score of 4 or higher (scores range from 0 to 10, with higher scores indicating a higher risk of venous thromboembolism) or a score of 2 or 3 plus a plasma d-dimer level of more than twice the upper limit of the normal range (defined according to local laboratory criteria) were assigned at hospital discharge to either once-daily rivaroxaban at a dose of 10 mg (with the dose adjusted for renal insufficiency) or placebo for 45 days. The primary efficacy outcome was a composite of symptomatic venous thromboembolism or death due to venous thromboembolism. The principal safety outcome was major bleeding. RESULTS: Of the 12,024 patients who underwent randomization, 12,019 were included in the intention-to-treat analysis. The primary efficacy outcome occurred in 50 of 6007 patients (0.83%) who were given rivaroxaban and in 66 of 6012 patients (1.10%) who were given placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.52 to 1.09; P=0.14). The prespecified secondary outcome of symptomatic nonfatal venous thromboembolism occurred in 0.18% of patients in the rivaroxaban group and 0.42% of patients in the placebo group (hazard ratio, 0.44; 95% CI, 0.22 to 0.89). Major bleeding occurred in 17 of 5982 patients (0.28%) in the rivaroxaban group and in 9 of 5980 patients (0.15%) in the placebo group (hazard ratio, 1.88; 95% CI, 0.84 to 4.23). CONCLUSIONS: Rivaroxaban, given to medical patients for 45 days after hospital discharge, was not associated with a significantly lower risk of symptomatic venous thromboembolism and death due to venous thromboembolism than placebo. The incidence of major bleeding was low. (Funded by Janssen Research and Development; MARINER ClinicalTrials.gov number, NCT02111564 .).
Assuntos
Inibidores do Fator Xa/uso terapêutico , Hospitalização , Rivaroxabana/uso terapêutico , Tromboembolia Venosa/prevenção & controle , Assistência ao Convalescente , Idoso , Método Duplo-Cego , Esquema de Medicação , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Alta do Paciente , Rivaroxabana/administração & dosagem , Rivaroxabana/efeitos adversos , Resultado do Tratamento , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/mortalidade , Trombose Venosa/prevenção & controleRESUMO
Background: Although not designated as guideline-recommended first-line anticoagulation therapy, patients are receiving rivaroxaban for the treatment and secondary prevention of cancer-associated venous thrombosis (CAT). We sought to estimate the cumulative incidence of recurrent venous thromboembolism (VTE), major bleeding, and mortality/hospice care in patients with CAT treated with outpatient rivaroxaban in routine practice. Methods: Using US MarketScan claims data from January 2012 through June 2015, we identified adults with active cancer (using SEER program coding) who had ≥1 primary hospitalization or emergency department discharge diagnosis code for VTE (index event) and received rivaroxaban as their first outpatient anticoagulant within 30 days of the index VTE. Patients were required to have ≥180 days of continuous medical/prescription benefits prior to the index VTE. Patients with a previous claim for VTE, atrial fibrillation, or valvular disease or receiving anticoagulation during the baseline period were excluded. We estimated the cumulative incidence with 95% CIs of recurrent VTE, major bleeding, and mortality or need for hospice care at 180 days, assuming competing risks. Results: A total of 949 patients with active cancer were initiated on rivaroxaban following their index VTE. Time from active cancer diagnosis to index CAT was ≤90 days for 27% of patients, 91 to 180 days for 19%, and >180 days for 54%. The mean [SD] age of patients was 62.5 [12.8] years, 43.6% had pulmonary embolism, and metastatic disease was present in 42.6%. During follow-up, there were 37 cases of recurrent VTE, 22 cases of major bleeding (17 gastrointestinal, 3 intracranial, 1 genitourinary, and 1 other bleed), and 105 deaths/hospice claims. The cumulative incidence estimate was 4.0% (95% CI, 2.8%-5.4%) for recurrent VTE, 2.7% (95% CI, 1.7%-4.0%) for major bleeding, and 11.3% (95% CI, 9.2%-13.6%) for mortality/hospice care. Conclusions: Event rates observed in this rivaroxaban-treated cohort were overall consistent with previous studies of patients with rivaroxaban- and warfarin-managed CAT.
