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1.
RMD Open ; 8(2)2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36323490

RESUMO

OBJECTIVE: In the ORAL (Oral Rheumatoid Arthritis triaL) Surveillance study of patients with rheumatoid arthritis aged ≥50 years with ≥1 additional cardiovascular risk factor, incidence of pulmonary embolism was higher with tofacitinib 10 mg two times per day than with tumour necrosis factor inhibitors (TNFi). This exploratory post hoc analysis examined whether biomarkers explained the associations of tofacitinib versus TNFi with venous thromboembolism (VTE). METHODS: ORAL Surveillance was a prospective, open-label, event-driven, non-inferiority, postauthorisation safety study. Patients were randomised 1:1:1 to receive tofacitinib 5 mg or 10 mg two times per day or a TNFi. For this analysis, 294 soluble, proteomic, genetic and antibody biomarkers (of which 79 had a known role in inflammation, coagulation, vascular biology or Janus kinase signalling) were quantified in serum collected at baseline, month 12 and study end. RESULTS: Overall, 4362 patients were randomised and treated. The exploratory biomarker data set included 285 patients (57 VTE cases; 228 matched controls). D-dimer was quantified in 3732 patients (54 VTE cases; 3678 controls). No biomarker demonstrated a clear mechanistic association with the increased risk of VTE for tofacitinib versus TNFi. Month 12 D-dimer levels were positively associated with risk of a subsequent VTE within the tofacitinib 5 mg and 10 mg two times per day arms. CONCLUSIONS: Overall, this post hoc analysis did not identify biomarkers that explained the increased VTE risk for tofacitinib versus TNFi. Individual VTE risk should be considered when making decisions about initiation or maintenance of tofacitinib treatment. TRIAL REGISTRATION NUMBER: NCT02092467; ClinicalTrials.gov.


Assuntos
Antirreumáticos , Artrite Reumatoide , Tromboembolia Venosa , Humanos , Inibidores do Fator de Necrose Tumoral , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia , Antirreumáticos/efeitos adversos , Proteômica , Estudos Prospectivos , Pirróis/efeitos adversos , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/induzido quimicamente , Biomarcadores
2.
Artigo em Inglês | MEDLINE | ID: mdl-36413608

RESUMO

Thrombus formation and infections caused by bacterial adhesion are the most common causes of failure in blood-contacting medical devices. Reducing the interaction of pathogens using repellent surfaces has proven to be a successful strategy in preventing device failure. However, designing scale-up methodologies to create large-scale repellent surfaces remains challenging. To address this need, we have created an all-polymeric lubricant-infused system using an industrially viable swelling-coagulation solvent (S-C) method. This induces hierarchically structured micro/nano features onto the surface, enabling improved lubricant infusion. Poly(3,3,3-trifluoropropylmethylsiloxane) (PTFS) was used as the lubricant of choice, a previously unexplored omniphobic nonvolatile silicone oil. This resulted in all-polymeric liquid-infused surfaces that are transparent and flexible with long-term stability. Repellent properties have been demonstrated using human whole blood and methicillin-resistant Staphylococcus aureus (MRSA) bacteria matrices, with lubricated surfaces showing 93% reduction in blood stains and 96.7% reduction in bacterial adherence. The developed material has the potential to prevent blood and pathogenic contamination for a range biomedical devices within healthcare settings.

