Potential of the Danish Comorbidity Index for Acute Myocardial Infarction to discriminate mortality in patients with infective endocarditis.

INTRODUCTION: Current risk score models for predicting mortality in infective endocarditis (IE) include data often unavailable in registries, limiting their use for confounding adjustment in population-based research. METHODS: This study assessed the Danish Comorbidity Index for Acute Myocardial Infarction (DANCAMI) for its ability to predict 30-day, 1-year, and 5-year mortality in IE patients, compared to the Charlson Comorbidity Index (CCI) and Elixhauser Comorbidity Index (ECI). The study included all adult Danish patients with first-time IE from 1995 to 2021. The area under the receiver operating characteristic curve (AUC) was estimated using logistic regression to measure discriminatory performance for all-cause and cardiovascular mortality at the specified time intervals. A baseline model included age and sex, while extended models incorporated continuous comorbidity scores. RESULTS: We identified 8966 patients with IE. Mortality rates were 12% at 30 days, 26% at 1 year, and 36% at 5 years. For all-cause mortality, AUCs for the baseline versus DANCAMI models were 0.64 vs. 0.69 at 30 days, 0.66 vs. 0.73 at 1 year, and 0.72 vs. 0.79 at 5 years. For cardiovascular mortality, AUCs for baseline versus DANCAMI models were 0.67 vs. 0.69 at 30 days, 0.67 vs. 0.69 at 1 year, and 0.70 vs. 0.71 at 5 years. CCI and ECI demonstrated comparable AUCs to the DANCAMI model. CONCLUSION: DANCAMI improved discrimination of short- and long-term mortality in IE patients and may be used for confounder adjustment similarly to CCI and ECI.

The Conclusion Generator.

PURPOSE: Reliance on null hypothesis significance testing often leads to misinterpretation of research results. Common misinterpretations include that a statistically nonsignificant difference (p≥0.05) implies no difference between groups, and that a statistically significant finding (p<0.05) is unbiased and clinically important. We aimed to develop a tool - the Conclusion Generator - to mitigate these misconceptions. METHODS: We reviewed the content of the Conclusion Generator and validated its output using published and simulated data. RESULTS: The Conclusion Generator is a free online application designed to generate conclusions for scientific papers based on the values and clinical interpretation of the point estimate and confidence interval. Both relative and absolute measures of effect are supported. It offers two modes for interpretation: (1) Statistical mode provides an accurate statistical interpretation of results, with an optional specification of superiority and noninferiority bounds; (2) Clinical mode evaluates the clinical importance of the point estimate and confidence limits as specified by the user. Both modes assume no uncontrolled biases. Users must specify the number of decimals, the direction of a beneficial effect (e.g., relative risk <1 vs. >1), and the level of detail (concise vs. elaborated) for the output. The validation confirmed the Conclusion Generator's capability to interpret research results, considering random error and clinical relevance, while avoiding common misinterpretations associated with null hypothesis significance testing. CONCLUSIONS: The Conclusion Generator facilitates an appropriate interpretation of research results by emphasizing estimation and clinical relevance over hypothesis testing.

Retrospective and prospective study designs.

The labels "retrospective" and "prospective" strongly connote study quality, often favouring prospective studies. However, three definitions of these terms exist, each suggesting distinct methodological limitations. In this review, we summarize and evaluate these definitions. Caution is warranted when labeling a study "retrospective": This label should only be used when implying a risk of recall bias, which can only occur in retrospective data collection. Generally, assessing random and systematic errors is necessary to appraise study quality rather than relying on ambiguous labels.

Validity of Prescription-Defined and Hospital-Diagnosed Hypertension Compared with Self-Reported Hypertension in Denmark.

