Danish Study Research Articles

A Danish questionnaire study of acute symptoms of SARS-CoV-2 infection by variant, vaccination status, sex and age

It is not well-described how the acute symptoms of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) differ by variant, vaccination, sex and age. A cross-sectional questionnaire study linked to national testing- and registry data was conducted among 148,874 SARS-CoV-2 first time reverse transcription polymerase chain reaction (RT-PCR) test-positive individuals and corresponding date-matched symptomatic test-negative controls. Major SARS-CoV-2 variants (Index/wild type, Alpha, Delta and Omicron) were defined using periods of predominance. Risk differences (RDs) were estimated for each of 21 predefined acute symptoms comparing: (1) test-positive and -negative individuals, by variant period, (2) vaccinated and unvaccinated test-positives, by variant period, (3) individuals tested positive during the Omicron and Delta periods, by vaccination status, and (4) vaccinated Omicron test-positive and -negative individuals, by age and sex. Compared to pre-Omicron, RDs between test-positive and test-negative individuals during the Omicron period were lower for most symptoms. RDs for altered sense of smell (dysosmia) and taste (dysgeusia) were highest for Delta (RD = 50.8 (49.4–52.0) and RD = 54.7 (53.4–56.0), respectively) and lowest for Omicron (RD = 12.8 (12.1–13.5) and RD = 11.8 (11.1–12.4), respectively). Across variants, vaccinated individuals reported fewer symptoms. During Omicron, females and 30–59 year-old participants reported more symptoms.

Incidence of sustained ventricular tachyarrhythmias in patients with non-ischemic cardiomyopathy in a multicenter multinational WCD cohort

Abstract Background Defibrillator use in patients with non-ischemic cardiomyopathy (NICM) and HFrEF remains controversial after the DANISH study. The new ESC guidelines recommend individualized risk stratification in these patients. The wearable cardioverter-defibrillator (WCD) seems to be appropriate to both protect and screen patients with HFrEF at risk for sudden cardiac death (SCD). Puropose: To evaluate the rate of ventricular tachyarrhythmias (VT/VF) in NICM vs. ICM patients receiving a WCD for temporary SCD protection. Methods 1157 patients were included in a multicenter registry from eight European centers. Among these patients, 602 patients received a WCD due to ischemic cardiomyopathy (ICM) and 555 patients for non-ischemic cardiomyopathy (NICM). Incidence of VT/VF and/or appropriate WCD shock discharge during WCD use were evaluated. The mean follow-up (FU) time of the whole cohort was 620.2±607.8 days. Results NICM patients were younger (mean 56.5±14.8a vs 63.9±11.6a; p<0.001) and less often male (75% vs. 87.2%; p<0.001) compared to ICM patients. Heart failure medication at hospital discharge did not differ between the two groups except for a higher prescription rate of aldosterone-antagonists in NICM compared to ICM patients (73.8% vs. 66.7%; p=0.02). The index left ventricular ejection fraction (LVEF) was significantly lower in NICM compared to ICM patients (mean 26.1±9.1% versus 29.5±9.2%; p<0.001). A larger extent of LVEF recovery was detected in NICM patients compared to ICM patients up to the end of WCD use (mean LVEF post WCD: 45.7±35.4% vs. 40.2±11.8%; p=0.02). Average daily WCD wear-time was significantly lower in NICM patients compared to ICM patients (mean 20.7±4.9h vs. 21.6±3.7h; p=0.01). NICM patients had a significantly lower incidence of sustained ventricular tachyarrhythmia (VT/VF) compared to ICM patients (3.4% vs. 6.6%; p=0.02). Consistently, rate of appropriate WCD shock was significantly lower in NICM vs. ICM patients (0.7% vs. 3.7%; p< 0.001), as was rate of re-hospitalization (30.2% vs. 46.1%; p<0.001). Both groups showed a similar mortality rate during FU. Conclusions Patients at risk for SCD with NICM showed a more pronounced LVEF recovery, significantly lower incidence of VT/VF with concomitant shocks and hospitalization, while overall mortality was unchanged compared to ICM patients. These results indicate that WCD use might facilitate individual SCD risk stratification in NICM patients.

