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1.
N Engl J Med ; 382(10): 893-902, 2020 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-32130813

RESUMEN

BACKGROUND: Patients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes. METHODS: In an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs - bedaquiline, pretomanid, and linezolid - that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated. RESULTS: A total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid. CONCLUSIONS: The combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799.).


Asunto(s)
Antituberculosos/administración & dosificación , Diarilquinolinas/administración & dosificación , Tuberculosis Extensivamente Resistente a Drogas/tratamiento farmacológico , Linezolid/administración & dosificación , Nitroimidazoles/administración & dosificación , Administración Oral , Adolescente , Adulto , Antituberculosos/efectos adversos , Carga Bacteriana , Diarilquinolinas/efectos adversos , Quimioterapia Combinada , Tuberculosis Extensivamente Resistente a Drogas/mortalidad , Femenino , Humanos , Análisis de Intención de Tratar , Linezolid/efectos adversos , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/aislamiento & purificación , Nitroimidazoles/efectos adversos , Resultado del Tratamiento , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Pulmonar/tratamiento farmacológico , Adulto Joven
2.
N Engl J Med ; 382(9): 810-821, 2020 02 27.
Artículo en Inglés | MEDLINE | ID: mdl-32101663

RESUMEN

BACKGROUND: Previous trials showed promising antitumor activity and an acceptable safety profile associated with pembrolizumab in patients with early triple-negative breast cancer. Whether the addition of pembrolizumab to neoadjuvant chemotherapy would significantly increase the percentage of patients with early triple-negative breast cancer who have a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery is unclear. METHODS: In this phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with previously untreated stage II or stage III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) every 3 weeks plus paclitaxel and carboplatin (784 patients; the pembrolizumab-chemotherapy group) or placebo every 3 weeks plus paclitaxel and carboplatin (390 patients; the placebo-chemotherapy group); the two groups then received an additional four cycles of pembrolizumab or placebo, and both groups received doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, the patients received adjuvant pembrolizumab or placebo every 3 weeks for up to nine cycles. The primary end points were a pathological complete response at the time of definitive surgery and event-free survival in the intention-to-treat population. RESULTS: At the first interim analysis, among the first 602 patients who underwent randomization, the percentage of patients with a pathological complete response was 64.8% (95% confidence interval [CI], 59.9 to 69.5) in the pembrolizumab-chemotherapy group and 51.2% (95% CI, 44.1 to 58.3) in the placebo-chemotherapy group (estimated treatment difference, 13.6 percentage points; 95% CI, 5.4 to 21.8; P<0.001). After a median follow-up of 15.5 months (range, 2.7 to 25.0), 58 of 784 patients (7.4%) in the pembrolizumab-chemotherapy group and 46 of 390 patients (11.8%) in the placebo-chemotherapy group had disease progression that precluded definitive surgery, had local or distant recurrence or a second primary tumor, or died from any cause (hazard ratio, 0.63; 95% CI, 0.43 to 0.93). Across all treatment phases, the incidence of treatment-related adverse events of grade 3 or higher was 78.0% in the pembrolizumab-chemotherapy group and 73.0% in the placebo-chemotherapy group, including death in 0.4% (3 patients) and 0.3% (1 patient), respectively. CONCLUSIONS: Among patients with early triple-negative breast cancer, the percentage with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy. (Funded by Merck Sharp & Dohme [a subsidiary of Merck]; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.).


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Epirrubicina/administración & dosificación , Femenino , Humanos , Análisis de Intención de Tratar , Estimación de Kaplan-Meier , Persona de Mediana Edad , Terapia Neoadyuvante , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Neoplasias de la Mama Triple Negativas/mortalidad , Neoplasias de la Mama Triple Negativas/patología
3.
N Engl J Med ; 382(6): 525-533, 2020 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-32023372

RESUMEN

BACKGROUND: We previously reported the results of a trial of prenatal vitamin D supplementation to prevent asthma and recurrent wheeze in young children, which suggested that supplementation provided a protective effect at the age of 3 years. We followed the children through the age of 6 years to determine the course of asthma and recurrent wheeze. METHODS: In this follow-up study, investigators and participants remained unaware of the treatment assignments through the children's sixth birthday. We aimed to determine whether, when maternal levels of 25-hydroxyvitamin D were taken into account, children born to mothers who had received 4400 IU of vitamin D3 per day during pregnancy (vitamin D group) would have a lower incidence of asthma and recurrent wheeze at the age of 6 years than would those born to mothers who had received 400 IU of vitamin D3 per day (control group). Time-to-event methods were used to compare the treatment groups with respect to time to the onset of asthma or recurrent wheeze. Multivariate methods were used to compare longitudinal measures of lung function between the treatment groups. RESULTS: There was no effect of maternal vitamin D supplementation on asthma and recurrent wheeze in either an intention-to-treat analysis or an analysis with stratification according to the maternal 25-hydroxyvitamin D level during pregnancy. There was no effect of prenatal vitamin D supplementation on most of the prespecified secondary outcomes. We found no effects of prenatal supplementation on spirometric indexes. Although there was a very small effect on airway resistance as measured by impulse oscillometry, this finding was of uncertain significance. CONCLUSIONS: Vitamin D supplementation during the prenatal period alone did not influence the 6-year incidence of asthma and recurrent wheeze among children who were at risk for asthma. (Funded by the National Heart, Lung, and Blood Institute; VDAART ClinicalTrials.gov number, NCT00920621.).


Asunto(s)
Resistencia de las Vías Respiratorias/efectos de los fármacos , Asma/prevención & control , Suplementos Dietéticos , Atención Prenatal , Vitamina D/administración & dosificación , Vitaminas/administración & dosificación , Asma/epidemiología , Niño , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Análisis de Intención de Tratar , Pulmón/efectos de los fármacos , Pulmón/embriología , Embarazo , Ruidos Respiratorios/efectos de los fármacos , Espirometría , Vitamina D/análogos & derivados , Vitamina D/sangre
4.
N Engl J Med ; 382(4): 341-352, 2020 01 23.
Artículo en Inglés | MEDLINE | ID: mdl-31971679

