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1.  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 
Background
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).
Conclusions
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.
doi:10.1161/JAHA.113.000382
PMCID: PMC3959680  PMID: 24449803
cardiovascular mortality; mortality; myocardial infarction; new‐onset atrial fibrillation; re‐myocardial infarction; stroke
2.  Use of secondary prevention pharmacotherapy after first myocardial infarction in patients with diabetes mellitus 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1471-2261-14-4
PMCID: PMC3897983  PMID: 24406095
3.  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.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1186/1471-2369-14-267
PMCID: PMC3879040  PMID: 24299462
Estimated glomerular filtration rate; Restrictive filling pattern; Heart failure; Mortality risk
4.  Statin treatment and risk of recurrent venous thromboembolism: a nationwide cohort study 
BMJ Open  2013;3(11):e003135.
Objectives
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.
Design
A prospective cohort study.
Setting
All hospitals in Denmark.
Participants
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.
Results
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.
Conclusions
Statin use was associated with a decreased risk of recurrent VTE.
doi:10.1136/bmjopen-2013-003135
PMCID: PMC3822311  PMID: 24202053
VASCULAR MEDICINE; EPIDEMIOLOGY
5.  Temporal trends in stroke admissions in Denmark 1997–2009 
BMC Neurology  2013;13:156.
Background
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.
Methods
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).
Results
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.
Conclusion
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.
doi:10.1186/1471-2377-13-156
PMCID: PMC3827842  PMID: 24171730
Stroke; Temporal trends; Epidemiology
6.  Unexplained Syncope and Diagnostic Yield of Tests in Syncope According to the ICD-10 Discharge Diagnosis 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.4021/jocmr1569w
PMCID: PMC3808262  PMID: 24171056
Syncope; Diagnostic techniques; Cardiovascular; Etiology
7.  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.
Aims
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).
Conclusion
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.
doi:10.1093/europace/eut293
PMCID: PMC3905706  PMID: 24072451
Dronedarone; Atrial fibrillation; Coronary heart disease
8.  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.
BACKGROUND
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.
METHODS
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.
RESULTS
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).
CONCLUSION
In the general population, we did not observe DP to add to risk stratification over and beyond SBP and PR.
doi:10.1093/ajh/hps119
PMCID: PMC3792705  PMID: 23391621
blood pressure; double product; systolic blood pressure; cardiovascular risk; hypertension; general population
9.  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.
Background
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.
Results
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.
Conclusions
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.
doi:10.1186/1472-6793-13-8
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
10.  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.
doi:10.1161/HYPERTENSIONAHA.111.00289
PMCID: PMC3631136  PMID: 23478096
ambulatory blood pressure; conventional blood pressure; diabetes mellitus; masked hypertension; population study
11.  Prevalence of Antidepressant Use during Pregnancy in Denmark, a Nation-Wide Cohort Study 
PLoS ONE  2013;8(4):e63034.
Aim
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1371/journal.pone.0063034
PMCID: PMC3636192  PMID: 23638179
12.  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.
doi:10.1161/HYPERTENSIONAHA.111.180653
PMCID: PMC3607330  PMID: 22252396
isolated systolic hypertension; ambulatory blood pressure; white-coat hypertension; white-coat effect; cardiovascular disease; epidemiology
13.  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.
doi:10.1161/HYPERTENSIONAHA.112.197376
PMCID: PMC3607362  PMID: 23172928
ambulatory blood pressure; population science; renal function; cardiovascular risk factors; epidemiology
14.  Uric Acid as a Risk Factor for Cardiovascular Disease and Mortality in Overweight/Obese Individuals 
PLoS ONE  2013;8(3):e59121.
Background
The predictive value of serum uric acid (SUA) for adverse cardiovascular events among obese and overweight patients is not known, but potentially important because of the relation between hyperuricaemia and obesity.
Methods
The relationship between SUA and risk of cardiovascular adverse outcomes (nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest or cardiovascular death) and all-cause mortality, respectively, was evaluated in a post-hoc analysis of the Sibutramine Cardiovascular OUTcomes (SCOUT) trial. Participants enrolled in SCOUT were obese or overweight with pre-existing diabetes and/or cardiovascular disease (CVD). Cox models were used to assess the role of SUA as an independent risk factor.
