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1.
JAMA Pediatr ; 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32176276

RESUMO

Importance: Proton pump inhibitor (PPI) use has been linked to increased risk of fracture in adults. Despite a trend in prescription of PPIs in children, there is scarce evidence regarding this safety concern in pediatric patients. Objective: To evaluate the association between PPI use and risk of fracture in children. Design: This nationwide register-based cohort study included data from Sweden from July 2006 to December 2016. Children younger than 18 years who initiated PPI use were matched on propensity score and age with those who did not initiate PPI use. Exposure: Initiation of PPI use. Main Outcomes and Measures: Cox regression was adopted to estimate hazard ratios (HRs) for a first fracture of any type and 5 subtypes of fracture, with follow-up for up to 5 years. To address potential residual confounding, high-dimensional propensity score matching and a direct comparison with histamine-2 receptor antagonists were performed. Results: There were a total of 115 933 pairs of children included. During a mean (SD) of 2.2 (1.6) years of follow-up, 5354 and 4568 cases of any fracture occurred among those who initiated PPIs vs those who did not, respectively (20.2 vs 18.3 events per 1000 person-years; hazard ratio [HR], 1.11 [95% CI, 1.06-1.15]). Use of PPIs was associated with increased risk of upper-limb fracture (HR, 1.08 [95% CI, 1.03-1.13]), lower-limb fracture (HR, 1.19 [95% CI, 1.10-1.29]), and other fractures (HR, 1.51 [95% CI, 1.16-1.97]) but not head fracture (HR, 0.93 [95% CI, 0.76-1.13]) or spine fracture (HR, 1.31 [95% CI, 0.95-1.81]). The HRs for fracture according to cumulative duration of PPI use were 1.08 (95% CI, 1.03-1.13) for 30 days or less, 1.14 (95% CI, 1.09-1.20) for 31 to 364 days, and 1.34 (95% CI, 1.13-1.58) for 365 days or more. The association was consistent in most sensitivity analyses, including high-dimensional propensity score matching (HR, 1.10 [95% CI, 1.06-1.15]), although the analysis of PPI vs histamine-2 receptor antagonist did not reach statistical significance (HR, 1.06 [95% CI, 0.97-1.15]). Conclusions and Relevance: In this large pediatric cohort, PPI use was associated with a small but significant increased risk of any fracture. Risk of fracture should be taken into account when weighing the benefits and risks of PPI treatment in children.

3.
Lancet Gastroenterol Hepatol ; 4(11): 845-853, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31494100

RESUMO

BACKGROUND: Studies have shown an association between use of tumour necrosis factor-α (TNFα) inhibitors and increased risk of serious infection in adult inflammatory bowel disease (IBD). However, data on this topic for paediatric patients are scarce and inconclusive. The aim of this study was to investigate whether there is an association between the use of TNFα inhibitors and the risk of serious infection in children with IBD. METHODS: In this nationwide Danish cohort study, we searched health registers (from Jan 1, 2007, to Dec 31, 2016) to identify episodes of children and adolescents (<18 years) with at least two recorded IBD diagnoses in specialist care. We categorised follow-up time in mutually exclusive episodes of incident TNFα inhibitor use or no TNFα inhibitor use from specialist care records. We used Cox proportional hazards models to estimate hazard ratios (HRs), adjusting using propensity score weighting for demographic characteristics, comorbidities, treatment history, health-care use, and indicators of disease severity. The primary outcome, incident serious infection, was defined as infection requiring a stay in hospital and was identified through hospital records. FINDINGS: Among 2817 paediatric patients with IBD, we identified 618 episodes of incident TNFα inhibitor use and 2925 episodes of no TNFα inhibitor use. In the cohort of exposed and not exposed episodes that was propensity-score weighted, 53·9% were of male sex, the mean age was 15·1 (SD 1·7) years, 69·9% had Crohn's disease, and 30·1% had ulcerative colitis or IBD-unclassified; median follow-up was 1·4 years (IQR 0·4-3·0). The weighted incidence of serious infection was 54·6 events per 1000 patient-years for the TNFα inhibitor episodes and 61·9 events per 1000 patient-years for the no-use episodes. The weighted HR of serious infection associated with TNFα inhibitor use was 0·81 (95% CI 0·54-1·21). INTERPRETATION: There was no significant association between use of TNFα inhibitors and the risk of serious infection in children with IBD, and, based on the upper bound of the confidence interval, a relatively small risk increase seems unlikely, contrary to previous findings in adults. Observational data such as these can support paediatric clinical practice. FUNDING: Swedish Research Council, Frimurare Barnhuset Foundation, and the Åke Wiberg Foundation.