RESUMEN

BACKGROUND: Thyroid eye disease is a debilitating, disfiguring, and potentially blinding periocular condition for which no Food and Drug Administration-approved medical therapy is available. Strong evidence has implicated the insulin-like growth factor I receptor (IGF-IR) in the pathogenesis of this disease. METHODS: In a randomized, double-masked, placebo-controlled, phase 3 multicenter trial, we assigned patients with active thyroid eye disease in a 1:1 ratio to receive intravenous infusions of the IGF-IR inhibitor teprotumumab (10 mg per kilogram of body weight for the first infusion and 20 mg per kilogram for subsequent infusions) or placebo once every 3 weeks for 21 weeks; the last trial visit for this analysis was at week 24. The primary outcome was a proptosis response (a reduction in proptosis of ≥2 mm) at week 24. Prespecified secondary outcomes at week 24 were an overall response (a reduction of ≥2 points in the Clinical Activity Score plus a reduction in proptosis of ≥2 mm), a Clinical Activity Score of 0 or 1 (indicating no or minimal inflammation), the mean change in proptosis across trial visits (from baseline through week 24), a diplopia response (a reduction in diplopia of ≥1 grade), and the mean change in overall score on the Graves' ophthalmopathy-specific quality-of-life (GO-QOL) questionnaire across trial visits (from baseline through week 24; a mean change of ≥6 points is considered clinically meaningful). RESULTS: A total of 41 patients were assigned to the teprotumumab group and 42 to the placebo group. At week 24, the percentage of patients with a proptosis response was higher with teprotumumab than with placebo (83% [34 patients] vs. 10% [4 patients], P<0.001), with a number needed to treat of 1.36. All secondary outcomes were significantly better with teprotumumab than with placebo, including overall response (78% of patients [32] vs. 7% [3]), Clinical Activity Score of 0 or 1 (59% [24] vs. 21% [9]), the mean change in proptosis (-2.82 mm vs. -0.54 mm), diplopia response (68% [19 of 28] vs. 29% [8 of 28]), and the mean change in GO-QOL overall score (13.79 points vs. 4.43 points) (P≤0.001 for all). Reductions in extraocular muscle, orbital fat volume, or both were observed in 6 patients in the teprotumumab group who underwent orbital imaging. Most adverse events were mild or moderate in severity; two serious events occurred in the teprotumumab group, of which one (an infusion reaction) led to treatment discontinuation. CONCLUSIONS: Among patients with active thyroid eye disease, teprotumumab resulted in better outcomes with respect to proptosis, Clinical Activity Score, diplopia, and quality of life than placebo; serious adverse events were uncommon. (Funded by Horizon Therapeutics; OPTIC ClinicalTrials.gov number, NCT03298867, and EudraCT number, 2017-002763-18.).


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Oftalmopatía de Graves/tratamiento farmacológico , Receptor IGF Tipo 1/antagonistas & inhibidores , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Diplopía/tratamiento farmacológico , Método Doble Ciego , Esquema de Medicación , Exoftalmia/tratamiento farmacológico , Oftalmopatía de Graves/diagnóstico por imagen , Humanos , Análisis de Intención de Tratar , Imagen por Resonancia Magnética , Persona de Mediana Edad , Órbita/diagnóstico por imagen , Receptor IGF Tipo 1/inmunología , Autoinforme
5.
N Engl J Med ; 382(9): 799-809, 2020 02 27.
Artículo en Inglés | MEDLINE | ID: mdl-31995682

RESUMEN

BACKGROUND: There are scant data on long-term clinical outcomes and bioprosthetic-valve function after transcatheter aortic-valve replacement (TAVR) as compared with surgical aortic-valve replacement in patients with severe aortic stenosis and intermediate surgical risk. METHODS: We enrolled 2032 intermediate-risk patients with severe, symptomatic aortic stenosis at 57 centers. Patients were stratified according to intended transfemoral or transthoracic access (76.3% and 23.7%, respectively) and were randomly assigned to undergo either TAVR or surgical replacement. Clinical, echocardiographic, and health-status outcomes were followed for 5 years. The primary end point was death from any cause or disabling stroke. RESULTS: At 5 years, there was no significant difference in the incidence of death from any cause or disabling stroke between the TAVR group and the surgery group (47.9% and 43.4%, respectively; hazard ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; P = 0.21). Results were similar for the transfemoral-access cohort (44.5% and 42.0%, respectively; hazard ratio, 1.02; 95% CI, 0.87 to 1.20), but the incidence of death or disabling stroke was higher after TAVR than after surgery in the transthoracic-access cohort (59.3% vs. 48.3%; hazard ratio, 1.32; 95% CI, 1.02 to 1.71). At 5 years, more patients in the TAVR group than in the surgery group had at least mild paravalvular aortic regurgitation (33.3% vs. 6.3%). Repeat hospitalizations were more frequent after TAVR than after surgery (33.3% vs. 25.2%), as were aortic-valve reinterventions (3.2% vs. 0.8%). Improvement in health status at 5 years was similar for TAVR and surgery. CONCLUSIONS: Among patients with aortic stenosis who were at intermediate surgical risk, there was no significant difference in the incidence of death or disabling stroke at 5 years after TAVR as compared with surgical aortic-valve replacement. (Funded by Edwards Lifesciences; PARTNER 2 ClinicalTrials.gov number, NCT01314313.).


Asunto(s)
Estenosis de la Válvula Aórtica/cirugía , Implantación de Prótesis de Válvulas Cardíacas/métodos , Prótesis Valvulares Cardíacas , Reemplazo de la Válvula Aórtica Transcatéter , Anciano , Anciano de 80 o más Años , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/cirugía , Insuficiencia de la Válvula Aórtica/etiología , Insuficiencia de la Válvula Aórtica/fisiopatología , Estenosis de la Válvula Aórtica/complicaciones , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/mortalidad , Estudios de Cohortes , Ecocardiografía , Femenino , Estado de Salud , Humanos , Incidencia , Análisis de Intención de Tratar , Estimación de Kaplan-Meier , Masculino , Análisis Multivariante , Complicaciones Posoperatorias/mortalidad , Factores de Riesgo , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Resultado del Tratamiento
6.
Bull Cancer ; 107(1): 48-53, 2020 Jan.
Artículo en Francés | MEDLINE | ID: mdl-31980143

RESUMEN

The adjuvant treatment of biliary tract cancers has long been poorly defined. In recent years, randomized trial data have been used to define treatment references. The French Prodige 12 and Japanese BCAT trials have not demonstrated any benefit of adjuvant chemotherapy. The English BILCAP trial tested adjuvant capecitabine for six months at the usual dose in a randomized, controlled-only trial involving nearly 450 patients. Although the results in intention to treat were borderline significant on the primary endpoint, overall survival (P=0.097), sensitivity analyzes adjusted for prognostic factors and relapse-free survival analyses are clearly positive. The absolute benefit of +5%/+10% overall survival, combined with low and known toxicity profile, leads to recommending treatment for any cancer of the resected bile ducts (with the exception of gallbladder cancer pT1N0).


