Incidence rate of venous thrombosis in women switching combined oral contraceptives: a cohort study.

Background: The incidence rate of venous thrombosis (VT) in women switching combined oral contraceptives (COCs) is unknown. Objectives: We hypothesize that women switching COCs may have a similar increased incidence rate of VT as women who start COCs. Switching means starting with a new COC, which may biologically approximate starting. Methods: We conducted a cohort study with data from the Netherlands and Denmark. First, we identified starters who were defined as women who did not use COCs in the 2 years prior to the start of their first COC prescription within the study period. Switchers were a subset of COC starters who redeemed a COC formulation different from their initial COC during follow-up but not longer than 12 months after starting. We estimated incidence rate ratios (adjusted incidence rate ratio [aIRR]) of VT with 95% CIs among COC switchers as compared with COC starters using Poisson regression adjusted for age, COC progestogen generation, and preexisting obesity. Results: In both countries, we found an increased risk of VT among switchers as compared with starters during the first 3 months of the follow-up (aIRR = 1.77; 95% CI, 1.22-2.56 in the Netherlands and aIRR = 1.50; 95% CI, 1.04-2.16 in Denmark). Conclusion: Switchers, particularly in the first 3 months after switching, may experience a renewed starter effect thereby increasing the risk of VT.

Risk of Bleeding and Venous Thromboembolism after Colorectal Cancer Surgery in Patients with and without Type 2 Diabetes: A Danish Cohort Study.

Background Bleeding and venous thromboembolism (VTE) are adverse outcomes after colorectal cancer (CRC) surgery. Type 2 diabetes (T2D) clusters with bleeding and VTE risk factors. We examined the bleeding and VTE risk in patients with T2D undergoing CRC surgery and the prognosis after these adverse outcomes. Methods We conducted a prognostic population-based cohort study of 48,295 patients with and without T2D undergoing surgery for incident CRC during 2005 to 2019. Patients with T2D were diagnosed in a hospital setting or had redeemed a glucose-lowering drug prescription; the remaining cohort was patients without diabetes. We estimated the 30-day and 1-year risks of bleeding and VTE and used a Fine-Gray model to compute age-, sex-, and calendar year-adjusted subdistribution hazard ratios (SHRs). The Kaplan-Meier method was used to calculate 1-year mortality after bleeding or VTE. Results Within 30 days after CRC surgery, the risk of bleeding was 2.7% in patients with T2D and 2.0% in patients without diabetes (SHR: 1.30 [95% confidence interval [CI]: 1.10-1.53]). For VTE, the 30-day risks were 0.6% for patients with T2D and 0.6% for patients without diabetes (SHR: 1.01 [95% CI: 0.71-1.42]). The SHRs for bleeding and VTE within 1 year after CRC surgery were similar. The 1-year mortality was 26.0% versus 24.9% in the bleeding cohort and 25.8% versus 27.5% in the VTE cohort for patients with T2D versus without diabetes, respectively. Conclusion Although absolute risks were low, patients with T2D have an increased risk of bleeding but not VTE after CRC surgery.

Prenatal exposure to pregabalin, birth outcomes and neurodevelopment - a population-based cohort study in four Nordic countries.

INTRODUCTION: Pregabalin is an antiepileptic drug frequently prescribed to pregnant women. Risks of adverse birth and postnatal neurodevelopmental outcomes following prenatal exposure to pregabalin are uncertain. OBJECTIVE: To investigate the association between prenatal exposure to pregabalin and the risks of adverse birth and postnatal neurodevelopmental outcomes. METHODS: This study was conducted using population-based registries in Denmark, Finland, Norway, and Sweden (2005-2016). We compared pregabalin exposure against no exposure to antiepileptics and against active comparators lamotrigine and duloxetine. We obtained pooled propensity score-adjusted estimates of association using fixed-effect and Mantel-Haenszel (MH) meta-analyses. RESULTS: The total number of pregabalin-exposed births was 325/666,139 (0.05%) in Denmark, 965/643,088 (0.15%) in Finland, 307/657,451 (0.05%) in Norway, and 1275/1,152,002 (0.11%) in Sweden. The adjusted prevalence ratios (aPRs) with 95% confidence interval (CI) following pregabalin exposure versus no exposure were 1.14 (0.98-1.34) for major congenital malformations and 1.72 (1.02-2.91) for stillbirth, which attenuated to 1.25 (0.74-2.11) in MH meta-analysis. For the remaining birth outcomes, the aPRs were close to or attenuated toward unity in analyses using active comparators. Adjusted hazard ratios (95% CI) contrasting prenatal pregabalin exposure versus no exposure were 1.29 (1.03-1.63) for ADHD and attenuated when using active comparators, 0.98 (0.67-1.42) for autism spectrum disorders, and 1.00 (0.78-1.29) for intellectual disability. CONCLUSIONS: Prenatal exposure to pregabalin was not associated with low birth weight, preterm birth, small for gestational age, low Apgar score, microcephaly, autism spectrum disorders, or intellectual disability. On the basis of the upper value of the 95% confidence interval, increased risks greater than 1.8 were unlikely for any major congenital malformation and ADHD. For stillbirth and most groups of specific major congenital malformations, the estimates attenuated in MH meta-analysis.