3.
J Am Heart Assoc ; 11(20): e026229, 2022 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-36205248

RESUMO

Background Venous thromboembolism (VTE) often occurs after hospitalization in medically ill patients, but the population benefit-risk of extended thromboprophylaxis remains uncertain. Methods and Results The MARINER (Medically Ill Patient Assessment of Rivaroxaban Versus Placebo in Reducing Post-Discharge Venous Thrombo-Embolism Risk) study (NCT02111564) was a randomized double-blind trial that compared thromboprophylaxis with rivaroxaban 10 mg daily versus placebo for 45 days after hospital discharge in medically ill patients with a creatinine clearance ≥50 mL/min. The benefit-risk balance in this population was quantified by calculating the between-treatment rate differences in efficacy and safety end points per 10 000 patients treated. Clinical characteristics of the study population were consistent with a hospitalized medical population at risk for VTE. Treating 10 000 patients with rivaroxaban resulted in 32.5 fewer symptomatic VTE and VTE-related deaths but was associated with 8 additional major bleeding events. The treatment benefit was driven by the prevention of nonfatal symptomatic VTE (26 fewer events). There was no between-treatment difference in the composite of critical site or fatal bleeding. Conclusions Extending thromboprophylaxis with rivaroxaban for 45 days after hospitalization provides a positive benefit-risk balance in medically ill patients at risk for VTE who are not at high risk for bleeding. Registration URL: https://clinicaltrials.gov/; Unique identifier: NCT02111564.


Assuntos
Rivaroxabana , Tromboembolia Venosa , Humanos , Rivaroxabana/efeitos adversos , Tromboembolia Venosa/epidemiologia , Anticoagulantes/uso terapêutico , Assistência ao Convalescente , Creatinina , Alta do Paciente , Hospitalização , Hemorragia/induzido quimicamente , Medição de Risco
4.
TH Open ; 6(3): e177-e183, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36046208

RESUMO

Background The MARINER trial evaluated whether postdischarge thromboprophylaxis with rivaroxaban could reduce the primary outcome of symptomatic venous thromboembolism (VTE) or VTE-related death in acutely ill medical patients at risk for VTE. Although aspirin use was not randomized, approximately half of the enrolled patients were receiving aspirin at baseline. We hypothesized that thromboprophylaxis with once-daily rivaroxaban (10 mg or, if creatinine clearance was 30-49 mL/min, 7.5 mg) plus aspirin (R/A) would be superior to placebo without aspirin (no thromboprophylaxis [no TP]). Methods We compared the primary and major secondary outcomes in the intention-to-treat population in four subgroups defined at baseline: (1) R/A ( N = 3,159); (2) rivaroxaban alone ( N = 2,848); (3) aspirin alone ( N = 3,046); and (4) no TP ( N = 2,966). Major bleeding (MB) and nonmajor clinically relevant (NMCR) bleeding were assessed in the safety population on treatment plus 2 days. Results Patients on R/A had reduced symptomatic VTE and VTE-related death compared with no TP (0.76 vs 1.28%, p = 0.042), and experienced less symptomatic VTE and all-cause mortality ( p = 0.005) and all-cause mortality alone ( p = 0.01) compared with no TP. Event incidences for rivaroxaban alone (0.91%) or aspirin alone (0.92%) were similar. MB was low in all groups but lowest in the no TP group. NMCR bleeding was increased with R/A compared with no TP ( p = 0.009). Limitations Aspirin use was not randomized. Conclusion Extended postdischarge thromboprophylaxis with R/A was associated with less symptomatic VTE and VTE-related death compared with no TP in previously hospitalized medical patients at risk for VTE. NMCR bleeding was increased with R/A compared with no TP. These post hoc findings need confirmation in a prospective trial.