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Colangiocarcinoma/tratamiento farmacológico , Neoplasias del Sistema Biliar/patología , Capecitabina/administración & dosificación , Quimioterapia Adyuvante , Colangiocarcinoma/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Humanos , Análisis de Intención de Tratar , Radioterapia Ayuvante , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento
7.
N Engl J Med ; 382(1): 9, 2020 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-31738483

RESUMEN

BACKGROUND: The use of intensive lipid-lowering therapy by means of statin medications is recommended after transient ischemic attack (TIA) and ischemic stroke of atherosclerotic origin. The target level for low-density lipoprotein (LDL) cholesterol to reduce cardiovascular events after stroke has not been well studied. METHODS: In this parallel-group trial conducted in France and South Korea, we randomly assigned patients with ischemic stroke in the previous 3 months or a TIA within the previous 15 days to a target LDL cholesterol level of less than 70 mg per deciliter (1.8 mmol per liter) (lower-target group) or to a target range of 90 mg to 110 mg per deciliter (2.3 to 2.8 mmol per liter) (higher-target group). All the patients had evidence of cerebrovascular or coronary-artery atherosclerosis and received a statin, ezetimibe, or both. The composite primary end point of major cardiovascular events included ischemic stroke, myocardial infarction, new symptoms leading to urgent coronary or carotid revascularization, or death from cardiovascular causes. RESULTS: A total of 2860 patients were enrolled and followed for a median of 3.5 years; 1430 were assigned to each LDL cholesterol target group. The mean LDL cholesterol level at baseline was 135 mg per deciliter (3.5 mmol per liter), and the mean achieved LDL cholesterol level was 65 mg per deciliter (1.7 mmol per liter) in the lower-target group and 96 mg per deciliter (2.5 mmol per liter) in the higher-target group. The trial was stopped for administrative reasons after 277 of an anticipated 385 end-point events had occurred. The composite primary end point occurred in 121 patients (8.5%) in the lower-target group and in 156 (10.9%) in the higher-target group (adjusted hazard ratio, 0.78; 95% confidence interval, 0.61 to 0.98; P = 0.04). The incidence of intracranial hemorrhage and newly diagnosed diabetes did not differ significantly between the two groups. CONCLUSIONS: After an ischemic stroke or TIA with evidence of atherosclerosis, patients who had a target LDL cholesterol level of less than 70 mg per deciliter had a lower risk of subsequent cardiovascular events than those who had a target range of 90 mg to 110 mg per deciliter. (Funded by the French Ministry of Health and others; Treat Stroke to Target ClinicalTrials.gov number, NCT01252875.).


Asunto(s)
Anticolesterolemiantes/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , LDL-Colesterol/sangre , Ezetimiba/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Ataque Isquémico Transitorio/tratamiento farmacológico , Accidente Cerebrovascular/tratamiento farmacológico , Adulto , Anciano , Anticolesterolemiantes/efectos adversos , Aterosclerosis/complicaciones , Aterosclerosis/tratamiento farmacológico , Isquemia Encefálica/tratamiento farmacológico , Enfermedades Cardiovasculares/mortalidad , Quimioterapia Combinada , Femenino , Humanos , Análisis de Intención de Tratar , Ataque Isquémico Transitorio/complicaciones , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Accidente Cerebrovascular/sangre
8.
N Engl J Med ; 382(2): 120-129, 2020 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-31733180

RESUMEN

BACKGROUND: Whether the direct factor Xa inhibitor rivaroxaban can prevent thromboembolic events after transcatheter aortic-valve replacement (TAVR) is unclear. METHODS: We randomly assigned 1644 patients without an established indication for oral anticoagulation after successful TAVR to receive rivaroxaban at a dose of 10 mg daily (with aspirin at a dose of 75 to 100 mg daily for the first 3 months) (rivaroxaban group) or aspirin at a dose of 75 to 100 mg daily (with clopidogrel at a dose of 75 mg daily for the first 3 months) (antiplatelet group). The primary efficacy outcome was the composite of death or thromboembolic events. The primary safety outcome was major, disabling, or life-threatening bleeding. The trial was terminated prematurely by the data and safety monitoring board because of safety concerns. RESULTS: After a median of 17 months, death or a first thromboembolic event (intention-to-treat analysis) had occurred in 105 patients in the rivaroxaban group and in 78 patients in the antiplatelet group (incidence rates, 9.8 and 7.2 per 100 person-years, respectively; hazard ratio with rivaroxaban, 1.35; 95% confidence interval [CI], 1.01 to 1.81; P = 0.04). Major, disabling, or life-threatening bleeding (intention-to-treat analysis) had occurred in 46 and 31 patients, respectively (4.3 and 2.8 per 100 person-years; hazard ratio, 1.50; 95% CI, 0.95 to 2.37; P = 0.08). A total of 64 deaths occurred in the rivaroxaban group and 38 in the antiplatelet group (5.8 and 3.4 per 100 person-years, respectively; hazard ratio, 1.69; 95% CI, 1.13 to 2.53). CONCLUSIONS: In patients without an established indication for oral anticoagulation after successful TAVR, a treatment strategy including rivaroxaban at a dose of 10 mg daily was associated with a higher risk of death or thromboembolic complications and a higher risk of bleeding than an antiplatelet-based strategy. (Funded by Bayer and Janssen Pharmaceuticals; GALILEO ClinicalTrials.gov number, NCT02556203.).