Purpose: Hypertension is an important risk factor in cardio-epidemiological research, but data quality remains a concern. We validated different registry-based definitions of hypertension. Patients and Methods: The cohort included all first-time responders of the Danish National Health Surveys (2010, 2013, or 2017). Prescription-defined hypertension was defined as ≥1 or ≥2 filled prescriptions of antihypertensive specific drugs in ≥1 or ≥2 different antihypertensive drug classes within 90, 180, or 365 days before survey response. Hospital-diagnosed hypertension was defined from hypertension diagnoses within five years before the survey response. Considering self-reported hypertension as the reference, we calculated the positive predictive value (PPV), the negative predictive value (NVP), the sensitivity, and the specificity of prescription-defined and hospital-diagnosed hypertension. Results: Among 442,490 survey responders, 127,247 (29%) had self-reported hypertension. For prescription-defined hypertension with 365-day lookback, the PPV was highest for ≥2 prescriptions in ≥2 drug classes (94%) and lowest for ≥1 prescription in ≥1 drug class (85%). The NPV was highest for ≥1 prescription in ≥2 drug classes (94%) and lowest for ≥1 prescription in ≥2 drug classes (80%). The sensitivity was highest for ≥1 prescription in ≥1 drug class (79%) and lowest for ≥2 prescriptions in ≥2 drug classes (30%). The specificity was ≥94% for all algorithms. The PPV and specificity did not change noteworthy with length of lookback period, whereas the NPV and the sensitivity generally were higher for longer lookback. The algorithm ≥1 prescription in ≥2 drug classes with 365-day lookback was among the best balanced across all measures of validity (PPV=88%, NPV=94%, sensitivity=75%, specificity=96%). For hospital-diagnosed hypertension, the PPV was 90%, the NPV was 76%, the sensitivity was 22%, and the specificity was 99%. Conclusion: Compared with self-reported hypertension, the algorithms for prescription-defined and hospital-diagnosed hypertension had high predictive values and specificity, but low sensitivity.

Influence of Low-Density Lipoprotein Cholesterol Levels on NSAID-Associated Cardiovascular Risks After Myocardial Infarction: A Population-Based Cohort Study.

Aim: To examine whether low-density lipoprotein cholesterol (LDL-C) levels influence the cardiovascular risk associated with non-aspirin non-steroidal anti-inflammatory drug (NSAID) use after myocardial infarction (MI). Methods: Using Danish health registries, we conducted a population-based cohort study of all adult patients with first-time MI during 2010-2020 with an LDL-C value before discharge. Based on the latest LDL-C value, we categorized patients into a low and a high LDL-C group (<3.0 vs ≥3.0 mmol/L). We used time varying Cox regression to compute hazard ratios (HRs) with 95% confidence intervals of the association between NSAID use and a major adverse cardiovascular event (MACE: recurrent MI, ischemic stroke, and all-cause death). Results: We followed 50,573 patients for a median of 3.1 years. While exposed, 521 patients experienced a MACE: 312 in the low LDL-C group and 209 in the high LDL-C group. The HRs for MACE comparing NSAID use with non-use were 1.21 (1.11-1.32) overall, 1.19 (1.06-1.33) in the low LDL-C group, and 1.23 (1.07-1.41) in the high LDL-group. The HRs for recurrent MI and ischemic stroke were comparable between the LDL-C subgroups. The HRs for all-cause death were 1.22 (1.07-1.39) in the low LDL-C group and 1.54 (1.30-1.83) in the high LDL-C group. Changing the cut-off value for LDL-C to 1.8 and 1.4 mmol/L showed consistent results. Conclusion: In patients with MI, LDL-C levels did not influence the increased risk of MACE associated with NSAID use, but might influence the association between NSAID use and all-cause death.

Cardiovascular safety of using non-steroidal anti-inflammatory drugs for gout: a Danish nationwide case-crossover study.