Changes in study enrollment of patients with non-ischemic cardiomyopathy receiving an ICD for primary prevention: Insights from the APPRAISE ATP study

Abstract Introduction The DANISH study called into question the effectiveness of the ICD in patients (pts) with non-ischemic cardiomyopathy (NIC) and resulted in a downgrade in ESC guidelines from Class I to Class IIA. The effect of these findings on implantation of ICDs in NIC pts in clinical studies has not been well established. Methods Two clinical studies were analyzed before and after the publication of DANISH: MADIT-RIT (2009-2012) and APPRAISE ATP (2017-present). These two studies enrolled globally and implanted ICDs in pts with primary prevention (PP) indications. The proportion of pts with NIC were analyzed between the two studies, both globally and by region: North America (NA) and European Union (EU). In addition, the APPRAISE ATP study was divided into halves to determine if any changes were observed whilst the study was in progress. Continuous variables were analyzed with a t-test and categorical variables were analyzed with a Chi-square test. Due to small numbers, implanted pts outside NA and the EU were not entered into the analysis. Results Demographics for the NIC subgroups are shown in the table below [MADIT-RIT (n=284) and APPRAISE ATP (n=1084)]. When compared to MADIT-RIT, pts in APPRAISE ATP were significantly older, had a higher mean LVEF, and greater prevalence of AF and diabetes. Globally, the proportion of pts with NIC who received ICDs was unchanged between the current APPRAISE ATP study and MADIT-RIT 10 years previously (38.1% vs 39.3%, p=0.91). When analyzed by geography, there was no change in North America (38.0% vs 41.6%, p=0.27). In Europe, however, there was a drop in enrollment of NIC ICD pts from 38.6% in MADIT-RIT to 29.1% in APPRAISE ATP. This decline was 24.6% in relative terms and approached, but did not achieve, statistical significance (p=0.074). Implant rates in NIC ICD pts were stable overall when comparing the first half of APPRAISE ATP to its second half. Rates were also stable across both halves in NA and while implant rates of NIC ICD pts appeared to rebound in the second half in the EU, that late increase was not statistically significant. Conclusions The results of the DANISH study appear to have had a limited global impact on enrollment of NIC pts requiring implant of a PP ICD into the APPRAISE ICD clinical study. Whilst there was no change in North America before and after DANISH, there is a signal in the data that investigators in the EU may have restricted implants initially but eventually relaxed as time progressed. Further investigation is needed to confirm whether physicians in general practice have altered their referral patterns.

Discovery of potential plasma protein biomarkers for ventricular fibrillation due to first ST-elevation myocardial infarction via proteomics

Abstract Background Although most sudden cardiac deaths are a consequence of ventricular fibrillation (VF) subsequent to myocardial infarction, the underlying biological mechanisms of VF in the setting of ischemia are largely unknown. We used an unbiased mass-spectrometry (MS)-based proteomic approach to improve our understanding of the molecular VF mechanisms. Purpose We aimed to identify and characterize proteins that are associated with VF during first ST-elevation myocardial infarction (STEMI). Methods We included 230 participants from a Danish ongoing case-control study on patients with first STEMI with VF (case, n=110) and without VF (control, n=120) before guided catheter insertion for primary percutaneous coronary intervention. Using MS-based proteomics on plasma samples collected within 24h of symptom onset, we investigated the plasma proteome. After quality control, one patient was excluded and the difference in the quantitative proteome composition between cases and controls were analysed using t-tests, and further corrected for multiple comparison using the Benjamini-Hochberg procedure (q-value). Cardiac enzymes and anterior infarct location were used in a subset as a proxy for large myocardial damage. Results In 229 STEMI patients (72% men, median age 62 years (interquartile range (IQR): 54-70)), a total of 401 unique proteins were identified with a median of 257 proteins (IQR: 244-281) quantified per patient. A total of 26 proteins were associated with VF, these proteins were involved in several biological processes. The most frequent processes were blood coagulation, hemostasis and immunity. After correcting for multiple testing, two up-regulated proteins remained significantly associated with VF, actin beta-like 2 (ACTBL2, FC 2.25, p<0.001, q=0.023) and coagulation factor XIII-A (F13A1, FC 1.48, p<0.001, q=0.023). The most up-regulated protein was ACTBL2, and the second most up-regulated protein was actin alpha 2 (ACTA2, FC 1.72, p=0.001, q=0.073). None of the three proteins were correlated with cardiac enzymes or anterior infarct location. Conclusion VF due to first STEMI was significantly associated with two up-regulated proteins (ACTBL2 and F13A1). None of these proteins were correlated with infarct size which could reflect novel underlying molecular VF mechanisms.