Asunto(s)
Aspirina/uso terapéutico , Clopidogrel/uso terapéutico , Inhibidores del Factor Xa/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Rivaroxabán/uso terapéutico , Reemplazo de la Válvula Aórtica Transcatéter , Anciano , Anciano de 80 o más Años , Aspirina/efectos adversos , Fibrilación Atrial/tratamiento farmacológico , Enfermedades Cardiovasculares/mortalidad , Clopidogrel/efectos adversos , Quimioterapia Combinada , Inhibidores del Factor Xa/efectos adversos , Femenino , Prótesis Valvulares Cardíacas , Hemorragia/inducido químicamente , Humanos , Análisis de Intención de Tratar , Estimación de Kaplan-Meier , Masculino , Inhibidores de Agregación Plaquetaria/efectos adversos , Rivaroxabán/efectos adversos , Tromboembolia/mortalidad
9.
N Engl J Med ; 382(2): 130-139, 2020 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-31733182

RESUMEN

BACKGROUND: Subclinical leaflet thickening and reduced leaflet motion of bioprosthetic aortic valves have been documented by four-dimensional computed tomography (CT). Whether anticoagulation can reduce these phenomena after transcatheter aortic-valve replacement (TAVR) is not known. METHODS: In a substudy of a large randomized trial, we randomly assigned patients who had undergone successful TAVR and who did not have an indication for long-term anticoagulation to a rivaroxaban-based antithrombotic strategy (rivaroxaban [10 mg] plus aspirin [75 to 100 mg] once daily) or an antiplatelet-based strategy (clopidogrel [75 mg] plus aspirin [75 to 100 mg] once daily). Patients underwent evaluation by four-dimensional CT at a mean (±SD) of 90±15 days after randomization. The primary end point was the percentage of patients with at least one prosthetic valve leaflet with grade 3 or higher motion reduction (i.e., involving >50% of the leaflet). Leaflet thickening was also assessed. RESULTS: A total of 231 patients were enrolled. At least one prosthetic valve leaflet with grade 3 or higher motion reduction was found in 2 of 97 patients (2.1%) who had scans that could be evaluated in the rivaroxaban group, as compared with 11 of 101 (10.9%) in the antiplatelet group (difference, -8.8 percentage points; 95% confidence interval [CI], -16.5 to -1.9; P = 0.01). Thickening of at least one leaflet was observed in 12 of 97 patients (12.4%) in the rivaroxaban group and in 33 of 102 (32.4%) in the antiplatelet group (difference, -20.0 percentage points; 95% CI, -30.9 to -8.5). In the main trial, the risk of death or thromboembolic events and the risk of life-threatening, disabling, or major bleeding were higher with rivaroxaban (hazard ratios of 1.35 and 1.50, respectively). CONCLUSIONS: In a substudy of a trial involving patients without an indication for long-term anticoagulation who had undergone successful TAVR, a rivaroxaban-based antithrombotic strategy was more effective than an antiplatelet-based strategy in preventing subclinical leaflet-motion abnormalities. However, in the main trial, the rivaroxaban-based strategy was associated with a higher risk of death or thromboembolic complications and a higher risk of bleeding than the antiplatelet-based strategy. (Funded by Bayer; GALILEO-4D ClinicalTrials.gov number, NCT02833948.).


Asunto(s)
Válvula Aórtica/fisiopatología , Aspirina/farmacología , Clopidogrel/farmacología , Inhibidores del Factor Xa/farmacología , Prótesis Valvulares Cardíacas , Inhibidores de Agregación Plaquetaria/farmacología , Rivaroxabán/farmacología , Reemplazo de la Válvula Aórtica Transcatéter , Anciano , Anciano de 80 o más Años , Válvula Aórtica/efectos de los fármacos , Válvula Aórtica/patología , Aspirina/efectos adversos , Aspirina/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Enfermedades Cardiovasculares/mortalidad , Clopidogrel/efectos adversos , Clopidogrel/uso terapéutico , Quimioterapia Combinada , Inhibidores del Factor Xa/efectos adversos , Inhibidores del Factor Xa/uso terapéutico , Femenino , Tomografía Computarizada Cuatridimensional , Hemorragia/inducido químicamente , Humanos , Análisis de Intención de Tratar , Masculino , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Rivaroxabán/efectos adversos , Rivaroxabán/uso terapéutico , Tromboembolia/etiología , Tromboembolia/mortalidad
10.
Br J Sports Med ; 54(1): 51-57, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31511232

RESUMEN

BACKGROUND: In randomised controlled trials (RCTs) of interventions that aim to prevent sports injuries, the intention-to-treat principle is a recommended analysis method and one emphasised in the Consolidated Standards of Reporting Trials (CONSORT) statement that guides quality reporting of such trials. However, an important element of injury prevention trials-compliance with the intervention-is not always well-reported. The purpose of the present educational review was to describe the compliance during follow-up in eight large-scale sports injury trials and address compliance issues that surfaced. Then, we discuss how readers and researchers might consider interpreting results from intention-to-treat analyses depending on the observed compliance with the intervention. METHODS: Data from seven different randomised trials and one experimental study were included in the present educational review. In the trials that used training programme as an intervention, we defined full compliance as having completed the programme within ±10% of the prescribed running distance (ProjectRun21 (PR21), RUNCLEVER, Start 2 Run) or time-spent-running in minutes (Groningen Novice Running (GRONORUN)) for each planned training session. In the trials using running shoes as the intervention, full compliance was defined as wearing the prescribed running shoe in all running sessions the participants completed during follow-up. RESULTS: In the trials that used a running programme intervention, the number of participants who had been fully compliant was 0 of 839 (0%) at 24-week follow-up in RUNCLEVER, 0 of 612 (0%) at 14-week follow-up in PR21, 12 of 56 (21%) at 4-week follow-up in Start 2 Run and 8 of 532 (1%) at 8-week follow-up in GRONORUN. In the trials using a shoe-related intervention, the numbers of participants who had been fully compliant at the end of follow-up were 207 of 304 (68%) in the 21 week trial, and 322 of 423 (76%), 521 of 577 (90%), 753 of 874 (86%) after 24-week follow-up in the other three trials, respectively. CONCLUSION: The proportion of runners compliant at the end of follow-up ranged from 0% to 21% in the trials using running programme as intervention and from 68% to 90% in the trials using running shoes as intervention. We encourage sports injury researchers to carefully assess and report the compliance with intervention in their articles, use appropriate analytical approaches and take compliance into account when drawing study conclusions. In studies with low compliance, G-estimation may be a useful analytical tool provided certain assumptions are met.