Type 2 diabetes, obesity, and risk of amyotrophic lateral sclerosis: A population-based cohort study.

BACKGROUND: Type 2 diabetes and obesity may be inversely associated with amyotrophic lateral sclerosis (ALS), but the evidence is controversial. METHODS: Using Danish, nationwide registries (1980-2016), we identified patients with a diagnosis of type 2 diabetes (N = 295,653) and patients with a diagnosis of obesity (N = 312,108). Patients were matched (1:3) to persons from the general population on birth year and sex. We computed incidence rates and Cox regression derived hazard ratios (HRs) of a diagnosis of ALS. In multivariable analyses, HRs were controlled for sex, birth year, calendar year, and comorbidities. RESULTS: We observed 168 incident cases of ALS (0.7 [95% confidence interval (CI): 0.6-0.8] per 10,000 person-years) among patients with type 2 diabetes and 859 incident cases of ALS (0.9 [95% CI: 0.9-1.0] per 10,000 person-years) among matched comparators. The adjusted HR was 0.87 (95% CI: 0.72-1.04). The association was present among men (adjusted HR: 0.78 [95% CI: 0.62-0.99]) but not women (adjusted HR: 1.03 [95% CI: 0.78-1.37]), and among those aged ≥60 years (adjusted HR: 0.75 [95% CI: 0.59-0.96]) but not younger. We observed 111 ALS events (0.4 [95% CI: 0.4-0.5] per 10,000 person-years) among obesity patients and 431 ALS events (0.5 [95% CI: 0.5-0.6] per 10,000 person-years) among comparators. The adjusted HR was 0.88 (95% CI: 0.70-1.11). CONCLUSIONS: Diagnoses of type 2 diabetes and obesity were associated with a reduced rate of ALS compared with general population comparators, particularly among men and patients aged 60 years or above. However, absolute rate differences were small.

Burden of Chronic Obstructive Pulmonary Disease Attributable to Tuberculosis: A Microsimulation Study.

Tuberculosis (TB) is a risk factor for chronic obstructive pulmonary disease (COPD), but COPD is also a predictor of TB. The excess life-years lost to COPD caused by TB can potentially be saved by screening for and treating TB infection. We examined the number of life-years that could be saved by preventing TB and TB-attributable COPD. We compared the observed (no intervention) and counterfactual microsimulation models constructed from observed rates in the Danish National Patient Registry (covering all Danish hospitals between 1995 and 2014). In the Danish population of TB and COPD-naive individuals (n = 5,206,922), 27,783 persons (0.5%) developed TB. Among those who developed TB, 14,438 (52.0%) developed TB with COPD. Preventing TB saved 186,469 life-years overall. The excess number of life-years lost to TB alone was 7.07 years per person, and the additional number of life-years lost among persons who developed COPD after TB was 4.86 years per person. The life-years lost to TB-associated COPD are substantial, even in regions where TB can be expected to be identified and treated promptly. Prevention of TB could prevent a substantial amount of COPD-related morbidity; the benefit of screening and treatment for TB infection is underestimated by considering morbidity from TB alone.

Risk of Parkinson Disease and Secondary Parkinsonism in Myocardial Infarction Survivors.

Background In addition to primary neurodegenerative processes, vascular disorders, such as stroke, can lead to parkinsonism. However, some cardiovascular risk factors, such as smoking and elevated cholesterol levels, are associated with reduced risk of Parkinson disease. We examined the risk of Parkinson disease and secondary parkinsonism in 1-year survivors of myocardial infarction (MI). Methods and Results We conducted a nationwide population-based matched cohort study using Danish medical registries from 1995 to 2016. We identified all patients with a first-time MI diagnosis and sampled a sex-, age-, and calendar year-matched general population comparison cohort without MI. Cox regression analysis was used to compute adjusted hazard ratios (aHRs) for Parkinson disease and secondary parkinsonism, controlled for matching factors and adjusted for relevant comorbidities and socioeconomic factors. We identified 181 994 patients with MI and 909 970 matched comparison cohort members (median age, 71 years; 62% men). After 21 years of follow-up, the cumulative incidence was 0.9% for Parkinson disease and 0.1% for secondary parkinsonism in the MI cohort. Compared with the general population cohort, MI was associated with a decreased risk of Parkinson disease (aHR, 0.80; 95% CI, 0.73-0.87) and secondary parkinsonism (aHR, 0.72; 95% CI, 0.54-0.94). Conclusions MI was associated with a 20% decreased risk of Parkinson disease and 28% decreased risk of secondary parkinsonism. Reduced risk may reflect an inverse relationship between cardiovascular risk factors and Parkinson disease.