Gout attacks are treated with uric-lowering and anti-inflammatory drugs. In patients with gout, non-steroidal anti-inflammatory drugs (NSAIDs) could be both cardiovascular beneficial, due to their anti-inflammatory actions, and cardiovascular hazardous, due to their prothrombotic, hypertensive, and proarrhythmic side effects. We, therefore, examined the risk of cardiovascular events associated with NSAID use in patients with gout. We conducted a nationwide, population-based case-crossover study of all Danes ≥ 18 years of age with first-time gout during 1997-2020, who experienced a cardiovascular event (myocardial infarction, ischemic stroke, congestive heart failure, atrial fibrillation/flutter, or cardiovascular death) (n = 59,150). The exposure was use of NSAIDs, overall and according to type (ibuprofen, naproxen, or diclofenac). We used the dates 300, 240, 180, and 120 before the outcome date as reference dates. We used the Mantel-Haenszel method to calculate odds ratios (ORs) with 95% confidence intervals (CIs) of the association between NSAID use and cardiovascular events. NSAID use was overall associated with 12% decreased odds of a cardiovascular event (OR = 0.88, 95% CI: 0.85-0.91). This decreased odds ratio was observed for the use of ibuprofen (OR = 0.92, 95% CI: 0.88-0.97) and naproxen (OR = 0.85, 95% CI: 0.74-0.97), but not for the use of diclofenac (OR = 0.97, 95% CI: 0.90-1.05). Overall, use of NSAIDs was associated with decreased odds of all the individual components of the composite outcome. NSAIDs were not associated with an increased cardiovascular event rate when used in gout patients. Ibuprofen and naproxen appeared to have better cardiovascular risk profiles than diclofenac.

Autoimmune blistering disorders and cardiovascular risks: A population-based cohort study.

BACKGROUND: Autoimmune blistering disorders (ABDs) might elevate cardiovascular risk, but studies are lacking. OBJECTIVE: The objective of this study was to examine if ABDs elevate the risk of atherosclerotic cardiovascular disease, heart failure, arrhythmia, venous thromboembolism, and cardiovascular death. METHODS: A population-based cohort of Danish patients with ABD (≥18 years of age) diagnosed during 1996-2021 (n = 3322) was compared with an age- and sex-matched comparison cohort from the general population (n = 33,195). RESULTS: Compared with the general population, patients with ABDs had higher 1-year risks of atherosclerotic cardiovascular disease (3.4% vs 1.6%), heart failure (1.9% vs 0.7%), arrhythmia (3.8% vs 1.3%), venous thromboembolism (1.9% vs 0.3%), and cardiovascular death (3.3% vs 0.9%). The elevated risk persisted after 10 years for all outcomes but arrhythmia. The hazard ratios associating ABDs with the outcomes during the entire follow-up were 1.24 (1.09-1.40) for atherosclerotic cardiovascular disease, 1.48 (1.24-1.77) for heart failure, 1.16 (1.02-1.32) for arrhythmia, 1.87 (1.50-2.34) for venous thromboembolism, and 2.01 (1.76-2.29) for cardiovascular death. The elevated cardiovascular risk was observed for both pemphigus and pemphigoid. LIMITATIONS: Our findings might only generalize to patients with ABDs without prevalent cardiovascular diseases. CONCLUSION: Patients with ABDs had an elevated cardiovascular risk compared with age- and sex-matched controls.

Risk of cardiovascular disease after hospital-diagnosed overweight or obesity.

Objective: The aim was to examine the association between hospital-diagnosed overweight/obesity and incident CVD according to the time period of the overweight/obesity diagnosis. Design: This is a cohort study. Methods: From Danish national health registries, we identified all residents with a first-time hospital-based overweight/obesity diagnosis code, 1977-2018 (n = 195,221), and an age and sex-matched general population comparison cohort (n = 1,952,210). We computed adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) using Cox regression. We adjusted for comorbidities and educational level and applied 10 years of follow-up. Results: The overall incidence rate was 10.1 (95% CI 10.0-10.1) per 1000 person-years for the comparison cohort and 25.1 (95% CI 24.8-25.4) per 1000 person-years for the overweight/obesity cohort, corresponding to an aHR of 2.5 (95% CI 2.4-2.5). The aHR was elevated for all subtypes of CVD: heart failure: 3.9 (95% CI 3.7-4.1), bradyarrhythmia: 2.9 (95% CI 2.7-3.1), angina pectoris: 2.7 (95% CI 2.7-2.8), atrial fibrillation or flutter: 2.6 (95% CI 2.5-2.6), acute myocardial infarction: 2.4 (95% CI 2.3-2.4), revascularization procedure: 2.4 (95% CI 2.2-2.5), valvular heart disease: 1.7 (95% CI 1.6-1.8), ischemic stroke: 1.6 (95% CI 1.4-1.7), transient ischemic attack: 1.6 (95% CI 1.5-1.7), and cardiovascular death: 1.6 (95% CI 1.5-1.6). The 1-10-year aHR of any CVD associated with an overweight/obesity diagnosis decreased from 2.8 (95% CI 2.7-2.9) in 1977-1987 to 1.8 (95% CI 1.8-1.9) in 2008-2018. Conclusion: Patients with hospital-diagnosed overweight/obesity had high rates of ischemic heart disease, heart failure, structural heart disease, arrhythmia, stroke, and death, although the strength of the association decreased in recent years. Significance statement: Obesity is linked to metabolic abnormalities that predispose individuals to an increased risk of subtypes of CVD. In this population-based nationwide 40-year cohort study, we found that of 195,221 patients with an overweight/obesity diagnosis, more than 31,000 (15.9%) were admitted to hospital within 10 years because of CVD; corresponding to a 2.5-fold greater relative risk of any CVD associated with overweight/obesity than in the general population. We observed an increased risk for most CVD subtypes, including ischemic heart disease, heart failure, structural heart disease, arrhythmia, stroke, and cardiovascular death, although the strength of the association decreased in recent years. Our study emphasizes the importance of improved clinical handling of obesity and underscores the need to prevent associated complications to alleviate the burden of obesity.