5.
Artigo em Inglês | MEDLINE | ID: mdl-36121587

RESUMO

OBJECTIVE: In this retrospective cohort study of consecutive patients with atrial fibrillation and surgical or transcatheter bioprosthetic valve, we compared the efficacy and safety of direct oral anticoagulants with warfarin. METHODS: Using linked health administrative databases housed at the Institute for Clinical Evaluative Sciences, we identified consecutive patients in Ontario (Canada) 65 years of age or older with AF who underwent bioprosthetic valve replacement between 1 April 2012 and 31 March 2017. We created a time-varying Cox model to examine the relationship between the type of anticoagulant and time to thrombotic or bleeding events after adjustment for baseline risk of thrombosis using the CHA2DS2-VASc score and risk of bleeding using the HAS-BLED scores. We conducted prespecified subgroup analyses according to whether valve implantation was surgical or transcatheter. RESULTS: We identified 2245 eligible patients. The mean age was 79 years, 41% were female, and 39% had transcatheter aortic valve replacement. Risk of death or thrombosis was not different between direct oral anticoagulants and warfarin after adjustment for CHA2DS2-VASc score (hazard ratio [HR] 1.02, 95% confidence interval [CI], 0.83-1.25). Risk of death or bleeding was not different between direct oral anticoagulants and warfarin after adjustment for HAS-BLED score (HR 0.89, 95% CI 0.75-1.07). Subgroup analyses of surgical or transcatheter valves were consistent with overall results. CONCLUSIONS: In a real-world population of patients with atrial fibrillation and bioprosthetic valve replacement, we found no difference between direct oral anticoagulants and warfarin with regard to the risk of thrombosis or bleeding.

6.
Nat Commun ; 13(1): 3264, 2022 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-35672320

RESUMO

Confinement of fibrous hydrogels in narrow capillaries is of great importance in biological and biomedical systems. Stretching and uniaxial compression of fibrous hydrogels have been extensively studied; however, their response to biaxial confinement in capillaries remains unexplored. Here, we show experimentally and theoretically that due to the asymmetry in the mechanical properties of the constituent filaments that are soft upon compression and stiff upon extension, filamentous gels respond to confinement in a qualitatively different manner than flexible-strand gels. Under strong confinement, fibrous gels exhibit a weak elongation and an asymptotic decrease to zero of their biaxial Poisson's ratio, which results in strong gel densification and a weak flux of liquid through the gel. These results shed light on the resistance of strained occlusive clots to lysis with therapeutic agents and stimulate the development of effective endovascular plugs from gels with fibrous structures for stopping vascular bleeding or suppressing blood supply to tumors.


Assuntos
Hidrogéis , Hidrogéis/química , Pressão
7.
J Thromb Haemost ; 20(7): 1515-1517, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35754017
8.
JAMA Cardiol ; 7(7): 747-759, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35648414

RESUMO

Importance: Dose-reduced regimens of direct oral anticoagulants (DOACs) may be used for 2 main purposes: dose-adjusted treatment intended as full-intensity anticoagulation (eg, for stroke prevention in atrial fibrillation [AF] in patients requiring dose reduction) or low-intensity treatment (eg, extended-duration treatment of venous thromboembolism [VTE]). We reviewed randomized clinical trials (RCTs) to understand the scenarios in which dose-adjusted or low-intensity DOACs were tested and reviewed the labeled indications by regulatory authorities, using data from large registries to assess whether the use of dose-reduced DOACs in routine practice aligned with the findings of RCTs. Observations: Among 4191 screened publications, 35 RCTs that used dose-adjusted DOACs were identified for dabigatran, apixaban, rivaroxaban, and edoxaban. Of these 35 RCTs, 29 were related to stroke prevention in AF. Efficacy and safety results for dose-adjusted DOACs in large RCTs of AF were similar to those found for full-dose DOACs. To our knowledge, dabigatran, apixaban, and rivaroxaban have not been studied as dose-adjusted therapy for acute VTE treatment. Low-intensity DOACs were identified in 37 RCTs. Low-intensity DOACs may be used for extended-duration treatment of VTE (apixaban and rivaroxaban), primary prevention in orthopedic surgeries (dabigatran, apixaban, and rivaroxaban), primary prevention in ambulatory high-risk cancer patients (apixaban and rivaroxaban) or (postdischarge) high-risk medical patients (rivaroxaban), in stable atherosclerotic vascular disease, or after a recent revascularization for peripheral artery disease in conjunction with aspirin (rivaroxaban). Minor variations exist between regulatory authorities in different regions regarding criteria for dose adjustment of DOACs. Data from large registries indicated that dose-reduced DOACs were used occasionally with doses or for clinical scenarios different from those studied in RCTs or recommended by regulatory authorities. Conclusions and Relevance: Dose adjustment and low-intensity treatment are 2 different forms of dose-reduced DOACs. Dose adjustment is mostly relevant for AF and should be done based on the approved criteria. Dose adjustment of DOACs should not be used for acute VTE treatment in most cases. In contrast, low-intensity DOACs may be used for primary or secondary VTE prevention for studied and approved indications. Attention should be given to routine practice patterns to align the daily clinical practice with existing evidence of safety and efficacy.