Asunto(s)
Traumatismos en Atletas/prevención & control , Cooperación del Paciente , Acondicionamiento Físico Humano/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/normas , Interpretación Estadística de Datos , Humanos , Análisis de Intención de Tratar , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Carrera/lesiones , Zapatos
11.
BMJ ; 367: l6395, 2019 12 04.
Artículo en Inglés | MEDLINE | ID: mdl-31801725

RESUMEN

OBJECTIVE: To investigate whether remote ischaemic preconditioning (RIPC) prevents myocardial injury in patients undergoing hip fracture surgery. DESIGN: Phase II, multicentre, randomised, observer blinded, clinical trial. SETTING: Three Danish university hospitals, 2015-17. PARTICIPANTS: 648 patients with cardiovascular risk factors undergoing hip fracture surgery. 286 patients were assigned to RIPC and 287 were assigned to standard practice (control group). INTERVENTION: The RIPC procedure was initiated before surgery with a tourniquet applied to the upper arm and consisted of four cycles of forearm ischaemia for five minutes followed by reperfusion for five minutes. MAIN OUTCOME MEASURES: The original primary outcome was myocardial injury within four days of surgery, defined as a peak plasma cardiac troponin I concentration of 45 ng/L or more caused by ischaemia. The revised primary outcome was myocardial injury within four days of surgery, defined as a peak plasma cardiac troponin I concentration of 45 ng/L or more or high sensitive troponin I greater than 24 ng/L (the primary outcome was changed owing to availability of testing). Secondary outcomes were peak plasma troponin I and total troponin I release during the first four days after surgery (cardiac and high sensitive troponin I), perioperative myocardial infarction, major adverse cardiovascular events, and all cause mortality within 30 days of surgery, length of postoperative stay, and length of stay in the intensive care unit. Several planned secondary outcomes will be reported elsewhere. RESULTS: 573 of the 648 randomised patients were included in the intention-to-treat analysis (mean age 79 (SD 10) years; 399 (70%) women). The primary outcome occurred in 25 of 168 (15%) patients in the RIPC group and 45 of 158 (28%) in the control group (odds ratio 0.44, 95% confidence interval 0.25 to 0.76; P=0.003). The revised primary outcome occurred in 57 of 286 patients (20%) in the RIPC group and 90 of 287 (31%) in the control group (0.55, 0.37 to 0.80; P=0.002). Myocardial infarction occurred in 10 patients (3%) in the RIPC group and 21 patients (7%) in the control group (0.46, 0.21 to 0.99; P=0.04). Statistical power was insufficient to draw firm conclusions on differences between groups for the other clinical secondary outcomes (major adverse cardiovascular events, 30 day all cause mortality, length of postoperative stay, and length of stay in the intensive care unit). CONCLUSIONS: RIPC reduced the risk of myocardial injury and infarction after emergency hip fracture surgery. It cannot be concluded that RIPC overall prevents major adverse cardiovascular events after surgery. The findings support larger scale clinical trials to assess longer term clinical outcomes and mortality. TRIAL REGISTRATION: ClinicalTrials.gov NCT02344797.


Asunto(s)
Fijación de Fractura/efectos adversos , Lesiones Cardíacas/prevención & control , Fracturas de Cadera/cirugía , Precondicionamiento Isquémico Miocárdico/métodos , Complicaciones Posoperatorias/prevención & control , Anciano , Anciano de 80 o más Años , Tratamiento de Urgencia , Femenino , Lesiones Cardíacas/etiología , Humanos , Análisis de Intención de Tratar , Masculino , Infarto del Miocardio/etiología , Infarto del Miocardio/prevención & control , Complicaciones Posoperatorias/etiología , Método Simple Ciego , Factores de Tiempo , Resultado del Tratamiento
12.
N Engl J Med ; 381(26): 2497-2505, 2019 12 26.
Artículo en Inglés | MEDLINE | ID: mdl-31733140

RESUMEN

BACKGROUND: Experimental and clinical evidence supports the role of inflammation in atherosclerosis and its complications. Colchicine is an orally administered, potent antiinflammatory medication that is indicated for the treatment of gout and pericarditis. METHODS: We performed a randomized, double-blind trial involving patients recruited within 30 days after a myocardial infarction. The patients were randomly assigned to receive either low-dose colchicine (0.5 mg once daily) or placebo. The primary efficacy end point was a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization. The components of the primary end point and safety were also assessed. RESULTS: A total of 4745 patients were enrolled; 2366 patients were assigned to the colchicine group, and 2379 to the placebo group. Patients were followed for a median of 22.6 months. The primary end point occurred in 5.5% of the patients in the colchicine group, as compared with 7.1% of those in the placebo group (hazard ratio, 0.77; 95% confidence interval [CI], 0.61 to 0.96; P = 0.02). The hazard ratios were 0.84 (95% CI, 0.46 to 1.52) for death from cardiovascular causes, 0.83 (95% CI, 0.25 to 2.73) for resuscitated cardiac arrest, 0.91 (95% CI, 0.68 to 1.21) for myocardial infarction, 0.26 (95% CI, 0.10 to 0.70) for stroke, and 0.50 (95% CI, 0.31 to 0.81) for urgent hospitalization for angina leading to coronary revascularization. Diarrhea was reported in 9.7% of the patients in the colchicine group and in 8.9% of those in the placebo group (P = 0.35). Pneumonia was reported as a serious adverse event in 0.9% of the patients in the colchicine group and in 0.4% of those in the placebo group (P = 0.03). CONCLUSIONS: Among patients with a recent myocardial infarction, colchicine at a dose of 0.5 mg daily led to a significantly lower risk of ischemic cardiovascular events than placebo. (Funded by the Government of Quebec and others; COLCOT ClinicalTrials.gov number, NCT02551094.).


Asunto(s)
Antiinflamatorios/administración & dosificación , Colchicina/administración & dosificación , Infarto del Miocardio/tratamiento farmacológico , Anciano , Angina de Pecho/epidemiología , Antiinflamatorios/efectos adversos , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/mortalidad , Colchicina/efectos adversos , Método Doble Ciego , Femenino , Humanos , Incidencia , Análisis de Intención de Tratar , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Infarto del Miocardio/terapia , Intervención Coronaria Percutánea , Modelos de Riesgos Proporcionales , Recurrencia , Accidente Cerebrovascular/epidemiología
13.
BMJ ; 367: l6131, 2019 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-31748223

