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1.  Exposure to Mebendazole and Pyrvinium during Pregnancy: A Danish Nationwide Cohort Study 
Purpose. Families with children are frequently exposed to pinworm infection and treatment involves the whole family. Information on consequences of exposure during, pregnancy is limited. The aim of this study was to investigate the exposure to pyrvinium and mebendazole before, during, and after pregnancy in a Danish nationwide cohort. Methods. From nationwide administrative registers, we identified 718, 900 births in Denmark between January 1997 and December 2007 as well as maternal prescription data of anthelmintics and maternal characteristics. Redemption of a prescription for pyrvinium or mebendazole was used to identify exposure. Results. 4715 women redeemed a prescription for pyrvinium or mebendazole during pregnancy; 1606 for pyrvinium, 2575 for mebendazole, and 534 for both drugs. Having >2 children compared to having no previous children was associated with exposure to pyrvinium (OR: 7.1, 95% CI: 5.8–8.7) and mebendazole (OR: 20.8, 95% CI: 17.3–24.9). Conclusion. 4715 pregnant women redeemed a prescription for either mebendazole or pyrvinium. We believe the exposure to be even higher since pyrvinium is also sold over-the-counter. Limited information on birth outcomes is available at present time, and considering the number of exposed pregnancies, we recommend that studies are to be undertaken to assess the safety of pyrvinium and mebendazole during pregnancy.
PMCID: PMC3458300  PMID: 23028209
2.  How Many Measurements Are Needed to Estimate Blood Pressure Variability Without Loss of Prognostic Information? 
Average real variability (ARV) is a recently proposed index for short-term blood pressure (BP) variability. We aimed to determine the minimum number of BP readings required to compute ARV without loss of prognostic information.
ARV was calculated from a discovery dataset that included 24-hour ambulatory BP measurements for 1,254 residents (mean age = 56.6 years; 43.5% women) of Copenhagen, Denmark. Concordance between ARV from full (≥80 BP readings) and randomly reduced 24-hour BP recordings was examined, as was prognostic accuracy. A test dataset that included 5,353 subjects (mean age = 54.0 years; 45.6% women) with at least 48 BP measurements from 11 randomly recruited population cohorts was used to validate the results.
In the discovery dataset, a minimum of 48 BP readings allowed an accurate assessment of the association between cardiovascular risk and ARV. In the test dataset, over 10.2 years (median), 806 participants died (335 cardiovascular deaths, 206 cardiac deaths) and 696 experienced a major fatal or nonfatal cardiovascular event. Standardized multivariable-adjusted hazard ratios (HRs) were computed for associations between outcome and BP variability. Higher diastolic ARV in 24-hour ambulatory BP recordings predicted (P < 0.01) total (HR = 1.12), cardiovascular (HR = 1.19), and cardiac (HR = 1.19) mortality and fatal combined with nonfatal cerebrovascular events (HR = 1.16). Higher systolic ARV in 24-hour ambulatory BP recordings predicted (P < 0.01) total (HR = 1.12), cardiovascular (HR = 1.17), and cardiac (HR = 1.24) mortality.
Forty-eight BP readings over 24 hours were observed to be adequate to compute ARV without meaningful loss of prognostic information.
PMCID: PMC3848629  PMID: 23955605
ambulatory blood pressure; blood pressure; blood pressure variability; epidemiology; hypertension; population science; risk factors.
3.  Association of Hypoglycemic Treatment Regimens With Cardiovascular Outcomes in Overweight and Obese Subjects With Type 2 Diabetes 
Diabetes Care  2013;36(11):3746-3753.
To assess the association of hypoglycemic treatment regimens with cardiovascular adverse events and mortality in a large population of type 2 diabetic patients at increased cardiovascular risk.
This analysis included 8,192 overweight patients with type 2 diabetes from the Sibutramine Cardiovascular Outcomes (SCOUT) trial randomized to lifestyle intervention with or without sibutramine for up to 6 years. Patients were grouped according to hypoglycemic treatment at baseline. The primary end point was the time from randomization to the first occurrence of a primary outcome event (POE), nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death. Multivariable Cox proportional hazards regression models were used to assess the impact of antiglycemic treatment on POE and all-cause mortality.
Treatments for type 2 diabetes were as follows: diet alone (n = 1,394 subjects), metformin monotherapy (n = 1,631), insulin monotherapy (n = 1,116), sulfonylurea monotherapy (n = 1,083), metformin plus sulfonylurea (n = 1,565), and metformin plus insulin (n = 1,000); 905 subjects experienced a POE and 708 died. Metformin monotherapy was associated with lower risk of POE than insulin (hazard ratio [HR], 0.74; 95% CI, 0.57–0.95; P = 0.02). Diet alone also was associated with lower risk of POE (HR, 0.65; 95% CI, 0.48–0.87; P = 0.004). Metformin monotherapy also was associated with lower mortality (HR, 0.73; 95% CI, 0.54–0.99; P < 0.05), whereas no other monotherapies or combination therapies were significantly associated with POE or all-cause mortality compared with insulin as monotherapy.
In obese patients with type 2 diabetes and high risk of cardiovascular disease, monotherapy with metformin or diet-only treatment was associated with lower risk of cardiovascular events than treatment with insulin.
PMCID: PMC3816850  PMID: 24089540
4.  Individual social capital and survival: a population study with 5-year follow-up 
BMC Public Health  2014;14(1):1025.
The concept of social capital has received increasing attention as a determinant of population survival, but its significance is uncertain. We examined the importance of social capital on survival in a population study while focusing on gender differences.
We used data from a Danish regional health survey with a five-year follow-up period, 2007–2012 (n = 9288, 53.5% men, 46.5% women). We investigated the association between social capital and all-cause mortality, performing separate analyses on a composite measure as well as four specific dimensions of social capital while controlling for covariates. Analyses were performed with Cox proportional hazard models by which hazard ratios and 95% confidence intervals were calculated.