Correction: Migraine and risk of premature myocardial infarction and stroke among men and women: A Danish population-based cohort study.

[This corrects the article DOI: 10.1371/journal.pmed.1004238.].

Combined Impact of Migraine and Pregnancy-Induced Hypertension on Long-term Risk of Premature Myocardial Infarction and Stroke.

BACKGROUND AND OBJECTIVES: Migraine and pregnancy-induced hypertension (PIH) are known to increase cardiovascular risk on their own. However, evidence is limited on the combined impact of migraine and PIH on risk of cardiovascular disease. The aim of this study was to examine the combined impact of migraine and PIH on risk of premature (age 60 years and younger) major adverse cardiovascular and cerebrovascular events (MACCE), a composite end point consisting of myocardial infarction, stroke, or death due to one of these diseases. METHODS: We conducted a population-based cohort study in Denmark (1996-2018) among women who had delivered at least one child. This population was stratified into 4 cohorts: women with neither migraine nor PIH, women with migraine, women with PIH, and women with both migraine and PIH. As a measure of absolute risk, we computed the 20-year cumulative incidence of premature MACCE, treating death by other causes than myocardial infarction and stroke as a competing risk. We used Cox regression to compute 20-year adjusted hazard ratios (HRs) of premature MACCE. Women with neither migraine nor PIH served as the comparison cohort. RESULTS: The 20-year absolute risk of premature MACCE was 1.3% (95% CI 1.2%; 1.3%) for women without migraine and without PIH (n = 1,288,541), 2.2% (95% CI 2.0%; 2.4%) for women with migraine (n = 54,827), 2.8% (95% CI 2.6%; 3.1%) for women with PIH (n = 49,008), and 3.1% (95% CI 2.1%; 4.4%) for women with both migraine and PIH (n = 3,140). The adjusted HR of premature MACCE was 1.66 (95% confidence interval [CI] 1.50-1.84) for women with migraine, 2.76 (95% CI 2.52-3.03) for women with PIH, and 2.41 (95% CI 1.61-3.61) for women with both migraine and PIH. DISCUSSION: Migraine and PIH separately increased the risk of premature MACCE. The risk of premature MACCE among women who had both migraine and PIH was similar to that among women with PIH only.

Long-term aspirin use and cancer risk: a 20-year cohort study.

