| 1. |
- Svanström, Henrik, et al.
(författare)
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Use of liraglutide and risk of major cardiovascular events: a register-based cohort study in Denmark and Sweden.
- 2019
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Ingår i: The lancet. Diabetes & endocrinology. - 2213-8595. ; 7:2, s. 106-114
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Tidskriftsartikel (refereegranskat)abstract
- 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.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.The study population consisted of 23402 users of liraglutide and 23402 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).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.Swedish Heart-Lung Foundation, Novo Nordisk Foundation, and Swedish Society for Medical Research.
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| 2. |
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| 3. |
- Ueda, Peter, et al.
(författare)
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Use of DPP4 Inhibitors and GLP-1 Receptor Agonists and Risk of Intestinal Obstruction: Scandinavian Cohort Study
- 2023
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Ingår i: Clinical Gastroenterology and Hepatology. - 1542-3565 .- 1542-7714.
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Concerns have been raised that the incretin-based diabetes drugs dipeptidyl peptidase 4 (DPP4) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists may increase the risk of intestinal obstruction. We aimed to assess the association between use of DPP4 inhibitors and GLP-1 receptor agonists and the risk of intestinal obstruction. Methods: Using data from nationwide registers in Sweden, Denmark, and Norway, 2013–2021, we conducted 2 cohort studies, one for DPP4 inhibitors and one for GLP-1 receptor agonists, to investigate the risk of intestinal obstruction as compared with an active comparator drug class (sodium-glucose co-transporter 2 [SGLT2] inhibitors). Results: Among 19,0321 new users of DPP4 inhibitors (median (interquartile range [IQR]) follow-up time, 1.3 [0.6–2.6] years) and 139,315 new users of SGLT2 inhibitors (median [IQR] follow-up time, 0.8 [0.4–1.7] years), 919 intestinal obstruction events occurred. Use of DPP4 inhibitors, as compared with SGLT2 inhibitors, was not associated with a statistically significant increase in risk of intestinal obstruction (adjusted incidence rate, 2.0 vs 1.8 per 1000 person-years; hazard ratio, 1.13; 95% confidence interval, 0.96–1.34). Among 121,254 new users of GLP-1 receptor agonists (median [standard deviation] follow-up time, 0.9 [0.4–1.9] years) and 185,027 new users of SGLT2 inhibitors (median [IQR] follow-up time, 0.8 [0.4–1.8] years), 557 intestinal obstruction events occurred. Use of GLP-1 receptor agonists was not associated with a statistically significant increase in risk of intestinal obstruction (adjusted incidence rate, 1.3 vs 1.6 per 1000 person-years; hazard ratio, 0.83; 95% confidence interval, 0.69–1.01). Conclusions: In this analysis of nationwide data from 3 countries, previous safety signals indicating an increased risk of intestinal obstruction with use of DPP4 inhibitors and GLP-1 receptor agonists were not confirmed.
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| 4. |
- Eliasson, Pernilla, et al.
(författare)
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Unloaded rat Achilles tendons continue to grow, but lose viscoelasticity
- 2007
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Ingår i: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 103:2, s. 459-463
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Tidskriftsartikel (refereegranskat)abstract
- Tendons can function as springs and thereby preserve energy during cyclic loading. They might also have damping properties, which, hypothetically, could reduce risk of microinjuries due to fatigue at sites of local stress concentration within the tendon. At mechanical testing, damping will appear as hysteresis. How is damping influenced by training or disuse? Does training decrease hysteresis, thereby making the tendon a better spring, or increase hysteresis and thus improve damping? Seventy-eight female 10-wk-old Sprague-Dawley rats were randomized to three groups. Two groups had botulinum toxin injected into the calf muscles to unload the left Achilles tendon through muscle paralysis. One of these groups was given doxycycline, as a systemic matrix metalloproteinase inhibitor. The third group served as loaded controls. The Achilles tendons were harvested after 1 or 6 wk for biomechanical testing. An increase with time was seen in tendon dry weight, wet weight, water content, transverse area, length, stiffness, force at failure, and energy uptake in all three groups (P < 0.001 for each parameter). Disuse had no effect on these parameters. Creep was decreased with time in all groups. The only significant effect of disuse was on hysteresis (P = 0.004) and creep (P = 0.007), which both decreased with disuse compared with control, and on modulus, which was increased (P = 0.008). Normalized glycosaminoglycan content was unaffected by time and disuse. No effect of doxycycline was observed. The results suggest that in growing animals, the tendons continue to grow regardless of mechanical loading history, whereas maintenance of damping properties requires mechanical stimulation.
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| 5. |
- Engstrom, Arvid, et al.
(författare)
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Association of glucagon-like peptide-1 receptor agonists with serious liver events among patients with type 2 diabetes: A Scandinavian cohort study
- 2023
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Ingår i: HEPATOLOGY. - 0270-9139 .- 1527-3350. ; 79:6, s. 1401-1411
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims:Clinical trials suggest that glucagon-like peptide-1 (GLP-1) receptor agonists may have beneficial effects on NAFLD, but the impact on hard hepatic end points is unknown. We assessed the association between the use of GLP-1 receptor agonists and the risk of serious liver events in routine clinical practice. Approach and Results:Cohort study using data from nationwide registers in Sweden, Denmark, and Norway, 2007-2020, including 91,479 initiators of GLP-1 receptor agonists and 244,004 initiators of the active comparator, dipeptidyl peptidase-4 inhibitors, without a history of chronic liver disease other than NAFLD/NASH. The primary outcome was serious liver events: a composite of incident compensated and decompensated cirrhosis and HCC. Secondary outcomes were the individual components of the primary outcome. Cox regression was used to estimate HRs, using propensity score weighting to control for confounding. Users of GLP-1 receptor agonists had 608 serious liver events (adjusted incidence rate: 16.9 events per 10,000 person-years), compared with 1770 events among users of dipeptidyl peptidase-4 inhibitors (19.2 events per 10,000 person-years). The adjusted HR was 0.85 (95% CI: 0.75 to 0.97), and the rate difference was -2.1 (-4.4 to 0.1) events per 10,000 person-years. In secondary outcome analyses, the adjusted HR was 0.85 (0.75 to 0.97) for compensated and decompensated cirrhosis and 1.05 (0.80 to 1.39) for HCC. Conclusions:The use of GLP-1 receptor agonists was associated with a significantly reduced risk of serious liver events, driven by a reduction of compensated and decompensated cirrhosis.
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| 6. |
- Engstrom, Arvid, et al.