Results
9742 subjects were included in the study; 83.6% had diabetes, and 75.1% had CVD. During an average follow-up time of 4.2 years, 1043 subjects had a primary outcome (myocardial infarction, resuscitated cardiac arrest, stroke, or cardiovascular death), and 816 died. In a univariate Cox model, the highest SUA quartile was associated with an increased risk of cardiovascular adverse outcomes compared with the lowest SUA quartile in women (hazard ratio [HR]: 1.59; 95% confidence interval [CI]: 1.20–2.10). In multivariate analyses, adjusting for known cardiovascular risk factors the increased risk for the highest SUA quartile was no longer statistically significant among women (HR: 0.99; 95% CI: 0.72–1.36) nor was it among men. Analyses of all-cause mortality found an interaction between sex and SUA. In a multivariate Cox model including women only, the highest SUA quartile was associated with an increased risk in all-cause mortality compared to the lowest SUA quartile (HR: 1.51; 95% CI: 1.08–2.12). No relationship was observed in men (HR: 1.06; 95% CI: 0.82–1.36).
Conclusion
SUA was not an independent predictor of cardiovascular disease and death in these high-risk overweight/obese people. However, our results suggested that SUA was an independent predictor of all-cause mortality in women.
doi:10.1371/journal.pone.0059121
PMCID: PMC3606441  PMID: 23533601
15.  New-Onset Atrial Fibrillation Is a Predictor of Subsequent Hyperthyroidism: A Nationwide Cohort Study 
PLoS ONE  2013;8(2):e57893.
Aims
To examine the long-term risk of hyperthyroidism in patients admitted to hospital with new-onset AF. Hyperthyroidism is a well-known risk factor for atrial fibrillation (AF), but it is unknown whether new-onset AF predicts later-occurring hyperthyroidism.
Methods and Results
All patients admitted with new-onset AF in Denmark from 1997–2009, and their present and subsequent use of anti-thyroid medication was identified by individual-level linkage of nationwide registries. Patients with previous thyroid diagnosis or thyroid medication use were excluded. Development of hyperthyroidism was assessed as initiation of methimazole or propylthiouracil up to a 13-year period. Risk of hyperthyroidism was analysed by Poisson regression models adjusted for important confounders such as amiodarone treatment. Non-AF individuals from the general population served as reference. A total of 145,623 patients with new-onset AF were included (mean age 66.4 years [SD ±13.2] and 55.3% males) of whom 3% (4,620 events; 62.2% women) developed hyperthyroidism in the post-hospitalization period compared to 1% (48,609 events; 82% women) in the general population (n = 3,866,889). In both women and men we found a significantly increased risk of hyperthyroidism associated with new-onset AF compared to individuals in the general population. The highest risk was found in middle-aged men and was consistently increased throughout the 13-year period of observation. The results were confirmed in a substudy analysis of 527,352 patients who had thyroid screening done.
Conclusion
New-onset AF seems to be a predictor of hyperthyroidism. Increased focus on subsequent risk of hyperthyroidism in patients with new-onset AF is warranted.
doi:10.1371/journal.pone.0057893
PMCID: PMC3585274  PMID: 23469097
16.  Disease Activity in Inflammatory Bowel Disease Is Associated with Increased Risk of Myocardial Infarction, Stroke and Cardiovascular Death – A Danish Nationwide Cohort Study 
PLoS ONE  2013;8(2):e56944.
Purpose
Chronic inflammatory diseases have been linked to increased risk of atherothrombotic events, but the risk associated with inflammatory bowel disease (IBD) is unclear. We therefore examined the risk of myocardial infarction (MI), stroke, and cardiovascular death in patients with IBD.