BACKGROUND: Long-term use of aspirin has been shown to reduce colorectal cancer risk, but the association remains inconclusive for individual noncolorectal cancers. We examined the association between long-term aspirin use and cancer risk in Denmark. METHODS: Using nationwide registries, we followed individuals aged 40-70 years at baseline (January 1, 1997) for cancer diagnoses through 2018. We assessed low-dose (75-150 mg) aspirin use according to continuity, duration, and cumulative amount. In addition, we explored associations with consistent high-dose (500 mg) aspirin use. Using Cox regression, we estimated multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) with aspirin use for overall and site-specific cancer. RESULTS: Among 1 909 531 individuals, 422 778 were diagnosed with cancer during mean follow-up of 18.2 years. Low-dose aspirin use did not reduce the hazard ratio for cancer overall irrespective of continuity and duration of use (continuous use: HR = 1.04, 95% CI = 1.03 to 1.06). However, long-term (≥5 or ≥10 years) use was associated with at least 10% reductions in hazard ratios for several cancer sites: colon, rectum, esophagus, stomach, liver, pancreas, small intestine, head and neck, brain tumors, meningioma, melanoma, thyroid, non-Hodgkin lymphoma, and leukemia. Substantially elevated hazard ratios were found for lung and bladder cancer. In secondary analyses, consistent high-dose aspirin use was associated with reduced hazard ratios for cancer overall (HR = 0.89, 95% CI = 0.85 to 0.93) and for several cancer sites. CONCLUSION: Long-term low-dose aspirin use was associated with slight to moderately reduced risks for several cancers but not for cancer overall owing to increased risk for some common cancers. Similar or slightly stronger inverse associations were observed for consistent use of high-dose aspirin.

Cohort Profile: Better Health in Late Life.

Purpose: Humans are living longer and may develop multiple chronic diseases in later life. The Better Health in Late Life cohort study aims to improve our understanding of the risks and outcomes of multimorbidity in the Danish population. Methods: A randomly-selected sample of Danish residents who were 50-65 years of age received a questionnaire and an invitation to participate in this study. Respondents completed an online survey between October 2021 and January 2022 which addressed topics that included self-assessed health, mental health, sleep, specific medical conditions, use of painkillers, diet, alcohol consumption, smoking, physical activity, and body composition. This information was linked to the Danish health and social registries (some established in 1943 and onwards) that maintain data on filled prescriptions, hospital records, socioeconomic status, and health care utilization. Results: Responses were received from 115,431 of the 301,244 residents invited to participate (38%). We excluded respondents who answered none of the questions as well as those who provided no information on sex or indicated an age other than 50-65 years. Of the 114,283 eligible respondents, 54.8% were female, 30.3% were overweight, and 16.7% were obese. Most participants reported a weekly alcohol consumption of less than seven units and 13.3% were current smokers; 5.2% had a history of hospitalization for solid cancer, and 3.0%, 2.3%, 2.0%, and 0.9% reported chronic pulmonary disease, diabetes, stroke, and myocardial infarction, respectively. The most frequently filled prescriptions were for medications used to treat the nervous system and cardiovascular diseases (38.1% and 37.4%, respectively).

Takotsubo syndrome and stroke risk: A nationwide register-based study.

AIMS: Previous small-scale studies have indicated a short-term stroke incidence of 1.0-1.3% following Takotsubo (syndrome). In this nationwide register-based study, we investigated the 90-day risk of ischemic stroke (IS) or transient ischemia attack (TIA) and mortality of patients with Takotsubo. METHODS AND RESULTS: Patients with incident Takotsubo between January 1st 2009 to September 30th 2018 were identified from Danish nationwide registries. Takotsubo patients were age- and sex-matched with background-, atrial fibrillation/flutter- (AF) and myocardial infarction (MI) cohorts. Cumulative incidences and Cox proportional-hazard regression models were used to analyze the following outcomes: 1) composite of IS/TIA and 2) all-cause mortality. A total of 890 patients with Takotsubo were followed for 90 days. The cumulative 90-day incidence of IS/TIA in the Takotsubo-, background-, AF- and MI cohort, was 2.1% (n = 19), 0.1% (n = 4), 1.1% (n = 47) and 1.5% (n = 66), respectively. The cumulative 90-day mortality in the Takotsubo-, background-, AF- and MI cohort was 5.1% (n = 45), 0.3% (n = 13), 1.7% (n = 75) and 5.6% (n = 230), respectively. The adjusted hazard ratio (HR) for 90-day IS/TIA was when compared to the background-, AF- and MI cohort, 26.43 (95% CI: 8.82-79.24), 1.91 (95% CI: 1.09-3.35) and 2.06 (95% CI: 1.12-3.79), respectively. The adjusted HR for 90-day mortality was when compared to the background-, AF- and MI cohort, 14.19 (95% CI: 7.43-27.09), 0.73 (95% CI: 0.52-1.02) and 1.96 (95% CI: 1.25-3.07), respectively. CONCLUSION: Patients with Takotsubo had an increased 90-day hazard for IS/TIA when compared to age- and sex-matched background-, AF- and MI cohorts.