Long-term Risk of Parkinson Disease Following Influenza and Other Infections.

Importance: Influenza has been associated with the risk of developing Parkinson disease, but the association is controversial. Objective: To examine whether prior influenza and other infections are associated with Parkinson disease more than 10 years after infection. Design, Setting, and Participants: This case-control study used data from 1977 to 2016 from the Danish National Patient Registry. All individuals with Parkinson disease, excluding those with drug-induced parkinsonism, were included and matched to 5 population controls on sex, age, and date of Parkinson diagnosis. Data were analyzed from December 2019 to September 2021. Exposures: Infections were ascertained between 1977 and 2016 and categorized by time from infection to Parkinson disease diagnosis. To increase specificity of influenza diagnoses, influenza exposure was restricted to months of peak influenza activity. Main Outcomes and Measures: Parkinson disease diagnoses were identified between January 1, 2000, and December 31, 2016. Crude and adjusted odds ratios (ORs) and 95% CIs were calculated by conditional logistic regression overall and stratified by time between infection and Parkinson disease (5 years or less, more than 5 to 10 years, more than 10 years). Results: Of 61 626 included individuals, 23 826 (38.7%) were female, and 53 202 (86.3%) were older than 60 years. A total of 10 271 individuals with Parkinson disease and 51 355 controls were identified. Influenza diagnosed at any time during a calendar year was associated with Parkinson disease more than 10 years later (OR, 1.73; 95% CI, 1.11-2.71). When influenza exposure was restricted to months of highest influenza activity, an elevated OR with a wider confidence interval was found (OR, 1.52; 95% CI, 0.80-2.89). There was no evidence of an association with any type of infection more than 10 years prior to Parkinson disease (OR, 1.04; 95% CI, 0.98-1.10). Several specific infections yielded increased odds of Parkinson disease within 5 years of infection, but results were null when exposure occurred more than 10 years prior. Conclusions and Relevance: In this case-control study, influenza was associated with diagnoses of Parkinson disease more than 10 years after infection. These observational data suggest a link between influenza and Parkinson disease but do not demonstrate causality. While other infections were associated with Parkinson disease diagnoses soon after infection, null associations after more than 10 years suggest these shorter-term associations are not causal.

Constipation and risk of cardiovascular diseases: a Danish population-based matched cohort study.

OBJECTIVES: To assess the risks of myocardial infarction, stroke, peripheral artery disease, venous thromboembolism, atrial fibrillation or atrial flutter and heart failure in patients with constipation compared with a general population cohort. DESIGN: Population-based matched cohort study. SETTING: All Danish hospitals and hospital outpatient clinics from 2004 to 2013. PARTICIPANTS: Patients with a constipation diagnosis matched on age, sex and calendar year to 10 individuals without constipation from the general population. MAIN OUTCOMES MEASURES: Comorbidity-adjusted and medication-adjusted hazard ratios (aHRs) for cardiovascular outcomes based on Cox regression analysis. RESULTS: 83 239 patients with constipation were matched to 832 384 individuals without constipation. The median age at constipation diagnosis was 46.5% and 41% were men. Constipation was strongly associated with venous thromboembolism (aHR 2.04, 95% CI 1.89 to 2.20), especially splanchnic venous thrombosis (4.23, 95% CI 2.45 to 7.31). Constipation was also associated with arterial events, including myocardial infarction (1.24, 95% CI 1.14 to 1.35), ischaemic stroke (1.50, 95% CI 1.41 to 1.60), haemorrhagic stroke (1.46, 95% CI 1.26 to 1.69), peripheral artery disease (1.34, 95% CI 1.20 to 1.50), atrial fibrillation or atrial flutter (1.27, 95% CI 1.20 to 1.34) and heart failure (1.52, 95% CI 1.42 to 1.62). The associations were strongest during the first year after the constipation diagnosis and strengthened with an increased number of laxative prescriptions. CONCLUSIONS: Constipation was associated with an increased risk of several cardiovascular diseases, in particular venous thromboembolism.

Combined hormonal contraceptive use in Europe before and after the European Commission mandated changes in product information.

