Reintervention rates following bioprosthetic surgical aortic valve replacement-a Danish Nationwide Cohort Study.

OBJECTIVES: Updated European guidelines recommend annual echocardiographic evaluation after bioprosthetic surgical aortic valve replacement (bio-SAVR). Given the increased demand on health care resources, only clinically relevant controls can be prioritized. We therefore aimed to explore reintervention rates following bio-SAVR. METHODS: From the nationwide Danish Register of Surgical Procedures, we identified all patients ≥40 years with isolated bio-SAVR ± concomitant coronary artery bypass graft surgery (CABG) during 2000-2016. In 90-day reintervention-free survivors, we assessed aortic valve reintervention rates (primary outcome) and all-cause mortality rates (secondary outcome) at 1, 3 and 5 years with total follow-up until 31 December 2017 and further estimated annual theoretical echocardiographic control visits. RESULTS: In 10 518 patients with bio-SAVR (+CABG 39.7%), we observed low reintervention rates at 1, 3 and 5 years, but with high rates of all-cause mortality; i.e. 5-year reintervention rate of 3.7/1000 person-years (≤1.5%) and 5-year mortality rate of 21.7/1000 person-years. Accounting for the competing risk of death, 5-year rates were inversely related to age group and remained relatively low across all age categories but increased gradually in the long term. A significant proportion of reinterventions were presumed due to infectious endocarditis (48% at 3 years, 37% at 5 years). With annual transthoracic echocardiography, the theoretical ratio of echocardiographies per reintervention in the first 5 years was 248, and 425 when endocarditis events were excluded. CONCLUSION: Reintervention rates within the first 5 years following bio-SAVR were relatively rare, and with a substantial number due to endocarditis.

Compliance in Primary Prevention With Statins and Associations With Cardiovascular Risk and Death in a Low-Risk Population With Type 2 Diabetes Mellitus.

Background We examined whether primary prevention with statins and high adherence to statins reduce the associated risk of cardiovascular events or death in a low-risk population with type 2 diabetes mellitus (T2D). Methods and Results Using Danish nationwide registers, we included patients with new-onset T2D, aged 40 to 89 years, between 2005 and 2011, who were alive 18 months following the T2D diagnosis (index date). In patients who purchased statins within 6 months following T2D diagnosis, we calculated the proportion of days covered (PDC) within 1 year after the initial 6-month period. We studied the combined end point of myocardial infarction, stroke, or all-cause mortality, whichever came first, with Cox regression. Reported were standardized 5-year risk differences for fixed comorbidity distribution according to statin treatment history, stratified by sex and age. Among 77 170 patients, 42 975 (56%) were treated with statins, of whom 31 061 (72%) had a PDC ≥80%. In men aged 70 to 79 years who were treated with statins, the standardized 5-year risk was 22.9% (95% CI, 21.5%-24.3%), whereas the risk was 29.1% (95% CI, 27.4%-30.7%) in men not treated, resulting in a significant risk reduction of 6.2% (95% CI, 4.0%-8.4%), P<0.0001. The risk reduction associated with statins increased with advancing age group (women: age 40-49 years, 0.0% [95% CI, -1.0% to 1.0%]; age 80-89 years, 10.8% [95% CI, 7.2%-14.4%]). Standardizing to all patients treated with statins, PDC <80% was associated with increased risk difference (reference PDC ≥80%; PDC <20%, 4.2% [95% CI, 2.9%-5.6%]). Conclusions This study supports the use of statins as primary prevention against cardiovascular diseases or death in 18-month surviving low-risk patients with T2D, with the highest effect in the elderly and adherent patients.

Cardiovascular complications in patients with total cavopulmonary connection: A nationwide cohort study.

BACKGROUND: Long-term outcomes are not well established at the population level after completion of the total cavopulmonary connection (TCPC) among patients with functional univentricular hearts. PURPOSE: To evaluate the incidence of cardiovascular events after TCPC completion. METHODS: From a validated population-based cohort, we identified 178 patients with TCPC circulation completed after January 1, 1995. We established a comparison cohort by frequency-matching patients 1:200 on sex, and month and year of birth to the general Danish population (n = 35,600 population controls). We started follow-up at date of TCPC completion for cases and, for controls, at the index date of their matched case. The risks of cardiovascular events were assessed using cumulative incidence rates and Poisson regression models adjusted for age, sex, and calendar year. RESULTS: The median age at TCPC completion was 3.3 years (interquartile range 2.6 to 5.3 years). Over a median follow-up of 12.5 years, 10 (5.6%) TCPC patients died and 7 (4.5%) had a heart transplantation compared with a 0.2% mortality in the matched population. In TCPC patients, 15.7% had an arrhythmia (11.8% supraventricular tachycardia), 3.4% had a stroke (all ischemic), and 21.4% of TCPC patients initiated a combination of a diuretic and a renin-angiotensin system (RAS)-inhibitor. These rates were >50-fold higher than in the comparison cohort: 0.2% arrhythmia, 0.06% stroke, and 0.04% starting a diuretic and a RAS-inhibitor. CONCLUSIONS: Patients with TCPC circulation face a high risk of cardiovascular events during intermediate term follow-up.

