RESUMO
BACKGROUND: The focus of most epidemiological studies has been mortality or clinical events, with less information on activity limitations related to basic daily functions and their consequences. Standardised data from multiple countries at different economic levels in different regions of the world on activity limitations and their associations with clinical outcomes are sparse. We aimed to quantify the prevalence of activity limitations and use of assistive devices and the association of limitations with adverse outcomes in 25 countries grouped by different economic levels. METHODS: In this analysis, we obtained data from individuals in 25 high-income, middle-income, and low-income countries from the Prospective Urban Rural Epidemiological (PURE) study (175 660 participants). In the PURE study, individuals aged 35-70 years who intended to continue living in their current home for a further 4 years were invited to complete a questionnaire on activity limitations. Participant follow-up was planned once every 3 years either by telephone or in person. The activity limitation screen consisted of questions on self-reported difficulty with walking, grasping, bending, seeing close, seeing far, speaking, hearing, and use of assistive devices (gait, vision, and hearing aids). We estimated crude prevalence of self-reported activity limitations and use of assistive devices, and prevalence standardised by age and sex. We used logistic regression to additionally adjust prevalence for education and socioeconomic factors and to estimate the probability of activity limitations and assistive devices by age, sex, and country income. We used Cox frailty models to evaluate the association between each activity limitation with mortality and clinical events (cardiovascular disease, heart failure, pneumonia, falls, and cancer). The PURE study is registered with ClinicalTrials.gov, NCT03225586. FINDINGS: Between Jan 12, 2001, and May 6, 2019, 175 584 individuals completed at least one question on the activity limitation questionnaire (mean age 50·6 years [SD 9·8]; 103 625 [59%] women). Of the individuals who completed all questions, mean follow-up was 10·7 years (SD 4·4). The most common self-reported activity limitations were difficulty with bending (23 921 [13·6%] of 175 515 participants), seeing close (22 532 [13·4%] of 167 801 participants), and walking (22 805 [13·0%] of 175 554 participants); prevalence of limitations was higher with older age and among women. The prevalence of all limitations standardised by age and sex, with the exception of hearing, was highest in low-income countries and middle-income countries, and this remained consistent after adjustment for socioeconomic factors. The use of gait, visual, and hearing aids was lowest in low-income countries and middle-income countries, particularly among women. The prevalence of seeing close limitation was four times higher (6257 [16·5%] of 37 926 participants vs 717 [4·0%] of 18 039 participants) and the prevalence of seeing far limitation was five times higher (4003 [10·6%] of 37 923 participants vs 391 [2·2%] of 18 038 participants) in low-income countries than in high-income countries, but the prevalence of glasses use in low-income countries was half that in high-income countries. Walking limitation was most strongly associated with mortality (adjusted hazard ratio 1·32 [95% CI 1·25-1·39]) and most consistently associated with other clinical events, with other notable associations observed between seeing far limitation and mortality, grasping limitation and cardiovascular disease, bending limitation and falls, and between speaking limitation and stroke. INTERPRETATION: The global prevalence of activity limitations is substantially higher in women than men and in low-income countries and middle-income countries compared with high-income countries, coupled with a much lower use of gait, visual, and hearing aids. Strategies are needed to prevent and mitigate activity limitations globally, with particular emphasis on low-income countries and women. FUNDING: Funding sources are listed at the end of the Article.
Assuntos
Atividades Cotidianas , Países em Desenvolvimento , Tecnologia Assistiva , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Desenvolvidos/estatística & dados numéricos , Países em Desenvolvimento/estatística & dados numéricos , Renda/estatística & dados numéricos , Prevalência , Estudos Prospectivos , Tecnologia Assistiva/estatística & dados numéricos , Fatores Socioeconômicos , Estudos Observacionais como AssuntoRESUMO
BACKGROUND: Patients treated with antithrombotic drugs are at risk of bleeding. Bleeding may be the first manifestation of underlying cancer. METHODS: We examined new cancers diagnosed in relation to gastrointestinal or genitourinary bleeding among patients enrolled in the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies) and determined the hazard of new cancer diagnosis after bleeding at these sites. RESULTS: Of 27 395 patients enrolled (mean age, 68 years; women, 21%), 2678 (9.8%) experienced any (major or minor) bleeding, 713 (2.6%) experienced major bleeding, and 1084 (4.0%) were diagnosed with cancer during a mean follow-up of 23 months. Among 2678 who experienced bleeding, 257 (9.9%) were subsequently diagnosed with cancer. Gastrointestinal bleeding was associated with a 20-fold higher hazard of new gastrointestinal cancer diagnosis (7.4% versus 0.5%; hazard ratio [HR], 20.6 [95% CI, 15.2-27.8]) and 1.7-fold higher hazard of new nongastrointestinal cancer diagnosis (3.8% versus 3.1%; HR, 1.70 [95% CI, 1.20-2.40]). Genitourinary bleeding was associated with a 32-fold higher hazard of new genitourinary cancer diagnosis (15.8% versus 0.8%; HR, 32.5 [95% CI, 24.7-42.9]), and urinary bleeding was associated with a 98-fold higher hazard of new urinary cancer diagnosis (14.2% versus 0.2%; HR, 98.5; 95% CI, 68.0-142.7). Nongastrointestinal, nongenitourinary bleeding was associated with a 3-fold higher hazard of nongastrointestinal, nongenitourinary cancers (4.4% versus 1.9%; HR, 3.02 [95% CI, 2.32-3.91]). CONCLUSIONS: In patients with atherosclerosis treated with antithrombotic drugs, any gastrointestinal or genitourinary bleeding was associated with higher rates of new cancer diagnosis. Any gastrointestinal or genitourinary bleeding should prompt investigation for cancers at these sites. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01776424.