Amiodarone and the risk for pulmonary fibrosis. A Danish nationwide study

Abstract Background Amiodarone may cause pulmonary fibrosis. However, very few studies have investigated this possible association. This study will evaluate whether amiodarone is associated with pulmonary fibrosis, and furthermore, if there is an exposure-response relationship. Method and results Using Danish national patient registries, we conducted an observational population-based study. Individuals diagnosed with pulmonary fibrosis were identified between 1996 and 2020 using ICD codes and then included in a nested case-control study, where cases were matched with 5 controls. The exposure to amiodarone was defined by dispensed amiodarone recipes from the national prescription registry. Cox regression analysis was used to derive the crude hazard ratio (HR) and the confidence interval (CI). The analyses were also adjusted and stratified for pre-specified comorbidities to derive multivariate Hazard ratio. Furthermore, we analysed the outcome in respect to amiodarone exposure time (<3 months, 3-6 months, 6-12 months, 1-3 years, 3-5 years, over 5 years) and also in respect to the cumulative dosage. A total of 27 948 cases diagnosed with pulmonary fibrosis over the 24 years period of study in Danish population were matched with 139 740 controls. The average age was 69 years and 45% was females. We found that amiodarone treatment was associated with significant risk of pulmonary fibrosis (HR: 4.20, 95%CI: [3.83-4.60], p<0.001). After adjusting for comorbidities including hypertension, diabetes mellitus, asthma, chronic obstructive pulmonary disease, ischemic heart disease, heart failure, stroke, any cancer, liver failure, chronic kidney disease, and alcohol, the association remained significant (HR:2.55, 95%CI: [2.30-2.82], p<0.001) (Figure 1), and its remained also significant after excluding COPD patients from the population (HR: 3.93, 95%CI: [3.50-4.40], p<0.001). Finally, the treatment exposure relationship, 0-3 months (HR:2.34, 95%CI [1.82-3.02], p<0.001), and over 5 years (HR: 5.90, 95%CI [4.56-7.65], p<0.001) (figure 2), and dose response relationship, 0-18gm (HR: 2.48, 95%CI: [1.93-3.18], p<0.001), 120-240gm (HR: 4.34, 95%CI: [3.46-5.45], p<0.001), and over 840gm (HR: 7.06, 95%CI: [3.08-16.15], p<0.001) (figure 3). Conclusion Amiodarone use was found associated with an independent incident pulmonary fibrosis, 4-fold crude risk and with a more than 2-fold hazard already within the first 3 months of treatment. The association showed also a dose- and duration relationship, where larger doses and longer treatment were associated with higher hazard of pulmonary fibrosis.

Sarcoidosis is associated with a higher long-term risk of ischaemic heart disease, venous thromboembolism, and ischaemic stroke: a nationwide study

Abstract Background Sarcoidosis shares a number of pathophysiological mechanisms and risk factors with ischaemic heart disease and thromboembolism. Patients with sarcoidosis are at risk of cardiac involvement with heart failure and arrhythmias, but unlike other inflammatory diseases, such as systemic lupus erythematosus and rheumatoid arthritis, data on the risk of ischaemic heart disease, venous thromboembolism, and ischaemic stroke in patients with sarcoidosis are sparse. This may prevent patients with sarcoidosis from the benefits of screening for these cardiovascular diseases. Purpose To examine the long-term risk of ischaemic heart disease, venous thromboembolism, and ischaemic stroke in patients with sarcoidosis compared to a matched background population. Methods In this Danish nationwide cohort study, all patients >18 years diagnosed with sarcoidosis between 1996-2020 were matched 1:4 by age, sex, and cardiovascular risk factors with individuals from the background population without sarcoidosis. Patients with a history of ischaemic heart disease, venous thromboembolism, and ischaemic stroke were excluded from the sarcoidosis and background population prior to matching. Absolute 10-year risks of outcomes were estimated using the Aalen-Johansen estimator, and rates of outcomes were compared between sarcoidosis patients and the background population using Cox regression. Results We identified 15,454 patients with sarcoidosis and 61,816 matched individuals from the background population (median age 43.8 years, 56% males). The median follow-up was 9.4 years. Absolute 10-year risks of outcomes were as follows: ischaemic heart disease, 5.2% (95% confidence interval [CI], 4.8-5.6%) vs. 3.8% (95% CI, 3.6-4.0%) in the sarcoidosis vs. background population; venous thromboembolism, 3.3% (95% CI, 3.0-3.6%) vs. 1.6% (95% CI, 1.5-1.8%) in the sarcoidosis vs. background population; ischaemic stroke, 2.5% (95% CI, 2.2-2.8%) vs. 2.0 (95% CI, 1.9-2.1%) in the sarcoidosis vs. background population. In multivariable Cox regression analysis, sarcoidosis was associated with an increased risk of ischaemic heart disease (hazard ratio [HR] 1.47 [95% CI, 1.31-1.65]), venous thromboembolism (HR 1.99 [95% CI, 1.70-2.31]), and ischaemic stroke (HR 1.41 [95% CI, 1.21-1.64]) compared with the matched background population (Figure 1). Conclusions In this nationwide cohort study, sarcoidosis was associated with a higher long-term risk of ischaemic heart disease, venous thromboembolism, and ischaemic stroke compared with a matched background population. Although further studies on pathophysiological mechanisms are needed, it may be relevant to screen for cardiovascular diseases in patients with sarcoidosis, as we do in patients with other inflammatory diseases.