Does type 2 diabetes confer higher relative rates of cardiovascular events in women compared with men?

AIMS: To investigate whether diabetes confers higher relative rates of cardiovascular events in women compared with men using contemporary data, and whether these sex-differences depend on age. METHODS AND RESULTS: All Danish residents aged 40-89 years without a history major adverse cardiovascular events, including heart failure, as of 1 January 2012 until 31 December 2016 were categorized by diabetes-status and characterized by individual-level linkage of Danish nationwide administrative registers. We used Poisson regression to calculate overall and age-dependent incidence rates, incidence rate ratios, and women-to-men ratios for myocardial infarction, heart failure, ischaemic stroke, or cardiovascular death (MACE-HF). Among 218 549 (46% women) individuals with diabetes, the absolute rate of MACE-HF was higher in men than in women (24.9 vs. 19.9 per 1000 person-years). Corresponding absolute rates in men and women without diabetes were 10.1 vs. 7.0 per 1000 person-years. Comparing individuals with and without diabetes, women had higher relative rates of MACE-HF than men [2.8 (confidence interval, CI 2.9-2.9) in women vs. 2.5 (CI 2.4-2.5) in men] with a women-to-men ratio of 1.15 (CI 1.11-1.19, P < 0.001). The relative rates of MACE-HF were highest in the youngest and decreased with advancing age for both men and women, but the relative rates were higher in women across all ages, with the highest women-to-men ratio between age 50 and 60 years. CONCLUSION: Although men have higher absolute rates of cardiovascular complications, the relative rates of cardiovascular complications associated with diabetes are higher in women than in men across all ages in the modern era.

Incidence of new onset cancer in patients with a myocardial infarction - a nationwide cohort study.

BACKGROUND: Few studies have suggested that patients with myocardial infarction (MI) may be at increased risk of cancer, but further large register-based studies are needed to evaluate this subject. The aim of this study was to assess the incident rates of cancer and death by history of MI, and whether an MI is independently associated with cancer in a large cohort study. METHOD: All Danish residents aged 30-99 in 1996 without prior cancer or MI were included and were followed until 2012. Patients were grouped according to incident MI during follow-up. Incidence rates (IR) of cancer and death in individuals with and without MI and incidence rate ratios (IRR, using multivariable Poisson regression analyses) of cancer associated with an MI were calculated. RESULTS: Of 2,871,168 individuals, 122,275 developed an MI during follow-up, 11,375 subsequently developed cancer (9.3%, IR 19.1/1000 person-years) and 65,225 died (53.3%, IR 106.0/1000 person-years). In the reference population, 372,397 developed cancer (13.0%, IR 9.3/1000 person-years) and 753,767 died (26.3%, IR 18.2/1000 person-years). Compared to the reference population, higher IRs of cancer and death were observed in all age groups (30-54, 55-69 and 70-99 years) and time since an MI (0-1, 1-5 and 5-17 years) in the MI population. MI was associated with an increased risk of overall cancer (IRR 1.14, 95% CI 1.10-1.19) after adjusting for age, sex and calendar year, also when additionally adjusting for chronic obstructive pulmonary disease, hypertension, dyslipidemia, diabetes and socioeconomic status (IRR 1.08, 95% CI 1.03-1.13), but not after further adjustment for the first 6 months post-MI (IRR 1.00, 95% CI 0.96-1.05). CONCLUSION: Patients after an MI have increased incidence of cancer, which may be explained by mutual risk, occult cancers and increased surveillance. Focus on risk factor management to reduce cancer and MI is warranted.

Staphylococcus aureus Bacteremia in Children Aged 5-18 Years-Risk Factors in the New Millennium.