Assuntos
Aterosclerose/tratamento farmacológico , Hemorragia Gastrointestinal/induzido quimicamente , Neoplasias/diagnóstico , Rivaroxabana/uso terapêutico , Idoso , Aspirina/uso terapêutico , Aterosclerose/complicações , Doença da Artéria Coronariana/tratamento farmacológico , Quimioterapia Combinada/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Doença Arterial Periférica/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológicoRESUMO
BACKGROUND: We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention. METHODS: In this double-blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months. RESULTS: The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=-4.126), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group. CONCLUSIONS: Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events. (Funded by Bayer; COMPASS ClinicalTrials.gov number, NCT01776424 .).
Assuntos
Aspirina/uso terapêutico , Aterosclerose/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Inibidores do Fator Xa/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Rivaroxabana/uso terapêutico , Idoso , Aspirina/efeitos adversos , Aterosclerose/complicações , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/mortalidade , Método Duplo-Cego , Quimioterapia Combinada , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/efeitos adversos , Rivaroxabana/efeitos adversos , Prevenção Secundária/métodosRESUMO
BACKGROUND & AIMS: Antiplatelets and anticoagulants are associated with increased upper gastrointestinal bleeding. We evaluated whether proton pump inhibitor therapy could reduce this risk. METHODS: We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease. Participants were randomly assigned to groups given pantoprazole 40 mg daily or placebo, as well as rivaroxaban 2.5 mg twice daily with aspirin 100 mg once daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg alone. The primary outcome was time to first upper gastrointestinal event, defined as a composite of overt bleeding, upper gastrointestinal bleeding from a gastroduodenal lesion or of unknown origin, occult bleeding, symptomatic gastroduodenal ulcer or ≥5 erosions, upper gastrointestinal obstruction, or perforation. RESULTS: There was no significant difference in upper gastrointestinal events between the pantoprazole group (102 of 8791 events) and the placebo group (116 of 8807 events) (hazard ratio, 0.88; 95% confidence interval [CI], 0.67-1.15). Pantoprazole significantly reduced bleeding of gastroduodenal lesions (hazard ratio, 0.52; 95% confidence interval, 0.28-0.94; P = .03); this reduction was greater when we used a post-hoc definition of bleeding gastroduodenal lesion (hazard ratio, 0.45; 95% confidence interval, 0.27-0.74), although the number needed to treat still was high (n = 982; 95% confidence interval, 609-2528). CONCLUSIONS: In a randomized placebo-controlled trial, we found that routine use of proton pump inhibitors in patients receiving low-dose anticoagulation and/or aspirin for stable cardiovascular disease does not reduce upper gastrointestinal events, but may reduce bleeding from gastroduodenal lesions. ClinicalTrials.gov ID: NCT01776424.
Assuntos
Anticoagulantes/efeitos adversos , Doenças Cardiovasculares/prevenção & controle , Hemorragia Gastrointestinal/prevenção & controle , Pantoprazol/administração & dosagem , Úlcera Péptica/prevenção & controle , Inibidores da Bomba de Prótons/administração & dosagem , Administração Oral , Idoso , Anticoagulantes/administração & dosagem , Aspirina/administração & dosagem , Aspirina/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Úlcera Péptica/induzido quimicamente , Úlcera Péptica/epidemiologia , Rivaroxabana/administração & dosagem , Rivaroxabana/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: Proton pump inhibitors (PPIs) are effective at treating acid-related disorders. These drugs are well tolerated in the short term, but long-term treatment was associated with adverse events in observational studies. We aimed to confirm these findings in an adequately powered randomized trial. METHODS: We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease randomly assigned to groups given pantoprazole (40 mg daily, n = 8791) or placebo (n = 8807). Participants were also randomly assigned to groups that received rivaroxaban (2.5 mg twice daily) with aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg) alone. We collected data on development of pneumonia, Clostridium difficile infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, cancer, hospitalizations, and all-cause mortality every 6 months. Patients were followed up for a median of 3.01 years, with 53,152 patient-years of follow-up. RESULTS: There was no statistically significant difference between the pantoprazole and placebo groups in safety events except for enteric infections (1.4% vs 1.0% in the placebo group; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). For all other safety outcomes, proportions were similar between groups except for C difficile infection, which was approximately twice as common in the pantoprazole vs the placebo group, although there were only 13 events, so this difference was not statistically significant. CONCLUSIONS: In a large placebo-controlled randomized trial, we found that pantoprazole is not associated with any adverse event when used for 3 years, with the possible exception of an increased risk of enteric infections. ClinicalTrials.gov Number: NCT01776424.