Assuntos
Inibidores do Fator Xa/uso terapêutico , Rivaroxabana/uso terapêutico , Trombose Venosa/tratamento farmacológico , Inibidores do Fator Xa/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rivaroxabana/farmacologia , Trombose Venosa/patologiaRESUMO
Background The perioperative management of patients who take a direct oral anticoagulant (DOAC) for atrial fibrillation and require treatment interruption for an elective surgery/procedure is a common clinical scenario for which best practices are uncertain. The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) study is designed to address this unmet clinical need. We discuss the rationale for the PAUSE design and analysis plan as well as the rationale supporting the perioperative DOAC protocol. Methods PAUSE is a prospective study with three parallel cohorts, one for each DOAC, to assess a standardized but patient-specific perioperative management protocol for DOAC-treated patients with atrial fibrillation. The perioperative protocol accounts for DOAC type, patient's renal function and surgery/procedure-related bleeding risk. The primary study aim is to demonstrate the safety of the PAUSE protocol for the perioperative management of each DOAC. The secondary aim is to determine the effect of the pre-procedure interruption on residual anticoagulation when measured by the dilute thrombin time for dabigatran and anti-factor Xa levels for rivaroxaban and apixaban. The study hypothesis is that the perioperative management protocol for each DOAC is safe for patient care, defined by expected risks for major bleeding of 1% (80% power to exclude 2%), and for arterial thromboembolism of 0.5% (80% power to exclude 1.5%) in each DOAC group. Conclusion The PAUSE study has the potential to establish a standard-of-care approach for the perioperative management of DOAC-treated patients. The PAUSE management protocol is designed to be easily applied in clinical practice, as it is standardized and also patient specific.
Assuntos
Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Procedimentos Cirúrgicos Cardíacos , Hemorragia/tratamento farmacológico , Período Perioperatório , Complicações Pós-Operatórias/tratamento farmacológico , Administração Oral , Adulto , Fibrilação Atrial/cirurgia , Canadá , Estudos de Coortes , Dabigatrana/uso terapêutico , Feminino , Hemorragia/etiologia , Humanos , Masculino , Medicina de Precisão , Estudos Prospectivos , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Rivaroxabana/uso terapêuticoRESUMO
Direct oral anticoagulants (DOACs) are a relatively recent addition to the oral anticoagulant armamentarium, and provide an alternative to the use of vitamin K antagonists such as warfarin. Regardless of the type of agent used, bleeding is the major complication of anticoagulant therapy. The decision to restart oral anticoagulation following a major hemorrhage in a previously anticoagulated patient is supported largely by retrospective studies rather than randomized clinical trials (mostly with vitamin K antagonists), and remains an issue of individualized clinical assessment: the patient's risk of thromboembolism must be balanced with the risk of recurrent major bleeding. This review provides guidance for clinicians regarding if and when a patient should be re-initiated on DOAC therapy following a major hemorrhage, based on the existing evidence.
Assuntos
Fibrilação Atrial/tratamento farmacológico , Inibidores do Fator Xa/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Tromboembolia/prevenção & controle , Antitrombinas/uso terapêutico , Fibrilação Atrial/complicações , Dabigatrana/uso terapêutico , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia , Humanos , Hemorragias Intracranianas/induzido quimicamente , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Recidiva , Medição de Risco , Rivaroxabana/uso terapêutico , Acidente Vascular Cerebral/etiologia , Tromboembolia/etiologiaRESUMO
Clinical trials of antithrombotic therapy require a cohesive assessment of benefit and risk. A new graphical method to represent the bivariate relation of benefit and risk in trials of antithrombotic drugs is described and illustrated using published data from the four major registration clinical trials of non-vitamin K oral anticoagulants (NOACs) totalling 71,683 patients for prevention of thromboembolic events (TE) in patients with atrial fibrillation (RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE-AF TIMI48). A curve representing a null hypothesis defines a region of benefit on a two-dimensional plane. Trial results are summarised by a rectangle defined by standard 95 % confidence intervals (CI) for thrombosis and bleeding risks. Benefit is judged by whether the confidence rectangle contains the null curve. The treatment effect is measured by the distance from the null curve to the opposing corners of the confidence rectangle (termed "corner distance (CD)"). Across trials NOACs reduced the absolute risk of TE compared to warfarin by 0.30 % (95 % CI: -0.56 % to -0.05 %) and reduced major bleeding by 0.88 % (95 % CI: -1.26 % to -0.51 %). Bivariate evaluation showed NOAC superiority to warfarin overall and elucidated dose differences; low dose edoxaban increased bivariate TE-bleeding risk 0.08 % (CD = -0.85 % to 0.78 %), whereas high dose edoxaban reduced risk 1.41 % (CD = -2.07 % to -0.70 %). In conclusion, bivariate evaluation facilitates visual assessment of the safety-efficacy profile of antithrombotic drugs. Its application to trials in atrial fibrillation found NOACs superior to warfarin without substantial differences between agents.