OBJECTIVES: To assess the association between comorbidities and Staphylococcus aureus bacteremia in children aged 5-18 years, thus, in children with a matured immune system. Further, we aimed to identify presumably healthy children acquiring bacteremia. STUDY DESIGN: By cross-linking nationwide registries, we consecutively included all children born from 1995 onward at their 5-year birthday or date of immigration during 2000-2015. We examined incidence rate ratios (IRR) between preselected exposures and microbiologically verified S aureus bacteremia (reference = children without exposure) using Poisson regression models. RESULTS: We followed 1 109 169 children in 2000-2015 during which 307 children (incidence rate: 3.7 per 100 000 person-years) acquired S aureus bacteremia (methicillin-resistant S aureus = 8; 2.6%). Children without known comorbidities or recent contact with the healthcare system comprised 37.1% of infected children. The highest IRRs were observed in children undergoing dialysis or plasmapheresis (IRR = 367.2 [95% CI) = 188.5-715.3]), children with organ transplantation (IRR = 149.5 [95% CI = 73.9-302.2]), and children with cancer (IRR = 102.9 [95% CI = 74.4-142.2]). Positive associations also were observed in children with chromosomal anomalies (IRR = 7.16 [95% CI = 2.96-17.34]), atopic dermatitis (IRR = 4.89 [95% CI = 3.11-7.69]), congenital heart disease (IRR = 3.14 [95% CI = 1.92-5.11]), and in children undergoing surgery (IRR = 3.34 [95% CI = 2.59-4.28]). Neither premature birth nor parental socioeconomic status was associated with increased disease rates. CONCLUSIONS: S aureus bacteremia is uncommon in children between 5 and 18 years of age. Risk factors known from the adult population, such as dialysis, plasmapheresis, organ transplantation, and cancer, were associated with the highest relative rates. However, prematurity and parental socioeconomic status were not associated with increased rates. Approximately one-third of infected children were presumably healthy.

The associations between socioeconomic status and risk of Staphylococcus aureus bacteremia and subsequent endocarditis - a Danish nationwide cohort study.

BACKGROUND: Staphylococcus aureus bacteremia (SAB) is the leading cause of infective endocarditis in several countries. Since socioeconomic status (SES) is known to influence the risk of infectious diseases in general, we aimed to investigate the association between SES and SAB, and risk of subsequent endocarditis in a nationwide adult population. METHODS: All Danish residents were consecutively included at age ≥ 30 years during 1996-2010. We obtained information on SES (highest attained educational level), comorbidities, and microbiologically verified SAB by cross-linking nationwide registries. The incidence rate ratios (IRRs) of SAB and later endocarditis were investigated using Poisson regression models adjusted for sex, age and year (reference = highest SES). RESULTS: Our study population comprised 3,394,936 individuals (median age = 43.2 years). Over a median follow-up of 15.9 years, 13,181 individuals acquired SAB. SES was inversely associated with SAB acquisition, which declined with increasing age, e.g. in individuals with lowest SES, IRRs were 3.78 (95% confidence interval [CI] = 2.89-4.95) in age 30-50 years, 1.87 (CI = 1.60-2.18) in age > 50-70 years and 1.31 (CI = 1.11-1.54) in age > 70 years (interaction-p < 0.0001). Adjustment for comorbidities attenuated the IRRs, but the pattern persisted. No association between SES and endocarditis risk among patients with SAB was observed. CONCLUSIONS: Decreasing SES was associated with an increased risk of SAB, particularly in younger adults. SES was not associated with risk of subsequent endocarditis.

Use of digoxin and risk of death or readmission for heart failure and sinus rhythm: A nationwide propensity score matched study.

BACKGROUND/OBJECTIVES: Digoxin is widely used as symptomatic treatment in heart failure (HF), but the role in contemporary treatment of HF with sinus rhythm (SR) is debatable. We investigated the risk of death and hospital readmission, according to digoxin use, in a nationwide cohort of digoxin-naïve patients with HF and SR. METHODS: From Danish nationwide registries, digoxin-naïve HF patients from 1996 to 2012 were identified. Patients with cardiac dysrhythmias or use of warfarin were excluded. Digoxin users and non-users were compared in propensity matched cox regression models with respect to primary outcomes of all-cause mortality and HF readmission. RESULTS: The study population comprised 5327 digoxin users and 10,654 matched non-users with a median age of 77. During follow-up 10,643 (66.6%) patients died and 7584 (47.5%) patients were readmitted due to HF. Use of digoxin was associated with increased risk of death (hazard ratio (HR): 1.19, 95%-CI: 1.15-1.24) and increased risk of HF readmission (HR: 1.19, 95%-CI: 1.13-1.25). Cumulative incidences of readmission, considering death as a competing risk was 50% for digoxin users and 47% for non-users. The associations applied regardless of concomitant HF treatment. In an exploratory analysis considering patients with previous digoxin use, no effect on mortality (HR: 1.00, 95%-CI: 0.94-1.06), nor on HF readmission (HR: 1.00, 95%-CI: 0.93-1.09) was observed. CONCLUSION: In chronic HF with SR, digoxin was associated with a slightly increased risk of death and was not associated with decreased HF readmission rates.

Familial Clustering of Staphylococcus aureus Bacteremia in First-Degree Relatives: A Danish Nationwide Cohort Study.