Assuntos
Aspirina/administração & dosagem , Doenças Cardiovasculares/tratamento farmacológico , Inibidores do Fator Xa/administração & dosagem , Hemorragia Gastrointestinal/prevenção & controle , Pantoprazol/administração & dosagem , Doença Arterial Periférica/tratamento farmacológico , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Bomba de Prótons/administração & dosagem , Rivaroxabana/administração & dosagem , Idoso , Aspirina/efeitos adversos , Doenças Cardiovasculares/diagnóstico , Método Duplo-Cego , Esquema de Medicação , Enterocolite Pseudomembranosa/induzido quimicamente , Enterocolite Pseudomembranosa/microbiologia , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Pantoprazol/efeitos adversos , Doença Arterial Periférica/diagnóstico , Inibidores da Agregação Plaquetária/efeitos adversos , Estudos Prospectivos , Inibidores da Bomba de Prótons/efeitos adversos , Medição de Risco , Fatores de Risco , Rivaroxabana/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Coronary artery disease is a major cause of morbidity and mortality worldwide, and is a consequence of acute thrombotic events involving activation of platelets and coagulation proteins. Factor Xa inhibitors and aspirin each reduce thrombotic events but have not yet been tested in combination or against each other in patients with stable coronary artery disease. METHODS: In this multicentre, double-blind, randomised, placebo-controlled, outpatient trial, patients with stable coronary artery disease or peripheral artery disease were recruited at 602 hospitals, clinics, or community centres in 33 countries. This paper reports on patients with coronary artery disease. Eligible patients with coronary artery disease had to have had a myocardial infarction in the past 20 years, multi-vessel coronary artery disease, history of stable or unstable angina, previous multi-vessel percutaneous coronary intervention, or previous multi-vessel coronary artery bypass graft surgery. After a 30-day run in period, patients were randomly assigned (1:1:1) to receive rivaroxaban (2·5 mg orally twice a day) plus aspirin (100 mg once a day), rivaroxaban alone (5 mg orally twice a day), or aspirin alone (100 mg orally once a day). Randomisation was computer generated. Each treatment group was double dummy, and the patients, investigators, and central study staff were masked to treatment allocation. The primary outcome of the COMPASS trial was the occurrence of myocardial infarction, stroke, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants. FINDINGS: Between March 12, 2013, and May 10, 2016, 27â395 patients were enrolled to the COMPASS trial, of whom 24â824 patients had stable coronary artery disease from 558 centres. The combination of rivaroxaban plus aspirin reduced the primary outcome more than aspirin alone (347 [4%] of 8313 vs 460 [6%] of 8261; hazard ratio [HR] 0·74, 95% CI 0·65-0·86, p<0·0001). By comparison, treatment with rivaroxaban alone did not significantly improve the primary outcome when compared with treatment with aspirin alone (411 [5%] of 8250 vs 460 [6%] of 8261; HR 0·89, 95% CI 0·78-1·02, p=0·094). Combined rivaroxaban plus aspirin treatment resulted in more major bleeds than treatment with aspirin alone (263 [3%] of 8313 vs 158 [2%] of 8261; HR 1·66, 95% CI 1·37-2·03, p<0·0001), and similarly, more bleeds were seen in the rivaroxaban alone group than in the aspirin alone group (236 [3%] of 8250 vs 158 [2%] of 8261; HR 1·51, 95% CI 1·23-1·84, p<0·0001). The most common site of major bleeding was gastrointestinal, occurring in 130 [2%] patients who received combined rivaroxaban plus aspirin, in 84 [1%] patients who received rivaroxaban alone, and in 61 [1%] patients who received aspirin alone. Rivaroxaban plus aspirin reduced mortality when compared with aspirin alone (262 [3%] of 8313 vs 339 [4%] of 8261; HR 0·77, 95% CI 0·65-0·90, p=0·0012). INTERPRETATION: In patients with stable coronary artery disease, addition of rivaroxaban to aspirin lowered major vascular events, but increased major bleeding. There was no significant increase in intracranial bleeding or other critical organ bleeding. There was also a significant net benefit in favour of rivaroxaban plus aspirin and deaths were reduced by 23%. Thus, addition of rivaroxaban to aspirin has the potential to substantially reduce morbidity and mortality from coronary artery disease worldwide. FUNDING: Bayer AG.
Assuntos
Aspirina/uso terapêutico , Doença da Artéria Coronariana/tratamento farmacológico , Inibidores do Fator Xa/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Rivaroxabana/uso terapêutico , Idoso , Aspirina/administração & dosagem , Aspirina/efeitos adversos , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/prevenção & controle , Doença da Artéria Coronariana/epidemiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Morbidade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/prevenção & controle , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/efeitos adversos , Rivaroxabana/administração & dosagem , Rivaroxabana/efeitos adversos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controleRESUMO
BACKGROUND: The large number of patients worldwide infected with the SARS-CoV-2 virus has overwhelmed health-care systems globally. The Anti-Coronavirus Therapies (ACT) outpatient trial aimed to evaluate anti-inflammatory therapy with colchicine and antithrombotic therapy with aspirin for prevention of disease progression in community patients with COVID-19. METHODS: The ACT outpatient, open-label, 2 × 2 factorial, randomised, controlled trial, was done at 48 clinical sites in 11 countries. Patients in the community aged 30 years and older with symptomatic, laboratory confirmed COVID-19 who were within 7 days of diagnosis and at high risk of disease progression were randomly assigned (1:1) to receive colchicine 0·6 mg twice daily for 3 days and then 0·6 mg once daily for 25 days versus usual care, and in a second (1:1) randomisation to receive aspirin 100 mg once daily for 28 days versus usual care. Investigators and patients were not masked to treatment allocation. The primary outcome was assessed at 45 days in the intention-to-treat population; for the colchicine randomisation it was hospitalisation or death, and for the aspirin randomisation it was major thrombosis, hospitalisation, or death. The ACT outpatient trial is registered at ClinicalTrials.gov, NCT04324463 and is ongoing. FINDINGS: Between Aug 27, 2020, and Feb 10, 2022, 3917 patients were randomly assigned to colchicine or control and to aspirin or control; after excluding 36 patients due to administrative reasons 3881 individuals were included in the analysis (n=1939 colchicine vs n=1942 control; n=1945 aspirin vs 1936 control). Follow-up was more than 99% complete. Overall event rates were 5 (0·1%) of 3881 for major thrombosis, 123 (3·2%) of 3881 for hospitalisation, and 23 (0·6%) of 3881 for death; 66 (3·4%) of 1939 patients allocated to colchicine and 65 (3·3%) of 1942 patients allocated to control experienced hospitalisation or death (hazard ratio [HR] 1·02, 95% CI 0·72-1·43, p=0·93); and 59 (3·0%) of 1945 of patients allocated to aspirin and 73 (3·8%) of 1936 patients allocated to control experienced major thrombosis, hospitalisation, or death (HR 0·80, 95% CI 0·57-1·13, p=0·21). Results for the primary outcome were consistent in all prespecified subgroups, including according to baseline vaccination status, timing of randomisation in relation to onset of symptoms (post-hoc analysis), and timing of enrolment according to the phase of the pandemic (post-hoc analysis). There were more serious adverse events with colchicine than with control (34 patients [1·8%] of 1939 vs 27 [1·4%] of 1942) but none in either group that led to discontinuation of study interventions. There was no increase in serious adverse events with aspirin versus control (31 [1·6%] vs 31 [1·6%]) and none that led to discontinuation of study interventions. INTERPRETATION: The results provide no support for the use of colchicine or aspirin to prevent disease progression or death in outpatients with COVID-19. FUNDING: Canadian Institutes for Health Research, Bayer, Population Health Research Institute, Hamilton Health Sciences Research Institute, and Thistledown Foundation. TRANSLATIONS: For the Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.