Assuntos
Fibrilação Atrial , Acidente Vascular Cerebral , Tromboembolia Venosa , Administração Oral , Anticoagulantes , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Dabigatrana/uso terapêutico , Humanos , Rivaroxabana/uso terapêutico , Acidente Vascular Cerebral/complicações , Tromboembolia Venosa/complicações , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/prevenção & controle
9.
Circulation ; 145(19): 1471-1479, 2022 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-35389229

RESUMO

BACKGROUND: Extended thromboprophylaxis has not been widely implemented in acutely ill medical patients because of bleeding concerns. The MAGELLAN (Multicenter, Randomized, Parallel Group Efficacy and Safety Study for the Prevention of Venous Thromboembolism in Hospitalized Medically Ill Patients Comparing Rivaroxaban With Enoxaparin) and MARINER (Medically Ill Patient Assessment of Rivaroxaban Versus Placebo in Reducing Post-Discharge Venous Thrombo-Embolism Risk) trials evaluated whether rivaroxaban compared with enoxaparin or placebo could prevent venous thromboembolism without increased bleeding. We hypothesized that patients with major bleeding but not those with nonmajor clinically relevant bleeding would be at an increased risk of all-cause mortality (ACM). METHODS: We evaluated all bleeding events in patients taking at least 1 dose of study drug and their association with ACM in 4 mutually exclusive groups: (1) no bleeding, or first event was (2) nonmajor clinically relevant bleeding, (3) major bleeding, or (4) trivial bleeding. Using a Cox proportional hazards model adjusted for differences in baseline characteristics associated with ACM, we assessed the risk of ACM after such events. RESULTS: Compared with patients with no bleeding, the risk of ACM for patients with nonmajor clinically relevant bleeding was not increased in MARINER (hazard ratio, 0.43; P=0.235) but was increased in MAGELLAN (hazard ratio, 1.74; P=0.021). Major bleeding was associated with a higher incidence of ACM in both studies, whereas trivial bleeding was not associated with ACM in either study. CONCLUSIONS: Patients with major bleeding had an increased risk of ACM, whereas nonmajor clinically relevant bleeding was not consistently associated with an increased risk of death. These results inform the risk-benefit calculus of extended thromboprophylaxis in medically ill patients. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: MAGELLAN, NCT00571649. URL: https://www. CLINICALTRIALS: gov; Unique identifier: MARINER, NCT02111564.


Assuntos
Rivaroxabana , Tromboembolia Venosa , Assistência ao Convalescente , Anticoagulantes/efeitos adversos , Enoxaparina/efeitos adversos , Hemorragia/induzido quimicamente , Hemorragia/complicações , Humanos , Alta do Paciente , Rivaroxabana/efeitos adversos , Tromboembolia Venosa/epidemiologia
10.
Small ; 18(15): e2108112, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35224860