Methods
In a nationwide Danish population-based setting, a cohort of patients with incident IBD between 1996 and 2009 were identified in national registers. Hospitalizations with IBD as primary diagnosis, initiation of biological treatment and dispensed prescriptions of corticosteroids were all used as surrogate markers for disease activity, with flares classified as the first 120 days after diagnosis of IBD, and 120 days after a new corticosteroid prescription, biological treatment or IBD hospitalization, respectively. Continued corticosteroid prescriptions or IBD hospitalizations were defined as persistent activity, and periods free of such events were defined as remissions. Poisson regression was used to examine risk of MI, stroke, and cardiovascular death using a matched population-based comparison cohort as reference
Results
We identified 20,795 IBD patients with a mean age of 40.3 years that were matched according to age and sex with 199,978 controls. During the study period, there were 365 patients with MI, 454 with stroke, and 778 with cardiovascular death. Patients with IBD had an overall increased risk of MI (rate ratio [RR] 1.17 [95% confidence interval 1.05–1.31]), stroke (RR 1.15 [1.04–1.27], and cardiovascular death (RR 1.35 [1.25–1.45]). During flares and persistent IBD activity the RRs of MI increased to 1.49 (1.16–1.93) and 2.05 (1.58–2.65), the RRs of stroke to 1.53 (1.22–1.92) and 1.55 (1.18–2.04) and for cardiovascular death 2.32 (2.01–2.68) and 2.50 (2.14–2.92). In remission periods, the risk of MI, stroke and cardiovascular death was similar to controls.
Conclusion
Inflammatory bowel disease is associated with increased risk of MI, stroke, and cardiovascular death during periods with active disease.
doi:10.1371/journal.pone.0056944
PMCID: PMC3574079  PMID: 23457642
17.  Trimethoprim Use prior to Pregnancy and the Risk of Congenital Malformation: A Register-Based Nationwide Cohort Study 
Objectives. The aim of the study was to investigate whether the use of the antifolate antibiotic trimethoprim during the 12 weeks before conception was associated with congenital malformations. Methods. We conducted a nationwide register-based cohort study including all Danish women giving birth from 1997 to 2004. All women with at least one prescription of trimethoprim dispensed during the 12 weeks before conception were identified. Results. There was a doubling of congenital malformations in offspring to women exposed to trimethoprim in the 12 weeks before conception. The adjusted odds ratio (OR) of major congenital malformation was 1.87, 95% confidence interval (CI) 1.25–2.81. There was a significant increase in major malformations of the heart (OR = 2.49; 1.18–5.26) and limbs (OR = 2.18; 1.13–4.23). Conclusions. In this study, we found an association between exposure to trimethoprim during the 12 weeks before conception and an increased risk of heart and limb defects.
doi:10.1155/2013/364526
PMCID: PMC3586486  PMID: 23476656
18.  Cause-Specific Cardiovascular Risk Associated with Nonsteroidal Anti-Inflammatory Drugs among Myocardial Infarction Patients - A Nationwide Study 
PLoS ONE  2013;8(1):e54309.
Background
Non steroidal anti-inflammatory drugs (NSAIDs) increase mortality and morbidity after myocardial infarction (MI). We examined cause-specific mortality and morbidity associated with NSAIDs in a nationwide cohort of MI patients.
Methods and Results
By individual-level linkage of nationwide registries of hospitalization and drug dispensing from pharmacies in Denmark, patients aged >30 years admitted with first-time MI during 1997–2009 and their subsequent NSAID use were identified. The risk of three cardiovascular specific endpoints: cardiovascular death, the composite of coronary death and nonfatal MI, and the composite of fatal and nonfatal stroke, associated with NSAID use was analyzed by Cox proportional hazard analyses. Of 97,698 patients included 44.0% received NSAIDs during follow-up. Overall use of NSAIDs was associated with an increased risk of cardiovascular death (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.36–1.49). In particular use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 inhibitor rofecoxib was associated with increased risk of cardiovascular death (HR 1.96 [1.79–2.15] and HR1.66 [1.44–1.91], respectively) with a dose dependent increase in risk. Use of ibuprofen was associated with increased risk of cardiovascular death (HR 1.34[1.26–1.44]), whereas naproxen was associated with the lowest risk of (e.g., HR 1.27[1.01–1.59].
Conclusion
Use of individual NSAIDs is associated with different cause-specific cardiovascular risk and in particular rofecoxib and diclofenac were associated with increased cardiovascular morbidity and mortality. These results support caution with use of all NSAIDs in patients with prior MI.
doi:10.1371/journal.pone.0054309
PMCID: PMC3559685  PMID: 23382889
19.  Cardiovascular and non-cardiovascular hospital admissions associated with atrial fibrillation: a Danish nationwide, retrospective cohort study 
BMJ Open  2013;3(1):e001800.