Temporal changes in stroke and heart failure following first-time atrial fibrillation/flutter in patients under 65 years of age: A Danish nationwide study

Abstract Background The incidence of atrial fibrillation/flutter (AF) has increased throughout the past two decades - also for patients under 65 years of age. Whether this increment in patients with AF under 65 years of age also influences the subsequent incidence of ischaemic stroke (stroke) and heart failure (HF) is yet to be elucidated. This patient group are of special interest as this population often is considered at low risk of stroke. Methods Using Danish nationwide registries, we identified all patients from 18–65 years with a first-time AF-diagnosis in 2000-2018. The cohort was categorised according to calendar periods into five groups: 2000-200, 2003-2006, 2007-2010, 2011-2014, and 2015-2018. Crude incidence rate (IR) of stroke and HF per 1,000 person years (PY) were calculated. The cumulative incidence (CI) of stroke and HF during one year of follow-up was computed accounting for death as a competing risk. The reverse Kaplan-Meier estimator was used to examine mortality during one year follow-up. Multivariable Cox proportional hazard analysis was used to compare outcomes between calendar periods with 2000-2002 as comparative reference. Hazard ratios (HR) were reported with 95% confidence intervals (95% CI). Results In this study 51,137 patients were included; 6,911 (median age 56, 64.5% males, 22.0% on OAC) in 2000-2002, 9,964 (median age 58, 65.5% males, 26.4% on OAC) in 2003-2006, 11,538 (median age 58, 64.7% males, 23.9% on OAC) in 2007-2010, 11,764 (median age 58, 63.6% males, in 29.2% on OAC) in 2011-2014, and 10,960 (median age 56, 65.9% males, 39.5% on OAC) in 2015-2018. For stroke, crude IR/1,000 PY [95% CI] declined through calendar time as seen in the Figure. The crude IR were 10.4 [8.0;13.5] in 2000-2002 and 6.3 [4.9;8.0] in 2015-2018 with corresponding CIs of 1.0%, 0.9%, 0.9%, 0.8%, and 0.6%, respectively (p-value for difference=0.08). The corresponding adjusted HRs [95% CI] were 0.94 [0.66;1.35] for calendar period 2003-2006, 0.87 [0.61;1.24] for 2007-2010, 0.86 [0.61;1.23] for 2011-2014, and 0.61 [0.41;0.91] for 2015-2018 as compared with 2000-2002. As seen in the Figure crude IR [95% CI] for HF were stagnant over time with 37.2 [32.4;42.8] in 2000-2002 and 38.3 [34.7;42.3] in 2015-2018 with corresponding CIs of 3.4%, 3.3%, 3.5%, 3.4%, and 3.3%, respectively (p-value for difference=0.89). The corresponding adjusted HRs [95% CI] were 0.93 [0.79;1.10] for calendar period 2003-2006, 0.99 [0.84;1.17] for 2007-2010, 0.99 [0.84;1.16] for 2011-2014, and 1.02 [0.86;1.20] for 2015-2018 as compared with 2000-2002. Mortality with one year of follow-up was 3.8%, 4.4%, 4.4%, 4.5%, and 3.7% in calendar period 1-5 respectively (p-value for difference=0.38). Conclusion From nationwide registries in patients with atrial fibrillation/flutter under 65 years of age, we found a stepwise decline in one-year rates of ischaemic stroke with more recent calendar periods. Heart failure and mortality incidence were stable across calendar time.Incidence rates of ischemic stroke

Factors associated with early and late Staphylococcus aureus bacteraemia after first cardiac implantable electronic device implantation a Danish nationwide cohort study