OBJECTIVES: We investigated combined hormonal contraceptives (CHC) prescribing patterns (focusing on combined oral contraceptives; COC) in three countries (Netherlands, Denmark, United Kingdom) in a time period preceding and in a time period following the European Commission's decision to update product information, and we estimated changes in incidence of venous thromboembolism (VTE) between the two periods. STUDY DESIGN: We conducted a drug utilization analysis and a cohort study using routinely collected data. We calculated number, proportion and incidence rate of new users, switchers, and stoppers of COC in both time periods. VTE incidence was calculated in new users of COC and in all women aged 18-49 years. RESULTS: In all countries, the largest proportion (> 75%) of new users used COC containing levonorgestrel, norethisterone, or norgestimate, (i.e., indicated by European Medicines Agency (EMA) as the safest preparations) in both time periods. Switching did not demonstrate a clear pattern towards these types of COC and distribution of stoppers was similar in both time periods. While the proportion of new users initiating COC containing levonorgestrel, norethisterone, or norgestimate increased slightly, this did not translate to a decrease in the overall VTE incidence. CONCLUSION: All three countries had the greatest proportion of women initiating a COC containing levonorgestrel, norethisterone, or norgestimate, and this proportion increased in the period after the European Commission decision albeit the increase was small due to the high percentage of use before the decision. This did not translate into a measureable change in the incidence of VTE. IMPLICATIONS: Both before and after the European Commission's decision, the largest proportion of new users started with combined oral contraceptives containing levonorgestrel, norethisterone, or norgestimate. Earlier studies had already indicated an increased risk of VTE associated with COC containing other progestogens compared with these preparations, so it is possible that physicians were already preferentially prescribing COC containing levonorgestrel, norethisterone, or norgestimate to new users.

Comorbidity and risk of venous thromboembolism after hospitalization for first-time myocardial infarction: A population-based cohort study.

BACKGROUND: Myocardial infarction (MI) is a risk factor for venous thromboembolism (VTE). Although comorbidities affect MI prognosis, it is unclear whether they affect VTE risk after MI. OBJECTIVES: We examined the impact of comorbidity on VTE risk after MI. METHODS: We used nationwide population-based registries to identify first-time hospitalizations for MI and subsequent occurrence of VTE in Denmark (1995-2013). We included a comparison cohort from the general population matched 5:1 with MI patients by sex, age, and comorbidities. We computed 30-day and 1- to 12-month cumulative risks, rates, and hazard ratios of VTE. We also assessed the interaction between MI and comorbidity, defined as excess VTE risk in patients with both MI and comorbidity, by computing interaction contrasts and attributable fractions relating to the interaction. RESULTS: Thirty-day and 1- to 12-month VTE risks were 0.6% and 0.5% in the MI cohort (n = 160 338) and 0.03% and 0.3% in the comparison cohort (n = 792 384). The 30-day hazard ratio for VTE in the MI cohort was 23 (95% confidence interval, 20-27), which decreased during 1-year follow-up. Thirty days after MI, interactions between MI and comorbidity accounted for 16% and 39% of VTE rates in MI patients with low-to-moderate and high comorbidity, respectively. The interactions were driven primarily by hemiplegia and cancer. CONCLUSIONS: Thirty-day VTE risk was substantially increased after MI compared with the general population. Although the absolute VTE risk was low, comorbidity substantially increased this risk, especially hemiplegia and cancer. VTE prophylaxis might be indicated in such high-risk patients but warrants further investigation.

Vascular Diseases In Patients With Chronic Myeloproliferative Neoplasms - Impact Of Comorbidity.

BACKGROUND: Patients with chronic myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), are at high risk of vascular complications. However, the magnitude of this is risk not well known and the possible effect of comorbidity is poorly understood. AIM: Our aim was to compare the risk of vascular diseases in patients with MPNs and matched comparisons from the general population and to study the effect modification of comorbidity. METHODS: We followed 3087 patients with ET, 6076 with PV, 3719 with PMF or unspecified MPN, and age- and sex-matched general population comparisons to estimate the risks of cardiovascular diseases such as myocardial infarction and stroke. We computed 5-year cumulative incidences (risks) for vascular disease in patients with MPNs and comparisons as well as 1-year and 5-year risks, risk differences, and hazard ratios (HRs) for vascular diseases comparing rates in each group of patients with their comparison cohort by level of comorbidity based on the Charlson Comorbidity Index (CCI) [score of 0 (low comorbidity), of 1-2 (moderate comorbidity), and of >2 (severe comorbidity)], as well as other comorbid conditions. RESULTS: The overall 5-year risk of vascular disease ranged from 0.5% to 7.7% in patients with MPNs, which was higher than the risk in the general population. In the same period, the adjusted HRs for vascular disease were 1.3 to 3.7 folds higher in patients with MPNs compared to the general population. An increase in CCI score was associated with an equally increased rate of most types of vascular diseases during the first 5 years of follow-up in both MPN and comparisons. CONCLUSION: Patients with MPNs have a higher risk of vascular diseases during the first 5 years than that of the general population; however, comorbidity modifies the rates similarly in MPN and in the general population.