BACKGROUND: A genetic predisposition to Staphylococcus aureus bacteremia has been demonstrated in animals, suggesting that genetic differences might influence susceptibility to S aureus in humans. OBJECTIVE: To determine whether a history of S aureus bacteremia in first-degree relatives increases the rate of the disease, and whether this rate is affected by the type of family relationship (that is, parent or sibling) or by how the relative acquired the infection. DESIGN: Register-based nationwide cohort study (1992 to 2011). SETTING: Denmark. PARTICIPANTS: First-degree relatives (children or siblings) of patients previously hospitalized with S aureus bacteremia. MEASUREMENTS: Poisson regression models were used to calculate standardized incidence ratios (SIRs) of S aureus bacteremia, with the incidence rate in the population as a reference. RESULTS: 34 774 individuals (the exposed cohort) with a first-degree relative (index case patient) previously hospitalized with S aureus bacteremia were followed up for a median of 7.8 years (interquartile range, 3.6 to 13.0). A higher rate of S aureus bacteremia was observed among these first-degree relatives (SIR, 2.49 [95% CI, 1.95 to 3.19]) than in the background population. The estimate was significantly higher if the index case patient was a sibling (SIR, 5.01 [CI, 3.30 to 7.62]) than a parent (SIR, 1.96 [CI, 1.45 to 2.67]; interaction P < 0.0001). No interaction was observed regarding the sex of the first-degree relative (interaction P for parents = 0.85; interaction P for siblings = 0.92). Stratifying by disease acquisition revealed the highest rates in individuals exposed to index case patients with non-hospital-acquired infection. Few were infected with genetically identical bacteremia isolates. LIMITATION: The rarity of the outcome limited the number of variables in the multiple regression analysis, and whether nonsignificant interactions were true or caused by insufficient statistical power remains uncertain. CONCLUSION: A significant familial clustering of S aureus bacteremia was found, with the greatest relative rate of disease observed in individuals exposed to siblings with a history of the disease. PRIMARY FUNDING SOURCE: The Danish Heart Foundation and the Christian Larsen and Judge Ellen Larsen Foundation.

Associations between metabolic disorders and risk of cancer in Danish men and women--a nationwide cohort study.

BACKGROUND: The prevalence of metabolic disorders is increasing and has been suggested to increase cancer risk, but the relation between metabolic disorders and risk of cancer is unclear, especially in young adults. We investigated the associations between diabetes, hypertension, and hypercholesterolemia on risk of all-site as well as site-specific cancers. METHODS: We consecutively included men and women from nationwide Danish registries 1996-2011, if age 20-89 and without cancer prior to date of entry. We followed them throughout 2012. Metabolic disorders were defined using discharge diagnosis codes and claimed prescriptions. We used time-dependent sex-stratified Poisson regression models adjusted for age and calendar year to assess associations between metabolic disorders, and risk of all-site and site-specific cancer (no metabolic disorders as reference). RESULTS: Over a mean follow-up of 12.6 (± 5.7 standard deviations [SD]) years, 4,826,142 individuals (50.2% women) with a mean age of 41.4 (± 18.9 SD) years had 423,942 incident cancers. Incidence rate ratios (IRRs) of all-site cancer in patients with diabetes or hypertension were highest immediately following diagnosis of metabolic disorder. In women, cancer risk associated with diabetes continued to decline albeit remained significant (IRRs of 1.18-1.22 in years 1-8 following diagnosis). For diabetes in men, and hypertension, IRRs stabilized and remained significantly increased after about one year with IRRs of 1.10-1.13 in men for diabetes, and 1.07-1.14 for hypertension in both sexes. Conversely, no association was observed between hypercholesterolemia (treatment with statins) and cancer risk. The association between hypertension and cancer risk was strongest in young adults aged 20-34 and decreased with advancing age. CONCLUSIONS: Diabetes and hypertension were associated with increased risk of all-site cancer.

Cost-Effectiveness of Adding Cardiac Resynchronization Therapy to an Implantable Cardioverter-Defibrillator Among Patients With Mild Heart Failure.