Objective
To examine the excess risk of hospitalisation in patients with incident atrial fibrillation (AF).
Design
A nationwide, retrospective cohort study.
Setting
Denmark.
Participants
Data on all admissions in Denmark from 1997 to 2009 were collected from nationwide registries. After exclusion of subjects previously admitted for AF, data on 4 602 264 subjects and 10 779 945 hospital admissions contributed to the study.
Primary and secondary outcome measures
Age-stratified and sex-stratified admission rates were calculated for cardiovascular and non-cardiovascular admissions. Temporal patterns of readmission, relative risk and duration of frequent types of admission were calculated.
Results
Of 10 779 945 hospital admissions, 729 088(6.8%) were associated with AF. Admissions for cardiovascular reasons after 1, 3 and 6 months occurred for 6.0, 14.3 and 28.4% of AF patients versus 0.2, 0.6 and 1.8 of non-AF patients. Admissions for non-cardiovascular reasons after 1, 3 and 6 months comprised 6.8, 16.1 and 33.3% of AF patients and 1.2, 3.2 and 9.7% of non-AF patients. When stratified for age, AF was associated with similar cardiovascular admission rates across all age groups, while non-cardiovascular admission rates were higher in older patients. Within each age group and for both cardiovascular and non-cardiovascular admissions, AF was associated with higher rates of admission. When adjusted for age, sex and time period, patients with AF had a relative risk of 8.6 (95% CI 8.5 to 8.6) for admissions for cardiovascular reasons and 4.0 (95% CI 4.0 to 4.0) for admission for non-cardiovascular reasons.
Conclusions
This study confirms that the burden of AF is considerable and driven by both cardiovascular and non-cardiovascular admissions. These findings underscore the importance of using clinical and pharmacological means to reduce the hospital burden of AF in Western healthcare systems.
doi:10.1136/bmjopen-2012-001800
PMCID: PMC3563138  PMID: 23355661
Cardiology; Epidemiology
20.  Out-of-Hospital Cardiac Arrests and Outdoor Air Pollution Exposure in Copenhagen, Denmark 
PLoS ONE  2013;8(1):e53684.
Cardiovascular disease is the number one cause of death globally and air pollution can be a contributing cause. Acute myocardial infarction and cardiac arrest are frequent manifestations of coronary heart disease. The objectives of the study were to investigate the association between 4 657 out-of-hospital cardiac arrests (OHCA) and hourly and daily outdoor levels of PM10, PM2.5, coarse fraction of PM (PM10-2.5), ultrafine particle proxies, NOx, NO2, O3 and CO in Copenhagen, Denmark, for the period 2000–2010. Susceptible groups by age and sex was also investigated. A case-crossover design was applied. None of the hourly lags of any of the pollutants were significantly associated with OHCA events. The strongest association with OHCA events was observed for the daily lag4 of PM2.5, lag3 of PM10, lag3 of PM10-2.5, lag3 of NOx and lag4 of CO. An IQR increase of PM2.5 and PM10 was associated with a significant increase of 4% (95% CI: 0%; 9%) and 5% (95% CI: 1%; 9%) in OHCA events with 3 days lag, respectively. None of the other daily lags or other pollutants was significantly associated with OHCA events. Adjustment for O3 slightly increased the association between OHCA and PM2.5 and PM10. No susceptible groups were identified.
doi:10.1371/journal.pone.0053684
PMCID: PMC3544842  PMID: 23341975
21.  Clarithromycin in Early Pregnancy and the Risk of Miscarriage and Malformation: A Register Based Nationwide Cohort Study 
PLoS ONE  2013;8(1):e53327.
Background
The antibiotic clarithromycin has been associated with fetal loss in animals and a study has found a doubling in the frequency of miscarriages among women using clarithromycin in pregnancy. The aim of the study was to investigate whether clarithromycin use in early pregnancy was associated with an increased risk for miscarriages and major malformations.