Ability of the DANCAMI to predict the risk ischemic stroke and mortality in patients with atrial fibrillation/flutter.

OBJECTIVES: Comparison of the danish comorbidity index for acute myocardial infarction (DANCAMI), the charlson comorbidity index (CCI), the elixhauser comorbidity index (ECI), and the CHA2DS2-VASc score to predict ischemic stroke, cardiovascular mortality, and all-cause mortality after atrial fibrillation/flutter. MATERIALS AND METHODS: A population-based cohort study of all Danish patients with incident atrial fibrillation/flutter during 2000-2020 (n=361,901). C-Statistics were used to evaluate the discriminatory performance for predicting 1 and 5-year risks of the outcomes for a baseline model (including age and sex) +/- the individual indices. RESULTS: For the DANCAMI, the 5-year risk did not increase with comorbidity burden for ischemic stroke (5.9% for low vs. 5.6% for severe) but did increase for cardiovascular mortality (10% for low vs. 16% for severe) and all-cause mortality (33% for low vs. 61% for severe). C-Statistics for predicting 5-year ischemic stroke risk were similar for all models (0.64). C-Statistics for predicting 5-year cardiovascular mortality risk were also similar for the baseline (0.76), the DANCAMI (0.77), the CCI (0.76), the ECI (0.76), and the CHA2DS2-VASc (0.76) models. C-Statistics for predicting 5-year all-cause mortality risk were lower for the baseline (0.71) and the CHA2DS2-VASc (0.71) models than for the DANCAMI (0.75), the CCI (0.74), and the ECI (0.74) models. The 1-year C-Statistics were comparable. CONCLUSION: The DANCAMI predicted ischemic stroke and cardiovascular mortality risks similar to the CCI, the ECI, and the CHA2DS2-VASc. The DANCAMI predicted all-cause mortality risk similar to the CCI and the ECI, but better than the baseline and the CHA2DS2-VASc.

Ten-year trends in incidence and prevalence of atrial fibrillation and flutter in Denmark according to demographics, ethnicity, educational level, and area of residence (2009-2018).

BACKGROUND: Atrial fibrillation is the most common cardiac arrhythmia and a major global health burden. Updated trends in the epidemiology of atrial fibrillation or flutter (AF) are needed. METHODS: Using the Danish Heart Statistics, we investigated nationwide trends 2009-2018 in incidence rate and prevalence of AF according to age as well as age-standardized incidence rate (ASIR) and prevalence (ASP) of AF according to sex, ethnicity, educational level, and area of residence. Comparing year 2018 to 2009, we calculated stratum-specific ASIR ratios (ASIRR) and changes in ASP. RESULTS: During 2009-2015 the ASIR for AF increased for both men and women, followed by a decline from 2015-2018. Overall, this resulted in a 9% increase among men (ASIRR: 1.09, 95% CI: 1.06-1.12), but no change among women (ASIRR: 1.00, 95% CI: 0.97-1.04). The ASP increased by 29% among men and 26% among women. An increase in ASIR was observed in all ethnic groups except men of Far Eastern ethnicity. Lower educational level was associated with greater increases in both ASIR and ASP. ASIR and ASP differed slightly between the Danish regions but increased in all of them. CONCLUSIONS: During 2009-2018 the incidence and prevalence of AF in Denmark increased although the increase in incidence was transient among women. Factors associated with higher incidence were male sex, higher age, Danish and Western ethnicity as well as Middle Eastern/North African ethnicity among women, and lower educational level. Within Denmark, we observed only minor regional differences in AF incidence and prevalence.