Initiation of statins and risk of venous thromboembolism: Population-based matched cohort study.

BACKGROUND: The effects of statins in prevention of venous thromboembolism (VTE) is not well established. OBJECTIVES: To examine the risks of first-time VTE in a cohort of patients initiating statin treatment and in a matched general population comparison cohort. METHODS: We conducted a nationwide, population-based, matched cohort study based on data from Danish health registries. The study period was 1 January 2005-31 December 2015. We identified statin initiators (without VTE, myocardial infarction, or ischemic stroke) and sex-, age-, and calendar year-matched (1,3) individuals from the general population (without statin use, VTE, myocardial infarction, or ischemic stroke). We computed cumulative risks and comorbidity-adjusted hazard ratios (HRs) of VTE, myocardial infarction, and ischemic stroke. RESULTS: Among 601,011 statin initiators and 1,803,033 matched population cohort members during 2005-2015, the cumulative risk after 11 years was 2.8% for VTE (both cohorts), 4.7% vs. 2.9% for myocardial infarction, and 7.1% vs. 5.2 for ischemic stroke. After adjustment, statin use was associated with a slightly decreased risk of VTE (adjusted HR: 0.95 [95% CI: 0.92-0.97]), driven by a reduced risk of unprovoked VTE (adjusted HR: 0.92 [95% CI: 0.89-0.95]). The reduced risks of VTE were more pronounced among patients who had an imaging examination performed. The adjusted HRs were elevated for myocardial infarction and ischemic stroke. CONCLUSION: Statin initiation was associated with a reduced risk of VTE, with no indication of a healthy-user effect. Based on available evidence, statins have weak thromboprophylactic effects.

Pregnancy, Birth, Neonatal, and Postnatal Neurological Outcomes After Pregnancy With Migraine.

BACKGROUND: Prevalence of migraine is high during the reproductive age. Although migraine often improves during pregnancy, the risk of adverse pregnancy, birth, neonatal, and neurological outcomes in mother and offspring remains poorly understood. OBJECTIVE: To investigate the associations between maternal migraine and risks of adverse pregnancy outcomes in the mother, and birth, neonatal and postnatal outcomes in the offspring. METHODS: We used Danish population registries to assemble a cohort of pregnancies among women with migraine and an age- and conception year-matched comparison cohort of pregnancies among women without migraine. The study period was 2005-2012. We computed adjusted prevalence ratios (aPRs) for pregnancy and birth outcomes and adjusted risk ratios (aRRs) for neonatal and postnatal outcomes, adjusting for age, preconception medical history, and preconception reproductive history. RESULTS: We identified 22,841 pregnancies among women with migraine and 228,324 matched pregnancies among women without migraine. Migraine was associated with an increased risk of pregnancy-associated hypertension disorders (aPR: 1.50 [95% confidence interval (CI): 1.39-1.61]) and miscarriage (aPR: 1.10 [95% CI: 1.05-1.15]). Migraine was associated with an increased prevalence of low birth weight (aPR: 1.14 [95% CI: 1.06-1.23]), preterm birth (aPR: 1.21 [95% CI: 1.13-1.30]) and cesarean delivery (aPR: 1.20 [95% CI: 1.15-1.25]), but not of small for gestational age offspring (aPR: 0.94 [95% CI: 0.88-0.99]) and birth defects (aPR: 1.01 [95% CI: 0.93-1.09]). Offspring prenatally exposed to maternal migraine had elevated risks of several outcomes in the neonatal and postnatal period, including intensive care unit admission (aRR: 1.22 [95% CI: 1.03-1.45]), hospitalization (aRR: 1.12 [95% CI: 1.06-1.18]), dispensed prescriptions (aRR: 1.34 [95% CI: 1.24-1.45]), respiratory distress syndrome (aRR: 1.20 [95% CI: 1.02-1.42]), and febrile seizures (aRR: 1.27 [95% CI: 1.03-1.57), but not of death (aRR: 0.67 [95% CI: 0.43-1.04]) and cerebral palsy (aRR: 1.00 [95% CI: 0.51-1.94]). CONCLUSIONS: Women with migraine and their offspring have greater risks of several adverse pregnancy outcomes than women without migraine.

Patterns of initial migraine treatment in Denmark: A population-based study.