4.
BMJ ; 366: l4772, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467044

RESUMO

OBJECTIVE: To investigate the cardiovascular effectiveness of sodium glucose cotransporter 2 (SGLT2) inhibitors in routine clinical practice. DESIGN: Cohort study using data from nationwide registers and an active-comparator new-user design. SETTING: Denmark, Norway, and Sweden, from April 2013 to December 2016. PARTICIPANTS: 20 983 new users of SGLT2 inhibitors and 20 983 new users of dipeptidyl peptidase 4 (DPP4) inhibitors, aged 35-84, matched by age, sex, history of major cardiovascular disease, and propensity score. MAIN OUTCOME MEASURES: Primary outcomes were major cardiovascular events (composite of myocardial infarction, stroke, and cardiovascular death) and heart failure (hospital admission for heart failure or death due to heart failure). Secondary outcomes were the individual components of the cardiovascular composite and any cause death. In the primary analyses, patients were defined as exposed from treatment start throughout follow-up (analogous to intention to treat); additional analyses were conducted with an as-treated exposure definition. Cox regression was used to estimate hazard ratios. RESULTS: Mean age of the study cohort was 61 years, 60% were men, and 19% had a history of major cardiovascular disease. Of the total 27 416 person years of follow-up in the SGLT2 inhibitor group, 22 627 (83%) was among patients who initiated dapagliflozin, 4521 (16%) among those who initiated empagliflozin, and 268 (1%) among those who initiated canagliflozin. During follow-up, 467 SGLT2 inhibitor users (incidence rate 17.0 events per 1000 person years) and 662 DPP4 inhibitor users (18.0) had a major cardiovascular event, whereas 130 (4.7) and 265 (7.1) had a heart failure event, respectively. Hazard ratios were 0.94 (95% confidence interval 0.84 to 1.06) for major cardiovascular events and 0.66 (0.53 to 0.81) for heart failure. Hazard ratios were consistent among subgroups of patients with and without history of major cardiovascular disease and with and without history of heart failure. Hazard ratios for secondary outcomes, comparing SGLT2 inhibitors with DPP4 inhibitors, were 0.99 (0.85 to 1.17) for myocardial infarction, 0.94 (0.77 to 1.15) for stroke, 0.84 (0.65 to 1.08) for cardiovascular death, and 0.80 (0.69 to 0.92) for any cause death. In the as-treated analyses, hazard ratios were 0.84 (0.72 to 0.98) for major cardiovascular events, 0.55 (0.42 to 0.73) for heart failure, 0.93 (0.76 to 1.14) for myocardial infarction, 0.83 (0.64 to 1.07) for stroke, 0.67 (0.49 to 0.93) for cardiovascular death, and 0.75 (0.61 to 0.91) for any cause death. CONCLUSIONS: In this large Scandinavian cohort, SGLT2 inhibitor use compared with DPP4 inhibitor use was associated with reduced risk of heart failure and any cause death, but not with major cardiovascular events in the primary intention-to-treat analysis. In the additional as-treated analyses, the magnitude of the association with heart failure and any cause death became larger, and a reduced risk of major cardiovascular events that was largely driven by the cardiovascular death component was observed. These data help inform patients, practitioners, and authorities regarding the cardiovascular effectiveness of SGLT2 inhibitors in routine clinical practice.


Assuntos
Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Insuficiência Cardíaca/epidemiologia , Infarto do Miocárdio/epidemiologia , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Acidente Vascular Cerebral/epidemiologia , Idoso , Dinamarca/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Seguimentos , Insuficiência Cardíaca/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/induzido quimicamente , Noruega/epidemiologia , Sistema de Registros/estatística & dados numéricos , Acidente Vascular Cerebral/induzido quimicamente , Suécia/epidemiologia
5.
Ann Intern Med ; 170(10): 691-701, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31009941

RESUMO

Background: Maternal type 1 diabetes (T1D) has been linked to preterm birth and other adverse pregnancy outcomes. How these risks vary with glycated hemoglobin (or hemoglobin A1c [HbA1c]) levels is unclear. Objective: To examine preterm birth risk according to periconceptional HbA1c levels in women with T1D. Design: Population-based cohort study. Setting: Sweden, 2003 to 2014. Patients: 2474 singletons born to women with T1D and 1 165 216 reference infants born to women without diabetes. Measurements: Risk for preterm birth (<37 gestational weeks). Secondary outcomes were neonatal death, large for gestational age, macrosomia, infant birth injury, hypoglycemia, respiratory distress, 5-minute Apgar score less than 7, and stillbirth. Results: Preterm birth occurred in 552 (22.3%) of 2474 infants born to mothers with T1D versus 54 287 (4.7%) in 1 165 216 infants born to mothers without diabetes. The incidence of preterm birth was 13.2% in women with a periconceptional HbA1c level below 6.5% (adjusted risk ratio [aRR] vs. women without T1D, 2.83 [95% CI, 2.28 to 3.52]), 20.6% in those with a level from 6.5% to less than 7.8% (aRR, 4.22 [CI, 3.74 to 4.75]), 28.3% in those with a level from 7.8% to less than 9.1% (aRR, 5.56 [CI, 4.84 to 6.38]), and 37.5% in those with a level of 9.1% or higher (aRR, 6.91 [CI, 5.85 to 8.17]). The corresponding aRRs for medically indicated preterm birth (n = 320) were 5.26 (CI, 3.83 to 7.22), 7.42 (CI, 6.21 to 8.86), 11.75 (CI, 9.72 to 14.20), and 17.51 (CI, 14.14 to 21.69), respectively. The corresponding aRRs for spontaneous preterm birth (n = 223) were 1.81 (CI, 1.31 to 2.52), 2.86 (CI, 2.38 to 3.44), 2.88 (CI, 2.23 to 3.71), and 2.80 (CI, 1.94 to 4.03), respectively. Increasing HbA1c levels were associated with the study's secondary outcomes: large for gestational age, hypoglycemia, respiratory distress, low Apgar score, neonatal death, and stillbirth. Limitation: Because HbA1c levels were registered annually at routine visits, they were not available for all pregnant women with T1D. Conclusion: The risk for preterm birth was strongly linked to periconceptional HbA1c levels. Women with HbA1c levels consistent with recommended target levels also were at increased risk. Primary Funding Source: Swedish Diabetes Foundation.