RESUMO

The surface fouling of biomedical devices has been an ongoing issue in healthcare. Bacterial and blood adhesion in particular, severely impede the performance of such tools, leading to poor patient outcomes. Various structural and chemical modifications have been shown to reduce fouling, but all existing strategies lack the combination of physical, chemical, and economic traits necessary for widespread use. Herein, a lubricant infused, hierarchically micro- and nanostructured polydimethylsiloxane surface is presented. The surface is easy to produce and exhibits the high flexibility and optical transparency necessary for incorporation into various biomedical tools. Tests involving two clinically relevant, priority pathogens show up to a 98.5% reduction in the biofilm formation of methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa. With blood, the surface reduces staining by 95% and suppresses thrombin generation to background levels. Furthermore, the surface shows applicability within applications such as catheters, extracorporeal circuits, and microfluidic devices, through its effectiveness in dynamic conditions. The perfusion of bacterial media shows up to 96.5% reduction in bacterial adhesion. Similarly, a 95.8% reduction in fibrin networks is observed following whole blood perfusion. This substrate stands to hold high applicability within biomedical systems as a means to prevent fouling, thus improving performance.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Trombose , Aderência Bacteriana , Biofilmes , Dimetilpolisiloxanos , Humanos , Propriedades de Superfície
11.
Thromb Haemost ; 122(8): 1279-1287, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35189662

RESUMO

Venous thromboembolism (VTE) and arterial thromboembolism (ATE) are linked by the common mechanism of thrombin generation. Historically these entities have been treated as separate pathophysiologic processes requiring different treatments: VTE, as the formation of fibrin-/coagulation-factor-derived thrombus in low-flow vasculature, requiring anticoagulants; versus ATE, as largely platelet-derived thrombus in high-flow vasculature, requiring antiplatelet agents. Observational studies have elucidated shared risk factors and comorbidities predisposing individuals with VTE to ATE, and vice versa, and have bolstered the strategy of dual-pathway inhibition (DPI)-the combination of low-dose anticoagulants with antiplatelet agents-to reduce thrombotic outcomes on both sides of the vasculature. Randomized clinical trials have evaluated the efficacy and safety of such regimens-mostly rivaroxaban and aspirin-in high-risk groups of patients, including those with recent acute or chronic coronary syndrome, as well as those with peripheral artery disease with or without revascularization. Studies of extended VTE prophylaxis in acutely ill medical patients have also contributed to the evidence evaluating DPI. The totality of available data supports the concept that DPI can reduce major and fatal thromboembolic outcomes, including stroke, myocardial infarction, VTE, and cardiovascular death in key patient cohorts, with acceptable risk of bleeding. Further data are needed to refine which patients derive the best net clinical benefit from such an approach. At the same time, other novel agents such as contact pathway inhibitors that reduce thrombin generation without affecting hemostasis-and thus maximize safety-should be assessed in appropriate populations.


Assuntos
Trombose , Tromboembolia Venosa , Anticoagulantes , Humanos , Inibidores da Agregação Plaquetária , Trombina
12.
ACS Appl Mater Interfaces ; 14(3): 3864-3874, 2022 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-35040309

RESUMO

High-touch surfaces are known to be a major route for the spread of pathogens in healthcare and public settings. Antimicrobial coatings have, therefore, garnered significant attention to help mitigate the transmission of infectious diseases via the surface route. Among antimicrobial coatings, pathogen-repellent surfaces provide unique advantages in terms of safety in public settings such as instant repellency, affordability, biocompatibility, and long-term stability. While there have been many advances in the fabrication of biorepellent surfaces in the past two decades, this area of research continues to suffer challenges in scalability, cost, compatibility with high-touch applications, and performance for pathogen repellency. These features are critical for high-touch surfaces to be used in public settings. Additionally, the environmental impact of manufacturing repellent surfaces remains a challenge, mainly due to the use of fluorinated coatings. Here, we present a flexible hierarchical coating with straightforward and cost-effective manufacturing without the use of fluorine or a lubricant. Hierarchical surfaces were prepared through the growth of polysiloxane nanostructures using n-propyltrichlorosilane (n-PTCS) on activated polyolefin (PO), followed by heat shrinking to induce microscale wrinkles. The developed coatings demonstrated repellency, with contact angles over 153° and sliding angles <1°. In assays mimicking touch, these hierarchical surfaces demonstrated a 97.5% reduction in transmission of Escherichia coli (E.coli), demonstrating their potential as antimicrobial coatings to mitigate the spread of infectious diseases. Additionally, the developed surfaces displayed a 93% reduction in blood staining after incubation with human whole blood, confirming repellent properties that reduce bacterial deposition.