PURPOSE: Population-based data are sparse on utilization of prophylactic versus acute therapies for newly diagnosed migraine. We examined initial migraine treatment patterns and associated patient characteristics in Denmark. METHODS: We used population-based health databases to assemble a nationwide cohort of adult migraine patients in 2005 to 2013. Migraine was defined as a first hospital diagnosis of migraine or a second redeemed outpatient prescription for triptans, ergots, pizotifen, or flunarizine. We classified the initial migraine treatment received after migraine onset as "no treatment," "acute only," "prophylactic only," and "both acute and prophylactic" and described distributions of sex, age, comorbidities, and comedications. RESULTS: Among 97 431 migraine patients (78% women, median age of 41 y [interquartile range of 32-50 y]), the initial migraine treatments received were "acute only" (88.2%), "prophylactic only" (1.9%), and "both acute and prophylactic" (5.2%) whereas 4.6% had no record of treatment. Initiators of prophylactic treatment-with or without acute treatment-were less likely than initiators of acute treatment to be women (71% and 77% versus 79%), were older (median ages: 45 and 44 y versus 41 y), and had more comorbidities (including hypertension [31% and 24% versus 7%] and diabetes [6% and 5% versus 3%]). Nonpersistence with initial prophylactic treatment was common: within the first year, 35% of initiators stopped therapy fully, 50% stopped and restarted, and 15% switched drugs. CONCLUSIONS: For 88% of patients with incident migraine, the initial migraine treatment was acute treatment only. Use of prophylactic medication as initial treatment was low and correlated with higher age and comorbidity.

Migraine and risk of cardiovascular diseases: Danish population based matched cohort study.

OBJECTIVE: To examine the risks of myocardial infarction, stroke (ischaemic and haemorrhagic), peripheral artery disease, venous thromboembolism, atrial fibrillation or atrial flutter, and heart failure in patients with migraine and in a general population comparison cohort. DESIGN: Nationwide, population based cohort study. SETTING: All Danish hospitals and hospital outpatient clinics from 1995 to 2013. PARTICIPANTS: 51 032 patients with migraine and 510 320 people from the general population matched on age, sex, and calendar year. MAIN OUTCOME MEASURES: Comorbidity adjusted hazard ratios of cardiovascular outcomes based on Cox regression analysis. RESULTS: Higher absolute risks were observed among patients with incident migraine than in the general population across most outcomes and follow-up periods. After 19 years of follow-up, the cumulative incidences per 1000 people for the migraine cohort compared with the general population were 25 v 17 for myocardial infarction, 45 v 25 for ischaemic stroke, 11 v 6 for haemorrhagic stroke, 13 v 11 for peripheral artery disease, 27 v 18 for venous thromboembolism, 47 v 34 for atrial fibrillation or atrial flutter, and 19 v 18 for heart failure. Correspondingly, migraine was positively associated with myocardial infarction (adjusted hazard ratio 1.49, 95% confidence interval 1.36 to 1.64), ischaemic stroke (2.26, 2.11 to 2.41), and haemorrhagic stroke (1.94, 1.68 to 2.23), as well as venous thromboembolism (1.59, 1.45 to 1.74) and atrial fibrillation or atrial flutter (1.25, 1.16 to 1.36). No meaningful association was found with peripheral artery disease (adjusted hazard ratio 1.12, 0.96 to 1.30) or heart failure (1.04, 0.93 to 1.16). The associations, particularly for stroke outcomes, were stronger during the short term (0-1 years) after diagnosis than the long term (up to 19 years), in patients with aura than in those without aura, and in women than in men. In a subcohort of patients, the associations persisted after additional multivariable adjustment for body mass index and smoking. CONCLUSIONS: Migraine was associated with increased risks of myocardial infarction, ischaemic stroke, haemorrhagic stroke, venous thromboembolism, and atrial fibrillation or atrial flutter. Migraine may be an important risk factor for most cardiovascular diseases.

Prediction of mortality in patients with chronic obstructive pulmonary disease with the new Global Initiative for Chronic Obstructive Lung Disease 2017 classification: a cohort study.