For women, higher levels of social capital were associated with lower all-cause mortality regardless of age, socioeconomic status, health, and health behaviour (HR = 0.586, 95% CI = 0.421-0.816) while no such association was found for men (HR = 0.949, 95% CI = 0.816-1.104). Analysing the specific dimensions of social capital, higher levels of trust and social network were significantly associated with lower all-cause mortality in women (HR = 0.827, 95% CI = 0.750-0.913 and HR = 0.832, 95% CI = 0.729-0.949, respectively). For men, strong social networks were associated with a higher risk of all-cause mortality (HR = 1.132, 95% CI = 1.017-1.260). Civic engagement had a similar effect for both men (HR = 0.848, 95% CI = 0.722-0.997) and women (HR = 0.848, 95% CI = 0.630-1.140).
We found differential effects of social capital in men compared to women. The predictive effects on all-cause mortality of four specific dimensions of social capital varied. Gender stratified analysis and the use of multiple indicators to measure social capital are thus warranted in future research.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2458-14-1025) contains supplementary material, which is available to authorized users.
PMCID: PMC4195999  PMID: 25273850
Social capital; Mortality; Proportional hazards models; Gender differences; Trust; Social participation; Social environment; Expectations of reciprocity; Effect modifier
5.  Diagnostic utility of musculoskeletal ultrasound in patients with suspected arthritis – a probabilistic approach 
This study aimed to assess the utility of musculoskeletal ultrasound (MSUS) in patients with joint symptoms using a probabilistic approach.
One hundred and three patients without prior rheumatologic diagnosis and referred to our clinic for evaluation of inflammatory arthritis were included. Patients were assessed clinically including joint examination, laboratory testing including acute-phase reactants, rheumatoid factor (RF) and anti citrulinated protein antibody (ACPA), and radiographs of hands and feet if clinically indicated. A diagnostic assessment was then performed by the responsible rheumatologist where the probability of a) any inflammatory arthritis and b) rheumatoid arthritis was given on a 5-point scale ranging from 0 to 20% up to 80 to 100% probability. Subsequently, an ultrasound examination of the wrist, metacarpophalangeal (MCP), proximal interphalangeal (PIP) joints 2 to 5 in both hands, metatarsophalangeal (MTP) joints 2 to 5 in both feet and any symptomatic joints was performed and the results presented to the same rheumatologist. The latter then assessed the diagnostic probabilities again, using the same scale.
The rheumatologists’ certainty for presence/absence of inflammatory arthritis and rheumatoid arthritis was increased significantly following ultrasound performance. The proportion of patient for whom diagnostic certainty for inflammatory arthritis was maximal was 33.0% before and 71.8% after musculoskeletal ultrasound (P <0.001). With regard to a diagnosis of RA, the proportions were 31.1% pre-test and 61.2% post-test (P <0.001). MSUS findings agreed with the final diagnosis in 95% of patients.
Musculoskeletal ultrasound, when added to routine rheumatologic investigation, greatly increases the diagnostic certainty in patients referred for the evaluation of inflammatory arthritis. The changes from pre-test to post-test probability quantify the diagnostic utility of musculoskeletal ultrasound in probabilistic terms.
PMCID: PMC4209056  PMID: 25270355
6.  Body mass index and risk of perioperative cardiovascular adverse events and mortality in 34,744 Danish patients undergoing hip or knee replacement 
Acta Orthopaedica  2014;85(5):456-462.
Background and purpose
Obesity is a risk factor for osteoarthritis in the lower limb, yet the cardiovascular risks associated with obesity in hip or knee replacement surgery are unknown. We examined associations between body mass index (BMI) and the risk of a major adverse cardiovascular event (MACE: ischemic stroke, acute myocardial infarction, or cardiovascular death) or the risk of all-cause mortality in a nationwide Danish cohort of patients who underwent primary hip or knee replacement surgery.
Using Danish nationwide registries, we identified 34,744 patients aged ≥ 20 years who underwent elective primary hip or knee replacement surgery between 2005 and 2011. We used multivariable Cox regression models to calculate the 30-day risks of MACE and mortality associated with 5 BMI groups (underweight (BMI < 18.5 kg/m2), normal weight (18.5–24 kg/m2), overweight (25–29 kg/m2), obese 1 (30–34 kg/m2), and obese 2 (≥ 35 kg/m2)).
In total, 232 patients (0.7%) had a MACE and 111 (0.3%) died. Compared with overweight, adjusted hazard ratios (HRs) were 1.2 (95% CI: 0.4–3.3), 1.3 (0.95–1.8), 1.6 (1.1–2.2), and 1.0 (0.6–1.9) for underweight, normal weight, obese 1, and obese 2 regarding MACE. Regarding mortality, the corresponding HRs were 7.0 (2.8–15), 2.0 (1.2–3.2), 1.5 (0.9–2.7), and 1.9 (0.9–4.2). Cubic splines suggested a significant U-shaped relationship between BMI and risks with nadir around 27–28.
In an unselected cohort of patients undergoing elective primary hip or knee replacement surgery, U-shaped risks of perioperative MACE and mortality were found in relation to BMI. Patients within the extreme ranges of BMI may warrant further attention.
PMCID: PMC4164861  PMID: 24954493
7.  Associations between follow-up screening after gestational diabetes and early detection of diabetes – a register based study 
BMC Public Health  2014;14(1):841.
Women whose pregnancy was complicated by gestational diabetes have a 7-fold higher risk of developing diabetes, primarily type 2. Early detection can prevent or delay the onset of late complications, for which follow-up screening is important. This study investigated the extent of participation in follow-up screening and the possible consequences of nonattendance in the Region of North Jutland, Denmark.
In Danish national registers covering the years 1994–2011 we identified 2171 birthing women whose pregnancy was complicated by first-time gestational diabetes. Control visits to general practitioners and biochemical departments after giving birth were charted. Following national guidelines we defined four intervals for assessment of participation in follow-up screening. Diagnosis of diabetes or treatment with glucose-lowering agents after giving birth were also identified. Participation in follow-up screening and risk of diabetes was calculated. Time to obtaining diagnosis of diabetes or initiating treatment was analysed by Cox regression models. All models were adjusted for age, ethnicity and income.
