RESUMEN
BACKGROUND: The combination of rivaroxaban plus aspirin compared with aspirin alone reduces the risk of major adverse cardiovascular and limb events for high-risk patients with peripheral artery disease. It is unknown whether rivaroxaban plus aspirin improves intermittent claudication for adults with lower-risk peripheral arterial disease. METHODS: In this randomized, open-label, multicenter, 24-week clinical trial, we randomly assigned patients with peripheral artery disease and intermittent claudication to receive either 2.5 mg of rivaroxaban twice daily plus 100 mg of aspirin once daily or 100 mg of aspirin once daily. The primary outcome was a 24-week change in total walking distance, measured by the 6-minute walking test. The primary safety outcome was the incidence of major bleeding or clinically relevant nonmajor bleeding. RESULTS: Eighty-eight patients were randomly assigned to either rivaroxaban plus aspirin (n=46) or aspirin alone (n=42). The mean age was 67 years, and 54% were female. The total walking distance measured by 6-minute walk test improved by 89 ± 18 m (mean±standard error) in the rivaroxaban-plus-aspirin group versus 21 ± 16 m in the aspirin-alone group. This corresponded to an absolute difference of 68 ± 24 m (95% confidence interval [CI], 19 to 116 m; P=0.007) and a relative improvement over the aspirin-alone group of 327% (95% CI, 94 to 560%). No major bleeding events were observed in either group. CONCLUSIONS: In patients with peripheral artery disease and intermittent claudication, 2.5 mg of rivaroxaban twice daily plus 100 mg of aspirin daily improved the total walking distance by a 6-minute walking test compared with 100 mg of aspirin daily alone. (Funded by Bayer S.A.; Clinicaltrials.gov number, NCT04853719.).
Asunto(s)
Aspirina , Inhibidores del Factor Xa , Claudicación Intermitente , Enfermedad Arterial Periférica , Rivaroxabán , Humanos , Rivaroxabán/uso terapéutico , Rivaroxabán/administración & dosificación , Rivaroxabán/efectos adversos , Claudicación Intermitente/tratamiento farmacológico , Femenino , Masculino , Anciano , Aspirina/uso terapéutico , Aspirina/administración & dosificación , Aspirina/efectos adversos , Persona de Mediana Edad , Inhibidores del Factor Xa/uso terapéutico , Inhibidores del Factor Xa/administración & dosificación , Inhibidores del Factor Xa/efectos adversos , Inhibidores del Factor Xa/farmacología , Enfermedad Arterial Periférica/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/efectos adversos , Quimioterapia Combinada , Resultado del Tratamiento , Hemorragia/inducido químicamenteRESUMEN
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.
Asunto(s)
Cuidados Posteriores , Coagulación Sanguínea/efectos de los fármacos , COVID-19/complicaciones , Inhibidores del Factor Xa/farmacología , Inhibidores del Factor Xa/uso terapéutico , Rivaroxabán/farmacología , Rivaroxabán/uso terapéutico , Tromboembolia Venosa/prevención & control , Adulto , Anciano , Femenino , Heparina/administración & dosificación , Heparina/uso terapéutico , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Alta del Paciente , Resultado del Tratamiento , Tratamiento Farmacológico de COVID-19RESUMEN
Interchangeability of drug products has very different features with small molecules and with biologicals. With small-molecule drugs, a statement of bioequivalence generally indicates therapeutic equivalence and interchangeability. In contrast, with the much more sensitive and complicated biological drugs, a declaration of biosimilarity emphatically does not imply that a patient could be switched from one product to another. Both formulations may be prescribed and administered to subjects who have not received yet the drug in any of its forms. However, regulatory agencies have been very cautious about enabling and permitting interchangeability. Notably, the Biologics Price Competition and Innovation Act of the USA sets very formidable and severe conditions for enabling the interchangeability of biological drug products. The background and conditions for the interchangeability of both small-molecule and biologic drug products are presented in detail.