BACKGROUND: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 classification separates the spirometric 1-4 staging from the ABCD groups defined by symptoms and exacerbations. Little is known about how this new classification predicts mortality in patients with chronic obstructive pulmonary disease (COPD). We aimed to establish the predictive ability of the GOLD 2017 classification, compared with earlier classifications, for all-cause and respiratory mortality, both when using its main ABCD groups and when further subdividing according to spirometric 1-4 staging. METHODS: In this nationwide cohort study, we enrolled patients with COPD with data available in the Danish registry for COPD. To be included in this registry, individuals must have been outpatients in hospital-based pulmonary clinics in Denmark. Eligible patients were aged 30 years or older; had received a primary diagnosis of COPD (International Classification of Diseases [ICD]-10 J44.X) or acute respiratory failure (ICD-10 J96.X) in combination with COPD (ICD-10 J44.X) as a secondary diagnosis; and had complete data on FEV1, body-mass index, modified Medical Research Council dyspnoea scale score, and smoking status. We categorised eligible patients with complete data according to the 2007, 2011, and 2017 GOLD classifications at the first contact with an outpatient clinic. For the GOLD 2017 classification, we further subdivided the patients by spirometry into 16 subgroups (1A to 4D). We calculated adjusted hazard ratios (HRs) for all-cause and respiratory mortality and compared the predictive ability of the three GOLD classifications (2007, 2011, and 2017) using receiver operating curves. FINDINGS: We enrolled 33 765 patients with COPD, who were outpatients in Danish hospitals between Jan 1, 2008, and Nov 30, 2013, in the main cohort assessed for all-cause mortality. 22 621 of these patients had data available on cause-specific mortality (respiratory) and were included in a subcohort followed from Jan 1, 2008, to Dec 31, 2011. For the GOLD 2017 classification, 3 year mortality increased with increasing exacerbations and dyspnoea from group A (all-cause mortality 10·0%, respiratory mortality 3·0%) to group D (all-cause mortality 36·9%, respiratory mortality 18·0%). However, 3 year mortality was higher for group B patients (all-cause mortality 23·8%, respiratory mortality 9·7%) than for group C patients (all-cause mortality 17·4%, respiratory mortality 6·4%). Compared with group A, adjusted HRs for all-cause mortality ranged from 2·05 (95% CI 1·87-2·26) for group B, to 1·47 (1·31-1·65) for group C, and to 3·01 (2·75-3·30) for group D. Area under the curve for all-cause mortality was 0·61 (95% CI 0·60-0·61) for GOLD 2007, 0·61 (0·60-0·62) for GOLD 2011, and 0·63 (0·53-0·73) for GOLD 2017. Area under the curve for respiratory mortality was 0·64 (0·62-0·65) for GOLD 2007, 0·63 (0·62-0·64) for GOLD 2011, and 0·65 (0·53-0·78) for GOLD 2017. The GOLD 2017 classification based on ABCD groups only did not predict mortality better than the earlier 2007 and 2011 GOLD classifications. However, when 16 subgroups (1A to 4D) were defined, the new classification predicted mortality more accurately than the previous systems (p<0·0001). INTERPRETATION: We showed that the new GOLD 2017 ABCD classification does not predict all-cause and respiratory mortality more accurately than the previous GOLD systems from 2007 and 2011. FUNDING: Danish Lung Association, Program for Clinical Research Infrastructure.

Tonsillectomy and risk of Parkinson's disease: A danish nationwide population-based cohort study.

BACKGROUND: We hypothesized that tonsillectomy modifies the risk of PD. OBJECTIVES: To test the hypothesis in a nationwide population-based cohort study. METHODS: We used Danish medical registries to construct a cohort of all patients in Denmark with an operation code of tonsillectomy 1980-2010 (n = 195,169) and a matched age and sex general population comparison cohort (n = 975,845). Patients were followed until PD diagnosis, death, censoring, or end of follow-up 30 November 2013. Using Cox regression, we computed hazard ratios for PD and corresponding 95% confidence intervals, adjusting for age and sex by study design, and potential confounders. RESULTS: We identified 100 and 568 patients diagnosed with PD among the tonsillectomy and general population comparison cohort, respectively, finding similar risks of PD (adjusted hazard ratio = 0.95 [95% confidence interval: 0.76-1.19]; for > 20 years' follow-up (adjusted hazard ratio = 0.96 [95% confidence interval: 0.64-1.41]). CONCLUSION: Tonsillectomy is not associated with risk of PD, especially early-onset PD. © 2017 International Parkinson and Movement Disorder Society.

Conditioning on future exposure to define study cohorts can induce bias: the case of low-dose acetylsalicylic acid and risk of major bleeding.