(författare)
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Comparative cardiovascular and renal effectiveness of empagliflozin and dapagliflozin: Scandinavian cohort study
- 2024
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Ingår i: EUROPEAN HEART JOURNAL-CARDIOVASCULAR PHARMACOTHERAPY. - 2055-6837 .- 2055-6845. ; 10:5, s. 432-443
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Tidskriftsartikel (refereegranskat)abstract
- Aims To assess the comparative cardiovascular and renal effectiveness and safety of empagliflozin vs. dapagliflozin among patients with type 2 diabetes in routine clinical practice.Methods and results Cohort study using data from nationwide registers in Sweden, Denmark, and Norway, from June 2014 to June 2021 included 141 065 new users of empagliflozin and 58 306 new users of dapagliflozin. Coprimary outcomes were major cardiovascular events (myocardial infarction, stroke, and cardiovascular death), heart failure (hospitalization or death because of heart failure) and serious renal events (renal replacement therapy, hospitalization for renal events, and death from renal causes). Secondary outcomes were the individual components of the primary outcomes, any cause death, and diabetic ketoacidosis. Use of empagliflozin vs. dapagliflozin was associated with similar risk of major cardiovascular events [adjusted incidence rate: 15.9 vs. 15.8 events per 1000 person-years; HR 1.02, (95% confidence interval 0.97-1.08)], heart failure [6.5 vs. 6.3 events per 1000 person-years; HR 1.05 (0.97-1.14)] and serious renal events [3.7 vs. 4.1 events per 1000 person-years; HR 0.97 (0.87-1.07)]. In secondary outcome analyses, the HRs for use of empagliflozin vs. dapagliflozin were 1.00 (0.93-1.07) for myocardial infarction, 1.03 (0.95-1.12) for stroke, 1.01 (0.92-1.13) for cardiovascular death, 1.06 (1.00-1.11) for any cause death, 0.77 (0.60-0.99) for renal replacement therapy, 1.20 (0.75-1.93) for renal death, 1.01 (0.90-1.12) for hospitalization for renal events and 1.12 (0.94-1.33) for diabetic ketoacidosis.Conclusion Use of empagliflozin and dapagliflozin was associated with similar risk of cardiovascular and renal outcomes, mortality, and diabetic ketoacidosis.
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| 7. |
- Engstrom, A., et al.
(författare)
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Sodium-Glucose Cotransporter 2 Inhibitor Treatment and Risk of Atrial Fibrillation: Scandinavian Cohort Study
- 2023
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 46:2, s. 351-360
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE To assess the association between use of sodium-glucose cotransporter 2 (SGLT2) inhibitors and the risk of new-onset atrial fibrillation (AF) in routine clinical practice. RESEARCH DESIGN AND METHODS We used nationwide registers in Denmark, Norway, and Sweden from 2013 to 2018 in order to include patients without a history of AF who were newly prescribed an SGLT2 inhibitor or an active comparator (glucagon-like peptide 1 [GLP-1] receptor agonist). We performed a cohort study to assess new-onset AF in intention-to-treat analyses using Cox regression, adjusted for baseline covariates with propensity score weighting. RESULTS We identified 79,343 new users of SGLT2 inhibitors (59.2% dapagliflozin, 40.0% empagliflozin, 0.8% canagliflozin, <0.1% ertugliflozin) and 57,613 new users of GLP-1 receptor agonists. Mean age of the study cohort was 61 years and 60% were men. The adjusted incidence rate of new-onset AF was 8.6 per 1,000 person-years for new users of SGLT2 inhibitors compared with 10.0 per 1,000 person-years for new users of GLP-1 receptor agonists. The adjusted hazard ratio (aHR) was 0.89 (95% CI 0.81-0.96), and the rate difference was 1.4 fewer events per 1,000 person-years (95% CI 0.6-2.1). Using an as-treated exposure definition, the aHR for new-onset AF was 0.87 (95% CI 0.76-0.99). No statistically significant heterogeneity of the aHRs was observed between subgroups of patients with and without a history of heart failure or major cardiovascular disease. CONCLUSIONS In this cohort study using nationwide data from three countries, use of SGLT2 inhibitors, compared with GLP-1 receptor agonists, was associated with a modestly reduced risk of new-onset AF.
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| 8. |
- Inghammar, Malin, et al.
(författare)
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Long-Term Risk of Cardiovascular Death with Use of Clarithromycin and Roxithromycin : A Nationwide Cohort Study
- 2018
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Ingår i: American Journal of Epidemiology. - : Oxford University Press (OUP). - 0002-9262 .- 1476-6256. ; 187:4, s. 777-785
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Forskningsöversikt (refereegranskat)abstract
- 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.
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| 9. |
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| 10. |
- Inghammar, Malin, et al.
(författare)
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Proton-Pump Inhibitor Use and the Risk of Community-Associated Clostridium difficile Infection
- 2021
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Ingår i: Clinical Infectious Diseases. - : Oxford University Press (OUP). - 1058-4838 .- 1537-6591. ; 72:12, s. 1084-1089
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Tidskriftsartikel (refereegranskat)abstract
- Background: Proton-pump inhibitors (PPIs) have been reported to increase the risk of community-associated Clostridium difficile infection (CDI), but the association remains disputed. Methods: A nationwide cohort study among adults in Denmark, 2010-2013, linking register data on C. difficile testing, filled prescriptions, and patient characteristics. All incident episodes of community-associated CDI (ie, positive culture, molecular assay, or toxin test in individuals without previous hospitalization in the prior 12 weeks and without a positive test for C. difficile in the prior 8 weeks) were identified in the Danish National Microbiological Database. Self-controlled case-series analyses were used to estimate incidence rate ratios (IRRs) for community-associated CDI, comparing periods with and without exposure to PPIs. By design, models took fixed confounders such as chronic disease, genetics, and socioeconomic status into account; further, time-varying confounders, including hospital stay and antibiotic and corticosteroid use were adjusted for. Results: 3583 episodes of community-associated CDI were identified, of which 964 occurred during current use of PPIs, 324 occurred 0-6 months after treatment cessation, 123 occurred 6-12 months after treatment cessation, and 2172 occurred during time periods without use of PPIs. The adjusted IRR was 2.03 (95% confidence interval, 1.74-2.36), comparing use of PPI with nonuse. The increased risk remained elevated in later time periods: 1.54 (1.31-1.80) for 0-6 months, 1.24 (1.00-1.53) for 6-12 months after current use. Conclusions: Use of PPIs was associated with moderately increased risk of community-associated CDI. The risk remained elevated up to 1 year after PPI treatment had ended.
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| 11. |
- Kader, Manzur, et al.
(författare)
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Depression and anxiety-related disorders and suicide among Swedish male elite football players : a nationwide cohort study.