BACKGROUND: Cardiac resynchronization therapy (CRT) reduces mortality and heart failure hospitalizations in patients with mild heart failure. OBJECTIVE: To estimate the cost-effectiveness of adding CRT to an implantable cardioverter-defibrillator (CRT-D) compared with implantable cardioverter-defibrillator (ICD) alone among patients with left ventricular systolic dysfunction, prolonged intraventricular conduction, and mild heart failure. DESIGN: Markov decision model. DATA SOURCES: Clinical trials, clinical registries, claims data from Centers for Medicare & Medicaid Services, and Centers for Disease Control and Prevention life tables. TARGET POPULATION: Patients aged 65 years or older with a left ventricular ejection fraction (LVEF) of 30% or less, QRS duration of 120 milliseconds or more, and New York Heart Association (NYHA) class I or II symptoms. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: CRT-D or ICD alone. OUTCOME MEASURES: Life-years, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). RESULTS OF BASE-CASE ANALYSIS: Use of CRT-D increased life expectancy (9.8 years versus 8.8 years), QALYs (8.6 years versus 7.6 years), and costs ($286 500 versus $228 600), yielding a cost per QALY gained of $61 700. RESULTS OF SENSITIVITY ANALYSES: The cost-effectiveness of CRT-D was most dependent on the degree of mortality reduction: When the risk ratio for death was 0.95, the ICER increased to $119 600 per QALY. More expensive CRT-D devices, shorter CRT-D battery life, and older age also made the cost-effectiveness of CRT-D less favorable. LIMITATIONS: The estimated mortality reduction for CRT-D was largely based on a single trial. Data on patients with NYHA class I symptoms were limited. The cost-effectiveness of CRT-D in patients with NYHA class I symptoms remains uncertain. CONCLUSION: In patients with an LVEF of 30% or less, QRS duration of 120 milliseconds or more, and NYHA class II symptoms, CRT-D appears to be economically attractive relative to ICD alone when a reduction in mortality is expected. PRIMARY FUNDING SOURCE: National Institutes of Health, University of Copenhagen, U.S. Department of Veterans Affairs.

Insulin Resistance and Risk of Cardiovascular Disease in Postmenopausal Women: A Cohort Study From the Women's Health Initiative.

BACKGROUND: Insulin resistance is associated with diabetes mellitus, but it is uncertain whether it improves cardiovascular disease (CVD) risk prediction beyond traditional cardiovascular risk factors. METHODS AND RESULTS: We identified 15,288 women from the Women's Health Initiative Biomarkers studies with no history of CVD, atrial fibrillation, or diabetes mellitus at baseline (1993-1998). We assessed the prognostic value of adding fasting serum insulin, HOMA-IR (homeostasis model assessment-insulin resistance), serum-triglyceride-to-serum-high-density lipoprotein-cholesterol ratio TG/HDL-C, or impaired fasting glucose (serum glucose ≥110 mg/dL) to traditional risk factors in separate Cox multivariable analyses and assessed risk discrimination and reclassification. The study end point was major CVD events (nonfatal and fatal coronary heart disease and ischemic stroke) within 10 years, which occurred in 894 (5.8%) women. Insulin resistance was associated with CVD risk after adjusting for age and race/ethnicity with hazard ratios (95% confidence interval [CI]) per doubling in insulin of 1.21 (CI, 1.12-1.31), in HOMA-IR of 1.19 (CI, 1.11-1.28), in TG/HDL-C of 1.35 (CI, 1.26-1.45), and for impaired fasting glucose of 1.31 (CI, 1.05-1.64). Although insulin, HOMA-IR, and TG/HDL-C remained associated with increased CVD risk after adjusting for most CVD risk factors, none remained significant after adjusting for HDL-C: hazard ratios for insulin, 1.06 (CI, 0.98-1.16); for HOMA-IR, 1.06 (CI, 0.98-1.15); for TG/HDL-C, 1.11 (CI, 0.99-1.25); and for glucose, 1.20 (CI, 0.96-1.50). Insulin resistance measures did not improve CVD risk discrimination and reclassification. CONCLUSIONS: Measures of insulin resistance were no longer associated with CVD risk after adjustment for high-density lipoprotein-cholesterol and did not provide independent prognostic information in postmenopausal women without diabetes mellitus. CLINICAL TRIAL REGISTRATION INFORMATION: URL: http://www.clinicaltrial.gov. Unique identifier: NCT00000611.

Race and ethnicity, obesity, metabolic health, and risk of cardiovascular disease in postmenopausal women.

BACKGROUND: It is unclear whether obesity unaccompanied by metabolic abnormalities is associated with increased cardiovascular disease risk across racial and ethnic subgroups. METHODS AND RESULTS: We identified 14 364 postmenopausal women from the Women's Health Initiative who had data on fasting serum lipids and serum glucose and no history of cardiovascular disease or diabetes at baseline. We categorized women by body mass index (in kg/m(2)) as normal weight (body mass index 18.5 to <25), overweight (body mass index 25 to <30), or obese (body mass index ≥30) and by metabolic health, defined first as the metabolic syndrome (metabolically unhealthy: ≥3 metabolic abnormalities) and second as the number of metabolic abnormalities. We used Cox proportional hazards regression to assess associations between baseline characteristics and cardiovascular risk. Over 13 years of follow-up, 1101 women had a first cardiovascular disease event (coronary heart disease or ischemic stroke). Among black women without metabolic syndrome, overweight women had higher adjusted cardiovascular risk than normal weight women (hazard ratio [HR] 1.49), whereas among white women without metabolic syndrome, overweight women had similar risk to normal weight women (HR 0.92, interaction P=0.05). Obese black women without metabolic syndrome had higher adjusted risk (HR 1.95) than obese white women (HR 1.07; interaction P=0.02). Among women with only 2 metabolic abnormalities, cardiovascular risk was increased in black women who were overweight (HR 1.77) or obese (HR 2.17) but not in white women who were overweight (HR 0.98) or obese (HR 1.06). Overweight and obese women with ≤1 metabolic abnormality did not have increased cardiovascular risk, regardless of race or ethnicity. CONCLUSIONS: Metabolic abnormalities appeared to convey more cardiovascular risk among black women.

