AbstractObjectiveTo 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.DesignNationwide, population based cohort study.SettingAll Danish hospitals and hospital outpatient clinics from 1995 to 2013.Participants51 032 patients with migraine and 510 320 people from the general population matched on age, sex, and calendar year.Main outcome measuresComorbidity adjusted hazard ratios of cardiovascular outcomes based on Cox regression analysis.ResultsHigher 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.ConclusionsMigraine 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.
Influenza has been associated with the risk of developing Parkinson disease, but the association is controversial.
To examine whether prior influenza and other infections are associated with ...Parkinson disease more than 10 years after infection.
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.
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.
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).
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.
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.
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.
Population-based matched cohort study.
All Danish hospitals and hospital outpatient clinics from 2004 to 2013.
Patients with a constipation diagnosis matched on age, sex and calendar year to 10 individuals without constipation from the general population.
Comorbidity-adjusted and medication-adjusted hazard ratios (aHRs) for cardiovascular outcomes based on Cox regression analysis.
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.
Constipation was associated with an increased risk of several cardiovascular diseases, in particular venous thromboembolism.
Abstract
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.
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.
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.
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).
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.
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).
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.
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.
Type 2 diabetes and obesity may be inversely associated with amyotrophic lateral sclerosis (ALS), but the evidence is controversial. In a nationwide cohort study, 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.
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.
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.
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