BACKGROUND: A principle of cohort studies is that cohort membership is defined by current rather than future exposure information. Pharmacoepidemiologic studies using existing databases are vulnerable to violation of this principle. We evaluated the impact of using data on future redemption of prescriptions to determine cohort membership, motivated by a published example seeking to emulate a "per-protocol" association between continuous versus never use of low-dose acetylsalicylic acid (ASA) and major bleeding (e.g., cerebral hemorrhage or gastrointestinal bleeding). MATERIALS AND METHODS: Danish medical registry data from 2004 to 2011 were used to construct two analytic cohorts. In Cohort 1, we used information about future redemption of low-dose ASA prescriptions to identify cohorts of continuous and never-ASA users. In Cohort 2, we identified ASA initiators and non-initiators using only contemporaneous data and censored follow-up for changes in use over time. We implemented propensity score-matched Poisson regression to evaluate associations between ASA use and major bleeding and estimated adjusted incidence rate differences (IRDs) per 1,000 person-years and ratios (IRRs) overall and stratified by time since initiation. RESULTS: Among >6 million eligible Danish adults, we identified 403,693 low-dose ASA initiators (Cohort 2), of whom 189,150 were defined as continuous users (Cohort 1). Overall, IRDs and IRRs were similar across cohorts. However, the IRD for major bleeding in the first 90 days was substantially larger in Cohort 1 (IRD=25 per 1,000 person-years) compared with Cohort 2 (IRD=10 per 1,000 person-years). CONCLUSION: Using future medication redemption data to define baseline cohorts violates basic epidemiologic principles. Compared with an approach using only contemporaneous data to define cohorts, the approach based on future redemption data generated a substantially higher short-term association between low-dose ASA use and major bleeding on the absolute, but not the relative, scale possibly due to selection and immortal time biases.

Hip Fracture, Comorbidity, and the Risk of Myocardial Infarction and Stroke: A Danish Nationwide Cohort Study, 1995-2015.

We evaluated risks of MI and stroke in elderly patients with hip fracture compared with the general population. We also examined the interaction between hip fracture and comorbidity with respect to risks of MI or stroke, defined as excess of risk explained by combining risks of hip fracture and comorbidity. We conducted a population-based cohort study using Danish health registries, in 1995 to 2015 including 110,563 hip fracture patients and 552,774 members of the comparison cohort from the general population. Thirty-day cumulative incidences of MI were 1.15% among patients with hip fracture and 0.09% in the general population (adjusted hazard ratio [aHR] = 12.97; 95% confidence interval [CI], 11.56 to 14.55). Thirty-day cumulative incidences of stroke were 2.16% for hip fracture patients and 0.21% in the general population (aHR = 9.42; 95% CI, 8.71 to 10.19). During the 31 to 365 days following hip fracture, the aHR for MI was 1.05 (95% CI, 0.97 to 1.14) and remained at this level during the remainder of follow-up (maximum of 20 years). The aHR for stroke was 1.29 (95% CI, 1.22 to 1.35) during the 31 to 365 days following hip fracture, remained elevated for up to 10 years, and then decreased to the general population level. The aHRs for MI and stroke were increased for both men and women, and in all age and comorbidity groups. During the first 30 days, up to 76% of MI and stroke risk was attributable to interaction between hip fracture and comorbidity. Patients with hip fracture are at increased risk of both MI and stroke up to 1 year following the fracture. Risk of stroke, but not of MI, was elevated during up to 10 years postfracture. Although the absolute risks were low, our finding underscores the importance of targeting multimorbidity, including prevention and adequate treatment, to improve the prognosis of hip fracture patients. © 2017 American Society for Bone and Mineral Research.

Thirty-five-year Trends in First-time Hospitalization for Hip Fracture, 1-year Mortality, and the Prognostic Impact of Comorbidity: A Danish Nationwide Cohort Study, 1980-2014.

BACKGROUND: We examined trends in hip fracture incidence in Denmark from 1980 to 2014, trends in subsequent 1-year mortality, and the prognostic impact of sex, age, and comorbidity. METHODS: This nationwide cohort study prospectively collected data from population-based Danish registries. We included 262,437 patients with incident hip fracture and assessed comorbidity using the Charlson Comorbidity Index (CCI). RESULTS: Despite slight increases in incidence rates (IRs) of hip fracture up to the mid-1990s, the annual IR decreased by 29% from 1980 to 2014 in women but remained stable in men. Decrease affected all age groups. IR decreased in patients without comorbidity but increased with increasing comorbidity (13% in patients with moderate and 510% in patients with very severe comorbidity). Adjusted mortality rate ratios (MRRs) following hip fracture in 2010-2014 compared with 1980-1984 were 0.68 (95% confidence interval [CI] = 0.65, 0.71) within 30 days and 0.63 (95% CI = 0.61, 0.66) within 31-365 days. The mortality decreased up to 40% irrespective of comorbidity. Compared with patients with no comorbidity, those with very severe comorbidity had adjusted MRRs of 2.48 (95% CI = 2.39, 2.56) and 2.81 (95% CI = 2.74, 2.88) within 30 days and 31-365 days post-hip fracture, respectively. CONCLUSIONS: Although the incidence rate of hip fracture increased substantially with increasing comorbidity, the following 1-year mortality decreased by 40% from 1980 through 2014 irrespective of sex, age, and comorbidity level, suggesting improvement in both treatment and rehabilitation of patients with hip fracture. Comorbidity burden was, however, a strong prognostic factor for 1-year mortality after hip fracture.