High attendance was found during the first control interval, after which attendance decreased with time after giving birth for both controls at general practitioners and biochemical departments. All differences in proportions were statistically significant. Women attending controls at general practitioners had a significantly higher risk of diabetes diagnosis and treatment after gestational diabetes than women not attending. The results for women attending testing at biochemical departments also showed an increased risk of initiation of treatment. Women attending at least one general practitioners control had a significantly higher risk of early diabetes diagnosis or treatment. Time to initiation of treatment was significantly higher for testing at biochemical departments. Women with high incomes had a significantly lower risk of diabetes diagnosis or initiation of treatment compared to low-income women.
Participation in follow-up screening after gestational diabetes is low in the North Denmark Region. Follow-up screening ensures early detection of diabetes and initiation of treatment. Our results emphasize the importance of development of interventions to improve early detection and prevention of diabetes after gestational diabetes.
PMCID: PMC4139613  PMID: 25115200
Follow-up screening; Gestational diabetes mellitus; Diabetes mellitus; Risk; Early detection
8.  Psoriasis and New-Onset Diabetes 
Diabetes Care  2013;36(8):2402-2407.
Psoriasis is associated with increased risk of cardiovascular events and increased prevalence of cardiovascular risk factors. Diabetes mellitus (DM) is a major contributor to cardiovascular morbidity and mortality that may be associated with psoriasis, but conflicting results have been presented and nationwide data on the risk of new-onset DM in patients with psoriasis have not been reported.
The study comprised a Danish population ≥10 years of age on 1 January 1997 who were followed until new-onset DM, death, or 31 December 2009. Information on comorbidity, concomitant medication, and socioeconomic status was linked on an individual level. The primary study end point was DM requiring pharmacotherapy. Incidence rates for the development of DM events per 1,000 observational years were calculated and adjusted. Incidence rate ratios (IRRs) were estimated by Poisson regression.
A total of 4,614,807 subjects were eligible for analysis, with a maximum follow-up of 13 years. In the study period, 52,613 patients with psoriasis, including 6,784 patients with severe psoriasis, were identified. The overall incidence rates for new-onset DM were 3.67 (CI 3.65–3.69), 6.93 (6.63–7.25), and 9.65 (8.68–10.73) for the reference population, mild psoriasis, and severe psoriasis, respectively. Compared with the reference population, the IRR of new-onset DM was increased in all patients with psoriasis, i.e., IRR 1.49 (CI 1.43–1.56) and 2.13 (1.91–2.37) for those with mild and severe psoriasis.
In this nationwide cohort, psoriasis was associated with increased incidence rates of new-onset DM. The association remained statistically significant after adjustment for confounding factors.
PMCID: PMC3714512  PMID: 23491525
9.  Benefit of Clopidogrel Therapy in Patients With Myocardial Infarction and Chronic Kidney Disease—A Danish Nation‐Wide Cohort Study 
The aim of the present study was to evaluate clopidogrel treatment after incident myocardial infarction (MI) in patients with and without chronic kidney disease (CKD).
Methods and Results
By linking nation‐wide registries, information about patients admitted with incident MI was found. Primary endpoints were all‐cause and cardiovascular (CV) mortality, a composite of all‐cause mortality and recurrent MI, and a composite of fatal and nonfatal bleedings. Effect of clopidogrel use versus clopidogrel nonuse was estimated using an adjusted Cox's regression model stratified according to percutaneous coronary intervention (PCI) treatment.
A total of 69 082 incident MI patients in the period 2002–2011 were included. Clopidogrel treatment was associated with hazard ratios (HRs) for the combined endpoint of all‐cause mortality and recurrent MI in PCI‐treated patients of 0.90 (95% confidence interval [CI], 0.47 to 1.72) in renal replacement therapy (RRT) patients, 0.59 (95% CI: 0.40 to 0.88) in non‐end‐stage CKD patients and 0.69 (95% CI, 0.61 to 0.77) in patients without kidney disease (P for interaction=0.60). In patients not treated with PCI, HRs were 0.90 (95% CI, 0.68 to 1.21) in RRT patients, 0.86 (95% CI, 0.75 to 0.99) in non‐end‐stage CKD patients, and 0.91 (95% CI, 0.87 to 0.95) in patients without kidney disease (P for interaction=0.74). An increase in bleeding events (not significant) was noted for clopidogrel‐treated patients not undergoing PCI and for non‐end‐stage CKD patients undergoing PCI, whereas clopidogrel was associated with less bleedings in PCI‐treated RRT patients and patients without kidney disease.
During a 1‐year follow‐up, after MI, clopidogrel was associated with improved outcomes in patients with non‐end‐stage CKD. Even though no effect difference, compared to patients without CKD, was observed, the benefit associated with the use of clopidogrel after MI in patients requiring RRT is less clear.
PMCID: PMC4310409  PMID: 25146707
kidney; myocardial infarction; revascularization
10.  Synovial explant inflammatory mediator production corresponds to rheumatoid arthritis imaging hallmarks: a cross-sectional study 
Arthritis Research & Therapy  2014;16(3):R107.
Despite the widespread use of magnetic resonance imaging (MRI) and Doppler ultrasound for the detection of rheumatoid arthritis (RA) disease activity, little is known regarding the association of imaging-detected activity and synovial pathology. The purpose of this study was to compare site-specific release of inflammatory mediators and evaluate the corresponding anatomical sites by examining colour Doppler ultrasound (CDUS) and MRI scans.