Time elapsed after ischemic stroke and risk of adverse cardiovascular events and mortality following elective noncardiac surgery.

IMPORTANCE: The timing of surgery in patients with recent ischemic stroke is an important and inadequately addressed issue. OBJECTIVE: To assess the safety and importance of time elapsed between stroke and surgery in the risk of perioperative cardiovascular events and mortality. DESIGN, SETTING, AND PARTICIPANTS: Danish nationwide cohort study (2005-2011) including all patients aged 20 years or older undergoing elective noncardiac surgeries (n=481,183 surgeries). EXPOSURES: Time elapsed between stroke and surgery in categories and as a continuous measure. MAIN OUTCOMES AND MEASURES: Risk of major adverse cardiovascular events (MACE; including ischemic stroke, acute myocardial infarction, and cardiovascular mortality) and all-cause mortality up to 30 days after surgery. Odds ratios (ORs) were calculated by multivariable logistic regression models. RESULTS: Crude incidence rates of MACE among patients with (n = 7137) and without (n = 474,046) prior stroke were 54.4 (95% CI, 49.1-59.9) vs 4.1 (95% CI, 3.9-4.2) per 1000 patients. Compared with patients without stroke, ORs for MACE were 14.23 (95% CI, 11.61-17.45) for stroke less than 3 months prior to surgery, 4.85 (95% CI, 3.32-7.08) for stroke 3 to less than 6 months prior, 3.04 (95% CI, 2.13-4.34) for stroke 6 to less than 12 months prior, and 2.47 (95% CI, 2.07-2.95) for stroke 12 months or more prior. MACE risks were at least as high for low-risk (OR, 9.96; 95% CI, 5.49-18.07 for stroke <3 months) and intermediate-risk (OR, 17.12; 95% CI, 13.68-21.42 for stroke <3 months) surgery compared with high-risk surgery (OR, 2.97; 95% CI, 0.98-9.01 for stroke <3 months) (P = .003 for interaction). Similar patterns were found for 30-day mortality: ORs were 3.07 (95% CI, 2.30-4.09) for stroke less than 3 months prior, 1.97 (95% CI, 1.22-3.19) for stroke 3 to less than 6 months prior, 1.45 (95% CI, 0.95-2.20) for stroke 6 to less than 12 months prior, and 1.46 (95% CI, 1.21-1.77) for stroke 12 months or more prior to surgery compared with patients without stroke. Cubic regression splines performed on the stroke subgroup supported that risk leveled off after 9 months. CONCLUSIONS AND RELEVANCE: A history of stroke was associated with adverse outcomes following surgery, in particular if time between stroke and surgery was less than 9 months. After 9 months, the associated risk appeared stable yet still increased compared with patients with no stroke. The time dependency of risk may warrant attention in future guidelines.

Associations between body mass index and development of metabolic disorders in fertile women--a nationwide cohort study.

BACKGROUND: Metabolic disorders are relatively uncommon in young women, but may increase with obesity. The associations between body mass index (BMI) and risks of diabetes, hypertension, and dyslipidemia in apparently healthy, young women have been insufficiently investigated, and are the aims of this study. METHODS AND RESULTS: Women giving birth during the years 2004-2009, with no history of cardiovascular disease, renal insufficiency, pregnancy-associated metabolic disorders, diabetes, hypertension, or dyslipidemia were identified in nationwide registers. Women were categorized as underweight (BMI<18.5 kg/m(2)), normal weight (BMI=18.5 to <25 kg/m(2)), overweight (BMI=25 to <30 kg/m(2)), obese-I (BMI=30 to <35 kg/m(2)), obese-II (BMI=35 to <40 kg/m(2)), and obese-III (BMI≥40 kg/m(2)). We assessed risks by Poisson regression models (adjusted for age, calendar year; reference=normal weight). The cohort comprised 252 472 women with a median age of 30.4 years (IQR=27.2;33.7) and a median follow-up of 5.5 years (IQR=3.9;6.8). In total, 2029 women developed diabetes, 3133 women developed hypertension, and 1549 women developed dyslipidemia. Rate ratios (RRs) of diabetes were: 0.84 (95% confidence interval [CI]=0.62 to 1.14) for underweight, 2.63 (CI=2.36 to 2.93) for overweight, 4.83 (CI=4.27 to 5.47) for obese grade-I, 7.17 (CI=6.10 to 8.48) for obese grade-II, and 6.93 (CI=5.47 to 8.79) for obese grade-III women. For hypertension, corresponding RRs were 0.86 (CI=0.69 to 1.09), 1.82 (CI=1.67 to 1.98), 2.81 (CI=2.52 to 3.13), 3.92 (CI=3.36 to 4.56), and 5.69 (CI=4.71 to 6.89), and for dyslipidemia, RRs were 1.18 (CI=0.85 to 1.65), 2.01 (CI=1.75 to 2.31), 3.11 (CI=2.61 to 3.70), 4.64 (CI=3.66 to 5.87), and 3.72 (CI=2.53 to 5.48). CONCLUSIONS: In this nationwide study of fertile, apparently healthy women, pre-pregnancy BMI was strongly associated with an increased risk of diabetes, hypertension, and dyslipidemia within 5.5 years following childbirth.