- 2024
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Ingår i: British Journal of Sports Medicine. - : BMJ Publishing Group Ltd. - 0306-3674 .- 1473-0480. ; 58:2, s. 66-72
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To assess whether male elite football players, during and after their active career, were at increased risk of depression and anxiety-related disorders and suicide, as compared with the general male population.METHODS: We included male football players active in the Swedish top division 1924-2019 and general male population (matched to football players based on age and region of residence) aged <65 years in 1997. Using nationwide registers, we followed the football players from their first season in the top division (or the date of their first registered residency in Sweden) or 1 January 1997, and compared the risk of depression and anxiety-related disorders (captured through diagnoses from hospital admissions and outpatient visits, and use of prescription drugs) among football players versus controls. In a secondary analysis using data from death certificates, we compared the risk of suicide between football players and general population males who were alive in 1969 (when cause of death became available) .RESULTS: During follow-up through 31 December 2020, 504 (13.6%) of 3719 football players and 7455 (22.3%) of 33 425 general population males had a depression or anxiety-related disorder. In analyses accounting for age, region of residence and calendar time, the risk of anxiety and depression-related disorders was lower among football players versus general population males (HR 0.61, 95% CI 0.55 to 0.66). The protective association was attenuated with increasing age, and from around age 70 years the risk was similar in the two groups. The risk of suicide was lower among football players versus general population males (HR 0.48, 95% CI 0.32 to 0.72).CONCLUSIONS: In this nationwide cohort study in Sweden, elite male football players had a lower risk of depression and anxiety-related disorders and suicide as compared with the general population.
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| 12. |
- Ludvigsson, Jonas F., 1969-, et al.
(författare)
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Maternal Glycemic Control in Type 1 Diabetes and the Risk for Preterm Birth : A Population-Based Cohort Study
- 2019
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Ingår i: Annals of Internal Medicine. - : American College of Physicians. - 0003-4819 .- 1539-3704. ; 170:10, s. 691-701
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Tidskriftsartikel (refereegranskat)abstract
- 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 A(1c) [HbA(1c)]) levels is unclear.Objective: To examine preterm birth risk according to periconceptional HbA(1c) 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 HbA(1c) 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 HbA(1c) 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 HbA(1c) 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 HbA(1c) levels. Women with HbA(1c) levels consistent with recommended target levels also were at increased risk. Primary Funding Source: Swedish Diabetes Foundation.
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| 13. |
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| 14. |
- Pasternak, Björn, et al.
(författare)
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Doxycycline-coated sutures improve mechanical strength of intestinal anastomoses.
- 2008
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Ingår i: International journal of colorectal disease. - : Springer Science and Business Media LLC. - 0179-1958 .- 1432-1262. ; 23:3, s. 271-6
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Forskningsöversikt (refereegranskat)abstract
- BACKGROUND AND AIMS: After resection and repair of the intestines, tissue degradation leads to weakening of the repair site and risk of postoperative leakage. Matrix metalloproteinases (MMPs) are thought to be responsible for collagenolysis in the direct vicinity of surgical sutures in many tissues. Several experimental studies show that MMP inhibitors administered systemically alleviate postoperative weakening of intestinal anastomoses. We hypothesised that local delivery of MMP inhibitors would achieve a similar effect. MATERIALS AND METHODS: Implementing a novel method for the coating of biomaterials, we coated sutures with a cross-linked fibrinogen film and bound the MMP inhibitor doxycycline into this film. The sutures were then used in a standard rat model for evaluating mechanical properties of colonic anastomoses 3 days after surgery. RESULTS: The breaking strength of the anastomoses on the critical third day after operation was 17% higher with doxycycline-coated sutures compared to controls (P = 0.026). Energy uptake at failure was enhanced by 20% (P = 0.047). CONCLUSION: Drug delivery by means of MMP-inhibitor-coated sutures appears to improve tissue integrity during anastomotic repair and may reduce postoperative complications.
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| 15. |
- Pasternak, Björn, et al.
(författare)
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Doxycycline-coated sutures improve the suture-holding capacity of the rat Achilles tendon.
- 2007
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Ingår i: Acta orthopaedica. - : Medical Journals Sweden AB. - 1745-3674 .- 1745-3682. ; 78:5, s. 680-6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There is evidence of high matrix metalloproteinase (MMP) activity around sutures inserted into tendons. This probably results in tissue breakdown, allowing the suture to cut through the tendon, and thus contributes to repair-site elongation and gap formation. We therefore hypothesized that treatment with the MMP inhibitor doxycycline would improve the sutureholding capacity of tendon. ANIMALS, METHODS AND RESULTS: In the first sub-study, rats received a suture in the Achilles tendon. One group was treated with systemic doxycycline and the other received no treatment. At 3, 5, and 7 days, suture-holding capacity was measured mechanically. The pull-out force and energy were reduced in all tendons, at 3 days compared to freshly inserted sutures, but no further reduction was detected at later time points. Doxycycline- treated tendons showed improved suture-holding capacity as measured by higher energy uptake than in untreated tendons. Force at failure showed a trend towards improvement. The effect was most evident on day 3. In the second sub-study, sutures were coated with doxycycline. At 3 days, local doxycycline treatment caused improved suture-holding capacity -- as measured by higher force at failure and higher energy uptake. INTERPRETATION: We provide proof of a novel treatment principle. MMP inhibitor-coated sutures improve suture-holding capacity during early repair of collagenous tissues.
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| 16. |
- Pasternak, Björn, et al.
(författare)
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Doxycycline impairs tendon repair in rats
- 2006
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Ingår i: Acta Orthopaedica Belgica. - Bruxelles : Acta Medica Belgica. - 0001-6462. ; 72:6, s. 756-760
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Tidskriftsartikel (refereegranskat)abstract
- Doxycycline exhibits various effects apart from its antimicrobial activity, such as inhibition of matrix metalloproteinases (MMPs). MMPs, mainly collagenases and gelatinases, are capable of degrading virtually all constituents of the extracellular matrix and are critical to connective tissue remodelling and healing. We therefore hypothesised that doxycycline would negatively influence the rat tendon healing process and impede tendon regeneration. The Achilles tendon of 60 Sprague Dawley rats was transected transversely. The animals were treated with doxycycline, 130 mg/kg body weight/day. The healing tendons were evaluated mechanically at 5, 8 and 14 days. Doxycycline significantly decreased force at failure (p < 0.005) and energy uptake (p < 0.001). Doxycycline serum concentration was 3.4 (SD 1.0) µg/ml. In conclusion, tendon healing can be affected by doxycycline at clinically relevant serum concentrations. This observation might be of relevance to further studies exploring effects of MMP-inhibitors on tendon tissue.
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| 17. |
- Pasternak, Björn, et al.