Assuntos
Diabetes Mellitus Tipo 1/sangue , Hemoglobina A Glicada/análise , Nascimento Prematuro/epidemiologia , Adulto , Feminino , Humanos , Incidência , Recém-Nascido , Gravidez , Resultado da Gravidez , Risco , Suécia/epidemiologia
7.
Lancet Child Adolesc Health ; 3(3): 158-165, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30685366

RESUMO

BACKGROUND: Studies have shown an association between use of azathioprine and increased risk of acute pancreatitis in adult inflammatory bowel disease. However, whether an association exists among paediatric patients is not known. We aimed to investigate whether use of azathioprine is associated with the risk of acute pancreatitis in children with inflammatory bowel disease. METHODS: We did a nationwide register-based cohort study in Sweden (2006-16) and Denmark (2000-16). All paediatric patients (<18 years of age) with inflammatory bowel disease during the study period were identified through hospital records. Episodes of incident azathioprine use and no use of any thiopurine were matched (1:1) using propensity scores, controlling for sociodemographic characteristics, comorbidities, previous treatment, indicators of disease severity, and health care use. Incident acute pancreatitis (physician-assigned diagnosis with ICD-10 code K85) occurring in the 90 days following treatment initiation were identified through outpatient and inpatient hospital records. FINDINGS: We identified 3574 azathioprine episodes and 18 700 no-use episodes, which resulted in 3374 pairs after propensity score matching; baseline characteristics in the matched cohort were well balanced. Among the matched azathioprine episodes, mean age was 14·3 years (SD 3·1), 1854 (54·9%) were male, 1923 (57·0%) had Crohn's disease, and 1451 (43·0%) had ulcerative colitis or unclassified inflammatory bowel disease. Within the first 90 days following initiation of azathioprine, 40 acute pancreatitis events occurred (incidence rate 49·1 events per 1000 person-years) compared with six events in the no-use group (8·4 events per 1000 person-years). Azathioprine use was associated with an increased risk of acute pancreatitis (incidence rate ratio 5·82 [95% CI 2·47-13·72]; absolute difference 1·0 [95% CI 0·3-2·6] events per 100 patients) during the 90-day risk period. INTERPRETATION: Use of azathioprine was associated with an increased risk of acute pancreatitis in children with inflammatory bowel disease during the first 90 days following treatment initiation, suggesting the need for regular and rigorous monitoring. The risk of acute pancreatitis needs to be considered when deciding on optimal treatment strategies. FUNDING: Swedish Research Council, Frimurare Barnhuset Foundation, and the Åke Wiberg Foundation.

8.
Lancet Diabetes Endocrinol ; 7(2): 106-114, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30527909

RESUMO

BACKGROUND: Trial evidence shows that the glucagon-like peptide-1 receptor agonist liraglutide significantly reduces the risk of major cardiovascular events among patients with type 2 diabetes who have established cardiovascular disease or are at high cardiovascular risk. We aimed to assess the cardiovascular effectiveness of liraglutide in routine clinical practice. METHODS: We used data from nationwide registers in Denmark and Sweden for the period from Jan 1, 2010, to Dec 31, 2016, to investigate the risk of major cardiovascular events associated with use of liraglutide, compared with an active comparator drug class, dipeptidyl peptidase-4 (DPP-4) inhibitors, in patients with type 2 diabetes. The cohort included incident users of liraglutide or DPP-4 inhibitors, who were also using metformin at baseline, matched 1:1 on age, sex, and propensity score. The main outcome was major cardiovascular events, a composite outcome consisting of myocardial infarction, stroke, and cardiovascular death. Other outcomes assessed were the individual components of the main composite outcome, heart failure, death from any cause, and an expanded composite major cardiovascular events outcome that also included other ischaemic heart disease, coronary revascularisation, and peripheral arterial disease. FINDINGS: The study population consisted of 23 402 users of liraglutide and 23 402 matched users of DPP-4 inhibitors; patients were followed up for a mean of 3·3 years (SD 2·0). A major cardiovascular event occurred in 1132 users of liraglutide (incidence rate 14·0 per 1000 person-years) and in 1141 users of DPP-4 inhibitors (15·4 per 1000 person-years; hazard ratio [HR] 0·90, 95% CI 0·83-0·98). The HRs were 0·81 (0·71-0·92) for patients with a history of major cardiovascular disease and 0·96 (0·86-1·06) for patients without such a history (p=0·057 [test of homogeneity], suggesting no statistical evidence of heterogeneity). Compared with use of DPP-4 inhibitors, use of liraglutide was associated with a significantly lower risk of cardiovascular death (HR 0·78, 95% CI 0·68-0·91), but no significant differences were identified for risk of myocardial infarction (0·94, 0·84-1·06) or stroke (0·88, 0·77-1·01). Furthermore, use of liraglutide was associated with a significantly lower risk of death from any cause (HR 0·83, 95% CI 0·77-0·90), but no significant differences were identified for risk of heart failure (0·90, 0·80-1·03) or for the expanded major cardiovascular events outcome (0·95, 0·89-1·01). INTERPRETATION: In this large Scandinavian cohort, use of liraglutide, as compared with use of DPP-4 inhibitors, was associated with significantly reduced risk of major cardiovascular events. Patients with history of cardiovascular disease seemed to derive the largest benefit from treatment with liraglutide. These data provide support for the cardiovascular effectiveness of liraglutide in routine clinical practice. FUNDING: Swedish Heart-Lung Foundation, Novo Nordisk Foundation, and Swedish Society for Medical Research.