Prepregnancy obesity and associations with stroke and myocardial infarction in women in the years after childbirth: a nationwide cohort study.

BACKGROUND: Cardiovascular events (stroke or myocardial infarction) are often associated with poorer prognosis in younger, compared with older individuals. We examined the associations between prepregnancy obesity and the risks of myocardial infarction and stroke in young, healthy women. METHODS AND RESULTS: All Danish women giving birth during 2004-2009 without a history of renal disease or cardiovascular disease were identified from national registers and followed for a median time of 4.5 years (interquartile range, 2.8-5.8). They were grouped according to prepregnancy body mass index (BMI) in underweight (BMI<18.5 kg/m(2)), normal weight (BMI=18.5-<25 kg/m(2)), overweight (BMI=25-<30 kg/m(2)), and obese (BMI≥30 kg/m(2)). The hazard ratios of myocardial infarction, ischemic stroke, and a composite outcome (myocardial infarction, stroke, cardiovascular death) were assessed using multivariable Cox regression models. We included 273 101 women with a median age of 30.4 years (interquartile range, 27.2-33.8). A total of 68 women experienced a myocardial infarction, and 175 women experienced an ischemic stroke. The adjusted hazard ratios of myocardial infarction compared with normal weight were 2.50 (95% confidence interval [95% CI], 0.97-6.50) in underweight, 1.68 (95% CI, 0.92-3.06) in overweight, and 2.63 (95% CI, 1.41-4.91) in obese women. For ischemic stroke the adjusted hazard ratios were 1.06 (95% CI, 0.44-2.28) in underweight, 1.27 (95% CI, 0.87-1.85) in overweight, and 1.89 (95% CI, 1.25-2.84) in obese women, respectively. For the composite outcome, hazard ratios were 1.34 (95% CI, 0.81-2.20), 1.43 (95% CI, 1.11-1.84), and 1.76 (95% CI, 1.31-2.34) for underweight, overweight, and obese women. CONCLUSIONS: In apparently healthy women of fertile age, prepregnancy obesity was associated with increased risks of ischemic stroke and myocardial infarction in the years after childbirth.

Risk factors for venous thromboembolism during pregnancy.

BACKGROUND: Pregnant women are at an increased risk of venous thromboembolism (VTE). Risk factors for VTE among pregnant women are not sufficiently investigated. PURPOSE: To examine pharmacological and non-pharmacological VTE risk factors during pregnancy (antepartum). METHODS: The population comprised all pregnant women in Denmark aged 15-50 giving birth 2003-2010. Pregnancies were linked on an individual level with national registers for hospital admissions and drug dispenses from pharmacies. Risk of first occurring VTE antepartum was examined with Cox regression models. RESULTS: Out of 299 810 pregnancies, 337 experienced a VTE, incidence rate 1.1 (95% confidence interval [CI] 1.0-1.3) per 1000 pregnancies. Being underweight (body mass index [BMI] < 18.5 kg/m(2) ) was associated with a decreased risk of VTE (hazard ratio [HR] 0.53 [CI 0.29-0.98]) compared to normal weight (18.5 ≤ BMI < 25 kg/m(2) ). Overweight (25 ≤ BMI < 30 kg/m(2) ) increased VTE risk (HR 1.30 [CI 1.01-1.67]) but obesity (BMI ≥ 30 kg/m(2) ) was insignificant (HR 1.14 [CI 0.82-1.58]). A history of VTE was highly significant (HR 72.65 [CI 51.17-103.15]). The youngest (<20 years) and oldest (≥35 years) had insignificantly increased risks (HR 1.45 [CI 0.80-2.62] and HR 1.31 [CI 0.98-1.75], respectively) compared to those aged 20-30 years. Sixteen groups of medications, including anti-infectious medications, hormones, aminosalicylic acid, insulin, and benzodiazepine derivatives, were associated with VTE. CONCLUSION: The risk of antepartum VTE was increased in women with prior VTE. Compared to normal weight women, being underweight decreased the risk of VTE whereas being overweight increased the risk. Also, the use of several medications was associated with increased risk of VTE.