RA patients were evaluated on the basis of CDUS and 3-T MRI scans and subsequently underwent synovectomy using a needle arthroscopic procedure of the hand joints. The synovial tissue specimens were incubated for 72 hours, and spontaneous release of monocyte chemoattractant protein 1 (MCP-1), interleukin 6 (IL-6), macrophage inflammatory protein 1β (MIP-1β) and IL-8 was measured by performing multiplex immunoassays. Bone marrow oedema (BME), synovitis and erosion scores were estimated on the basis of the rheumatoid arthritis magnetic resonance imaging score (RAMRIS). Mixed models were used for the statistical analyses. Parsimony was achieved by omitting covariates with P > 0.1 from the statistical model.
Tissue samples from 58 synovial sites were obtained from 25 patients. MCP-1 was associated with CDUS activity (P = 0.009, approximate Spearman’s ρ = 0.41), RAMRIS BME score (P = 0.01, approximate Spearman’s ρ = 0.42) and RAMRIS erosion score (P = 0.03, approximate Spearman’s ρ = 0.31). IL-6 was associated with RAMRIS synovitis score (P = 0.04, approximate Spearman’s ρ = 0.50), BME score (P = 0.04, approximate Spearman’s ρ = 0.31) and RAMRIS erosion score (P = 0.03, approximate Spearman’s ρ = 0.35). MIP-1β was associated with CDUS activity (P = 0.02, approximate Spearman’s ρ = 0.38) and RAMRIS synovitis scores (P = 0.02, approximate Spearman’s ρ = 0.63). IL-8 associations with imaging outcome measures did not reach statistical significance.
The association between imaging activity and synovial inflammatory mediators underscores the high sensitivity of CDUS and MRI in the evaluation of RA disease activity. The associations found in our present study have different implications for synovial mediator releases and corresponding imaging signs. For example, MCP-1 and IL-6 were associated with both general inflammation and bone destruction, in contrast to MIP-1β, which was involved solely in general synovitis. The lack of association of IL-8 with synovitis was likely underestimated because of a large proportion of samples above assay detection limits among the patients with the highest synovitis scores.
PMCID: PMC4078218  PMID: 24886513
11.  Associations Between Body Mass Index and Development of Metabolic Disorders in Fertile Women—A Nationwide Cohort Study 
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/m2), normal weight (BMI=18.5 to <25 kg/m2), overweight (BMI=25 to <30 kg/m2), obese‐I (BMI=30 to <35 kg/m2), obese‐II (BMI=35 to <40 kg/m2), and obese‐III (BMI≥40 kg/m2). 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).
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.
PMCID: PMC4187494  PMID: 24721798
body mass index; diabetes; hypercholesterolemia; hypertension; women
12.  New‐Onset Atrial Fibrillation is Associated With Cardiovascular Events Leading to Death in a First Time Myocardial Infarction Population of 89 703 Patients With Long‐Term Follow‐Up: A Nationwide Study 
New‐onset atrial fibrillation (AF) is reported to increase the risk of death in myocardial infarction (MI) patients. However, previous studies have reported conflicting results and no data exist to explain the underlying cause of higher death rates in these patients.
Methods and Results
All patients with first acute MI between 1997 and 2009 in Denmark, without prior AF, were identified from Danish nationwide administrative registers. The impact of new‐onset AF on all‐cause mortality, cardiovascular death, fatal/nonfatal stroke, fatal/nonfatal re‐infarction and noncardiovascular death, were analyzed by multiple time‐dependent Cox models and additionally in propensity score matched analysis. In 89 703 patients with an average follow‐up of 5.0±3.5 years event rates were higher in patients developing AF (n=10 708) versus those staying in sinus‐rhythm (n=78 992): all‐cause mortality 173.9 versus 69.4 per 1000 person‐years, cardiovascular death 137.2 versus 50.0 per 1000 person‐years, fatal/nonfatal stroke 19.6/19.9 versus 6.2/5.6 per 1000 person‐years, fatal/nonfatal re‐infarction 29.0/60.7 versus 14.2/37.9 per 1000 person‐years. In time‐dependent multiple Cox analyses, new‐onset AF remained predictive of increased all‐cause mortality (HR: 1.9 [95% CI: 1.8 to 2.0]), cardiovascular death (HR: 2.1 [2.0 to 2.2]), fatal/nonfatal stroke (HR: 2.3 [2.1 to 2.6]/HR: 2.5 [2.2 to 2.7]), fatal/nonfatal re‐infarction (HR: 1.7 [1.6 to 1.8]/HR: 1.8 [1.7 to 1.9]), and non‐ cardiovascular death (HR: 1.4 [1.3 to 1.5]) all P<0.001). Propensity‐score matched analyses yielded nearly identical results (all P<0.001).
New‐onset AF after first‐time MI is associated with increased mortality, which is largely explained by more cardiovascular deaths. Focus on the prognostic impact of post‐infarct AF is warranted.
PMCID: PMC3959680  PMID: 24449803
cardiovascular mortality; mortality; myocardial infarction; new‐onset atrial fibrillation; re‐myocardial infarction; stroke
13.  Use of secondary prevention pharmacotherapy after first myocardial infarction in patients with diabetes mellitus 
Despite recommended pharmacotherapies the use of secondary prevention therapy after myocardial infarction (MI) remains suboptimal. Patients with diabetes mellitus (DM) have worse prognosis after MI compared to patients without DM and aggressive secondary prevention pharmacotherapy in this population is therefore warranted. We examined the changes in use of evidence-based secondary prevention pharmacotherapy in patients with and without DM discharged after first MI.
All patients aged 30 years or older admitted with first MI in Denmark during 1997–2006 were identified by individual-level linkage of nationwide registries of hospitalizations. Univariate and multivariate logistic regression models were used to identify patient characteristics associated with initiation of acetylsalicylic acid, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, β-blockers, and clopidogrel within 90 days, and statins within 180 days of discharge, respectively.