9.
BMJ ; 363: k4365, 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30429124

RESUMO

OBJECTIVE: To assess the association between the use of sodium glucose cotransporter 2 (SGLT2) inhibitors and seven serious adverse events of current concern. DESIGN: Register based cohort study. SETTING: Sweden and Denmark from July 2013 to December 2016. PARTICIPANTS: A propensity score matched cohort of 17 213 new users of SGLT2 inhibitors (dapagliflozin, 61%; empagliflozin, 38%; canagliflozin, 1%) and 17 213 new users of the active comparator, glucagon-like peptide 1 (GLP1) receptor agonists. MAIN OUTCOME MEASURES: The primary outcomes were lower limb amputation, bone fracture, diabetic ketoacidosis, acute kidney injury, serious urinary tract infection, venous thromboembolism, and acute pancreatitis, as identified from hospital records. Hazard ratios and 95% confidence intervals were estimated by using Cox proportional hazards models. RESULTS: Use of SGLT2 inhibitors, as compared with GLP1 receptor agonists, was associated with an increased risk of lower limb amputation (incidence rate 2.7 v 1.1 events per 1000 person years, hazard ratio 2.32, 95% confidence interval 1.37 to 3.91) and diabetic ketoacidosis (1.3 v 0.6, 2.14, 1.01 to 4.52) but not with bone fracture (15.4 v 13.9, 1.11, 0.93 to 1.33), acute kidney injury (2.3 v 3.2, 0.69, 0.45 to 1.05), serious urinary tract infection (5.4 v 6.0, 0.89, 0.67 to 1.19), venous thromboembolism (4.2 v 4.1, 0.99, 0.71 to 1.38) or acute pancreatitis (1.3 v 1.2, 1.16, 0.64 to 2.12). CONCLUSIONS: In this analysis of nationwide registers from two countries, use of SGLT2 inhibitors, as compared with GLP1 receptor agonists, was associated with an increased risk of lower limb amputation and diabetic ketoacidosis, but not with other serious adverse events of current concern.


Assuntos
Compostos Benzidrílicos/efeitos adversos , Canagliflozina/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/efeitos adversos , Hipoglicemiantes/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Adulto , Amputação/estatística & dados numéricos , Estudos de Coortes , Dinamarca/epidemiologia , Cetoacidose Diabética/epidemiologia , Feminino , Fraturas Ósseas/epidemiologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Pancreatite/epidemiologia , Pontuação de Propensão , Suécia/epidemiologia , Infecções Urinárias/epidemiologia , Tromboembolia Venosa/epidemiologia
10.
Int J Cardiol ; 269: 310-316, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30072148

RESUMO

BACKGROUND: Concomitant use of statins metabolized by the cytochrome P450 isoenzyme 3A4 (CYP3A4) and CYP3A4-inhibiting macrolide antibiotics may confer an increased risk of renal failure. We investigated the risk of serious renal events associated with concomitant use of such statins and such macrolides. METHODS: In a nationwide register-based cohort study (Denmark, 1999-2017), we identified 906,423 new users (40-79 years old), of CYP3A4-metabolized statins. In propensity score-matched analyses, we compared the risk of serious renal events during episodes of concomitant use of statins and CYP3A4-inhibiting macrolides (n = 71,521) with episodes of use of statins alone (n = 285,488) and, as the primary analysis, with episodes of concomitant use of statins and an active comparator (penicillin V, n = 139,446). Using proportional hazards regression, we estimated hazard ratios (HRs) for serious renal events within 30 days of start of follow-up. RESULTS: We observed 25 serious renal events during concomitant use of statins and macrolides (incidence rate [IR], 4.9 per 1000 person-years). Compared with use of statins alone (50 events; IR, 2.3), concomitant use of statins and macrolides was associated with a significantly increased risk of serious renal events (HR 2.16, 95% confidence interval [CI] 1.33, 3.49). Compared with concomitant use of statins and penicillin V (52 events; IR, 5.3), however, we observed no increased risk (HR 0.93, 95% CI 0.58, 1.49). CONCLUSIONS: In this nationwide cohort study concomitant use of statins and macrolides was not associated with a significantly increased risk of serious renal events.


Assuntos
Antibacterianos/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Nefropatias/diagnóstico , Nefropatias/epidemiologia , Macrolídeos/administração & dosagem , Adulto , Idoso , Antibacterianos/efeitos adversos , Estudos de Coortes , Dinamarca/epidemiologia , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Nefropatias/induzido quimicamente , Macrolídeos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sistema de Registros , Fatores de Risco
11.
BMJ ; 362: k2638, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29976596