RESUMEN

OBJECTIVE: To evaluate if induction of labour at 41 weeks improves perinatal and maternal outcomes in women with a low risk pregnancy compared with expectant management and induction of labour at 42 weeks. DESIGN: Multicentre, open label, randomised controlled superiority trial. SETTING: 14 hospitals in Sweden, 2016-18. PARTICIPANTS: 2760 women with a low risk uncomplicated singleton pregnancy randomised (1:1) by the Swedish Pregnancy Register. 1381 women were assigned to the induction group and 1379 were assigned to the expectant management group. INTERVENTIONS: Induction of labour at 41 weeks and expectant management and induction of labour at 42 weeks. MAIN OUTCOME MEASURES: The primary outcome was a composite perinatal outcome including one or more of stillbirth, neonatal mortality, Apgar score less than 7 at five minutes, pH less than 7.00 or metabolic acidosis (pH <7.05 and base deficit >12 mmol/L) in the umbilical artery, hypoxic ischaemic encephalopathy, intracranial haemorrhage, convulsions, meconium aspiration syndrome, mechanical ventilation within 72 hours, or obstetric brachial plexus injury. Primary analysis was by intention to treat. RESULTS: The study was stopped early owing to a significantly higher rate of perinatal mortality in the expectant management group. The composite primary perinatal outcome did not differ between the groups: 2.4% (33/1381) in the induction group and 2.2% (31/1379) in the expectant management group (relative risk 1.06, 95% confidence interval 0.65 to 1.73; P=0.90). No perinatal deaths occurred in the induction group but six (five stillbirths and one early neonatal death) occurred in the expectant management group (P=0.03). The proportion of caesarean delivery, instrumental vaginal delivery, or any major maternal morbidity did not differ between the groups. CONCLUSIONS: This study comparing induction of labour at 41 weeks with expectant management and induction at 42 weeks does not show any significant difference in the primary composite adverse perinatal outcome. However, a reduction of the secondary outcome perinatal mortality is observed without increasing adverse maternal outcomes. Although these results should be interpreted cautiously, induction of labour ought to be offered to women no later than at 41 weeks and could be one (of few) interventions that reduces the rate of stillbirths. TRIAL REGISTRATION: Current Controlled Trials ISRCTN26113652.


Asunto(s)
Edad Gestacional , Enfermedades del Recién Nacido , Trabajo de Parto Inducido , Espera Vigilante/estadística & datos numéricos , Adulto , Cesárea/estadística & datos numéricos , Femenino , Humanos , Lactante , Mortalidad Infantil , Recién Nacido , Enfermedades del Recién Nacido/epidemiología , Enfermedades del Recién Nacido/etiología , Análisis de Intención de Tratar , Trabajo de Parto Inducido/efectos adversos , Trabajo de Parto Inducido/métodos , Trabajo de Parto Inducido/estadística & datos numéricos , Embarazo , Resultado del Embarazo/epidemiología , Mortinato/epidemiología , Suecia/epidemiología , Nacimiento a Término
14.
JAMA ; 322(16): 1570-1579, 2019 10 22.
Artículo en Inglés | MEDLINE | ID: mdl-31638680

RESUMEN

Importance: The World Health Organization recommends cryotherapy or loop electrosurgical excision procedure (LEEP) for histologically confirmed cervical intraepithelial neoplasia (CIN) grade 2 or higher regardless of HIV status. Cryotherapy is more feasible in resource-limited settings but may be less effective for women living with HIV. Objective: To evaluate whether cryotherapy or LEEP is a more effective treatment for high-grade cervical lesions among women with HIV. Design, Setting, and Participants: Single-center randomized trial conducted among women with HIV and CIN grade 2 or 3. From June 2011 to September 2016, women with HIV in Kenya underwent cervical screening with Papanicolaou testing and confirmatory biopsy. The final date on which a study procedure was administered was September 7, 2016. Interventions: Women with HIV infection and CIN grade 2 or 3 were randomized 1:1 to receive cryotherapy (n = 200) or LEEP (n = 200) and were followed up every 6 months for 24 months with a Papanicolaou test and confirmatory biopsy. Main Outcome and Measures: The primary outcome was disease recurrence, defined as CIN grade 2 or higher on cervical biopsy, during the 24-month follow-up period. Results: Among 400 women who were randomized (median age, 37.4 [interquartile range, 31.9-43.8] years), 339 (85%) completed the trial. Over 2 years, 60 women (30%) randomized to cryotherapy had recurrent CIN grade 2 or higher vs 37 (19%) in the LEEP group (relative risk, 1.71 [95% CI, 1.12-2.65]; risk difference, 7.9% [95% CI, 1.9%-14.0%]; P = .01). Adverse events occurred in 40 women (45 events, including change in pathology and death due to other causes) in the cryotherapy group and in 30 women (38 events, including change in pathology and unrelated gynecological complications) in the LEEP group. Conclusions and Relevance: In this single-center study of women with HIV infection and CIN grade 2 or 3, treatment with LEEP compared with cryotherapy resulted in a significantly lower rate of cervical neoplasia recurrence over 24 months. Cost-effectiveness analysis is necessary to determine whether the additional benefit of LEEP represents an efficient use of the additional resources that would be required. Trial Registration: ClinicalTrials.gov Identifier: NCT01298596.


Asunto(s)
Neoplasia Intraepitelial Cervical/cirugía , Criocirugia , Electrocirugia , Infecciones por VIH/complicaciones , Neoplasias del Cuello Uterino/cirugía , Adolescente , Adulto , Recuento de Linfocito CD4 , Neoplasia Intraepitelial Cervical/complicaciones , Neoplasia Intraepitelial Cervical/patología , Colposcopía , Femenino , Humanos , Incidencia , Análisis de Intención de Tratar , Kenia , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/prevención & control , Modelos de Riesgos Proporcionales , Neoplasias del Cuello Uterino/complicaciones , Neoplasias del Cuello Uterino/patología , Adulto Joven
15.
N Engl J Med ; 381(17): 1632-1643, 2019 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-31566309

RESUMEN

BACKGROUND: Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling. METHODS: In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis. RESULTS: The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group. CONCLUSIONS: A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/administración & dosificación , Carbamatos/administración & dosificación , Cetuximab/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Sulfonamidas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Progresión de la Enfermedad , Electrocorticografía , Femenino , Humanos , Análisis de Intención de Tratar , Irinotecán/uso terapéutico , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis de Supervivencia
16.
N Engl J Med ; 381(14): 1347-1357, 2019 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-31577876