A total of 78,230 patients were included, the mean age was 68.3 years (SD 13.0), 63.5% were men and 9,797 (12.5%) had diabetes. Comparison of claimed prescriptions in the period 1997–2002 and 2003–2006 showed significant (p < 0.001) increases in claims for acetylsalicylic acid (38.9% vs. 69.7%), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (38.7% vs. 50.4%), β-blockers (69.2% vs. 77.9%), clopidogrel (16.7% vs. 66.3%), and statins (41.3% vs. 77.3%). During 2003–2006, patients with DM claimed significantly less acetylsalicylic acid (odds ratio [OR] 0.81 [95% confidence interval [CI] 0.74–0.88) and clopidogrel (OR 0.91 [95% CI 0.83–1.00]) than patients without DM.
Despite sizeable increase in use of evidence-based secondary prevention pharmacotherapy after MI from 1997 to 2006, these drugs are not used in a substantial proportion of subjects and patients with DM received significantly less antiplatelet therapy than patients without DM. Increased focus on initiation of secondary prevention pharmacotherapy after MI is warranted, especially in patients with DM.
PMCID: PMC3897983  PMID: 24406095
14.  Temporal summation of pain and ultrasound Doppler activity as predictors of treatment response in patients with rheumatoid arthritis: protocol for the Frederiksberg hospitals Rheumatoid Arthritis, pain assessment and Medical Evaluation (FRAME-cohort) study 
BMJ Open  2014;4(1):e004313.
Chronic pain is common in rheumatoid arthritis (RA) and may still persist despite regression of objective signs of inflammation. This has led researchers to hypothesise that central pain sensitisation may play a role in the generation of chronic pain in RA. Application of the disease activity score DAS28 can classify some patients with active RA solely based on a high tender joint count and poor patient global health score. In such cases, intensified treatment with anti-inflammatory drugs would be expected to yield poorer results than in cases with DAS28 elevation due to a high score for swollen joints and C reactive protein (CRP). Evaluation of central pain sensitisation in patients with few inflammatory indices may be a predictive tool regarding the effect of anti-inflammatory treatment. Computerised pneumatic cuff pressure algometry (CPA) is a method for assessing temporal summation (ie, degree of central sensitisation). The main objective of this study was to examine the prognostic values of pressure pain-induced temporal summation, ultrasound Doppler activity and the interaction between them in relation to treatment response (DAS28-CRP change) in patients with RA initiating any anti-inflammatory therapy.
Method and analysis
120 participants ≥18 years of age will be recruited. Furthermore, they must be either (1) diagnosed with RA, untreated with disease-modifying antirheumatic drugs for at least 6 months and about to initiate disease-modifying antirheumatic drug treatment or (2) about to begin or switch treatment with any biological drug for their RA. Data (clinical, imaging, blood samples, patient reported outcomes and CPA measurements) will be collected from each participant at baseline and after 4 months of anti-inflammatory treatment.
Ethics and dissemination
This study has been approved by the ethics committee for the Copenhagen region (H-4-2013-007). Dissemination will occur through presentations and publication in international peer-reviewed journals.
PMCID: PMC3902530  PMID: 24390385
rheumatoid arthritis; central nervous system sensitization; pain measurement; ultrasound doppler; inflammation
15.  Renal dysfunction, restrictive left ventricular filling pattern and mortality risk in patients admitted with heart failure: a 7-year follow-up study 
BMC Nephrology  2013;14:267.
Renal dysfunction is associated with a variety of cardiac alterations including left ventricular (LV) hypertrophy, LV dilation, and reduction in systolic and diastolic function. It is common and associated with an increased mortality risk in heart failure (HF) patients. This study was designed to evaluate whether severe diastolic dysfunction contribute to the increased mortality risk observed in HF patients with renal dysfunction.
Using Cox Proportional Hazard Models on data (N = 669) from the EchoCardiography and Heart Outcome Study (ECHOS) study we evaluated whether estimated glomerular filtration rate (eGFR) was associated with mortality risk before and after adjustment for severe diastolic dysfunction. Severe diastolic dysfunction was defined by a restrictive left ventricular filling pattern (RF) (=deceleration time < 140 ms) by Doppler echocardiography.
Median eGFR was 58 ml/min/1.73 m2, left ventricular ejection fraction was 33% and RF was observed in 48%. During the 7 year follow up period 432 patients died. Multivariable adjusted eGFR was associated with similar mortality risk before (Hazard Ratio(HR)eGFR 10 ml increase: 0.94 (95% CI: 0.89-0.99, P = 0.024) and after (HReGFR 10 ml increase: 0.93 (0.89-0.99), P = 0.012) adjustment for RF (HR: 1.57 (1.28-1.93), P < 0.001).
In patients admitted with HF RF does not contribute to the increased mortality risk observed in patients with a decreased eGFR. Factors other than severe diastolic dysfunction may explain the association between renal function and mortality risk in HF patients.
PMCID: PMC3879040  PMID: 24299462
Estimated glomerular filtration rate; Restrictive filling pattern; Heart failure; Mortality risk
16.  Statin treatment and risk of recurrent venous thromboembolism: a nationwide cohort study 
BMJ Open  2013;3(11):e003135.
Statins may decrease the risk of primary venous thromboembolism (VTE), that is, deep vein thrombosis (DVT) and pulmonary embolism (PE) but the effect of statins in preventing recurrent VTE is less clear. The aim of this study was therefore to investigate the association between statin therapy and risk of recurrent VTE.
A prospective cohort study.
All hospitals in Denmark.
All patients with a hospital diagnosis of VTE in Denmark during 1997–2009 associated with a warfarin or heparin prescription were identified.
Main outcome measures
Adjusted HR of recurrent hospitalised VTE (ie, fatal or non-fatal DVT or PE) associated with use of statins.
44 330 patients with VTE were included in the study. Of these 3914 were receiving statin therapy at baseline. Patients receiving statins were older (68±11 compared to 62±18 years), had more comorbidity and used more medications. The incidence rate for recurrent VTE was 24.4 (95% CI 22.8 to 26.2) per 1000 person-years among statin users and 48.5 (95% CI 47.4 to 49.7) per 1000 person-years among non-statin users. Statin use was associated with a significantly lower risk of a recurrent VTE, adjusted HR 0.74 (95% CI 0.68 to 0.80), compared with no statin use. The association between statin use and risk of recurrent VTE was significantly affected by age. Among younger individuals (≤80 years), statin use was associated with lower risk of recurrent VTE, HR 0.70 (95% CI 0.65 to 0.76) whereas in older individuals (>80 years) statin use was significantly associated with higher risk of recurrent VTE, HR 1.28 (95% CI 1.02 to 1.60), p for interaction=<0.0001.