RESUMO

OBJECTIVE: To examine the association between maternal type 1 diabetes and the risk of major birth defects according to levels of glycated haemoglobin (HbA1C) within three months before or after estimated conception. DESIGN: Population based historical cohort study using nationwide health registers. SETTING: Sweden, 2003-15. PARTICIPANTS: 2458 singleton liveborn infants of mothers with type 1 diabetes and a glycated haemoglobin measurement within three months before or after estimated conception and 1 159 865 infants of mothers without diabetes. MAIN OUTCOME MEASURES: Major cardiac and non-cardiac birth defects according to glycated haemoglobin levels. RESULTS: 122 cases of major cardiac defects were observed among 2458 infants of mothers with type 1 diabetes. Compared with 15 cases of major cardiac defects per 1000 infants of mothers without diabetes, the rates among infants of mothers with type 1 diabetes were 33 per 1000 for a glycated haemoglobin level of <6.5% (adjusted risk ratio 2.17, 95% confidence interval 1.37 to 3.42), 49 per 1000 for 6.5% to <7.8% (3.17, 2.45 to 4.11), 44 per 1000 for 7.8% to <9.1% (2.79, 1.90 to 4.12), and 101 per 1000 for ≥9.1% (6.23, 4.32 to 9.00). The corresponding adjusted risk differences were 17 (5 to 36), 32 (21 to 46), 26 (13 to 46), and 77 (49 to 118) cases of major cardiac defects per 1000 infants, respectively. 50 cases of major non-cardiac defects were observed among infants of mothers with type 1 diabetes. Compared with 18 cases of major non-cardiac defects per 1000 infants of mothers without diabetes, the rates among infants of mothers with type 1 diabetes were 22 per 1000 for a glycated haemoglobin level of <6.5% (adjusted risk ratio 1.18, 0.68 to 2.07), 19 per 1000 for 6.5% to <7.8% (1.01, 0.66 to 1.54), 17 per 1000 for 7.8% to <9.1% (0.89, 0.46 to 1.69), and 32 per 1000 for ≥9.1% (1.68, 0.85 to 3.33). CONCLUSION: Among liveborn infants of mothers with type 1 diabetes, increasingly worse glycaemic control in the three months before or after estimated conception was associated with a progressively increased risk of major cardiac defects. Even with glycated haemoglobin within target levels recommended by guidelines (<6.5%), the risk of major cardiac defects was increased more than twofold. The risk of major non-cardiac defects was not statistically significantly increased at any of the four glycated haemoglobin levels examined; the study had limited statistical power for this outcome and was based on live births only.


Assuntos
Anormalidades Congênitas/epidemiologia , Diabetes Mellitus Tipo 1/epidemiologia , Gravidez em Diabéticas/epidemiologia , Adulto , Biomarcadores/metabolismo , Estudos de Coortes , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Lactente , Recém-Nascido , Gravidez , Gravidez em Diabéticas/metabolismo , Fatores de Risco , Suécia/epidemiologia
13.
Int J Cardiol ; 268: 113-119, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29934230

RESUMO

BACKGROUND: The comparative effectiveness and safety of individual direct oral anticoagulants (DOACs) in clinical practice is largely unknown. The study objectives were to compare effectiveness and safety of DOACs in patients with non-valvular atrial fibrillation (NVAF). METHODS: Based on nationwide registers we established a population-based historical cohort study of 12,638 new users of standard dose DOACs (apixaban 5 mg twice daily, dabigatran 150 mg twice daily and rivaroxaban 20 mg once daily) with NVAF in Denmark, July 2013 to March 2016. Patients were matched on propensity scores in a 1:1 ratio comparing apixaban vs. dabigatran (for a total of 6470 patients), apixaban vs. rivaroxaban (7352 patients), and rivaroxaban vs. dabigatran (5440 patients). Hazard ratios (HRs) for stroke or systemic embolism (effectiveness outcome) and major bleeding (safety outcome) were estimated. RESULTS: In propensity-matched comparisons of the risk of stroke or systemic embolism, the HRs were 1.27 (95% confidence interval [CI], 0.82-1.96) for apixaban vs. dabigatran, 1.25 (95% CI, 0.87-1.79) for apixaban vs. rivaroxaban, and 1.17 (95% CI, 0.69-1.96) for rivaroxaban vs. dabigatran. For the risk of major bleeding, the HRs were 0.94 (95% CI, 0.62-1.41) for apixaban vs. dabigatran, 0.88 (95% CI, 0.64-1.22) for apixaban vs. rivaroxaban, and 1.35 (95% CI, 0.91-2.00) for rivaroxaban vs. dabigatran. CONCLUSIONS: Among patients with NVAF in routine clinical practice, there were no statistically significant differences in risk of stroke or systemic embolism or major bleeding in propensity-matched comparisons between apixaban, dabigatran, and rivaroxaban used in standard doses. While analyses indicate that more than moderate differences can be excluded, smaller differences cannot be ruled out.


Assuntos
Antitrombinas/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Dabigatrana/uso terapêutico , Inibidores do Fator Xa/uso terapêutico , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Rivaroxabana/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antitrombinas/efeitos adversos , Fibrilação Atrial/diagnóstico , Estudos de Coortes , Dabigatrana/efeitos adversos , Embolia/induzido quimicamente , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Pirazóis/efeitos adversos , Piridonas/efeitos adversos , Sistema de Registros , Rivaroxabana/efeitos adversos , Acidente Vascular Cerebral/induzido quimicamente , Resultado do Tratamento
14.
Pharmacoepidemiol Drug Saf ; 27(8): 885-893, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29797447