Assuntos
COVID-19 , Trombose , Humanos , Aspirina/uso terapêutico , SARS-CoV-2 , Colchicina/uso terapêutico , Resultado do Tratamento , Canadá , Progressão da DoençaRESUMO
BACKGROUND: COVID-19 disease is accompanied by a dysregulated immune response and hypercoagulability. The Anti-Coronavirus Therapies (ACT) inpatient trial aimed to evaluate anti-inflammatory therapy with colchicine and antithrombotic therapy with the combination of rivaroxaban and aspirin for prevention of disease progression in patients hospitalised with COVID-19. METHODS: The ACT inpatient, open-label, 2 × 2 factorial, randomised, controlled trial was done at 62 clinical centres in 11 countries. Patients aged at least 18 years with symptomatic, laboratory confirmed COVID-19 who were within 72 h of hospitalisation or worsening clinically if already hospitalised were randomly assigned (1:1) to receive colchicine 1·2 mg followed by 0·6 mg 2 h later and then 0·6 mg twice daily for 28 days versus usual care; and in a second (1:1) randomisation, to the combination of rivaroxaban 2·5 mg twice daily plus aspirin 100 mg once daily for 28 days versus usual care. Investigators and patients were not masked to treatment allocation. The primary outcome, assessed at 45 days in the intention-to-treat population, for the colchicine randomisation was the composite of the need for high-flow oxygen, mechanical ventilation, or death; and for the rivaroxaban plus aspirin randomisation was the composite of major thrombosis (myocardial infarction, stroke, acute limb ischaemia, or pulmonary embolism), the need for high-flow oxygen, mechanical ventilation, or death. The trial is registered at www. CLINICALTRIALS: gov, NCT04324463 and is ongoing. FINDINGS: Between Oct 2, 2020, and Feb 10, 2022, at 62 sites in 11 countries, 2749 patients were randomly assigned to colchicine or control and the combination of rivaroxaban and aspirin or to the control. 2611 patients were included in the analysis of colchicine (n=1304) versus control (n=1307); 2119 patients were included in the analysis of rivaroxaban and aspirin (n=1063) versus control (n=1056). Follow-up was more than 98% complete. Overall, 368 (28·2%) of 1304 patients allocated to colchicine and 356 (27·2%) of 1307 allocated to control had a primary outcome (hazard ratio [HR] 1·04, 95% CI 0·90-1·21, p=0·58); and 281 (26·4%) of 1063 patients allocated to the combination of rivaroxaban and aspirin and 300 (28·4%) of 1056 allocated to control had a primary outcome (HR 0·92, 95% CI 0·78-1·09, p=0·32). Results were consistent in subgroups defined by vaccination status, disease severity at baseline, and timing of randomisation in relation to onset of symptoms. There was no increase in the number of patients who had at least one serious adverse event for colchicine versus control groups (87 [6·7%] of 1304 vs 90 [6·9%] of 1307) or with rivaroxaban and aspirin versus control groups (85 [8·0%] vs 91 [8·6%]). Among patients assigned to colchicine, 8 (0·61%) had adverse events that led to discontinuation of study drug, mostly gastrointestinal in nature. 17 (1·6%) patients assigned to the combination of rivaroxaban and aspirin had bleeding compared with seven (0·66%) of those allocated to control (p=0·042); the number of serious bleeding events was two (0·19%) versus six (0·57%), respectively (p=0·18). No patients assigned to rivaroxaban and aspirin had serious adverse events that led to discontinuation of study drug. INTERPRETATION: Among patients hospitalised with COVID-19, neither colchicine nor the combination of rivaroxaban and aspirin prevent disease progression or death. FUNDING: Canadian Institutes for Health Research, Bayer, Population Health Research Institute, Hamilton Health Sciences Research Institute, Thistledown Foundation. TRANSLATIONS: For the Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.