(författare)
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Elevated intraperitoneal matrix metalloproteinases-8 and -9 in patients who develop anastomotic leakage after rectal cancer surgery: a pilot study
- 2010
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Ingår i: Colorectal Disease. - Chichester, West Sussex, United Kingdom : Wiley-Blackwell. - 1462-8910 .- 1463-1318. ; 12:7, s. e93-e98
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Tidskriftsartikel (refereegranskat)abstract
- Objective Experimental studies suggest that matrix metalloproteinase (MMP) enzymes mediate the early tissue breakdown that leads to a decrease in intestinal anastomotic strength. Patients with upregulation of MMPs in intestinal biopsies have an increased rate of anastomotic leakage. We measured MMPs and their inhibitors [tissue inhibitors of metalloproteinases (TIMPs)] in postoperative intraperitoneal fluid after rectal cancer surgery, and hypothesized that they would be elevated in patients who later would develop anastomotic leakage.Method Twenty-nine patients with rectal carcinoma underwent low anterior resection of the rectum for cancer. Intraperitoneal fluid was collected via a pelvic drain at a median of 4 h postoperatively. MMP-1, -2, -3, -7, -8, -9 and -13 were determined using particle-based multiplex flow-cytometry. TIMP-1 and -2 were measured by enzyme-linked immunosorbent assays. MMP-9 was considered the main outcome variable.Results Ten patients developed anastomotic leakage. These patients had increased intraperitoneal MMP-9 [median difference (m.d.) 29%; P = 0.03] and MMP-8 (m.d. 58%; P = 0.02), compared with patients who did not develop leakage. There were no differences between the groups for other MMPs and TIMPs.Conclusion Matrix metalloproteinase-8 and -9 appear to have an important role in the development of anastomotic leakage and may be promising pharmacological targets to protect anastomotic integrity. We suggest further investigation of MMPs as markers for anastomotic leakage.
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| 18. |
- Pasternak, Björn, et al.
(författare)
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Elevation of systemic matrix metalloproteinase-2 and -7 and tissue inhibitor of metalloproteinases-2 in patients with a history of Achilles tendon rupture
- 2010
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Ingår i: British Journal of Sports Medicine. - : BMJ. - 0306-3674 .- 1473-0480. ; 38, s. 308-317
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To compare serum levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) between patients with a history of Achilles tendon rupture and blood donor controls, and to relate MMPs and TIMPs to mechanical properties of the tendons during healing. Methods: More than three years after injury, we measured serum levels of MMP-1, -2, -3, -7, -8, -9 and -13 and TIMP-1 and -2 in eight patients who had suffered Achilles tendon rupture. Twelve blood donors served as controls. During the early phase of healing, the tendon modulus of elasticity was calculated from radiostereometric data and tendon cross-sectional area. Results: Patients with a history of Achilles tendon rupture had increased levels of MMP-2 (median difference (m.d.) 10 %; p = 0.01), MMP-7 (m.d. 15 %; p = 0.02) and TIMP-2 (m.d. 36%; p = 0.02), as compared to controls. Levels of MMP-7, measured three years after injury, correlated inversely to tendon modulus of elasticity (rs = -0.83; p = 0.02), and positively to tendon elongation (rs = 0.74; p = 0.05) during the early phase of healing. There was a trend towards positive correlation between MMP-7 and cross-sectional area during the early phase of healing (rs = 0.67; p = 0.08). Conclusions: Patients with a history of Achilles tendon rupture appear to have elevated levels of MMP-2, MMP-7 and TIMP-2 in serum. These pilot data support the view that the MMP-TIMP system is involved in tendinopathy and suggest that disturbances in proteolytic control might be generalised.
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| 19. |
- Pasternak, Björn, et al.
(författare)
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Fluoroquinolone use and risk of aortic aneurysm and dissection : Nationwide cohort study
- 2018
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Ingår i: BMJ (Online). - : BMJ. - 0959-8138 .- 1756-1833. ; 360
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 20. |
- Pasternak, Björn, et al.
(författare)
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Metalloproteinases and their inhibitors-diagnostic and therapeutic opportunities in orthopedics.
- 2009
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Ingår i: Acta Orthopaedica. - London, UK : Informa Healthcare. - 1745-3674 .- 1745-3682. ; 80:6, s. 693-703
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Forskningsöversikt (refereegranskat)abstract
- Matrix metalloproteinases (MMPs) and related enzymes (ADAMs, ADAMTS) and their inhibitors control matrix turnover and function. Recent advances in our understanding of musculoskeletal conditions such as tendinopathy, arthritis, Dupuytren's disease, degenerative disc disease, and bone and soft tissue healing suggest that MMPs have prominant roles. Importantly, MMPs are amenable to inhibition by cheap, safe, and widely available drugs such as the tetracycline antibiotics and the bisphosphonates. This indicates that these MMP inhibitors, if proven effective for any novel indication, may be quickly brought into clinical practice.
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| 21. |
- Pasternak, Björn, 1980-
(författare)
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Towards surgical use of matrix metalloproteinase biology
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Matrix metalloproteinases (MMPs), such as collagenases, are a family of enzymes capable of degrading most constituents of the extracellular matrix. MMPs are thought to be involved in the aetiopathogenesis of tendon rupture. Additionally, failure of healing has in some instances been associated with elevated levels of MMPs. We have studied (a) the effects of the MMP-inhibitor doxycycline on healing of tendons and intestines in experimental models and (b) systemic levels of MMPs and their endogenous inhibitors (TIMPs) in patients with tendon rupture.In the first study, systemic doxycycline treatment lead to weakened rat Achilles tendons during healing after injury.Subsequently, systemic doxycycline was shown to improve biomechanical properties of tendon suture fixation in the rat Achilles tendon. Sutures were also coated with doxycycline, leading to similar improvement in mechanical strength of the suture construct during healing.In the third study, doxycycline-coated sutures improved the strength of healing intestinal anastomoses in an experimental model.Finally, we showed that patients with a history of Achilles tendon rupture had elevated levels of MMP-2, MMP-7 and TIMP-2 in serum. In addition, MMP-7 correlated inversely to mechanical strength of the tendon during healing.In conclusion, MMP-inhibitors can be administered systemically and locally to manipulate healing of tendons and intestines. Generalised alterations in the MMP-TIMP system may be involved in the pathogenesis of Achilles tendon rupture and associated with differences in outcome of healing.
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| 22. |
- Pasternak, B., et al.