Statin use was associated with a decreased risk of recurrent VTE.
PMCID: PMC3822311  PMID: 24202053
17.  Temporal trends in stroke admissions in Denmark 1997–2009 
BMC Neurology  2013;13:156.
The Stroke burden is increasing in many populations where health institutions may experience more patients. We wanted to examine whether incidence rates and absolute number of hospitalized stroke patients remained stable in Denmark during a 13 years period where exposure to major stroke risk factors decreased, changes in stroke treatment was implemented, and the age of the population increased.
The Danish National Patient Register was used to identify all subjects 25 years of age or above admitted with a first time stroke in Denmark from 1997–2009. Incidence rates (IRs) and age-adjusted Poisson regression analyses were used to examine trends in age-, gender- and stroke subtype (ischaemic or unspecified).
During the 13-year observation period there were 53.5 million person-years at risk (PY) and a total of 84,626 male and 84,705 female stroke patients were admitted to Danish hospitals. The IRs of hospitalized strokes per 1000 PY was 3.21 (95% confidence interval [CI] 3.16-3.27) in 1997, 3.85 (95% CI 3.79-3.91) in 2003 and 3.22 (95% CI 3.16-3.28) in 2009, respectively.
Incidence rate ratios of hospitalized stroke events adjusted for age in the period 2007–2009 compared to 1997–2000 were 0.89 (95% CI 0.87- 0.91) for men and 0.92 (95% CI 0.90-0.94) for women.
The incidence of hospitalized unspecified strokes decreased from 1997 to 2009 whereas there was a steep rise in incidence for hospitalization with specified ischemic stroke during this period.
This study found a constant rate of stroke hospitalization in Denmark from 1997–2009. The overall rate of hospitalized strokes adjusted for age decreased during this period.
PMCID: PMC3827842  PMID: 24171730
Stroke; Temporal trends; Epidemiology
18.  Unexplained Syncope and Diagnostic Yield of Tests in Syncope According to the ICD-10 Discharge Diagnosis 
The etiology of syncope according to the discharge diagnosis from hospital admissions has not been examined before. Therefore the aims of this study were to examine the diagnostic yield of tests and frequency of unexplained cases during admission and after workup after an ICD-10 diagnosis of syncope.
A retrospective chart review of 600 patients discharged with the primary ICD-10 discharge diagnosis of syncope R55.9 was performed. Causes and clinical characteristics of syncope according to the physician were noted both after initial discharge and after workup.
During a mean follow-up period of 2.5 years (SD: ± 1.30) several diagnostic tests were used (mean number of tests per patient was 4.7 (SD: ± -2.0)) and the mean length of admission was 2.1 days (± 1.5).The final diagnosis after workup was reflex syncope in 21%, cardiac 18%, orthostatic hypotension 10%, other causes 4% and unknown/unexplained syncope in 48% with wide age differences. The diagnostic yield of tests was generally low and differed widely depending on usage during admission or usage during subsequent workup.
The underlying etiology of syncope remains difficult to establish despite the high use of diagnostic tests and the diagnostic yield of many tests implemented in the care path is generally low.
PMCID: PMC3808262  PMID: 24171056
Syncope; Diagnostic techniques; Cardiovascular; Etiology
19.  Effect of dronedarone on clinical end points in patients with atrial fibrillation and coronary heart disease: insights from the ATHENA trial 
Europace  2013;16(2):174-181.
This study aimed to assess safety and cardiovascular outcomes of dronedarone in patients with paroxysmal or persistent atrial fibrillation (AF) with coronary heart disease (CHD). Coronary heart disease is prevalent among AF patients and limits antiarrhythmic drug use because of their potentially life-threatening ventricular proarrhythmic effects.
Methods and results
This post hoc analysis evaluated 1405 patients with paroxysmal or persistent AF and CHD from the ATHENA trial. Follow-up lasted 2.5 years, during which patients received either dronedarone (400 mg twice daily) or a double-blind matching placebo. Primary outcome was time to first cardiovascular hospitalization or death due to any cause. Secondary end points included first hospitalization due to cardiovascular events. The primary outcome occurred in 350 of 737 (47%) placebo patients vs. 252 of 668 (38%) dronedarone patients [hazard ratio (HR) = 0.73; 95% confidence interval (CI) = 0.62–0.86; P = 0.0002] without a significant increase in number of adverse events. In addition, 42 of 668 patients receiving dronedarone suffered from a first acute coronary syndrome compared with 67 of 737 patients from the placebo group (HR = 0.67; 95% CI = 0.46–0.99; P = 0.04).
In this post hoc analysis, dronedarone on top of standard care in AF patients with CHD reduced cardiovascular hospitalization or death similar to that in the overall ATHENA population, and reduced a first acute coronary syndrome. Importantly, the safety profile in this subpopulation was also similar to that of the overall ATHENA population, with no excess in proarrhythmias. The mechanism of the cardiovascular protective effects is unclear and warrants further investigation.
PMCID: PMC3905706  PMID: 24072451
Dronedarone; Atrial fibrillation; Coronary heart disease
20.  Double Product Reflects the Predictive Power of Systolic Pressure in the General Population: Evidence from 9,937 Participants 
American journal of hypertension  2013;26(5):665-672.
The double product (DP), consisting of the systolic blood pressure (SBP) multiplied by the pulse rate (PR), is an index of myocardial oxygen consumption, but its prognostic value in the general population remains unknown.