Assuntos
Antibacterianos/farmacologia , Materiais Biocompatíveis/farmacologia , Escherichia coli/efeitos dos fármacos , Siloxanas/farmacologia , Antibacterianos/química , Materiais Biocompatíveis/química , Teste de Materiais , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Siloxanas/química , Propriedades de Superfície
15.
J Thromb Haemost ; 20(2): 366-374, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34714962

RESUMO

BACKGROUND: Inferior vena cava (IVC) thrombosis is a rare form of venous thromboembolism (VTE). The optimal treatment strategies and outcomes are unclear in patients with this presentation. OBJECTIVE: We aimed to compare baseline characteristics, treatment patterns and 24-month outcomes in IVC thrombosis patients (n = 100) with lower extremity deep vein thrombosis (LEDVT) patients (n = 7629). METHODS: GARFIELD-VTE is a prospective, observational registry of 10 868 patients with objectively diagnosed VTE from 415 sites in 28 countries. RESULTS: IVC thrombosis patients were younger (51.9 vs. 59.8 years), more frequently had active cancer (26.0% vs. 8.9%) or history of cancer (21.0% vs. 12.2%), and less frequently had recent trauma or surgery than LEDVT patients. IVC thrombosis was more frequently treated with parenteral anticoagulants alone (35.1% vs. 15.9%), whereas patients with LEDVT more commonly received vitamin K antagonists (32.0% vs. 25.8%) or direct oral anticoagulants (49.0% vs. 35.1%). Thrombolysis (11.0% vs. 3.6%) and surgical/mechanical interventions (4.0% vs. 1.4%) were more frequent in IVC thrombosis. At 24-months, the rate per 100 person-years (95% confidence interval) of all-cause mortality was higher in patients with IVC thrombosis than LEDVT (13.28 [8.57-20.58] vs. 4.91 [4.55-5.3]); the incidence of cancer-associated mortality was comparable as was the incidence of VTE recurrence (4.11 [1.85-9.15] vs. 4.18 [3.84-4.55]). Major bleeding was slightly higher in IVC thrombosis (2.03 [0.66-6.31] vs. 1.66 [1.45-1.89]). CONCLUSION: In summary, IVC thrombosis patients have higher all-cause mortality rates than those with LEDVT, a finding only partly attributable to malignancy.


Assuntos
Embolia Pulmonar , Tromboembolia Venosa , Trombose Venosa , Humanos , Estudos Prospectivos , Embolia Pulmonar/epidemiologia , Veia Cava Inferior , Tromboembolia Venosa/epidemiologia , Trombose Venosa/diagnóstico , Trombose Venosa/tratamento farmacológico
16.
Eur Heart J Cardiovasc Pharmacother ; 8(7): 695-706, 2022 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34962979

RESUMO

AIMS: In patients with atrial fibrillation (AF), peripheral artery disease (PAD) is associated with higher rates of stroke and bleeding. Both higher dose edoxaban (60/30 mg) and lower dose edoxaban (30/15 mg) were non-inferior to warfarin for stroke and systemic embolism (SSE) and significantly reduced major bleeding in AF patients in the global study to assess the safety and effectiveness of edoxaban vs standard practice of dosing with warfarin in patients with atrial fibrillation (ENGAGE AF-TIMI 48) trial. Whether the efficacy and safety of these dosing strategies vs. warfarin are consistent in patients with AF and PAD has not been described. METHODS AND RESULTS: Of 21 105 patients with AF randomized to warfarin, edoxaban 60/30 mg, or edoxaban 30/15 mg, 841 were identified with PAD. Endpoints included major adverse cardiovascular events (MACEs), SSE, and major bleeding. Patients with PAD had higher risk of MACEs [adjusted hazard ratio (HRadj) 1.33, 95% confidence interval (CI) 1.12-1.57, P = 0.001] and cardiovascular (CV) death (HRadj 1.49, 95% CI 1.21-1.83, P < 0.001) than those without PAD, but not major bleeding. The efficacy of edoxaban 60/30 mg vs. warfarin was consistent regardless of PAD (SSE HR; PAD 1.16, 95% CI 0.42-3.20; no-PAD 0.86, 95% CI 0.74-1.02, P-interaction 0.57) as was major bleeding (PAD 0.96, 95% CI 0.54-1.70; no-PAD 0.80, 95% CI 0.70-0.91, P-interaction 0.54). Edoxaban 30/15 mg was inferior for SSE, with significant heterogeneity when stratified by PAD status (P-interaction 0.039). CONCLUSION: Patients with AF and PAD are at heightened risk of MACEs and CV death vs. those without PAD. The efficacy and safety of edoxaban 60/30 mg vs. warfarin in AF are consistent regardless of PAD; however, edoxaban 30/15 mg is inferior for stroke prevention in AF patients with PAD. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT00781391.