Methods
We conducted a nationwide cohort study including all women in Denmark with a known conception between 1997 and 2007. The Fertility Database was used to identify all women giving birth and the National Hospital Register was used to identify all women with a record of miscarriage or induced abortion. Prescription data was obtained from the National Prescription Register. The primary outcome was the number of miscarriages and offspring with major congenital malformations among users of clarithromycin compared to non-users.
Results
We identified 931 504 pregnancies (705 837 live births, 77 553 miscarriages, and 148 114 induced abortions). 401 women redeemed a prescription of clarithromycin in the first trimester of which 40 (10.0%) experienced a miscarriage and among the live born nine (3.6%) had offspring with malformations. The hazard ratio (HR) of having a miscarriage after exposure to clarithromycin was 1.56 (CI95% 1.14–2.13). There was no increased hazard of having a miscarriage when being exposed to penicillin or erythromycin. There was no increased prevalence (OR = 1.03 (CI95% 0.52–2.00)) of having offspring with malformations after exposure to clarithromycin.
Conclusions
We found an increased hazard of miscarriage but no increased prevalance of having offspring with malformations among women redeeming a prescription of clarithromycin in early pregnancy. This is supported by previous studies in animals and humans. However, further research is required to explore the possible effect of treatment indication on the associations found.
doi:10.1371/journal.pone.0053327
PMCID: PMC3534696  PMID: 23301061
22.  Hormone Replacement Therapy and Risk of New-Onset Atrial Fibrillation after Myocardial Infarction - A Nationwide Cohort Study 
PLoS ONE  2012;7(12):e51580.
Objectives
Our aim was to assess the association between use of hormone replacement therapy (HRT) and risk of new-onset atrial fibrillation (AF) after myocardial infarction.
Design, Setting and Participants
We used Danish nationwide registers of hospitalizations and prescriptions to identify all women admitted with myocardial infarction in the period 1997 to 2009 and with no known diagnosis of AF. Their use of overall HRT and HRT categories was assessed. Multivariable Cox proportional hazards analysis was used to calculate the risk of new-onset AF first year after discharge, comparing use of HRT to no use.
Main Outcome Measures
New-onset atrial fibrillation.
Results
In the period 1997 to 2009, 32 925 women were discharged alive after MI. In the first year after MI, new-onset AF was diagnosed in 1381 women (4.2%). Unadjusted incidence rates of AF decreased with use of HRT (incidence rate 37.4 for use of overall HRT and 53.7 for no use). Overall HRT was associated with a decreased risk of AF (HR 0.82, 95% confidence interval [CI] 0.68–1.00). The lowest risk of AF was found in women ≥80 years old for use of overall HRT and vaginal estrogen (HR 0.63, CI 0.42–0.94, and HR 0.58, CI 0.34–0.99, respectively). Decreased risk of AF with use of overall HRT and HRT categories was also found in other age groups.
Conclusions
Use of HRT is associated with a decreased risk of new-onset AF in women with myocardial infarction first year after discharge. The underlying mechanisms remain to be determined. Unmeasured confounding might be one of them.
doi:10.1371/journal.pone.0051580
PMCID: PMC3524193  PMID: 23284717
23.  Prognosis after percutaneous coronary intervention in patients with psoriasis: a cohort study using Danish nationwide registries 
Background
Psoriasis is an inflammatory disease associated with increased risk of coronary artery disease. However, the potential impact of psoriasis on the prognosis following percutaneous coronary revascularization (PCI) is unknown.
Methods
The study comprised the entire Danish population undergoing first-time PCI in the period 2002–09. Cox regression models, controlling for age, gender, socioeconomic status, pharmacological treatment, and comorbidity were used to assess the risk of 1) all-cause mortality and 2) a composite endpoint of death, myocardial infarction, and stroke.
Results
A total of 53,141 patients with first-time PCI in the study period were identified. Of these, 1074 had mild psoriasis and 315 had severe psoriasis. Patients with severe psoriasis, but not those with mild disease had increased risk of both endpoints compared to patients without psoriasis. The incidence rates for all-cause mortality were 30.5 (CI 29.7-31.3), 29.9 (CI 24.7-36.1), and 47.2 (CI 35.0-63.6) per 1000 patient years for patients without psoriasis, with mild psoriasis, and with severe psoriasis, respectively. Hazard ratios were 1.10 (CI 0.91-1.33) and 1.67 (CI 1.24-2.26) for mild and severe psoriasis, respectively. Patients with severe psoriasis were less likely to receive secondary prevention pharmacotherapy with betablockers, statins and platelet inhibitors.