Assuntos
Tratamento Farmacológico da COVID-19 , Rivaroxabana , Humanos , Adolescente , Adulto , Rivaroxabana/uso terapêutico , Rivaroxabana/efeitos adversos , Aspirina/uso terapêutico , Colchicina/efeitos adversos , Canadá , Progressão da Doença , Oxigênio , Resultado do TratamentoRESUMO
Background: Effective treatments for COVID-19 are urgently needed, but conducting randomized trials during the pandemic has been challenging. Methods: The Anti-Coronavirus Therapy (ACT) trials are parallel factorial international trials that aimed to enroll 3500 outpatients and 2500 inpatients with symptomatic COVID-19. The outpatient trial is evaluating colchicine vs usual care, and aspirin vs usual care. The primary outcome for the colchicine randomization is hospitalization or death, and for the aspirin randomization, it is major thrombosis, hospitalization, or death. The inpatient trial is evaluating colchicine vs usual care, and the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily vs usual care. The primary outcome for the colchicine randomization is need for high-flow oxygen, need for mechanical ventilation, or death, and for the rivaroxaban plus aspirin randomization, it is major thrombotic events, need for high-flow oxygen, need for mechanical ventilation, or death. Results: At the completion of enrollment on February 10, 2022, the outpatient trial had enrolled 3917 patients, and the inpatient trial had enrolled 2611 patients. Challenges encountered included lack of preliminary data about the interventions under evaluation, uncertainties related to the expected event rates, delays in regulatory and ethics approvals, and in obtaining study interventions, as well as the changing pattern of the COVID-19 pandemic. Conclusions: The ACT trials will determine the efficacy of anti-inflammatory therapy with colchicine, and antithrombotic therapy with aspirin given alone or in combination with rivaroxaban, across the spectrum of mild, moderate, and severe COVID-19. Lessons learned from the conduct of these trials will inform planning of future trials.
Contexte: Il est urgent de mettre au point des traitements efficaces contre la COVID-19, mais il n'est pas facile de réaliser des essais à répartition aléatoire dans un contexte pandémique. Méthodologie: Les essais internationaux factoriels ACT (Anti-Coronavirus Therapy) avaient un objectif d'inscription de 3 500 patients externes et de 2 500 patients hospitalisés présentant une COVID-19 symptomatique. L'essai mené auprès de patients externes visait à évaluer la colchicine par rapport aux soins habituels, et l'aspirine par rapport aux soins habituels. Le paramètre d'évaluation principal au terme de la répartition aléatoire des patients était l'hospitalisation ou le décès dans le groupe traité par la colchicine, et la thrombose majeure, l'hospitalisation ou le décès dans le groupe traité par l'aspirine. L'essai mené auprès de patients hospitalisés visant à évaluer la colchicine par rapport aux soins habituels, et un traitement associant le rivaroxaban à 2,5 mg deux fois par jour et l'aspirine à 100 mg une fois par jour par rapport aux soins habituels. Le paramètre d'évaluation principal au terme de la répartition aléatoire des patients était le recours à l'oxygénothérapie à haut débit ou à la ventilation mécanique ou le décès dans le groupe traité par la colchicine, et la survenue de manifestations thrombotiques majeures, le recours à l'oxygénothérapie à haut débit ou à la ventilation mécanique ou le décès dans le groupe traité par l'association rivaroxaban-aspirine. Résultats: À la fin de la période d'inscription, le 10 février 2022, 3 917 patients externes et 2 611 patients hospitalisés formaient la population des essais. Certains aspects se sont révélés problématiques, notamment le manque de données préliminaires sur les interventions à évaluer, les incertitudes liées aux taux d'événements prévus, les retards touchant les approbations réglementaires et éthiques et les interventions de recherche, de même que l'évolution de la pandémie de COVID-19. Conclusions: Les essais ACT détermineront l'efficacité du traitement anti-inflammatoire par la colchicine et du traitement antithrombotique par l'aspirine, administrée seule ou en association avec le rivaroxaban, contre la COVID-19 légère, modérée ou sévère. Les leçons tirées de ces essais orienteront la planification d'essais ultérieurs.
RESUMO
Metabolic syndrome (MetS) and type 2 diabetes (T2D) are metabolic alterations associated with high morbidity and mortality, particularly in low and middle-income countries. Diet has a significant impact on the risk to develop MetS and T2D; in this regard, consumption of fruits, vegetables, and protein rich foods (from plant and animals) are important to prevent and manage these pathologies. There are limited studies regarding the potential association between Andean foods rich in proteins and the presence of cardio-metabolic conditions in Ecuador. It is necessary to develop new low-cost, local-culturally acceptable strategies to reduce the burden of cardio-metabolic diseases. We describe the prevalence (baseline data) of MetS and T2D in the Ecuadorian cohort of the Prospective Urban and Rural Epidemiology (PURE) study and their potential association with the consumption of protein rich foods, including beef, white meat, dairy and legumes. In this cross-sectional study, we assessed 1,997 individuals aged 35-70 years (mean age 51 years, 72% women), included in the Ecuadorian cohort of the PURE study, from February to December 2018. The prevalence of MetS was 42% for male and 44% for female participants; the prevalence of T2D was 9% for male and 10% for female. Metabolic syndrome and T2D were more common in women older than 50 years of age with primary education or less, low economic income, and with obesity; MetS was more frequent in the rural area while T2D was more frequent in the urban area. Using logistic regression analysis, we observed a significant protective effect of higher consumption of dairy and legumes in the prevalence of MetS and T2D compared with low consumption. It will be important to develop policies for ample production and consumption of protein rich foods such as legumes and dairy, part of traditional diets, to reduce the burden of cardio-metabolic diseases.
Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Dieta/estatística & dados numéricos , Síndrome Metabólica/epidemiologia , Adulto , Idoso , Laticínios/estatística & dados numéricos , Dieta/efeitos adversos , Fibras na Dieta/estatística & dados numéricos , Equador , Fabaceae , Feminino , Humanos , Masculino , Produtos da Carne/estatística & dados numéricos , Pessoa de Meia-Idade , Fatores SocioeconômicosRESUMO
BACKGROUND/AIMS: To examine how measuring adherence at 3 weeks by self-report and pill counts compares to measurements at 7 weeks in a pre-randomization run-in period. METHODS: Study within a trial of an international parallel group randomized controlled trial (RCT) that compares spironolactone to placebo. Adults receiving dialysis enter an 8-week active run-in period with spironolactone. Adherence was assessed by both self-report and pill counts in a subgroup of participants at both 3 weeks and 7 weeks. RESULTS: 332 participants entered the run-in period of which 166 had complete data. By self-report, 146/166 (94.0%) and 153/166 (92.2%) had at least 80% adherence at 3 and 7 weeks respectively (kappa = 0.27 (95% C.I. 0.16 to 0.38). By pill counts, the mean (SD) adherence was 96.5% (16.1%) and 92.4% (18.2%) at 3 and 7 weeks respectively (r = 0.32) with a mean (SD) difference of 3.1% (17.8%) and a 95% limit of agreement from -31.7% to +37.9%. The proportion of adherent participants by self-report and pill counts at 3 weeks agreed in 87.4% of participants (McNemar's p-value 0.58, kappa 0.11, p = 0.02) and at 7 weeks agreed in 92.2% (McNemar's p-value 0.82, kappa 0.47, p < 0.001). CONCLUSIONS: Three and seven-week run-in periods and both self-reported and pill count assessments performed similarly. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03020303.
Assuntos
Adesão à Medicação , Diálise Renal , Adulto , Humanos , Distribuição Aleatória , AutorrelatoRESUMO
BACKGROUND: The combination of 2.5 mg rivaroxaban twice daily and 100 mg aspirin once daily compared with 100 mg aspirin once daily reduces major adverse cardiovascular (CV) events in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD). OBJECTIVES: The aim of this work was to report the effects of the combination on overall and cause-specific mortality. METHODS: The COMPASS trial enrolled 27,395 patients of whom 18,278 were randomized to the combination (n = 9,152) or aspirin alone (n = 9,126). Deaths were adjudicated by a committee blinded to treatment allocation. Previously identified high-risk baseline features were polyvascular disease, chronic kidney disease, mild or moderate heart failure, and diabetes. RESULTS: During a median of 23 months of follow-up (maximum 47 months), 313 patients (3.4%) allocated to the combination and 378 patients (4.1%) allocated to aspirin alone died (hazard ratio [HR]: 0.82; 95% confidence interval [CI]: 0.71-0.96; P = 0.01). Compared with aspirin, the combination reduced CV death (160 [1.7%] vs 203 [2.2%]; HR: 0.78; 95% CI: 0.64-0.96; P = 0.02) but not non-CV death. There were fewer deaths following MI, stroke, and CV procedures, as well as fewer sudden cardiac, other, and unknown causes of CV deaths and coronary heart disease deaths. Patients with 0, 1, 2, and 3 or 4 high-risk features at baseline had 4.2, 4.8, 25.0, and 53.9 fewer deaths, respectively, per 1000 patients treated for 30 months. CONCLUSIONS: The combination of rivaroxaban and aspirin compared with aspirin reduced overall and CV mortality with consistent reductions in cause specific CV mortality in patients with chronic CAD or PAD. The absolute mortality benefits are greater with increasing baseline risk. (Cardiovascular Outcomes for People Using Anticoagulant Strategies [COMPASS]; NCT01776424).
Assuntos
Aspirina , Doença da Artéria Coronariana , Doença Arterial Periférica , Rivaroxabana , Idoso , Aspirina/administração & dosagem , Aspirina/efeitos adversos , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/mortalidade , Diabetes Mellitus/epidemiologia , Quimioterapia Combinada , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Feminino , Insuficiência Cardíaca/epidemiologia , Humanos , Masculino , Avaliação de Resultados em Cuidados de Saúde , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/tratamento farmacológico , Doença Arterial Periférica/mortalidade , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/efeitos adversos , Medição de Risco , Fatores de Risco , Rivaroxabana/administração & dosagem , Rivaroxabana/efeitos adversos , Índice de Gravidade de DoençaRESUMO
The major burden of hypertension (HTN) occurs in low-middle-income countries (LMIC) and it is the main modifiable risk factor for cardiovascular diseases (CVD). Few population studies on HTN prevalence have been carried out in Ecuador where there is limited information regarding its prevalence, awareness, treatment, and control. Thus, the aim of the present study was to determine the prevalence, awareness, treatment, and control of HTN and its association with socio-economic, nutritional, and lifestyle habits in urban and rural Andean communities of Pichincha province in Ecuador. The authors studied 2020 individuals aged 35-70 years (mean age 50.8 years, 72% women), included in the Ecuadorian cohort of the Prospective Urban and Rural Epidemiology (PURE) study, from February to December 2018. The hypertension prevalence (>140/90 mmHg) was 27% and was greater in urban than in rural communities, more common in men, in individuals older than 50 years of age, in people with low monthly income and low level of education. Higher prevalence was also observed in subjects with obesity, and among former smokers and those who consumed alcohol. Only 49% of those with HTN were aware of their condition, 40% were using antihypertensive medications, and 19% had their blood pressure under control (<140/90 mmHg). These results showed low levels of awareness, treatment, and control of HTN in the Andean region of Ecuador, suggesting the urgent necessity of implementing programs to improve the diagnosis and management of HTN.