(författare)
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Use of Glucagon-Like Peptide 1 Receptor Agonists and Risk of Serious Renal Events: Scandinavian Cohort Study
- 2020
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Ingår i: Diabetes care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 43:6, s. 1326-1335
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE To assess the association between use of glucagon-like peptide 1 (GLP-1) receptor agonists and risk of serious renal events in routine clinical practice. RESEARCH DESIGN AND METHODS This was a cohort study using an active-comparator, new-user design and nationwide register data from Sweden, Denmark, and Norway during 2010-2016. The cohort included 38,731 new users of GLP-1 receptor agonists (liraglutide 92.5%, exenatide 6.2%, lixisenatide 0.7%, and dulaglutide 0.6%), matched 1:1 on age, sex, and propensity score to a new user of the active comparator, dipeptidyl peptidase 4 (DPP-4) inhibitors. The main outcome was serious renal events, a composite including renal replacement therapy, death from renal causes, and hospitalization for renal events. Secondary outcomes were the individual components of the main outcome. Hazard ratios (HRs) were estimated using Cox models and an intention-to-treat exposure definition. Mean (SD) follow-up time was 3.0 (1.7) years. RESULTS Mean (SD) age of the study population was 59 (10) years, and 18% had cardiovascular disease. A serious renal event occurred in 570 users of GLP-1 receptor agonists (incidence rate 4.8 events per 1,000 person-years) and in 722 users of DPP-4 inhibitors (6.3 events per 1,000 person-years, HR 0.76 [95% CI 0.68-0.85], absolute difference -1.5 events per 1,000 person-years [-2.1 to -0.9]). Use of GLP-1 receptor agonists was associated with a significantly lower risk of renal replacement therapy (HR 0.73 [0.62-0.87]) and hospitalization for renal events (HR 0.73 [0.65-0.83]) but not death from renal causes (HR 0.72 [0.48-1.10]). When we used an as-treated exposure definition in which patients were censored at treatment cessation or switch to the other study drug, the HR for the primary outcome was 0.60 (0.49-0.74). CONCLUSIONS In this large cohort of patients seen in routine clinical practice in three countries, use of GLP-1 receptor agonists, as compared with DPP-4 inhibitors, was associated with a reduced risk of serious renal events.
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| 23. |
- Pasternak, B., et al.
(författare)
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Use of sodium glucose cotransporter 2 inhibitors and risk of major cardiovascular events and heart failure: Scandinavian register based cohort study
- 2019
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Ingår i: Bmj-British Medical Journal. - : BMJ. - 1756-1833 .- 0959-8138. ; 366
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE To investigate the cardiovascular effectiveness of sodium glucose cotransporter 2 (SGLT2) inhibitors in routine clinical practice. Cohort study using data from nationwide registers and an active-comparator new-user design. 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. 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. 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. 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.
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| 24. |
- Pasternak, Björn, et al.
(författare)
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Vaccination against pandemic A/H1N1 2009 influenza in pregnancy and risk of fetal death: cohort study in Denmark
- 2012
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Ingår i: BMJ: British Medical Journal. - : BMJ. - 1756-1833. ; 344
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Tidskriftsartikel (refereegranskat)abstract
- Objective To investigate whether an adjuvanted pandemic A/H1N1 2009 influenza vaccine in pregnancy was associated with an increased risk of fetal death. Design Nationwide register based cohort study. Setting Denmark. Participants All clinically recognised singleton pregnancies that ended between November 2009 and September 2010. Individual level data on exposure to an inactivated AS03 pandemic A/H1N1 2009 influenza vaccine (Pandemrix) and potential confounders were linked to the study cohort using a unique person identifier. Main outcome measures The primary outcome measure was risk of fetal death (spontaneous abortion and stillbirth combined) in H1N1 vaccinated compared with unvaccinated pregnancies, adjusting for propensity scores. Secondary outcome measures were spontaneous abortion (between seven and 22 weeks' gestation) and stillbirth (after 22 completed weeks' gestation). Results The cohort comprised 54 585 pregnancies; 7062 (12.9%) women were vaccinated against pandemic A/H1N1 2009 influenza during pregnancy. Overall, 1818 fetal deaths occurred (1678 spontaneous abortions and 140 stillbirths). Exposure to the H1N1 vaccine was not associated with an increased risk of fetal death (adjusted hazard ratio 0.79, 95% confidence interval 0.53 to 1.16), or the secondary outcomes of spontaneous abortion (1.11, 0.71 to 1.73) and stillbirth (0.44, 0.20 to 0.94). Estimates for fetal death were similar in pregnant women with (0.82, 0.44 to 1.53) and without comorbidities (0.77, 0.47 to 1.25). Conclusion This large cohort study found no evidence of an increased risk of fetal death associated with exposure to an adjuvanted pandemic A/H1N1 2009 influenza vaccine during pregnancy.
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| 25. |
- Ueda, Peter, et al.
(författare)
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Alcohol related disorders among elite male football players in Sweden : nationwide cohort study
- 2022
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Ingår i: BMJ. British Medical Journal. - : BMJ Publishing Group Ltd. - 0959-8146 .- 0959-535X. ; 379
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To assess whether male elite football players are at increased risk of alcohol related disorders compared with men from the general population, and whether such an increased risk would vary on the basis of calendar year of the first playing season in the top tier of competition, age, career length, and goal scoring abilities.DESIGN: Nationwide cohort study.SETTING: Sweden, 1924-2020.PARTICIPANTS: 6007 male football players who had played in the Swedish top division, Allsvenskan, from 1924 to 2019 and 56 168 men from the general population matched to players based on age and region of residence.MAIN OUTCOME MEASURES: Primary outcome was alcohol related disorders (diagnoses recorded in death certificates, during hospital admissions and outpatient visits, or use of prescription drugs for alcohol addiction); secondary outcome was disorders related to misuse of other drugs.RESULTS: During follow-up up to 31 December 2020, 257 (4.3%) football players and 3528 (6.3%) men from the general population received diagnoses of alcohol related disorders. In analyses accounting for age, region of residence, and calendar time, risk of alcohol related disorders was lower among football players than among men from the general population (hazard ratio 0.71, 95% confidence interval 0.62 to 0.81). A reduced risk of alcohol related disorders was observed for football players who played their first season in the top tier in the early 1960s and later, while no significant difference versus men from the general population was seen in the risk for football players from earlier eras. The hazard ratio was lowest at around age 35 years, and then increased with age; at around age 75 years, football players had a higher risk of alcohol related disorders than men from the general population. No significant association was seen between goal scoring, number of games, and seasons played in the top tier and the risk of alcohol related disorders. Risk of disorders related to other drug misuse was significantly lower among football players than the general population (hazard ratio 0.22, 95% confidence interval 0.15 to 0.34).CONCLUSIONS: In this nationwide cohort study, male football players who had played in the Swedish top tier of competition had a significantly lower risk of alcohol related disorders than men from the general population.
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| 26. |
- Ueda, Peter, et al.