RESUMEN

BACKGROUND: The World Health Organization has set ambitious targets for the global elimination of tuberculosis. However, these targets will not be achieved at the current rate of progress. METHODS: We performed a cluster-randomized, controlled trial in Ca Mau Province, Vietnam, to evaluate the effectiveness of active community-wide screening, as compared with standard passive case detection alone, for reducing the prevalence of tuberculosis. Persons 15 years of age or older who resided in 60 intervention clusters (subcommunes) were screened for pulmonary tuberculosis, regardless of symptoms, annually for 3 years, beginning in 2014, by means of rapid nucleic acid amplification testing of spontaneously expectorated sputum samples. Active screening was not performed in the 60 control clusters in the first 3 years. The primary outcome, measured in the fourth year, was the prevalence of microbiologically confirmed pulmonary tuberculosis among persons 15 years of age or older. The secondary outcome was the prevalence of tuberculosis infection, as assessed by an interferon gamma release assay in the fourth year, among children born in 2012. RESULTS: In the fourth-year prevalence survey, we tested 42,150 participants in the intervention group and 41,680 participants in the control group. A total of 53 participants in the intervention group (126 per 100,000 population) and 94 participants in the control group (226 per 100,000) had pulmonary tuberculosis, as confirmed by a positive nucleic acid amplification test for Mycobacterium tuberculosis (prevalence ratio, 0.56; 95% confidence interval [CI], 0.40 to 0.78; P<0.001). The prevalence of tuberculosis infection in children born in 2012 was 3.3% in the intervention group and 2.6% in the control group (prevalence ratio, 1.29; 95% CI, 0.70 to 2.36; P = 0.42). CONCLUSIONS: Three years of community-wide screening in persons 15 years of age or older who resided in Ca Mau Province, Vietnam, resulted in a lower prevalence of pulmonary tuberculosis in the fourth year than standard passive case detection alone. (Funded by the Australian National Health and Medical Research Council; ACT3 Australian New Zealand Clinical Trials Registry number, ACTRN12614000372684.).


Asunto(s)
Enfermedades Endémicas/prevención & control , Tamizaje Masivo/métodos , Mycobacterium tuberculosis/aislamiento & purificación , Tuberculosis Pulmonar/diagnóstico , Adolescente , Adulto , Niño , Servicios de Salud Comunitaria , Femenino , Humanos , Análisis de Intención de Tratar , Masculino , Mycobacterium tuberculosis/genética , Técnicas de Amplificación de Ácido Nucleico , Prevalencia , Esputo/microbiología , Tuberculosis Pulmonar/epidemiología , Tuberculosis Pulmonar/prevención & control , Vietnam/epidemiología , Adulto Joven
17.
Lancet ; 394(10210): 1713-1723, 2019 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-31623894

RESUMEN

BACKGROUND: Tranexamic acid reduces surgical bleeding and decreases mortality in patients with traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury (TBI) and can cause brain herniation and death. We aimed to assess the effects of tranexamic acid in patients with TBI. METHODS: This randomised, placebo-controlled trial was done in 175 hospitals in 29 countries. Adults with TBI who were within 3 h of injury, had a Glasgow Coma Scale (GCS) score of 12 or lower or any intracranial bleeding on CT scan, and no major extracranial bleeding were eligible. The time window for eligibility was originally 8 h but in 2016 the protocol was changed to limit recruitment to patients within 3 h of injury. This change was made blind to the trial data, in response to external evidence suggesting that delayed treatment is unlikely to be effective. We randomly assigned (1:1) patients to receive tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was head injury-related death in hospital within 28 days of injury in patients treated within 3 h of injury. We prespecified a sensitivity analysis that excluded patients with a GCS score of 3 and those with bilateral unreactive pupils at baseline. All analyses were done by intention to treat. This trial was registered with ISRCTN (ISRCTN15088122), ClinicalTrials.gov (NCT01402882), EudraCT (2011-003669-14), and the Pan African Clinical Trial Registry (PACTR20121000441277). RESULTS: Between July 20, 2012, and Jan 31, 2019, we randomly allocated 12 737 patients with TBI to receive tranexamic acid (6406 [50·3%] or placebo [6331 [49·7%], of whom 9202 (72·2%) patients were treated within 3 h of injury. Among patients treated within 3 h of injury, the risk of head injury-related death was 18·5% in the tranexamic acid group versus 19·8% in the placebo group (855 vs 892 events; risk ratio [RR] 0·94 [95% CI 0·86-1·02]). In the prespecified sensitivity analysis that excluded patients with a GCS score of 3 or bilateral unreactive pupils at baseline, the risk of head injury-related death was 12·5% in the tranexamic acid group versus 14·0% in the placebo group (485 vs 525 events; RR 0·89 [95% CI 0·80-1·00]). The risk of head injury-related death reduced with tranexamic acid in patients with mild-to-moderate head injury (RR 0·78 [95% CI 0·64-0·95]) but not in patients with severe head injury (0·99 [95% CI 0·91-1·07]; p value for heterogeneity 0·030). Early treatment was more effective than was later treatment in patients with mild and moderate head injury (p=0·005) but time to treatment had no obvious effect in patients with severe head injury (p=0·73). The risk of vascular occlusive events was similar in the tranexamic acid and placebo groups (RR 0·98 (0·74-1·28). The risk of seizures was also similar between groups (1·09 [95% CI 0·90-1·33]). INTERPRETATION: Our results show that tranexamic acid is safe in patients with TBI and that treatment within 3 h of injury reduces head injury-related death. Patients should be treated as soon as possible after injury. FUNDING: National Institute for Health Research Health Technology Assessment, JP Moulton Charitable Trust, Department of Health and Social Care, Department for International Development, Global Challenges Research Fund, Medical Research Council, and Wellcome Trust (Joint Global Health Trials scheme). TRANSLATIONS: For the Arabic, Chinese, French, Hindi, Japanese, Spanish and Urdu translations of the abstract see Supplementary Material.


Asunto(s)
Antifibrinolíticos/administración & dosificación , Lesiones Traumáticas del Encéfalo/complicaciones , Hemorragia Intracraneal Traumática/tratamiento farmacológico , Ácido Tranexámico/administración & dosificación , Adulto , Anciano , Antifibrinolíticos/efectos adversos , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/mortalidad , Esquema de Medicación , Femenino , Humanos , Análisis de Intención de Tratar , Cooperación Internacional , Hemorragia Intracraneal Traumática/mortalidad , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Tiempo de Tratamiento , Ácido Tranexámico/efectos adversos , Resultado del Tratamiento , Enfermedades Vasculares/epidemiología , Enfermedades Vasculares/etiología , Adulto Joven
18.
N Engl J Med ; 381(25): 2403-2415, 2019 12 19.
Artículo en Inglés | MEDLINE | ID: mdl-31562800