Assuntos
Fibrilação Atrial , Embolia , Doença Arterial Periférica , Acidente Vascular Cerebral , Anticoagulantes , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Embolia/prevenção & controle , Inibidores do Fator Xa , Hemorragia/induzido quimicamente , Humanos , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/tratamento farmacológico , Piridinas , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Tiazóis , Varfarina
18.
J Thromb Haemost ; 20(4): 821-832, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34967109

RESUMO

BACKGROUND: Previously, we showed that histidine-rich glycoprotein (HRG) binds factor (F) XIIa with high affinity, inhibits FXII autoactivation and FXIIa-mediated activation of FXI, and attenuates ferric chloride-induced arterial thrombosis in mice. Therefore, HRG downregulates the contact pathway in vitro and in vivo. OBJECTIVE: To identify the domains on HRG responsible for contact pathway inhibition. METHODS: Recombinant HRG domain constructs (N-terminal [N1, N2, and N1N2], proline-rich regions, histidine-rich region [HRR], and C-terminal) were expressed and purified. The affinities of plasma-derived HRG, HRG domain constructs, and synthetic HRR peptides for FXII, FXIIa, ß-FXIIa, and polyphosphate (polyP) were determined using surface plasmon resonance, and their effects on polyP-induced FXII autoactivation, FXIIa-mediated activation of FXI and prekallikrein, the activated partial thromboplastin time (APTT), and thrombin generation were examined. RESULTS: HRG and HRG domain constructs bind FXIIa, but not FXII or ß-FXII. HRR, N1, and N1N2 bind FXIIa with affinities comparable with that of HRG, whereas the remaining domains bind with lower affinity. Synthetic HRR peptides bind FXIIa and polyP with high affinity. HRG and HRR significantly inhibit FXII autoactivation and prolong the APTT. Like HRG, synthetic HRR peptides inhibit FXII autoactivation, attenuate FXIIa-mediated activation of prekallikrein and FXI, prolong the APTT, and attenuate thrombin generation. CONCLUSION: The interaction of HRG with FXIIa and polyP is predominantly mediated by the HRR domain. Like intact HRG, HRR downregulates the contact pathway and contributes to HRG-mediated down regulation of coagulation.


Assuntos
Pré-Calicreína , Trombina , Animais , Fator XII/metabolismo , Fator XIIa/metabolismo , Humanos , Camundongos , Peptídeos/farmacologia , Polifosfatos , Pré-Calicreína/metabolismo , Proteínas , Trombina/metabolismo
19.
N Engl J Med ; 385(23): 2161-2172, 2021 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-34780683