Abstract Background Staphylococcus aureus bacteraemia (SAB) is a serious condition with high morbidity and mortality. Patients with a cardiac implantable electronic device (CIED) and SAB carries a risk of up to 50 % for device related infection. Yet, little is known about risk factors for early and late SAB in CIED patients in real-world clinical practice. Purpose We aimed to identify risk factors associated with first-time early and late SAB following de novo CIED implantation among adult Danish patients. Methods Using the Danish Pacemaker and ICD Register, we identified all Danish patients aged 18 to 99 years with a first CIED implantation between 2000 and 2020. The primary outcome of first-time post-CIED implantation SAB was identified from The National Danish Staphylococcus Aureus Bacteriemia Database. Early SAB was defined as SAB ≤ 6 months from CIED implantation. Late SAB was defined as first-time SAB after CIED, occurring > 6 months from CIED implantation. Multivariable Cox regression with backward elimination was used to identify factors associated with increased risk of developing early and late SAB. Age, sex, device type, implantation year, preexisting co-morbidity, procedure related factors and prior surgery (thoracic, abdominal, orthopedic, gynecologic, or urologic) was evaluated. Statistically significant variables were fitted to the final models to obtain hazard ratios with 95% confidence intervals. Results We identified 87,216 patients with first-time CIED implantation within the study period: PM n = 66,151 (75.8%); Implantable Cardioverter Defibrillator (ICD) n = 13,498 (15.5%); Cardiac resynchronization therapy PM (CRT-P) n = 3,491 (4.0 %); Cardiac resynchronization therapy with defibrillator (CRT-D) n = 4,076 (4.7 %). Median age across the population was 75 years (IQR 66-82) and 62.6% were males. Median time to SAB in the early SAB group was 46 days (IQR 18-105) and 2,9 years (IQR 1.5-5.1) in the late SAB group. Post implantation SAB was observed in 1,399 (1.6%) patients; with 363 (25.9%) early SAB events and 1,036 (74.1%) late SAB events. Factors associated with early SAB included previous SAB, renal dialysis, COPD, surgery 1 year prior to CIED implantation, liver disease, diabetes, and congestive heart failure (Figure 1). Male sex, increasing age, previous SAB, congestive heart failure, aortic valve disease, diabetes, renal dialysis, COPD, cancer, liver disease and the use of systemic corticosteroids were associated with an increased risk of late SAB. Conclusions Renal dialysis, previous SAB, diabetes, congestive heart failure, COPD and liver disease were associated with an increased risk of both early and late SAB. Increasing age, male sex, aortic valve disease and cancer were associated with an increased risk of late SAB, while surgery within 1 year prior to CIED implantation was associated with early SAB. Most of the identified factors were non-modifiable and comparable to known risk factors for SAB in non-CIED patients.Figure 1

Cardiovascular safety of non-steroidal anti-inflammatory drug use for gout: A Danish nationwide case-crossover study

Abstract Background Gout is associated with increased cardiovascular risk through inflammation and shared risk factors. Gout attacks are treated with a uric-lowering drug, such as allopurinol, and an anti-inflammatory drug, such as a non-steroidal anti-inflammatory drug (NSAID). Thus, NSAIDs could be both cardiovascular beneficial, due to their anti-inflammatory actions, and cardiovascular hazardous, due to their prothrombotic, hypertensive, and proarrhythmic actions. Yet, no study has examined the cardiovascular safety of NSAIDs for the treatment of gout. Purpose To examine the risk of major adverse cardiovascular events (MACEs) associated with NSAID use in gout patients. Methods We conducted a nationwide, population-based case-crossover study of all Danes ≥18 years of age with first-time gout during 1997–2020, who experienced a MACE (myocardial infarction, ischemic stroke, congestive heart failure, atrial fibrillation or flutter, or all-cause death) (n=103,522). The patients were identified either via a hospital diagnosis for gout (12%) or via a filling of an allopurinol prescription (88%). The exposures were use of NSAIDs overall and according to subtype (ibuprofen, naproxen, or diclofenac). An individual was considered exposed from the time of a filled prescription until the end of a use period, estimated from average use of two tablets per day. In the case-crossover design, we used four reference dates at 120, 180, 240, and 300 days before the outcome. An individual was considered exposed if the use period covered a reference date or the outcome date. We used the Mantel-Haenszel method to calculate odds ratios (ORs) with 95% confidence intervals (CIs) of the association between NSAID use and MACE. Results NSAID use was overall associated with a 15% decreased risk of MACE (OR=0.85, 95% CI: 0.83–0.87). The ORs of the association between NSAID use and the individual cardiovascular events were 0.91 (95% CI: 0.84–0.99) for myocardial infarction, 0.88 (95% CI: 0.81–0.95) for ischemic stroke, 0.89 (95% CI: 0.83–0.94) for congestive heart failure, 0.80 (95% CI: 0.75–0.85) for atrial fibrillation or flutter, and 0.77 (95% CI: 0.75–0.80) for all-cause death. The decreased risk of MACE was observed for use of ibuprofen (OR=0.91, 95% CI: 0.88–0.95) and naproxen (OR=0.78, CI: 0.70–0.86), but not for use of diclofenac (OR=1.03, 95% CI: 0.97–1.09). Conclusions In patients with first-time gout, use of ibuprofen and naproxen was associated with a slightly decreased cardiovascular risk, whereas diclofenac was not.