Assuntos
Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Hemorragia/etiologia , Tromboembolia/etiologia , Administração Oral , Anticoagulantes/administração & dosagem , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Humanos , Modelos Estatísticos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Fatores de Risco , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Tiazóis/uso terapêutico , Varfarina/efeitos adversos , Varfarina/uso terapêuticoRESUMO
Hospital-associated venous thromboembolism (VTE) is a leading cause of premature death and disability worldwide. Evidence-based guidelines recommend that anticoagulant thromboprophylaxis be given to hospitalised medical patients at risk of VTE, but suggest against routine use of thromboprophylaxis beyond the hospital stay. The MARINER study is a randomised, double-blind, placebo-controlled trial to evaluate the efficacy and safety of thromboprophylaxis using rivaroxaban, begun at hospital discharge and continued for 45 days, for preventing symptomatic VTE in high-risk medical patients. Eligible patients are identified using the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE VTE) risk score, combined with a laboratory test, D-dimer. The rivaroxaban regimen is 10 mg once daily for patients with CrCl ≥ 50 ml/min, or 7.5 mg once daily for patients with CrCl ≥ 30 ml/min and < 50 ml/min. The primary efficacy outcome is the composite of symptomatic VTE (lower extremity deep-vein thrombosis and non-fatal pulmonary embolism) and VTE-related death. The principal safety outcome is major bleeding. A blinded clinical events committee adjudicates all suspected outcome events. The sample size is event-driven with an estimated total of 8,000 patients to acquire 161 primary outcome events. Study design features that distinguish MARINER from previous and ongoing thromboprophylaxis trials in medically ill patients are: (i) use of a validated risk assessment model (IMPROVE VTE) and D-dimer determination for identifying eligible patients at high risk of VTE, (ii) randomisation at the time of hospital discharge, (iii) a 45-day treatment period and (iv) restriction of the primary efficacy outcome to symptomatic VTE events.
Assuntos
Inibidores do Fator Xa/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Rivaroxabana/uso terapêutico , Tromboembolia Venosa/prevenção & controle , Adulto , Idoso , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Método Duplo-Cego , Esquema de Medicação , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Alta do Paciente , Fatores de Risco , Rivaroxabana/administração & dosagem , Rivaroxabana/efeitos adversos , Fatores de TempoRESUMO
BACKGROUND: Venous thromboembolism (VTE) comprises both deep vein thrombosis and pulmonary embolism. VTE is a leading cause of morbidity and mortality worldwide and its increasing incidence and prevalence are a major health concern. The primary medical objective during the acute phase of VTE treatment is to prevent thrombus extension and embolization. Extended treatment aims to prevent or minimize long-term complications, such as recurrent VTE, post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension. SCOPE: Anticoagulant therapy has been the mainstay of treatment for VTE and traditionally involves initial therapy with heparin, overlapping with and followed by a vitamin K antagonist. Although effective, standard heparin/vitamin K antagonist therapy has several limitations that can be overcome by more recently developed target-specific oral anticoagulants (TSOACs). These agents have predictable pharmacokinetics, a rapid onset of action and few drug-drug or drug-food interactions. Furthermore, TSOACs offer convenient anticoagulation without the need for routine coagulation monitoring and dose adjustment. FINDINGS: The efficacy and safety data from phase III clinical trials support the use of TSOACs for VTE treatment, including in special patient populations. Risk-stratification tools and strategies have been developed to assist physicians in managing anticoagulation treatment. CONCLUSIONS: Rivaroxaban is the first TSOAC to gain widespread approval for the treatment of acute deep vein thrombosis and pulmonary embolism and the long-term prevention of recurrent VTE as monotherapy. Dabigatran has also been approved for this indication recently. TSOACs, especially as monotherapy, represent a paradigm shift in clinical practice for the management of patients with VTE.