(författare)
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Neurodegenerative disease among male elite football (soccer) players in Sweden : a cohort study
- 2023
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Ingår i: The Lancet Public Health. - : Elsevier. - 2468-2667. ; 8:4, s. e256-e265
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Football (soccer) players might be at increased risk of neurodegenerative disease, which has led to questions regarding the safety of the sport and recent measures introduced by football associations to reduce heading of the ball. We aimed to assess the risk of neurodegenerative disease among male football players in the Swedish top division Allsvenskan, compared with matched controls.METHODS: In this cohort study, we identified all male football players (amateurs and professionals) who had played at least one game in Allsvenskan from Aug 1, 1924 to Dec 31, 2019 and excluded players whose personal identity number could not be retrieved or be identified in the Total Population Register, and those who were not born in Sweden and who had immigrated to the country after age 15 years. Football players were matched with up to ten controls from the general population according to sex, age, and region of residence. We used nationwide registers to compare the risk of neurodegenerative disease (diagnoses recorded in death certificates, during hospital admissions and outpatient visits, or use of prescription drugs for dementia) among football players versus controls. We also assessed each type of neurodegenerative disease (Alzheimer's disease and other dementias, motor neuron disease, and Parkinson's disease) separately, and compared the risk of neurodegenerative disease among outfield players versus goalkeepers.FINDINGS: Of 7386 football players who had played at least one game in the top Swedish division between Aug 1, 1924, and Dec 31, 2019, 182 players were excluded for an unretrievable personal identity number, and 417 were excluded due to their number not being identified in the Total Population Register. After a further exclusion of 780 players and 11 627 controls who were born outside of Sweden and who had immigrated to the country after age 15 years, 6007 football players (510 goalkeepers) were included in the study population along with 56 168 matched controls. During follow-up to Dec 31, 2020, 537 (8·9%) of 6007 football players and 3485 (6·2%) of 56 168 controls were diagnosed with neurodegenerative disease. The risk of neurodegenerative disease was higher among football players than controls (hazard ratio [HR] 1·46 [95% CI 1·33-1·60]). Alzheimer's disease and other dementias were more common among football players than controls (HR 1·62 [95% CI 1·47-1·78]), significant group differences were not observed for motor neuron disease (HR 1·27 [0·73-2·22]), and Parkinson's disease was less common among football players (HR 0·68 [0·52-0·89]). The risk of neurodegenerative disease was higher for outfield players than controls (HR 1·50 [95% CI 1·36-1·65]) but not for goalkeepers versus controls (HR 1·07 [0·78-1·47]), and outfield players had a higher risk of neurodegenerative disease than did goalkeepers (HR 1·43 [1·03-1·99]). All-cause mortality was slightly lower among football players than controls (HR 0·95 [95% CI 0·91-0·99]).INTERPRETATION: In this cohort study, male football players who had played in the Swedish top division had a significantly increased risk of neurodegenerative disease compared with population controls. The risk increase was observed for Alzheimer's disease and other dementias but not for other types of neurodegenerative disease, and among outfield players, but not among goalkeepers. Our study expands on the data that can be used to assess and manage risks in the sport.FUNDING: Karolinska Institutet, The Swedish Research Council for Sport Science, Folksam Research Foundation, Hedberg Foundation, Neurofonden, and Åhlen Foundation.
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| 27. |
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| 28. |
- Ueda, P., et al.
(författare)
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Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study
- 2018
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Ingår i: BMJ (Clinical research ed.). - : BMJ. - 1756-1833 .- 0959-8138. ; 363
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Tidskriftsartikel (refereegranskat)abstract
- 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 17213 new users of SGLT2 inhibitors (dapagliflozin, 61%; empagliflozin, 38%; canagliflozin, 1%) and 17213 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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| 29. |
- Ueda, P., et al.
(författare)
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The comparative cardiovascular and renal effectiveness of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists: A Scandinavian cohort study
- 2022
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Ingår i: Diabetes Obesity & Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 24:3, s. 473-485
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Tidskriftsartikel (refereegranskat)abstract
- Aim To assess the comparative cardiovascular and renal effectiveness of sodium-glucose co-transporter-2 (SGLT2) inhibitors versus glucagon-like peptide-1 (GLP-1) receptor agonists in routine clinical practice. Materials and Methods A cohort study of nationwide registers from Sweden, Denmark, and Norway, including 87 525 new users of SGLT2 inhibitors and 63 921 new users of GLP-1 receptor agonists, was conducted using data from 2013-2018. Co-primary outcomes, analysed using an intention-to-treat exposure definition, were major adverse cardiovascular events (MACE; myocardial infarction, stroke, and cardiovascular death), heart failure (hospitalization or death because of heart failure), and serious renal events (renal replacement therapy, hospitalization for renal events, and death from renal causes). Results Use of SGLT2 inhibitors versus GLP-1 receptor agonists was associated with a higher risk of MACE (adjusted incidence rate: 15.2 vs. 14.4 events per 1000 person-years; HR 1.07 [95% CI 1.01-1.15]), a similar risk of heart failure (6.0 vs. 6.0 events per 1000 person-years; HR 1.02 [0.92-1.12]), and a lower risk of serious renal events (2.9 vs. 4.0 events per 1000 person-years; HR 0.76 [0.66-0.87]). In as-treated analyses, the HR (95% CI) was 1.11 (1.00-1.24) for MACE, 0.88 (0.74-1.04) for heart failure, and 0.60 (0.47-0.77) for serious renal events. In secondary outcome analyses, use of SGLT2 inhibitors versus GLP-1 receptor agonists was not associated with statistically significant differences for the risk of myocardial infarction (HR 1.09 [95% CI 1.00-1.19]), cardiovascular death (HR 0.97 [95% CI 0.84-1.12]), death from renal causes (HR 0.75 [95% CI 0.41-1.35]), or any cause death (HR 1.01 [95% CI 0.94-1.09]), while the risk of stroke was higher (HR 1.14 [95% CI 1.03-1.26]), and the risk of renal replacement therapy (HR 0.74 [95% CI 0.56-0.97]) and hospitalization for renal events (HR 0.75 [95% CI 0.65-0.88]) were lower among users of SGLT2 inhibitors. Conclusions Use of SGLT2 inhibitors versus GLP-1 receptor agonists was associated with a similar risk of heart failure and a lower risk of serious renal events, while use of GLP-1 receptor agonists versus SGLT2 inhibitors was associated with a slightly lower risk of MACE. In as-treated analyses, the associations with MACE and serious renal events increased in magnitude, and the HR for heart failure tended towards a protective association for SGLT2 inhibitors.
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| 30. |
- Ueda, P., et al.
(författare)
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Use of incretin-based drugs and risk of cholangiocarcinoma: Scandinavian cohort study
- 2021
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428.