RESUMO

PURPOSE: Case reports and pharmacokinetic studies have suggested that concomitant use of low-dose methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with increased risk of methotrexate toxicity. This study aimed to investigate the risk of serious adverse events associated with concomitant use of low-dose methotrexate and NSAIDs, compared with use of methotrexate alone, among patients with rheumatoid arthritis. METHODS: The study was conducted as a register-based cohort study in Denmark, 2004 to 2015, including episodes of concomitant use of methotrexate and NSAIDs (n = 21 536) and control episodes of use of methotrexate alone (n = 21 725). The primary outcome was the composite end point any serious adverse event, including liver toxicity, acute renal failure, and cytopenia. Secondary outcomes were the individual outcome components. Analyses were conducted using proportional-hazards regression, with adjustment using inverse-probability-of-treatment weighting based on propensity scores. RESULTS: During follow-up, 110 cases of the primary outcome occurred during concomitant use of methotrexate and NSAIDs (unadjusted incidence rate 12.1 per 1000 person-years) and 129 during control episodes (11.0 per 1000 person-years). Concomitant use of methotrexate and NSAIDs was associated with a significantly increased risk of any serious adverse event (weighted hazard ratio 1.40; 95% CI, 1.07-1.82). In secondary analyses, concomitant use of methotrexate and NSAIDs was associated with a significantly increased risk of acute renal failure and cytopenia. CONCLUSIONS: Concomitant use of low-dose methotrexate and NSAIDs was associated with a significantly increased risk of serious adverse events, expanding on the evidence base for current regulatory recommendations that advocate caution when low-dose methotrexate and NSAID are coprescribed.


Assuntos
Lesão Renal Aguda/epidemiologia , Anti-Inflamatórios não Esteroides/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doenças Hematológicas/epidemiologia , Metotrexato/efeitos adversos , Lesão Renal Aguda/induzido quimicamente , Adulto , Idoso , Anti-Inflamatórios não Esteroides/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Dinamarca/epidemiologia , Relação Dose-Resposta a Droga , Interações de Medicamentos , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Feminino , Doenças Hematológicas/sangue , Doenças Hematológicas/induzido quimicamente , Humanos , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Sistema de Registros/estatística & dados numéricos
15.
Drug Saf ; 41(8): 817-826, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29603109

RESUMO

INTRODUCTION: Recent observational studies have indicated that use of proton pump inhibitors may be associated with adverse renal outcomes. The objective of this study was to investigate whether the use of proton pump inhibitors increases the risk of acute kidney injury among patients with rheumatoid arthritis. METHODS: We conducted the study as a historical prospective cohort study, including patients with rheumatoid arthritis, 30-84 years of age, during 2004-2015. Among these, we identified and matched episodes of use and non-use of proton pump inhibitors (control episodes) 1:4 on the propensity score, including 24,579 episodes of use of proton pump inhibitors and 98,230 control episodes. The primary outcome was a first diagnosis of acute kidney injury and the secondary outcome was any serious renal event (acute kidney injury or chronic kidney disease). The primary time point for analysis was 120 days after study entry. RESULTS: The incidence rate of acute kidney injury was 2.2 per 1000 person-years during episodes of use of proton pump inhibitors and 0.9 during control episodes. Use of proton pump inhibitors was associated with a significantly increased risk of acute kidney injury (hazard ratio 2.30, 95% confidence interval 1.26-4.20). The absolute risk difference was 40 (95% confidence interval 8-99) events of acute kidney injury per 100,000 episodes of use of proton pump inhibitors. Use of proton pump inhibitors was also associated with a significantly increased risk of the secondary outcome of any serious renal event (hazard ratio 2.61, 95% confidence interval 1.80-3.80). CONCLUSIONS: This cohort study among patients with rheumatoid arthritis found a significantly increased risk of acute kidney injury associated with the use of proton pump inhibitors. These findings may help inform clinical decision making when considering the risks and benefits of proton pump inhibitor treatment in rheumatoid arthritis.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/diagnóstico , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Inibidores da Bomba de Prótons/efeitos adversos , Lesão Renal Aguda/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/epidemiologia , Estudos de Coortes , Dinamarca/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores da Bomba de Prótons/uso terapêutico , Sistema de Registros
16.
BMJ ; 360: k678, 2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29519881

RESUMO

OBJECTIVE: To investigate whether oral fluoroquinolone use is associated with an increased risk of aortic aneurysm or dissection. DESIGN: Nationwide historical cohort study using linked register data on patient characteristics, filled prescriptions, and cases of aortic aneurysm or dissection. SETTING: Sweden, July 2006 to December 2013. PARTICIPANTS: 360 088 treatment episodes of fluoroquinolone use (78%ciprofloxacin) and propensity score matched comparator episodes of amoxicillin use (n=360 088). MAIN OUTCOME MEASURES: Cox regression was used to estimate hazard ratios for a first diagnosis of aortic aneurysm or dissection, defined as admission to hospital or emergency department for, or death due to, aortic aneurysm or dissection, within 60 days from start of treatment. RESULTS: Within the 60 day risk period, the rate of aortic aneurysm or dissection was 1.2 cases per 1000 person years among fluoroquinolone users and 0.7 cases per 1000 person years among amoxicillin users. Fluoroquinolone use was associated with an increased risk of aortic aneurysm or dissection (hazard ratio 1.66 (95% confidence interval 1.12 to 2.46)), with an estimated absolute difference of 82 (95% confidence interval 15 to 181) cases of aortic aneurysm or dissection by 60 days per 1 million treatment episodes. In a secondary analysis, the hazard ratio for the association with fluoroquinolone use was 1.90 (1.22 to 2.96) for aortic aneurysm and 0.93 (0.38 to 2.29) for aortic dissection. CONCLUSIONS: In a propensity score matched cohort, fluoroquinolone use was associated with an increased risk of aortic aneurysm or dissection. This association appeared to be largely driven by aortic aneurysm.