RESUMEN

BACKGROUND: Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance as initial treatment in patients with high-grade serous ovarian carcinoma. METHODS: In an international, phase 3, placebo-controlled trial, we assessed the efficacy of veliparib added to first-line induction chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. Patients were randomly assigned in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance (control), chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only), or chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout). Cytoreductive surgery could be performed before initiation or after 3 cycles of trial treatment. Combination chemotherapy was 6 cycles, and maintenance therapy was 30 additional cycles. The primary end point was investigator-assessed progression-free survival in the veliparib-throughout group as compared with the control group, analyzed sequentially in the BRCA-mutation cohort, the cohort with homologous-recombination deficiency (HRD) (which included the BRCA-mutation cohort), and the intention-to-treat population. RESULTS: A total of 1140 patients underwent randomization. In the BRCA-mutation cohort, the median progression-free survival was 34.7 months in the veliparib-throughout group and 22.0 months in the control group (hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.28 to 0.68; P<0.001); in the HRD cohort, it was 31.9 months and 20.5 months, respectively (hazard ratio, 0.57; 95 CI, 0.43 to 0.76; P<0.001); and in the intention-to-treat population, it was 23.5 months and 17.3 months (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). Veliparib led to a higher incidence of anemia and thrombocytopenia when combined with chemotherapy as well as of nausea and fatigue overall. CONCLUSIONS: Across all trial populations, a regimen of carboplatin, paclitaxel, and veliparib induction therapy followed by veliparib maintenance therapy led to significantly longer progression-free survival than carboplatin plus paclitaxel induction therapy alone. The independent value of adding veliparib during induction therapy without veliparib maintenance was less clear. (Funded by AbbVie; VELIA/GOG-3005 ClinicalTrials.gov number, NCT02470585.).


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/uso terapéutico , Cistadenocarcinoma Seroso/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bencimidazoles/efectos adversos , Carboplatino/administración & dosificación , Terapia Combinada , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/cirugía , Método Doble Ciego , Femenino , Genes BRCA1 , Genes BRCA2 , Humanos , Análisis de Intención de Tratar , Quimioterapia de Mantención , Persona de Mediana Edad , Mutación , Neoplasias Ováricas/genética , Neoplasias Ováricas/cirugía , Paclitaxel/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Supervivencia sin Progresión , Calidad de Vida
19.
N Engl J Med ; 381(11): 1035-1045, 2019 09 12.
Artículo en Inglés | MEDLINE | ID: mdl-31509674

RESUMEN

BACKGROUND: Previous studies have suggested that maternal supplementation with n-3 long-chain polyunsaturated fatty acids may reduce the incidence of preterm delivery but may also prolong gestation beyond term; however, more data are needed regarding the role of n-3 long-chain polyunsaturated fatty acids in pregnancy. METHODS: We performed a multicenter, double-blind, randomized trial in which women who were pregnant with single or multiple fetuses were assigned to receive either fish-oil capsules that contained 900 mg of n-3 long-chain polyunsaturated fatty acids (n-3 group) or vegetable-oil capsules that contained trace n-3 long-chain polyunsaturated fatty acids (control group) daily, beginning before 20 weeks of gestation and continuing to 34 weeks of gestation or delivery, whichever occurred first. The primary outcome was early preterm delivery, defined as delivery before 34 completed weeks of gestation. Other pregnancy and neonatal outcomes were also assessed. RESULTS: A total of 5544 pregnancies in 5517 women were randomly assigned at six centers in Australia; 5486 pregnancies were included in the primary analysis. Early preterm delivery occurred in the case of 61 of 2734 pregnancies (2.2%) in the n-3 group and 55 of 2752 pregnancies (2.0%) in the control group; the between-group difference was not significant (adjusted relative risk, 1.13; 95% confidence interval [CI], 0.79 to 1.63; P = 0.50). There were no significant differences between the groups in the incidence of interventions in post-term (>41 weeks of gestation) deliveries, in adverse events, or in other pregnancy or neonatal outcomes, except that a higher percentage of infants born to women in the n-3 group than in the control group were very large for gestational age at birth (adjusted relative risk, 1.30; 95% CI, 1.02 to 1.65). Percentages of serious adverse events did not differ between the groups. Minor gastrointestinal disturbances were more commonly reported in the n-3 group than in the control group. CONCLUSIONS: Supplementation with n-3 long-chain polyunsaturated fatty acids from early pregnancy (<20 weeks of gestation) until 34 weeks of gestation did not result in a lower incidence of early preterm delivery or a higher incidence of interventions in post-term deliveries than control. (Funded by the Australian National Health and Medical Research Council and the Thyne Reid Foundation; ORIP Australian New Zealand Clinical Trials Registry number, ACTRN12613001142729.).


Asunto(s)
Suplementos Dietéticos , Ácidos Grasos Omega-3/uso terapéutico , Nacimiento Prematuro/prevención & control , Adulto , Método Doble Ciego , Femenino , Macrosomía Fetal , Edad Gestacional , Humanos , Incidencia , Recién Nacido , Análisis de Intención de Tratar , Aceites Vegetales/uso terapéutico , Embarazo , Resultado del Embarazo , Nacimiento Prematuro/epidemiología , Atención Prenatal , Insuficiencia del Tratamiento
20.
Res Dev Disabil ; 94: 103458, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31525613

RESUMEN

BACKGROUND: People with intellectual disabilities (ID) are usually cared for by their own parents, families or informal caregivers. Caring for a person with ID can have a negative impact on caregivers' mental health (burden, depression, anxiety). The main aim of the EDUCA-IV trial was testing the efficacy of a psychoeducational intervention program (PIP) versus standard practice and to see whether the PIP intervention would reduce the caregiver's burden at post-intervention (4 months) and at follow-up (8 months). METHOD: This was a multi-centre randomised controlled trial including 194 caregivers (96 randomised to PIP, 98 to control condition). PIP intervention consists of 12 weekly group sessions. The control group received treatment as usual. Primary outcomes measured included the Zarit Burden Interview (ZBI). Secondary outcomes were caregivers' mental health (GHQ-28), anxiety (STAI) and depression (CES-D). RESULTS: The decrease of ZBI scores was not significant at 4 months. There was significant decrease in the GHQ scores at 4 and 8 months. CES-D showed relevant results at follow-up. Intention to treat analyses showed similar results. CONCLUSIONS: The PIP intervention seems not to be effective reducing burden, but appears to have a positive result on general mental health. The program was well received and valued by caregivers.


Asunto(s)
Adaptación Psicológica , Ansiedad , Cuidadores , Depresión , Educación en Salud/métodos , Discapacidad Intelectual/psicología , Calidad de Vida , Adulto , Ansiedad/etiología , Ansiedad/psicología , Cuidadores/educación , Cuidadores/psicología , Costo de Enfermedad , Depresión/etiología , Depresión/psicología , Femenino , Humanos , Análisis de Intención de Tratar , Masculino , Salud Mental , Estrés Psicológico/etiología , Estrés Psicológico/psicología
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