Association between obstructive sleep apnea and heart failure in patients with and without obesity: a population-based cohort study

Abstract Background Obstructive sleep apnea (OSA) is a prevalent disorder characterized by partial or complete airway collapse during sleep, which often leads to sleep disruption and intermittent hypoxia. Previous research has suggested that patients with heart failure (HF) are more likely to have OSA. However, not enough evidence is available for association between new-onset OSA and HF. A recent Danish cohort study found that OSA, without continuous positive airway pressure therapy, is linked to a higher risk of HF across all age groups (1). In addition, the association between OSA and HF in patients with and without obesity has not been extensively studied in a large Asian cohort. Purpose To investigate the association between obstructive sleep apnea (OSA) and heart failure (HF) in a large Asian cohort stratified by obesity, as defined by World Health Organization (WHO) criteria for the Asian population, in both patients with and without obesity. Methods Using a nationally representative cohort of Korean adults over 40 years old who underwent national health screening between 2009 and 2010 with no prior history of HF or cardiovascular disease, we identified OSA using outpatient visit records (ICD-10: G47.3). Participants were tracked from January 1, 2011 to December 31, 2019 for new HF events, death from HF or other causes, or the end of follow-up, whichever occurred first. A Cox proportional hazards model adjusted for sociodemographic factors, health status, health behavior, and family history of heart disease was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Obesity was defined as a body mass index greater than 25.0 kg/m2 based on WHO criteria for the Asian population. Results The final study population included 326,662 participants (32.7% of them were with obesity). Among obese patients, those with OSA had a higher risk of developing HF (HR=1.52; 95% CI: 1.07-2.19) than those without OSA. The association between OSA and HF was less pronounced in non-obese patients (HR=1.07; 95% CI: 0.65-1.78 for HF in patients with OSA compared to those without OSA) with a significant interaction between obesity and OSA-HF association (P-value for interaction<0.001). Conclusions Our findings suggest that OSA is linked to an increased risk of HF, particularly in obese patients. Further research is necessary to examine important clinical subgroups regarding prevention of HF in patients with OSA.

Five-year changes in weight and risk of atrial fibrillation in women and men from the Danish diet, cancer, and health cohort

Abstract Background Overweight and obesity are causal risk factors for atrial fibrillation (AF).(1) Mendelian randomization studies indicated a higher risk of AF with each unit increase in body mass index (BMI).(1) In observational studies, weight gain was associated with a higher risk of incident AF compared to stable weight.(2,3) However, the results are conflicting regarding the association between weight loss and risk of incident AF.(4,5). Purpose We aimed to assess the association between five-year changes in weight and absolute and relative rates of incident AF in women and men from the Danish Diet, Cancer, and Health Cohort. Methods In the Danish cohort study Diet, Cancer, and Health, participants were invited to attend a recruitment research examination and a second examination 5 years later. Height, weight, and several lifestyle factors were assessed at both examinations. We calculated BMI and BMI changes between first and second examination. BMI changes were categorized into following groups: <-5 kg/m2, ≥-5 to <-2.5 kg/m2, ≥-2.5 to <2.5 kg/m2, ≥2.5 to <5 kg/m2 and ≥5 kg/m2. Diagnoses of AF and comorbidities were retrieved from the Danish National Patient Registry. We used multivariable-adjusted Cox proportional hazards models to assess hazard ratios (HR) of AF according to changes in BMI. Results 43,758 participants without prior AF were included in the study. The median age was 62 (25th-75th percentile, 58-66) years and 54% were women. Over 15.7 years median follow-up time 5,312 participants had incident AF. From the first to the second measure, 39,076 (89%) of participants had stable weight, 2,627 (6%) lost weight, and 2,055 (5%) gained weight. The incidence rates of AF per 1,000 person-years were 8.4 (95% CI 8.1-8.6) among participants with stable weight, 12.4 (95% CI 9.6-16.1) among those with weight loss ≥5 kg/m2, and 15.4 (95% CI 11.7-20.2) among those who gained ≥5 kg/m2. Compared to participants with stable weight, individuals who gained ≥2.5 to <5 kg/m2 had a higher hazard of AF (HR 1.24, 95% CI 1.09-1.41). Among participants who gained ≥5 kg/m2 the rate of AF was also higher compared to stable weight (HR 1.95, 95% CI 1.48-2.56). There was no statistically significant association between weight loss, regardless of degree, and rate of AF. Figure 1 shows the HR of AF by BMI changes from first to second measure compared to stable weight using restricted cubic splines. In sex-stratified analyses, the association between weight gain of ≥5 BMI units (kg/m2) and higher AF rate was present for both women and men. Conclusions In this cohort study, five-year weight gain was associated with higher long-term risk of AF compared to stable weight. However, we found no associations between weight loss and long-term risk of AF.Figure 1