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Concerns have been raised regarding a potential association of use of the incretin-based drugs dipeptidyl peptidase 4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1)-receptor agonists with risk of cholangiocarcinoma. We examined this association in nationwide data from three countries. Methods We used data from nationwide registers in Sweden, Denmark and Norway, 2007-2018, to conduct two cohort studies, one for DPP4 inhibitors and one for GLP-1-receptor agonists, to investigate the risk of incident cholangiocarcinoma compared with an active-comparator drug class (sulfonylureas). The cohorts included patients initiating treatment episodes with DPP4 inhibitors vs sulfonylureas, and GLP-1-receptor agonists vs sulfonylureas. We used Cox regression models, adjusted for potential confounders, to estimate hazard ratios from day 366 after treatment initiation to account for cancer latency. Results The main analyses of DPP4 inhibitors included 1,414,144 person-years of follow-up from 222,577 patients receiving DPP4 inhibitors (median [IQR] follow-up time, 4.5 [2.6-7.0] years) and 123,908 patients receiving sulfonylureas (median [IQR] follow-up time, 5.1 [2.9-7.8] years) during which 350 cholangiocarcinoma events occurred. Use of DPP4 inhibitors, compared with sulfonylureas, was not associated with a statistically significant increase in risk of cholangiocarcinoma (incidence rate 26 vs 23 per 100,000 person-years; adjusted HR, 1.15 [95% CI 0.90, 1.46]; absolute rate difference 3 [95% CI -3, 10] events per 100,000 person-years). The main analyses of GLP-1-receptor agonists included 1,036,587 person-years of follow-up from 96,813 patients receiving GLP-1-receptor agonists (median [IQR] follow-up time, 4.4 [2.4-6.9] years) and 142,578 patients receiving sulfonylureas (median [IQR] follow-up time, 5.5 [3.2-8.1] years) during which 249 cholangiocarcinoma events occurred. Use of GLP-1-receptor agonists was not associated with a statistically significant increase in risk of cholangiocarcinoma (incidence rate 26 vs 23 per 100,000 person-years; adjusted HR, 1.25 [95% CI 0.89, 1.76]; absolute rate difference 3 [95% CI -5, 13] events per 100,000 patient-years). Conclusions/interpretation In this analysis using nationwide data from three countries, use of DPP4 inhibitors and GLP-1-receptor agonists, compared with sulfonylureas, was not associated with a significantly increased risk of cholangiocarcinoma.
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| 31. |
- Wang, Yun-Han, et al.
(författare)
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Association Between Proton Pump Inhibitor Use and Risk of Asthma in Children
- 2021
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Ingår i: JAMA pediatrics. - : American Medical Association. - 2168-6203 .- 2168-6211. ; 175:4, s. 394-403
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: The use of proton pump inhibitors (PPIs) in children has increased substantially in recent years, concurrently with emerging concerns that these drugs may increase the risk of asthma. Whether PPI use in the broad pediatric population is associated with increased risk of asthma is not known.OBJECTIVE: To investigate the association between PPI use and risk of asthma in children.DESIGN, SETTING, AND PARTICIPANTS: This nationwide cohort study collected registry data in Sweden from January 1, 2007, to December 31, 2016. Children and adolescents 17 years or younger were matched by age and propensity score into 80 870 pairs of those who initiated PPI use and those who did not. Data were analyzed from February 1 to September 1, 2020.EXPOSURES: Initiation of PPI use.MAIN OUTCOMES AND MEASURES: The primary analysis examined the risk of incident asthma with a median follow-up to 3.0 (interquartile range, 2.1-3.0) years. Cox proportional hazards regression was used to estimate hazard ratios (HRs).RESULTS: Among the 80 870 pairs (63.0% girls; mean [SD] age, 12.9 [4.8] years), those who initiated PPI use had a higher incidence rate of asthma (21.8 events per 1000 person-years) compared with noninitiators (14.0 events per 1000 person-years), with an HR of 1.57 (95% CI, 1.49-1.64). The risk of asthma was significantly increased across all age groups and was highest for infants and toddlers with an HR of 1.83 (95% CI, 1.65-2.03) in the group younger than 6 months and 1.91(95% CI, 1.65-2.22) in the group 6 months to younger than 2 years (P < .001for interaction). The HRs for individual PPIs were 1.64 (95% CI, 1.50-1.79) for esomeprazole, 1.49 (95% CI, 1.25-1.78) for lansoprazole. 1.43 (95% CI, 1.35-1.51) for omeprazole, and 2.33 (95% CI, 1.30-4.18) for pantoprazole. In analyses of the timing of asthma onset after PPI initiation, the HRs were 1.62 (95% Cl. 1.42-1.85) for 0 to 90 days, 1.73 (95% CI, 1.52-1.98) for 91to 180 days. and 1.53 (95% CI, 1.45-1.62) for 181days to end of follow-up. The association was consistent through all sensitivity analyses, including high-dimensional propensity score matching (HR, 1.48; 95% CI, 1.41-1.55).CONCLUSIONS AND RELEVANCE: In this cohort study, initiation of PPI use compared with nonuse was associated with an increased risk of asthma in children. Proton pump inhibitors should be prescribed to children only when clearly indicated, weighing the potential benefit against potential harm.
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| 32. |
- Wang, Yun-Han, et al.
(författare)
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Association Between Proton Pump Inhibitor Use and Risk of Fracture in Children
- 2020
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Ingår i: JAMA pediatrics. - : American Medical Association. - 2168-6203 .- 2168-6211. ; 29, s. 452-452
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Tidskriftsartikel (refereegranskat)abstract
- This study of a Swedish national registry cohort assesses the association between proton pump inhibitor use and risk of fracture in children.Question: Is proton pump inhibitor (PPI) use associated with increased risk of fracture in children?Findings: This pediatric cohort compared 115933 patients who initiated PPI use with 115933 matched individuals who did not initiate use and found that PPI use was associated with an 11% increased risk of fracture, a significant difference.Meaning: These data suggest that PPI use is associated with a small increased risk of fracture in children; the findings inform safety considerations when these drugs are prescribed to pediatric patients.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 115933 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.
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| 33. |
- Wang, Yun-Han, et al.
(författare)
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Association between proton pump inhibitor use and risk of fracture in children
- 2020
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Ingår i: Pharmacoepidemiology and Drug Safety. - : John Wiley & Sons. - 1053-8569 .- 1099-1557. ; 29:Suppl. 3, s. 452-452
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Proton pump inhibitor (PPI) use has been linked to increased risk of fracture in adults. Despite an increasing trend in prescription of PPIs in children, there is scarce evidence regarding this safety concern in pediatric patients.Objectives: To evaluate the association between PPI use and risk of fracture in children.Methods: We conducted a nationwide register-based cohort study of children aged <18 years in Sweden between July, 2006 to December, 2016. The analyzed cohort included 115,933 pairs of PPI initiators and non-initiators matched on propensity score and age. Cox regression was used to estimate hazard ratios (HRs) for a first fracture of any type and 5 subtypes of fracture with follow-up up to 5 years. To address potential residual confounding, high-dimensional propensity score-matching and a direct comparison with histamine-2-receptorant agonists (H2RA) were performed.Results: During mean 2.2 (standard deviation 1.6) years of follow-up, 5,354 and 4,568 cases of any fracture occurred among PPI initiators and non-initiators, respectively (20.2 versus 18.3 events per 1000 person-years; HR, 1.11; 95%CI, 1.06-1.15). PPI 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), other fracture (HR, 1.51; 95%CI, 1.16-1.97) but not head fracture (HR, 0.93; 95%CI, 0.76-1.13) and 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, 1.14 (95% CI, 1.09-1.20) for31-364 days and 1.34 (95% CI, 1.13-1.58) ≥365 days. 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 H2RA did not reach statistical significance (HR,1.06; 95%CI, 0.97-1.15).Conclusions: In this large pediatric cohort, PPI use was associated with a small but statistically 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.