Cardiovascular risks of continuing vs. initiating NSAIDs after first-time myocardial infarction or heart failure: a nationwide cohort study.

AIMS: It is unknown whether the cardiovascular risks associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs) shortly after first-time myocardial infarction (MI) or heart failure (HF) differ between patients continuing and initiating use. METHODS AND RESULTS: Using nationwide health registries, we conducted a cohort study of all patients with first-time MI or HF during 1996-2018 (n = 273 682). NSAID users (n = 97 966) were categorized as continuing (17%) and initiating (83%) users according to prescription fillings < 60 days before index diagnosis. The primary outcome was a composite of new MI, HF admission, and all-cause death. Follow-up started 30 days after the index discharge date. We used Cox regression to compute hazard ratios (HRs) with 95% confidence intervals (CIs) comparing NSAID users vs. non-users. The most commonly filled NSAIDs were ibuprofen (50%), diclofenac (20%), etodolac (8.5%), and naproxen (4.3%). The composite outcome HR of 1.25 (CI: 1.23-1.27) was driven by initiators (HR = 1.39, 1.36-1.41) and not continuing users (HR = 1.03, 1.00-1.07). The lack of association among continuing users was also observed for individual NSAIDs (ibuprofen and naproxen), except diclofenac (HR = 1.11, 95% CI: 1.05-1.18). Among initiators, the HR was 1.63 (CI: 1.57-1.69) for diclofenac, 1.31 (CI: 1.27-1.35) for ibuprofen, and 1.19 (CI: 1.08-1.31) for naproxen. The results were consistent for both MI and HF patients, the individual components of the composite outcome, and various sensitivity analyses. CONCLUSION: NSAID initiators were more susceptible to adverse cardiovascular outcomes after first-time MI or HF than continuing users.

Migraine and risk of premature myocardial infarction and stroke among men and women: A Danish population-based cohort study.

BACKGROUND: Migraine carries risk of myocardial infarction (MI) and stroke. The risk of premature MI (i.e., among young adults) and stroke differs between men and women; previous studies indicate that migraine is mainly associated with an increased risk of stroke among young women. The aim of this study was to examine impact of migraine on the risk of premature (age ≤60 years) MI and ischemic/hemorrhagic stroke among men and women. METHODS AND FINDINGS: Using Danish medical registries, we conducted a nationwide population-based cohort study (1996 to 2018). Redeemed prescriptions for migraine-specific medication were used to identify women with migraine (n = 179,680) and men with migraine (n = 40,757). These individuals were matched on sex, index year, and birth year 1:5 with a random sample of the general population who did not use migraine-specific medication. All individuals were required to be between 18 and 60 years old. Median age was 41.5 years for women and 40.3 years for men. The main outcome measures to assess impact of migraine were absolute risk differences (RDs) and hazard ratios (HRs) with 95% confidence intervals (CIs) of premature MI, ischemic, and hemorrhagic stroke, comparing individuals with migraine to migraine-free individuals of the same sex. HRs were adjusted for age, index year, and comorbidities. The RD of premature MI for those with migraine versus no migraine was 0.3% (95% CI [0.2%, 0.4%]; p < 0.001) for women and 0.3% (95% CI [-0.1%, 0.6%]; p = 0.061) for men. The adjusted HR was 1.22 (95% CI [1.14, 1.31]; p < 0.001) for women and 1.07 (95% CI [0.97, 1.17]; p = 0.164) for men. The RD of premature ischemic stroke for migraine versus no migraine was 0.3% (95% CI [0.2%, 0.4%]; p < 0.001) for women and 0.5% (95% CI [0.1%, 0.8%]; p < 0.001) for men. The adjusted HR was 1.21 (95% CI [1.13, 1.30]; p < 0.001) for women and 1.23 (95% CI [1.10, 1.38]; p < 0.001) for men. The RD of premature hemorrhagic stroke for migraine versus no migraine was 0.1% (95% CI [0.0%, 0.2%]; p = 0.011) for women and -0.1% (95% CI [-0.3%, 0.0%]; p = 0.176) for men. The adjusted HR was 1.13 (95% CI [1.02, 1.24]; p = 0.014) for women and 0.85 (95% CI [0.69, 1.05]; p = 0.131) for men. The main limitation of this study was the risk of misclassification of migraine, which could lead to underestimation of the impact of migraine on each outcome. CONCLUSIONS: In this study, we observed that migraine was associated with similarly increased risk of premature ischemic stroke among men and women. For premature MI and hemorrhagic stroke, there may be an increased risk associated with migraine only among women.