Conclusion
This first study of the prognosis following PCI in patients with psoriasis demonstrated an increased risk of all-cause mortality and of a composite of death, myocardial infarction and stroke, respectively, in patients with severe psoriasis compared to patients without psoriasis. Further studies of this novel association are needed.
doi:10.1186/1471-2261-12-79
PMCID: PMC3507678  PMID: 23006590
Coronary revascularization; Cardiovascular disease; Inflammation; Psoriasis; Prognosis
24.  Long-Term Prognostic Importance of Diabetes After a Myocardial Infarction Depends on Left Ventricular Systolic Function 
Diabetes Care  2011;34(8):1788-1790.
OBJECTIVE
This study was performed to understand how left ventricular function modulates the prognostic importance of diabetes after myocardial infarction (MI).
RESEARCH DESIGN AND METHODS
Consecutively hospitalized MI patients screened for three clinical trials were followed for a median of 7 years. Multivariable Cox regression models were used to assess the risk of mortality associated with diabetes, and the importance of diabetes was examined independently within defined left ventricular ejection fraction (LVEF) subgroups.
RESULTS
A total of 16,912 patients were included; 1,819 (11%) had diabetes. Diabetes and 15% unit depression in LVEF were of similar prognostic importance: hazard ratios (HRs) were 1.45 (95% CI 1.37–1.54) and 1.41 (1.37–1.45) for diabetes and LVEF depression, respectively. LVEF modified the outcomes associated with diabetes, with HRs being 1.29 (1.19–1.40) and 1.61 (1.49–1.74) in patients with LVEF <40% and LVEF ≥40%, respectively (P = 0.03).
CONCLUSIONS
Patients within the higher LVEF categories have a greater mortality risk attributable to diabetes than patients within the lower LVEF categories.
doi:10.2337/dc11-0154
PMCID: PMC3142062  PMID: 21715523
25.  Initiation and Persistence with Warfarin Therapy in Atrial Fibrillation According to Ethnicity 
The aim of this study was to investigate initiation of and persistence with warfarin treatment in patients with atrial fibrillation (AF) according to ethnicity. Patients hospitalized with first-time AF from 1997 to 2009, prescription claims of warfarin and country of birth were identified by individual-level linkage of nationwide administrative agencies. Cox proportional hazards models were used to estimate the relationship between covariates affecting initiation and non-persistence with warfarin treatment. A total of 151,537 patients were included in the study and 5,061(3.3%) were of non-Danish origin. CHADS2 score distribution varied substantially according to ethnicity, the proportion of patients with CHADS2 score ≥1 being 79.2, 78.1, 65.9, and 46.0% for patients of Danish, Western, Eastern, and African origin, respectively. 79,239(52.4%) of all patients initiated treatment with warfarin at some point in time. Multivariable Cox proportional hazard analyses indicated patients of Eastern and African origin were less likely to initiate warfarin therapy (HR 0.75; 95% CI 0.69–0.82 and HR 0.58; 95% CI 0.44–0.76, respectively). Patients of Eastern origin were more likely to interrupt treatment (HR 1.23; 95% CI 1.02–1.47; for all patients; HR 1.62; 95% CI 1.22–2.16; for patients with CHADS2 score >1). African origin was associated with a trend to interrupt treatment (HR 1.44; 95% CI 0.46–4.47; for patients with CHADS2 score >1). Initiation of and persistence with warfarin in AF patients is lower among patients of Eastern and African origin compared to patients of Danish and Western origin, despite equal access to health care and medication. Future studies should address, beyond ethnicity, all possible driving factors of (non)initiation and persistence with treatment in general. This will be particularly interesting in light of the new generation of anticoagulants, which might render different adherence to treatment.
doi:10.3389/fphar.2012.00123
PMCID: PMC3385210  PMID: 22754529
atrial fibrillation; ethnicity; VKA treatment; warfarin; adherence

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