Assuntos
Aneurisma Dissecante/epidemiologia , Aneurisma Aórtico/epidemiologia , Fluoroquinolonas/uso terapêutico , Administração Oral , Idoso , Amoxicilina/uso terapêutico , Antibacterianos/uso terapêutico , Causas de Morte , Estudos de Coortes , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco/métodos , Fatores de Risco , Estatística como Assunto , Suécia/epidemiologia , Fatores de Tempo
17.
Am J Epidemiol ; 187(4): 777-785, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29155931

RESUMO

Recent studies have raised concern that macrolide antibiotics may be associated with an increased long-term risk of cardiovascular death. We examined the 1-year risk associated with treatment with clarithromycin (n = 187,887) or roxithromycin (n = 698,899) compared with penicillin V (n = 3,473,081), matched 1:4 on propensity score, in a nationwide, registry-based cohort study in Danish outpatients, 1997-2011. Among clarithromycin courses, the rate ratio for cardiovascular death was 1.24 (95% confidence interval (CI): 0.96, 1.59). Among roxithromycin courses, the rate ratio was 0.99 (95% CI: 0.86, 1.16). In analyses by time after treatment start, the rate ratio associated with clarithromycin was 1.66 (95% CI: 0.98, 2.79) during days 0-7. This was attenuated in later time periods (days 8-89, rate ratio = 1.30, 95% CI: 0.88, 1.94; and days 90-364, rate ratio = 0.96, 95% CI: 0.63, 1.47). For roxithromycin, the rate ratios were 0.88 (95% CI: 0.59, 1.32) during days 0-7, 1.17 (95% CI: 0.92, 1.48) during days 8-89, and 0.88 (95% CI: 0.70, 1.10) during days 90-364. We found no increased risk of cardiovascular death in a general outpatient population. With clarithromycin, we observed a transient increased risk during days 0-7 after treatment start, which corresponds to the period of active treatment. This association was absent in later time periods, which is consistent with no long-term toxicity resulting in cardiovascular death.


Assuntos
Antibacterianos/efeitos adversos , Doenças Cardiovasculares/mortalidade , Claritromicina/efeitos adversos , Roxitromicina/efeitos adversos , Fatores Etários , Idoso , Estudos de Coortes , Dinamarca/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Penicilinas/administração & dosagem , Pontuação de Propensão , Estudos Retrospectivos , Fatores Sexuais , Fatores de Tempo
18.
BMJ ; 357: j2563, 2017 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-28615173

RESUMO

Objective To estimate the risks of major congenital malformations in the offspring of mothers who are underweight (body mass index (BMI) <18.5), overweight (BMI 25 to <30), or in obesity classes I (BMI 30 to <35), II (35 to <40), or III (≥40) compared with offspring of normal weight mothers (BMI 18.5 to <25) in early pregnancy.Design Population based cohort study.Setting Nationwide Swedish registries.Participants 1 243 957 liveborn singleton infants from 2001 to 2014 in Sweden. Data on maternal and pregnancy characteristics were obtained by individual record linkages.Exposure Maternal BMI at the first prenatal visit.Main outcome measures Offspring with any major congenital malformation, and subgroups of organ specific malformations diagnosed during the first year of life. Risk ratios were estimated using generalised linear models adjusted for maternal factors, sex of offspring, and birth year.Results A total of 43 550 (3.5%) offspring had any major congenital malformation, and the most common subgroup was for congenital heart defects (n=20 074; 1.6%). Compared with offspring of normal weight mothers (risk of malformations 3.4%), the proportions and adjusted risk ratios of any major congenital malformation among the offspring of mothers with higher BMI were: overweight, 3.5% and 1.05 (95% confidence interval 1.02 to 1.07); obesity class I, 3.8% and 1.12 (1.08 to 1.15), obesity class II, 4.2% and 1.23 (1.17 to 1.30), and obesity class III, 4.7% and 1.37 (1.26 to 1.49). The risks of congenital heart defects, malformations of the nervous system, and limb defects also progressively increased with BMI from overweight to obesity class III. The largest organ specific relative risks related to maternal overweight and increasing obesity were observed for malformations of the nervous system. Malformations of the genital and digestive systems were also increased in offspring of obese mothers.Conclusions Risks of any major congenital malformation and several subgroups of organ specific malformations progressively increased with maternal overweight and increasing severity of obesity. For women who are planning pregnancy, efforts should be encouraged to reduce adiposity in those with a BMI above the normal range.


Assuntos
Anormalidades Congênitas/epidemiologia , Mães , Sobrepeso/epidemiologia , Complicações na Gravidez/epidemiologia , Magreza/epidemiologia , Adulto , Índice de Massa Corporal , Estudos de Coortes , Anormalidades Congênitas/etiologia , Feminino , Humanos , Lactente , Recém-Nascido , Razão de Chances , Sobrepeso/complicações , Sobrepeso/fisiopatologia , Gravidez , Complicações na Gravidez/etiologia , Complicações na Gravidez/fisiopatologia , Vigilância de Evento Sentinela , Suécia/epidemiologia , Magreza/complicações , Magreza/fisiopatologia
19.
BMJ ; 356: j629, 2017 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-28246106