A randomized clinical trial of sex and population-specific troponin cutoffs for ruling out acute MI - the danish study of sex and population-specific cutoffs of troponin (DANSPOT)

Abstract Background Measurements of high-sensitivity cardiac troponin (cTn) T/I are used as the gold standard and are the preferred biomarkers to diagnose acute myocardial infarction (MI) in conjugation with symptoms and changes in the ECG. The URL is based on the 99th percentile of troponin concentrations in a healthy reference population. Currently, a sex-uniform manufacturer provided 99th percentile URL of troponin is utilized at Danish hospitals as a diagnostic cutoff for acute MI for both men and women. Reportedly, healthy men have twofold the troponin level compared to healthy women, suggesting that the use of a uniform URL for troponins may lead to the under-diagnostication of acute MI in women and potentially over-diagnostication in men. Purpose The purpose of the DANSPOT study is to evaluate the clinical effect on diagnosis, treatment and outcomes in men and women presenting with acute MI of implementing international guidelines recommended sex-specific 99th percentile URLs for troponin into clinical practice. Methods First, to determine the sex-specific 99th percentile URLs of troponins (table) based on a healthy Danish reference population, blood samples from Danish blood donors, were analyzed using five high-sensitivity (hs) cTn assays (Siemens Atellica and Vista hs-cTnI, Roche hs-cTnT, Abbott Alinity hs-cTnI and Orthos VITROS hs-cTnI). Second, the DANSPOT study is a nationwide cluster-randomized trial with "stepped-wedge" design (figure) with participation of 22 Danish hospital center. With one-month intervals, each of the 22 centers have been randomized to shift from the presently applied sex-uniform 99th percentile URL of troponin to the population and sex-specific 99th percentiles URLs. First center started implementing the new 99th percentiles URLs on April 1, 2022, and the last center is planned to enroll on January 1, 2024. Patients are followed up in Danish registries for 12 months after index admission. The primary endpoint is a composite of myocardial infarction, unplanned revascularization (after index admission) and all-cause mortality and is calculated for the cohort of women and men with ≥2 measurements of troponin within the first 24 hours of admission with maximal troponin level between the new sex-specific 99th percentile URLs and the old sex-uniform 99th percentile URL. Perspective The clinical significance of sex-specific 99th percentile URLs of troponin is poorly investigated and for the same reason not yet implemented in Denmark or many other countries. With the implementation of population and sex-specific 99th URLs of troponin, we expect to detect significantly more women with acute MI, theoretically resulting in a more accurate diagnosis and treatment of women and men with acute MI. This would be guideline-defining for implementing sex-specific cutoffs for troponin in Denmark as well as internationally as recommended in guidelines by professional cardiological societies.Schematic presentation of study designTable of the new 99th percentiles of cTn

Effect of implantable cardioverter-defibrillator in non-ischaemic systolic heart failure according to the Heart Failure Collaboratory Medical Therapy Score: extended follow-up of the DANISH trial

Abstract Background The Heart Failure Collaboratory (HFC) has developed a medical therapy score which integrates types and doses of guideline-directed pharmacotherapies in patients with systolic heart failure, providing a measure of treatment quality. In clinical trials, this score may help determine the additive effect of new treatments. In the Danish Study to Assess the Efficacy of Implantable Cardioverter Defibrillators (ICDs) in Patients with Non-ischaemic Systolic Heart Failure on Mortality (DANISH) trial, ICD implantation did not provide an overall survival benefit in patients with non-ischaemic systolic heart failure. Purpose Adding four years of additional follow-up to the DANISH trial, we examined the effect of ICD implantation according to baseline modified HFC (mHFC) medical therapy score. Methods In the DANISH trial, 1,116 patients with non-ischaemic systolic heart failure were randomised to receive an ICD (N = 556) or usual clinical care (N = 560, control group). The primary outcome was death from any cause. In the mHFC score, patients were assigned a score for each drug class of the original cornerstones of systolic heart failure treatment (renin-angiotensin-system inhibitor, beta-blocker, and mineralocorticoid receptor antagonist). The maximum score was 100%, corresponding to optimal medical therapy with all three types of medication (=>50% of target dose). Results The median mHFC score at baseline was 67% (25th-75th percentile, 67%-100%; range, 17%-100%). During a median follow-up of 9.5 years, the ICD group did not have significantly lower all-cause mortality compared with the control group (hazard ratio [HR] 0.89 [95% CI, 0.74-1.08]). The results were independent of the mHFC score at baseline (mHFC score = < median: HR 0.91 [95% CI, 0.70-1.19]; mHFC score > median: HR 0.87 [95% CI, 0.66-1.14]; P for interaction, 0.94). Similarly, ICD implantation did not reduce the rate of cardiovascular death overall (HR 0.87 [95% CI, 0.70-1.09]), and this association was not modified by the mHFC score (mHFC score = < median: HR 0.90 [95% CI, 0.65-1.24]; mHFC score > median: HR 0.84 [95% CI, 0.61-1.15]; P for interaction, 0.89). The ICD group had a significantly lower rate of sudden cardiovascular death in the overall population (HR, 0.60 [95% CI, 0.40-0.92]), and this association was not modified by the mHFC score (mHFC score = < median: HR 0.72 [95% CI, 0.40-1.29]; mHFC score > median: HR 0.53 [95% CI, 0.28-0.99]; P for interaction, 0.59). See Figure for results. Conclusions In this extended follow-up study of the DANISH trial, ICD implantation did not provide an overall survival benefit in patients with non-ischaemic systolic heart failure regardless of baseline medical heart failure therapy, assessed by the mHFC score.Modified HFC score in the DANISH trial