Long-term risk of atrial fibrillation or flutter after transcatheter patent foramen ovale closure: a nationwide Danish study.

AIMS: Transcatheter closure of patent foramen ovale (PFO) is the recommended stroke prevention treatment in patients ≤60 years with cryptogenic ischemic stroke and PFO. Atrial fibrillation or flutter (AF) is a known potential procedure-related complication, but long-term risk of developing AF remains unknown. This paper studied the long-term risk of developing AF following PFO closure. METHODS AND RESULTS: A Danish nationwide cohort study was conducted. During 2008-2020, this study identified a PFO closure cohort, a PFO diagnosis cohort without PFO closure, and a general population comparison cohort matched 10:1 to the PFO closure cohort on age and sex. The outcome was first-time AF diagnosis. Risk of AF and multivariable-adjusted hazard ratio (HR) of the association between PFO closure or PFO diagnosis and AF were calculated. A total of 817 patients with PFO closure, 1224 with PFO diagnosis, and 8170 matched individuals were identified. The 5 year risk of AF was 7.8% [95% confidence interval (CI): 5.5-10] in the PFO closure cohort, 3.1% (95% CI: 2.0-4.2) in the PFO diagnosis cohort, and 1.2% (95% CI: 0.8-1.6) in the matched cohort. The HR of AF comparing PFO closure with PFO diagnosis was 2.3 (95% CI: 1.3-4.0) within the first 3 months and 0.7 (95% CI: 0.3-1.7) thereafter. The HR of AF comparing PFO closure with the matched cohort was 51 (95% CI: 21-125) within the first 3 months and 2.5 (95% CI: 1.2-5.0) thereafter. CONCLUSION: Patent foramen ovale closure was not associated with any substantial increased long-term risk of developing AF beyond the well-known procedure-related short-term risk.

Impact of hemoglobin A1c level on the association between non-steroidal anti-inflammatory drug use and cardiovascular events in patients with type 2 diabetes: A population-based cohort study.

OBJECTIVE: Non-steroidal anti-inflammatory drugs (NSAIDs) should be used cautiously in patients with type 2 diabetes. We examined whether the cardiovascular risks associated with NSAID use depended on HbA1c level in patients with type 2 diabetes. METHODS: We conducted a population-based cohort study of all adult Danes with a first-time HbA1c measurement ≥48 mmol/mol during 2012-2020 (n = 103 308). We used information on sex, age, comorbidity burden, and drug use to calculate time-varying inverse probability of treatment weights. After applying these weights in a pooled logistic regression, we estimated hazard ratios (HRs) of the association between use of NSAIDs (ibuprofen, naproxen, or diclofenac) and cardiovascular events (a composite of myocardial infarction, ischemic stroke, congestive heart failure, atrial fibrillation or flutter, and all-cause death). We stratified all analyses by HbA1c level (<53 or ≥53 mmol/mol). RESULTS: For ibuprofen use, the HR of a cardiovascular event was 1.53 (95% confidence interval [CI]: 1.34-1.75) in patients with HbA1c <53 and 1.24 (95% CI: 1.00-1.53) in patients with HbA1c ≥53 mmol/mol. For naproxen use, the HR was 1.14 (95% CI: 0.59-2.21) in patients with HbA1c <53 and 1.30 (95% CI: 0.49-3.49) in patients with HbA1c ≥53 mmol/mol. For diclofenac use, the HR was 2.40 (95% CI: 1.62-3.56) in patients with HbA1c <53 and 2.89 (95% CI: 1.65-5.04) in patients with HbA1c ≥53 mmol/mol. CONCLUSIONS: In patients with type 2 diabetes, glycemic dysregulation did not affect the cardiovascular risk associated with NSAID use.