RESUMO

Objective To evaluate the possible effects of exposure to neuraminidase inhibitors during embryo-fetal life with respect to adverse neonatal outcomes and congenital malformations.Design Population based multinational observational cohort study and meta-analysis.Setting National registers covering information on maternal healthcare, births, and prescriptions in Denmark, Norway, and Sweden and the EFEMERIS database from the Haute-Garonne district in France.Participants All women together with their singleton infants born between 1 January 2008 and 31 December 2010. Only infants born at 154 days of gestation or later were included. Infants were defined as exposed if the women filled a prescription during pregnancy for either of the two neuraminidase inhibitors oseltamivir or zanamivir.Main outcomes Low birth weight, low Apgar score, preterm birth, small for gestational age birth, stillbirth, neonatal mortality, neonatal morbidity, and congenital malformations. Crude and adjusted hazard ratios of preterm birth were estimated using Cox regression models. Crude and adjusted odds ratios for other outcomes were estimated by logistic regression models.Results The study included 5824 (0.8%) exposed women and their infants and 692 232 who were not exposed. Exposure to neuraminidase inhibitors in utero was not associated with increased risks of any of the investigated neonatal outcomes, including low birth weight (adjusted odds ratio 0.77, 95% confidence interval 0.65 to 0.91), low Apgar score (adjusted odds ratio 0.87, 0.67 to 1.14), preterm birth (adjusted hazard ratio 0.97, 0.86 to 1.10), small for gestational age birth (adjusted odds ratio 0.72, 0.59 to 0.87), stillbirth (adjusted odds ratio 0.81, 0.51 to 1.30), neonatal mortality (adjusted odds ratio 1.13, 0.56 to 2.28), and neonatal morbidity (adjusted odds ratio 0.92, 0.86 to 1.00). No increased risk of congenital malformations overall associated with maternal exposure was observed during the first trimester (adjusted odds ratio 1.06, 0.77 to 1.48). Similarly, no significantly increased risks of any of the outcomes were observed in an analysis restricted to oseltamivir alone.Conclusions This large multinational register study found no increased risks of adverse neonatal outcomes or congenital malformations associated with exposure to neuraminidase inhibitors during embryo-fetal life. The results support previously reported findings that the use of neuraminidase inhibitors is not associated with increased risks of adverse fetal or neonatal outcomes.


Assuntos
Anormalidades Induzidas por Medicamentos/epidemiologia , Inibidores Enzimáticos/efeitos adversos , Neuraminidase/antagonistas & inibidores , Resultado da Gravidez/epidemiologia , Adolescente , Adulto , Estudos de Coortes , Comorbidade , Europa (Continente)/epidemiologia , Feminino , Humanos , Recém-Nascido , Masculino , Metanálise como Assunto , Gravidez , Sistema de Registros , Fatores de Risco , Fumar/epidemiologia , Adulto Jovem
20.
N Engl J Med ; 376(13): 1223-1233, 2017 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-28355499

RESUMO

BACKGROUND: The quadrivalent human papillomavirus (HPV) vaccine is recommended for all girls and women 9 to 26 years of age. Some women will have inadvertent exposure to vaccination during early pregnancy, but few data exist regarding the safety of the quadrivalent HPV vaccine in this context. METHODS: We assessed a cohort that included all the women in Denmark who had a pregnancy ending between October 1, 2006, and November 30, 2013. Using nationwide registers, we linked information on vaccination, adverse pregnancy outcomes, and potential confounders among women in the cohort. Women who had vaccine exposure during the prespecified time windows were matched for propensity score in a 1:4 ratio with women who did not have vaccine exposure during the same time windows. Outcomes included spontaneous abortion, stillbirth, major birth defect, small size for gestational age, low birth weight, and preterm birth. RESULTS: In matched analyses, exposure to the quadrivalent HPV vaccine was not associated with significantly higher risks than no exposure for major birth defect (65 cases among 1665 exposed pregnancies and 220 cases among 6660 unexposed pregnancies; prevalence odds ratio, 1.19; 95% confidence interval [CI], 0.90 to 1.58), spontaneous abortion (20 cases among 463 exposed pregnancies and 131 cases among 1852 unexposed pregnancies; hazard ratio, 0.71; 95% CI, 0.45 to 1.14), preterm birth (116 cases among 1774 exposed pregnancies and 407 cases among 7096 unexposed pregnancies; prevalence odds ratio, 1.15; 95% CI, 0.93 to 1.42), low birth weight (76 cases among 1768 exposed pregnancies and 277 cases among 7072 unexposed pregnancies; prevalence odds ratio, 1.10; 95% CI, 0.85 to 1.43), small size for gestational age (171 cases among 1768 exposed pregnancies and 783 cases among 7072 unexposed pregnancies; prevalence odds ratio, 0.86; 95% CI, 0.72 to 1.02), or stillbirth (2 cases among 501 exposed pregnancies and 4 cases among 2004 unexposed pregnancies; hazard ratio, 2.43; 95% CI, 0.45 to 13.21). CONCLUSIONS: Quadrivalent HPV vaccination during pregnancy was not associated with a significantly higher risk of adverse pregnancy outcomes than no such exposure. (Funded by the Novo Nordisk Foundation and the Danish Medical Research Council.).


Assuntos
Vacina Quadrivalente Recombinante contra HPV tipos 6, 11, 16, 18/efeitos adversos , Resultado da Gravidez , Vacinação , Aborto Espontâneo/epidemiologia , Adulto , Estudos de Coortes , Anormalidades Congênitas/epidemiologia , Dinamarca/epidemiologia , Feminino , Humanos , Recém-Nascido de Baixo Peso , Gravidez , Nascimento Prematuro/epidemiologia , Natimorto/epidemiologia , Adulto Jovem
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