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| 34. |
- Wang, Yun-Han, et al.
(författare)
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Association between proton pump inhibitor use and risk of pneumonia in children : nationwide self-controlled case series study in Sweden
- 2022
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To evaluate the association between use of proton pump inhibitors (PPIs) and risk of pneumonia in children.Design: Nationwide register-based self-controlled case series study.Setting: Sweden, July 2006 to December 2016.Participants: Children aged <18 years who were treated with PPIs and had a hospitalisation or hospital emergency care visit for pneumonia within 1 year before and 2 years after PPI initiation.Main outcomes and measures: The primary analysis examined the risk of pneumonia during the risk period (ongoing PPI treatment), the pre-exposure period (<= 30 days preceding PPI treatment) and the postexposure period (days 1-365 after PPI discontinuation), comparing to the unexposed period. Conditional Poisson regression was used to estimate incidence rate ratios (IRRs) and 95% CIs.Results: A total of 2356 cases of pneumonia were included. Compared with the unexposed period, the risk of pneumonia was significantly increased during ongoing PPI treatment, with an adjusted IRR of 1.40 (95% CI 1.21 to 1.62). The risk of pneumonia was also increased in the pre-exposure period (adjusted IRR, 1.80, 95% CI 1.51 to 2.13), but not in the postexposure period (adjusted IRR 0.98, 95% CI 0.89 to 1.08). Dividing the risk period by time since treatment initiation, the increased risk of pneumonia was highest in the first 30 days (adjusted IRR 1.63, 95% CI 1.35 to 1.97), remained during days 31-90 (adjusted IRR 1.32, 95% CI 1.04 to 1.69), but waned in days >= 91 (IRR 1.06, 95% CI 0.79 to 1.41).Conclusions and relevance: An increased risk of pneumonia was observed both immediately before and immediately after PPI initiation. This pattern of association can likely be explained by an underlying risk of pneumonia due to factors transiently present at the time around PPI initiation. Thus, our findings do not support a causal relationship between PPI use and risk of pneumonia.
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| 35. |
- Wang, Yun-Han, et al.
(författare)
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Proton pump inhibitor use and risk of depression and anxiety in children : nationwide cohort study
- 2022
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Ingår i: Clinical and Translational Science. - : John Wiley & Sons. - 1752-8054 .- 1752-8062. ; 15:5, s. 1112-1122
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Tidskriftsartikel (refereegranskat)abstract
- Although some data have linked proton pump inhibitor (PPI) use to risk of depression and anxiety, there are no studies investigating this safety issue in children. This study investigated the association between PPI use and risk of depression and anxiety in children. We conducted a nationwide register-based cohort study in Sweden, July 1, 2007, to December 31, 2016. Following matching on age and propensity score, we included 29,320 pairs of PPI initiators and noninitiators among children aged 7-17 years old. The primary analysis examined the risk of incident depression and anxiety, a composite outcome defined as a diagnosis of depression, anxiety, or a prescription for an antidepressant. Children who initiated PPI use had higher hazards for risk of depression and anxiety compared with noninitiators (hazard ratios [HRs], 2.61; 95% confidence interval [CI], 2.32-2.94). In analyses of the timing of depression and anxiety onset after PPI initiation, the HRs were 3.71 (95% CI, 2.17-6.34) for 1-30 days, 3.47 (95% CI, 2.33-5.18) for 31-90 days, 2.71 (2.04-3.60) for 91-180 days, 2.52 (2.00-3.16) for 181-365 days, and 2.34 (1.94-2.82) for 366-730 days. Significant associations were observed across all age groups. The magnitude of the association increased with longer duration of PPI use (p for trend < 0.0001). The association was consistent through all sensitivity analyses, including high-dimensional propensity score matching (HR, 2.31, 95% CI, 2.05-2.61). PPI use was associated with increased risk of depression and anxiety in children. Further investigation is warranted to confirm or refute this potential association.
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| 36. |
- Wintzell, Viktor, et al.
(författare)
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Association between use of azathioprine and risk of acute pancreatitis in children with inflammatory bowel disease : a Swedish-Danish nationwide cohort study
- 2019
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Ingår i: Lancet Child and Adolescent Health. - : Elsevier. - 2352-4642 .- 2352-4650. ; 3:3, s. 158-165
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 37. |
- Wintzell, Viktor, et al.
(författare)
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Data Mining for Adverse Events of Tumor Necrosis Factor-Alpha Inhibitors in Pediatric Patients : Tree-Based Scan Statistic Analyses of Danish Nationwide Health Data
- 2020
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Ingår i: Clinical drug investigation. - : Springer. - 1173-2563 .- 1179-1918. ; 40:12, s. 1147-1154
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: Tumor necrosis factor-alpha (TNF-α) inhibitors are efficacious and considered generally safe in adults. However, pediatric-specific safety evidence is scarce. The aim of this study was to screen for signals of previously unknown adverse events of TNF-α inhibitors in pediatric patients.METHODS: We conducted a data-mining study based on routinely collected, nationwide Danish healthcare data for 2004-2016. Using tree-based scan statistics to identify events with unexpectedly high incidence during TNF-α inhibitor use among patients with inflammatory bowel disease or juvenile idiopathic arthritis, two analyses were performed: comparison with episodes of no use and with other time periods from the same patient. Based on incident physician-assigned diagnosis codes from outpatient and inpatient visits in specialist care, we screened thousands of potential adverse events while adjusting for multiple testing.RESULTS: We identified 1310 episodes of new TNF-α inhibitor use that met the eligibility criteria. Two signals of adverse events of TNF-α inhibitors, as compared with no use, were detected. First, there were excess events of dermatologic complications (ICD-10: L00-L99, 87 vs. 44 events, risk difference [RD] 3.3%), which have been described previously in adults and children. Second, there were excess events of psychiatric diagnosis adjustment disorders (ICD-10: F432, 33 vs. 7 events, RD 2.0%), which was likely associated with the underlying disease and its severity, rather than with the treatment. The self-controlled analysis generated no signal.CONCLUSIONS: No signals of previously unknown adverse events of TNF-α inhibitors in pediatric patients were detected. The study showed that real-world data and newly developed methods for adverse events data mining can play a particularly important role in pediatrics where pre-approval drug safety data are scarce.
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| 38. |
- Wintzell, Viktor, et al.
(författare)
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Use of tumour necrosis factor-α inhibitors and the risk of serious infection in paediatric inflammatory bowel disease in Denmark : a nationwide cohort study
- 2019
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Ingår i: The Lancet Gastroenterology & Hepatology. - : Elsevier. - 2468-1253. ; 4:11, s. 845-853
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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