We recorded health outcomes in 9,937 subjects (median age, 53.2 years; 47.3% women) randomly recruited from 11 populations and enrolled in the International Database on Ambulatory blood pressure in relation to Cardiovascular Outcomes (IDACO) study. We obtained the SBP, PR, and DP for these subjects as determined through 24-hour ambulatory monitoring.
Over a median period of 11.0 years, 1,388 of the 9,937 study subjects died, of whom 536 and 794, respectively, died of cardiovascular (CV) and non-CV causes, and a further 1,161, 658, 494, and 465 subjects, respectively, experienced a CV, cardiac, coronary, or cerebrovascular event. In multivariate-adjusted Cox models, not including SBP and PR, DP predicted total, CV, and non-CV mortality (standardized hazard ratio [HR], ≥ 1.10; P ≤ 0.02), and all CV, cardiac, coronary, and stroke events (HR, ≥ 1.21; P < 0.0001). For CV mortality (HR, 1.34 vs. 1.30; P = 0.71) and coronary events (1.28 vs. 1.21; P = 0.26), SBP and the DP were equally predictive. As compared with DP, SBP was a stronger predictor of all CV events (1.39 vs. 1.27; P = 0.002) and stroke (1.61 vs. 1.36; P < 0.0001), and a slightly stronger predictor of cardiac events (1.32 vs. 1.22; P = 0.06). In fully adjusted models, including both SBP and PR, the predictive value of DP disappeared for fatal endpoints (P ≥ 0.07), coronary events (P = 0.06), and stroke (P = 0.12), or DP was even inversely associated with the risk of all CV and cardiac events (both P ≤ 0.01).
In the general population, we did not observe DP to add to risk stratification over and beyond SBP and PR.
PMCID: PMC3792705  PMID: 23391621
blood pressure; double product; systolic blood pressure; cardiovascular risk; hypertension; general population
21.  Significance of KATP channels, L-type Ca2+ channels and CYP450-4A enzymes in oxygen sensing in mouse cremaster muscle arterioles In vivo 
BMC Physiology  2013;13:8.
ATP-sensitive K+ channels (KATP channels), NO, prostaglandins, 20-HETE and L-type Ca2+ channels have all been suggested to be involved in oxygen sensing in skeletal muscle arterioles, but the role of the individual mechanisms remain controversial. We aimed to establish the importance of these mechanisms for oxygen sensing in arterioles in an in vivo model of metabolically active skeletal muscle. For this purpose we utilized the exteriorized cremaster muscle of anesthetized mice, in which the cremaster muscle was exposed to controlled perturbation of tissue PO2.
Change from “high” oxygen tension (PO2 = 153.4 ± 3.4 mmHg) to “low” oxygen tension (PO2 = 13.8 ± 1.3 mmHg) dilated cremaster muscle arterioles from 11.0 ± 0.4 μm to 32.9 ± 0.9 μm (n = 28, P < 0.05). Glibenclamide (KATP channel blocker) caused maximal vasoconstriction, and abolished the dilation to low oxygen, whereas the KATP channel opener cromakalim caused maximal dilation and prevented the constriction to high oxygen. When adding cromakalim on top of glibenclamide or vice versa, the reactivity to oxygen was gradually restored. Inhibition of L-type Ca2+ channels using 3 μM nifedipine did not fully block basal tone in the arterioles, but rendered them unresponsive to changes in PO2. Inhibition of the CYP450-4A enzyme using DDMS blocked vasoconstriction to an increase in PO2, but had no effect on dilation to low PO2.
We conclude that: 1) L-type Ca2+ channels are central to oxygen sensing, 2) KATP channels are permissive for the arteriolar response to oxygen, but are not directly involved in the oxygen sensing mechanism and 3) CYP450-4A mediated 20-HETE production is involved in vasoconstriction to high PO2.
PMCID: PMC3663688  PMID: 23663730
Hypoxic vasodilation; Hyperoxic vasoconstriction; Oxygen sensing; ATP-sensitive K+ channels; 20-HETE; L-type Ca2+ channels; Prostaglandin; NO-synthase; Skeletal muscle; Arterioles
22.  Masked Hypertension in Diabetes Mellitus 
Hypertension  2013;61(5):964-971.
Although distinguishing features of masked hypertension in diabetics are well known, the significance of antihypertensive treatment on clinical practice decisions has not been fully explored. We analyzed 9691 subjects from the population-based 11-country International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcomes. Prevalence of masked hypertension in untreated normotensive participants was higher (P<0.0001) among 229 diabetics (29.3%, n=67) than among 5486 nondiabetics (18.8%, n=1031). Over a median of 11.0 years of follow-up, the adjusted risk for a composite cardiovascular end point in untreated diabetic-masked hypertensives tended to be higher than in normotensives (hazard rate [HR], 1.96; 95% confidence interval [CI], 0.97–3.97; P=0.059), similar to untreated stage 1 hypertensives (HR, 1.07; CI, 0.58–1.98; P=0.82), but less than stage 2 hypertensives (HR, 0.53; CI, 0.29–0.99; P=0.048). In contrast, cardiovascular risk was not significantly different in antihypertensive-treated diabetic-masked hypertensives, as compared with the normotensive comparator group (HR, 1.13; CI, 0.54–2.35; P=0.75), stage 1 hypertensives (HR, 0.91; CI, 0.49–1.69; P=0.76), and stage 2 hypertensives (HR, 0.65; CI, 0.35–1.20; P=0.17). In the untreated diabetic-masked hypertensive population, mean conventional systolic/diastolic blood pressure was 129.2±8.0/76.0±7.3 mm Hg, and mean daytime systolic/diastolic blood pressure 141.5±9.1/83.7±6.5 mm Hg. In conclusion, masked hypertension occurred in 29% of untreated diabetics, had comparable cardiovascular risk as stage 1 hypertension, and would require considerable reduction in conventional blood pressure to reach daytime ambulatory treatment goal. Importantly, many hypertensive diabetics when receiving antihypertensive therapy can present with normalized conventional and elevated ambulatory blood pressure that mimics masked hypertension.