Assuntos
Hipertensão , Adulto , Idoso , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Conscientização , Pressão Sanguínea/efeitos dos fármacos , Estudos Transversais , Equador/epidemiologia , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Fatores de RiscoRESUMO
Preeclampsia is a disorder specific of the human being that appears after 20 weeks of pregnancy, characterized by new onset of hypertension and proteinuria. Abnormal placentation and reduced placental perfusion associated to impaired trophoblast invasion and alteration in the compliance of uterine spiral arteries are the early pathological findings that are present before the clinical manifestations of preeclampsia. Later on, the endothelial and vascular dysfunction responsible of the characteristic vasoconstriction of preeclampsia appear. Different nutritional risk factors such as a maternal deficit in the intake of calcium, protein, vitamins and essential fatty acids, have been shown to play a role in the genesis of preeclampsia, but also an excess of weight gain during pregnancy or a pre-pregnancy state of obesity and overweight, which are associated to hyperinsulinism, insulin resistance and maternal systemic inflammation, are proposed as one of the mechanism that conduce to endothelial dysfunction, hypertension, proteinuria, thrombotic responses, multi-organ damage, and high maternal mortality and morbidity. Moreover, it has been demonstrated that pregnant women that suffer preeclampsia will have an increased risk of future cardiovascular disease and related mortality in their later life. In this article we will discuss the results of studies performed in different populations that have shown an interrelationship between obesity and overweight with the presence of preeclampsia. Moreover, we will review some of the common mechanisms that explain this interrelationship, particularly the alterations in the L-arginine/nitric oxide pathway as a crucial mechanism that is common to obesity, preeclampsia and cardiovascular diseases.
RESUMO
BACKGROUND: Long-term aspirin prevents vascular events but is only modestly effective. Rivaroxaban alone or in combination with aspirin might be more effective than aspirin alone for vascular prevention in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD). Rivaroxaban as well as aspirin increase upper gastrointestinal (GI) bleeding and this might be prevented by proton pump inhibitor therapy. METHODS: Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) is a double-blind superiority trial comparing rivaroxaban 2.5 mg twice daily combined with aspirin 100 mg once daily or rivaroxaban 5 mg twice daily vs aspirin 100 mg once daily for prevention of myocardial infarction, stroke, or cardiovascular death in patients with stable CAD or PAD. Patients not taking a proton pump inhibitor were also randomized, using a partial factorial design, to pantoprazole 40 mg once daily or placebo. The trial was designed to have at least 90% power to detect a 20% reduction in each of the rivaroxaban treatment arms compared with aspirin and to detect a 50% reduction in upper GI complications with pantoprazole compared with placebo. RESULTS: Between February 2013 and May 2016, we recruited 27,395 participants from 602 centres in 33 countries; 17,598 participants were included in the pantoprazole vs placebo comparison. At baseline, the mean age was 68.2 years, 22.0% were female, 90.6% had CAD, and 27.3% had PAD. CONCLUSIONS: COMPASS will provide information on the efficacy and safety of rivaroxaban, alone or in combination with aspirin, in the long-term management of patients with stable CAD or PAD, and on the efficacy and safety of pantoprazole in preventing upper GI complications in patients receiving antithrombotic therapy.
Assuntos
Anticoagulantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Terapia Trombolítica/normas , HumanosRESUMO
El sistema inmune cumple un rol fundamental en la defensa contra microorganismos y células anómalas. Históricamente, el concepto de vigilancia inmunológica se fundamenta en el control de múltiples funciones incluyendo la regulación de células cancerígenas a través de diversos mecanismos, en los cuales están involucrados: células, moléculas y tejidos del sistema inmune. El objetivo de analizar la respuesta inmune frente al cáncer, es entender los mecanismos de presentación del antígeno y los mecanismos desencadenados por el sistema adaptativo e innato que participan en la destrucción del tumor a expensas de un proceso inflamatorio agudo que podría llevar al control o destrucción del cáncer. La propuesta de esta revisión es resumir y esquematizar los aspectos cardinales de los diferentes procesos inmunológicos que participan en la fisiopatología de las enfermedades malignas, así como los mecanismos que emplea el sistema inmune para la defensa del cáncer.
The Inmune System plays an essential role in the defense of the organism against microorganisms and alters cells. Historically, the concept of immune surveillance its based in the control of multiple functions including the regulation of cancer cells through diverse mechanisms such as cells, molecules and tissue from the immune system. Therefore, it is important to understand the mechanisms of antigen presentation and other mechanisms of the innate and adaptive system which participate in the defense of the organism against the tumor. This process is enhancing by an inflammatory acute process that could lead to the control or de destruction of the tumor. The purpose of this review is to develop the cardinal aspects of the immunologic process that take part in the defense against malignant diseases, and also to explain its mechanisms.