RESUMO

BACKGROUND: Factor XIa inhibitors for the prevention and treatment of venous and arterial thromboembolism may be more effective and result in less bleeding than conventional anticoagulants. Additional data are needed regarding the efficacy and safety of milvexian, an oral factor XIa inhibitor. METHODS: In this parallel-group, phase 2 trial, we randomly assigned 1242 patients undergoing knee arthroplasty to receive one of seven postoperative regimens of milvexian (25 mg, 50 mg, 100 mg, or 200 mg twice daily or 25 mg, 50 mg, or 200 mg once daily) or enoxaparin (40 mg once daily). The primary efficacy outcome was venous thromboembolism (which was a composite of asymptomatic deep-vein thrombosis, confirmed symptomatic venous thromboembolism, or death from any cause). The principal safety outcome was bleeding. RESULTS: Among the patients receiving milvexian twice daily, venous thromboembolism developed in 27 of 129 (21%) taking 25 mg, in 14 of 124 (11%) taking 50 mg, in 12 of 134 (9%) taking 100 mg, and in 10 of 131 (8%) taking 200 mg. Among those receiving milvexian once daily, venous thromboembolism developed in 7 of 28 (25%) taking 25 mg, in 30 of 127 (24%) taking 50 mg, and in 8 of 123 (7%) taking 200 mg, as compared with 54 of 252 patients (21%) taking enoxaparin. The dose-response relationship with twice-daily milvexian was significant (one-sided P<0.001), and the 12% incidence of venous thromboembolism with twice-daily milvexian was significantly lower than the prespecified benchmark of 30% (one-sided P<0.001). Bleeding of any severity occurred in 38 of 923 patients (4%) taking milvexian and in 12 of 296 patients (4%) taking enoxaparin; major or clinically relevant nonmajor bleeding occurred in 1% and 2%, respectively; and serious adverse events were reported in 2% and 4%, respectively. CONCLUSIONS: Postoperative factor XIa inhibition with oral milvexian in patients undergoing knee arthroplasty was effective for the prevention of venous thromboembolism and was associated with a low risk of bleeding. (Funded by Bristol Myers Squibb and Janssen Research and Development; AXIOMATIC-TKR ClinicalTrials.gov number, NCT03891524.).


Assuntos
Anticoagulantes/uso terapêutico , Artroplastia do Joelho , Fator XIa/antagonistas & inibidores , Complicações Pós-Operatórias/prevenção & controle , Pirimidinas/uso terapêutico , Triazóis/uso terapêutico , Tromboembolia Venosa/prevenção & controle , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Relação Dose-Resposta a Droga , Enoxaparina/efeitos adversos , Enoxaparina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Triazóis/administração & dosagem , Triazóis/efeitos adversos
20.
Thromb Haemost ; 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34753191

RESUMO

BACKGROUND: The long-term risk of major bleeding after discontinuing anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. OBJECTIVES: To determine the incidence of major bleeding up to 5 years after discontinuing anticoagulation for a first unprovoked VTE. METHODS: We searched MEDLINE, EMBASE, and Cochrane CENTRAL (from inception to January 2021) to identify relevant randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding after discontinuing anticoagulation in patients with a first unprovoked or weakly provoked VTE who had completed (IMAGE_)3 months of initial treatment. Unpublished data on major bleeding events and person-years were obtained from authors of included studies to calculate study-level incidence rates. Random-effects meta-analysis was used to pool results across studies. RESULTS: Of 1,123 records identified by the search, 20 studies (17 RCTs) and 8,740 patients were included in the analysis. During 13,011 person-years of follow-up after discontinuing anticoagulation, the pooled incidence of major bleeding (n = 41) and fatal bleeding (n = 7) per 100 person-years was 0.35 (95% confidence interval [CI]: 0.20-0.54) and 0.09 (95% CI: 0.05-0.15). The 5-year cumulative incidence of major bleeding was of 1.0% (95% CI: 0.4-2.4%). The case-fatality rate of major bleeding after discontinuing anticoagulation was 19.9% (95% CI: 10.6-31.1%). CONCLUSION: The risk of major bleeding once anticoagulants are discontinued in patients with a first unprovoked VTE is not zero. Estimates from this study can help clinicians counsel patients about the incremental risk of major bleeding with extended anticoagulation to guide decision making about treatment duration for unprovoked VTE.

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