PMCID: PMC3631136  PMID: 23478096
ambulatory blood pressure; conventional blood pressure; diabetes mellitus; masked hypertension; population study
23.  Prevalence of Antidepressant Use during Pregnancy in Denmark, a Nation-Wide Cohort Study 
PLoS ONE  2013;8(4):e63034.
The aim of this study was to assess the prevalence and patterns of exposure to antidepressants before, during and after pregnancy in a cohort including all pregnant women in Denmark between 1997 and 2010.
We performed a retrospective cohort study including 912 322 pregnancies. Information was retrieved from the Danish Birth Registry and The Register of Medicinal Product Statistics to identify women redeeming an antidepressant prescription during pregnancy. Exposure periods were based on standard treatment doses and dispensed pack sizes.
We identified 19 740 pregnancies exposed to an antidepressant at some point during pregnancy. The rate of exposure increased from 0.2% in 1997 to 3.2% in 2010. We found that the rate of exposure was halved during the first 3 months of pregnancy. In contrast, we describe a clear increase in exposure after pregnancy among pre-delivery treatment-naïve women.
In spite of uncertainty concerning antidepressants’ safety during pregnancy we find a 16-fold increase in exposure rates between 1997 and 2010. The rates describe a sharp decrease in exposure during pregnancy that is probably caused by physicians’ hesitation to prescribe antidepressants and women’s fear of unwanted effects on the unborn child. More studies are needed to clarify the consequences of antidepressant discontinuation during pregnancy.
PMCID: PMC3636192  PMID: 23638179
24.  Significance of White-Coat Hypertension in Older Persons With Isolated Systolic Hypertension 
Hypertension  2012;59(3):564-571.
The significance of white-coat hypertension in older persons with isolated systolic hypertension remains poorly understood. We analyzed subjects from the population-based 11-country International Database on Ambulatory Blood Pressure Monitoring in Relation to Cardiovascular Outcomes database who had daytime ambulatory blood pressure (BP; ABP) and conventional BP (CBP) measurements. After excluding persons with diastolic hypertension by CBP (≥90 mm Hg) or by daytime ABP (≥85 mm Hg), a history of cardiovascular disease, and persons <18 years of age, the present analysis totaled 7295 persons, of whom 1593 had isolated systolic hypertension. During a median follow-up of 10.6 years, there was a total of 655 fatal and nonfatal cardiovascular events. The analyses were stratified by treatment status. In untreated subjects, those with white-coat hypertension (CBP ≥140/<90 mm Hg and ABP <135/<85 mm Hg) and subjects with normal BP (CBP <140/<90 mm Hg and ABP <135/<85 mm Hg) were at similar risk (adjusted hazard rate: 1.17 [95% CI: 0.87–1.57]; P=0.29). Furthermore, in treated subjects with isolated systolic hypertension, the cardiovascular risk was similar in elevated conventional and normal daytime systolic BP as compared with those with normal conventional and normal daytime BPs (adjusted hazard rate: 1.10 [95% CI: 0.79–1.53]; P=0.57). However, both treated isolated systolic hypertension subjects with white-coat hypertension (adjusted hazard rate: 2.00; [95% CI: 1.43–2.79]; P<0.0001) and treated subjects with normal BP (adjusted hazard rate: 1.98 [95% CI: 1.49–2.62]; P<0.0001) were at higher risk as compared with untreated normotensive subjects. In conclusion, subjects with sustained hypertension who have their ABP normalized on antihypertensive therapy but with residual white-coat effect by CBP measurement have an entity that we have termed, “treated normalized hypertension.” Therefore, one should be cautious in applying the term “white-coat hypertension” to persons receiving antihypertensive treatment.
PMCID: PMC3607330  PMID: 22252396
isolated systolic hypertension; ambulatory blood pressure; white-coat hypertension; white-coat effect; cardiovascular disease; epidemiology
25.  Risk Stratification by 24-Hour Ambulatory Blood Pressure and Estimated Glomerular Filtration Rate in 5322 Subjects From 11 Populations 
Hypertension  2012;61(1):18-26.
No previous study addressed whether in the general population estimated glomerular filtration rate (eGFR [Chronic Kidney Disease Epidemiology Collaboration formula]) adds to the prediction of cardiovascular outcome over and beyond ambulatory blood pressure. We recorded health outcomes in 5322 subjects (median age, 51.8 years; 43.1% women) randomly recruited from 11 populations, who had baseline measurements of 24-hour ambulatory blood pressure (ABP24) and eGFR. We computed hazard ratios using multivariable-adjusted Cox regression. Median follow-up was 9.3 years. In fully adjusted models, which included both ABP24 and eGFR, ABP24 predicted (P≤0.008) both total (513 deaths) and cardiovascular (206) mortality; eGFR only predicted cardiovascular mortality (P=0.012). Furthermore, ABP24 predicted (P≤0.0056) fatal combined with nonfatal events as a result of all cardiovascular causes (555 events), cardiac disease (335 events), or stroke (218 events), whereas eGFR only predicted the composite cardiovascular end point and stroke (P≤0.035). The interaction terms between ABP24 and eGFR were all nonsignificant (P≥0.082). For cardiovascular mortality, the composite cardiovascular end point, and stroke, ABP24 added 0.35%, 1.17%, and 1.00% to the risk already explained by cohort, sex, age, body mass index, smoking and drinking, previous cardiovascular disease, diabetes mellitus, and antihypertensive drug treatment. Adding eGFR explained an additional 0.13%, 0.09%, and 0.14%, respectively. Sensitivity analyses stratified for ethnicity, sex, and the presence of hypertension or chronic kidney disease (eGFR <60 mL/min per 1.73 m2) were confirmatory. In conclusion, in the general population, eGFR predicts fewer end points than ABP24. Relative to ABP24, eGFR is as an additive, not a multiplicative, risk factor and refines risk stratification 2- to 14-fold less.
PMCID: PMC3607362  PMID: 23172928
ambulatory blood pressure; population science; renal function; cardiovascular risk factors; epidemiology

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