Assuntos
Humanos , Sistema Imunitário , Imunidade , Formação de Anticorpos , Antígenos CD4 , Antígenos CD8 , AntígenosRESUMO
Las litiasis vesicales de gran tamaño son infrecuentes. Se manifiestan clínicamente por sepsis urinaria a repetición, polaquiuria y estranguria. Se presenta un nuevo caso de litiasis vesical gigante, así como aspectos de su diagnóstico y tratamiento. La paciente de 64 años de edad, asistió a la consulta y refirió padecer de infecciones urinarias reiteradas, incontinencia por urgencia miccional y dolor posmiccional en hipogastrio y uretra. Tenía el antecedente de haber sido operada, siete meses atrás, de un prolapso uterino total por vía vaginal. En el cultivo de orina se aisló Escherichia coli y, en el ultrasonido abdominal, se detectó una litiasis vesical de gran tamaño, la cual se confirmó en la radiografía simple de la pelvis. Se le realizó la cistolitotomía retropúbica, extrayéndose una litiasis de 9 x 6 x 5 cm de tamaño y 186 g de peso. La paciente evolucionó favorablemente con la desaparición total de los síntomas. La litiasis vesical gigante es rara, pero se debe sospechar en pacientes con síntomas urinarios sépticos e irritativos bajos persistentes. El ultrasonido del tracto urinario y la radiografía simple de la pelvis, son suficientes para establecer el diagnóstico de certeza. La cistolitotomía continúa siendo el tratamiento de elección de esta afección.
Giant bladder calculi are uncommon. Their clinical manifestations are recurrent urinary sepsis, polachiuria and strangury. A new case is presented of giant bladder calculus, as well as aspects of its diagnosis and treatment. A 64-year-old female patient attended consultation and stated that she suffered from recurrent urinary infection, urinary urgency incontinence and hypogastric and urethral post-miction pain. Seven months before she had undergone surgery for total uterine prolapse via the vagina. Escherichia coli was isolated from the urine culture, and abdominal ultrasonography revealed a large bladder calculus, which was confirmed by simple pelvic radiography. Retropubic cystolithotomy resulted in the removal of a 9 x 6 x 5 cm, 186 g calculus. The patient evolved favorably with total disappearance of all symptoms. Giant bladder calculus is a rare condition which should be suspected in patients with persistent irritative symptoms of lower urinary sepsis. Urinary-tract ultrasonography and simple pelvic radiography are sufficient to establish the certainty diagnosis. Cystolithotomy continues to be the treatment of choice for this condition.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Adulto Jovem , Diabetes Mellitus Tipo 2/terapia , Telemonitoramento , Telemetria/métodos , Hemoglobinas Glicadas/análise , Automonitorização da Glicemia/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto , Telemedicina/métodos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatologiaRESUMO
Las enfermedades cardiovasculares han experimentado un incremento epidémico en los países del tercer mundo durante las últimas décadas. Las causas son multifactoriales y se asocian con un aumento em la expectativa de vida y con cambios en los hábitos nutricionales y estilos de vida. Los países desarrollados, que hace cuarenta años sufrieron una situación similar, identificaron y están combatiendo los factores de riesgo clásicos (hipertensión arterial, tabaquismo, obesidad,inactividad física, dislipidemia, diabetes mellitus). Esto les ha permitido disminuir la prevalencia de accidentes cerebrovasculares y enfermedad cardiaca coronaria. Sin embargo, los resultados epidemiológicos de estos rígidos programas de control de los factores de riesgo fueron los esperados, por lo que han comenzado a identificar y estudiar los denominados factores de riesgo emergentes (infección, inflamación, hiperhomocisteinemia, deficit de ácido fólico y vitaminas antioxidantes, Síndrome X metabólico, hiperinsulinismo y resistencia a la insulina), los cuales estarían contribuyendo a la génesis y manifestaciones de las enfermedades cardiovasculares. En latinoamérica, por sus particulares condiciones étnicas, nutricionales y culturales, se vuelve inprescindible la realización de investigaciones observacionales, clínicas y básicas que permitan definir el peso específico de cada uno de los factores de riesgo clásicos y emergentes en nuestras poblaciones. La necesidad de optimizar los limitados recursos disponibles demanda de estrategias de intervención efectivas, las cuales deben priorizar bajo nuestras propias condiciones sociales, económicas y culturales, aquellos factores de mayor riesgo y que sean posibles de transformarse
Assuntos
Colesterol , Ácido Fólico , Infecções , Inflamação , Óxido Nítrico , Fatores de RiscoRESUMO
En 1980 se planteó la posible relación entre una baja ingesta nutricional de calcio y una alta incidencia de hipertensión inducida por el embarazo (HIE). En Ecuador esta enfermedad constituye la primera causa de mortalidad materna y es un importante factor de riesgo para bajo peso al nacer y alta mortalidad neonatal. Presentamos los resultados de nueve años de investigaciones del metabolismo de calcio en la gestación en los cuales demostramos que las embarazadas ecuatorianas que acuden al Hospital Gineco-Obstétrico Isidro Ayora de Quito consumen diariamente apenas el 77 por ciento de las recomendaciones internacionales para calcio y del 31 al 62 por cient opara hierro,en tanto que la ingesta de energía, proteína, fósforo, vitamina C, tiamina, riboflavina y niacina alcanzan o exceden las recomendaciones. Las concentraciones de calcio iónico sérico en las mujeres controles no embarazadas (1.18 ñ 0.01 mM) y en las embarazadas normotensas (1.17 ñ 0.02 mM) fueron significativamente mayores que en las preeclámpticas (1.13 ñ 0.01 mM),la parathormona región media de la molécula estuvo incrementada en las pacientes preeclánticas (85.3 ñ 47.4 pmol/l) y embarazadas normales (63.6 ñ 15.7 pmol/l) en relación a las no embarazadas (26.2 ñ 12.6 pmol/l; p<0.05).