Obesity is a risk factor for atrial fibrillation among fertile young women: a nationwide cohort study.

AIMS: Obesity has been associated with increased risk of atrial fibrillation (AF), but whether this risk is also prevalent in younger individuals is unknown. We therefore investigated the risk of AF in relation to body mass index (BMI) among young fertile women. METHODS AND RESULTS: By cross-linkage of nationwide registers of childbirth and hospitalization, we identified 271 203 women without prior AF who gave birth in Denmark between 2004 and 2009. Body mass index (kg/m(2)) was examined as a risk factor for AF using proportional hazard models. Mean age was 30.6 years (4.7 SD) and median follow-up was 4.6 years (interquartile range 2.9-5.8). During the follow-up, 110 women were hospitalized with first-time AF; very few individuals had known risk factors for AF. Overall incidence rate of AF was 9.3 [95% confidence interval (CI): 7.7-11.2] per 100 000 person-years. According to BMI, the incidence rate of AF per 100 000 person-years was 7.4 (5.6-9.7) in normal weight (BMI: 18.5-24.9), 8.5 (5.5-13.1) in overweight (BMI: 25-29.9), 15.8 (9.3-26.7) in obese (BMI: 30-35), and 27.3 (15.5-48.1) in very obese (BMI >35) individuals. Multivariable regression analyses adjusted for age, hyperthyroidism, and previous use of beta-blockers revealed a hazard ratio of 2.04 (95% CI: 1.13-3.69) in the obese and 3.50 (1.86-6.58) in the very obese individuals compared with normal weight. CONCLUSION: Obesity is a risk factor for AF among young and essentially healthy fertile women despite the low incidence of AF. These results may have implications for prevention of AF.

Relation of body mass index to risk of stent thrombosis after percutaneous coronary intervention.

Stent thrombosis is a devastating complication after percutaneous coronary intervention (PCI), but the influence of obesity on risk of stent thrombosis is unclear, and it is unknown if this relation is dependent on stent type. The objective of this study was to examine the relation between body mass index (BMI) and stent thrombosis after PCI with bare-metal stent (BMS) or drug-eluting stent (DES). We followed 5,515 patients who underwent PCI with implantation of ≥1 BMS or DES at a high-volume tertiary invasive cardiology center from 2000 through 2006. Only patients with a single type of stent (BMS or DES) implanted at the index PCI were included. Median follow-up period was 26 months (interquartile range 12 to 44) and definite stent thrombosis occurred in 78 patients. Hazard ratio of definite stent thrombosis adjusted for number of stents at the index PCI was 0.92 (95% confidence interval [CI] 0.86 to 0.97) for each increase in kilograms per square meter of BMI. There was no significant interaction between stent type and BMI (p = 0.48). Hazard ratios for probable stent thrombosis and possible stent thrombosis adjusted for numbers of stents at the index PCI were 1.01 (CI 0.99 to 1.03) and 0.99 (CI 0.98 to 1.01) for each increase in kilograms per square meter of BMI, respectively. In conclusion, BMI was inversely correlated with risk of definite stent thrombosis after PCI irrespective of stent type.

Risk of cancer in patients using glucose-lowering agents: a nationwide cohort study of 3.6 million people.

OBJECTIVES: To study the association between exposures to glucose-lowering therapy and risk of cancer using the nationwide administrative registers in Denmark. DESIGN: Nationwide cohort study. SETTING: All hospitals in Denmark. PARTICIPANTS: All individuals aged ≥35 years in 1998-2009 who were naive to glucose-lowering treatment and had no history of cancer. Primary measures outcomes: first cancer diagnosis between 1998 and 2009. The RR of cancer as dependent on exposure to individual glucose-lowering agents was assessed by multivariable Poisson regression models. RESULTS: Of 159 894 patients that initiated treatment with glucose-lowering agents, 12 789 developed cancer, incidence rate 17.4/1000 person-years. Of the remaining 3 447 904 individuals not using glucose-lowering agents, 293 878 developed cancer, incidence rate 7.9/1000 person-years. Use of different types of glucose-lowering agents including human insulin, insulin analogues, as well as sulfonylureas were associated with a quantitatively similar and significantly increased RR of cancer of 1.2-1.3 compared with unexposed individuals after multivariable adjustment. For the majority of agents, the authors identified the highest RR of cancer during the first 30 treatment days with a subsequent decline of risk approaching the cancer risk of the background population only 6-12 months after initiation of treatments. CONCLUSIONS: Use of most glucose-lowering agents including sulfonylureas was associated with a comparable increased risk of cancer shortly after initiation of treatment and subsequently a decline to the risk of the background population. This suggests that the relation is not causal.