Efficacy of implantable cardioverter-defibrillator in non-ischemic systolic heart failure in patients with and without chronic kidney disease: an extended follow-up analysis of the DANISH trial

Abstract Background Patients with heart failure (HF) and chronic kidney disease (CKD) may have an increased risk of death from causes competing with arrhythmic death, which could have implications for the efficacy of implantable cardioverter defibrillators (ICDs). Purpose In this extended follow-up study of the Danish Study to Assess the Efficacy of primary prevention of Implantable Cardioverter Defibrillators in Patients with Non-ischemic Systolic Heart failure on Mortality (DANISH), adding four years of additional follow-up, we examined the long-term effects of primary-prevention ICD implantation, compared with usual medical care, according to baseline CKD status. Methods In the DANISH trial, 1,116 patients with non-ischemic systolic HF were randomized to receive an ICD (N=556) or usual care (N=550). Outcomes were analyzed according to CKD status (eGFR ≥/< 60 mL/min/1.73 m2) at baseline. The primary outcome was death from any cause. Secondary outcomes were cardiovascular death and sudden cardiovascular death. Results In total, 1,113 patients had an available eGFR measurement at baseline (median eGFR 73 ml/min/1.73 m2), and 316 (28%) had CKD. During a median follow-up of 9.5 years, ICD implantation, compared with usual medical care, did not reduce the rate of death from any cause (no CKD, HR 0.81 [95% CI, 0.64-1.03]; CKD, HR 0.92 [0.68-1.26]; P for interaction=0.31) or cardiovascular death (no CKD, HR 0.76 [0.57-1.02]; CKD, HR 0.95 [0.66-1.36]; P for interaction=0.21), irrespective of baseline CKD status. Similarly, baseline CKD status did not modify the beneficial effects of ICD implantation on sudden cardiovascular death (no CKD, HR 0.57 [0.32-1.00]; CKD, HR 0.60 [0.31-1.14]; P for interaction=0.70). Conclusions Primary-prevention ICD implantation did not provide an overall survival benefit regardless of baseline kidney function in patients with non-ischemic systolic heart failure.Figure

Myocardial salvage and infarct characteristics in patients with ST-elevation myocardial infarction classified by ORBI risk score

Abstract Background The Observatoire Régional Breton sur l'Infarctus (ORBI) [1] risk score was developed to predict in-hospital cardiogenic shock (CS) development in patients with ST elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention. The association between infarct characteristics determined by cardiac magnetic resonance imaging (CMR) and ORBI risk classification have not previously been reported in patients with STEMI. Methods The Third DANish Study of Optimal Acute Treatment of Patients With ST-Segment Elevation Myocardial Infarction (DANAMI 3) trial investigated multiple revascularization strategies in patients with STEMI. CS on admission was an exclusion criterion, thus only low and intermediate scores were included. Stratification into ‘low’ (0-7) and ‘intermediate-high’ (>=8) ORBI risk score was performed (n=1,396), and CMR data from admission and three months follow-up at the largest participating centre were analysed using logistic- and Cox-regression (n=534, 38%). Results A total of 1,149 (82%) were ‘low’ risk, and 247 (18%) ‘intermediate-high’ risk. Patients with ‘intermediate-high’ risk were older (median age 71 (interquartile range (IQR) 61-78) vs. 60 (52-68), p<0.001), and more had an admission systolic blood pressure < 90 mm Hg (4.9% vs. 1.4%, p=0.002), and heart rate > 100 bpm (30% vs. 5%, p<0.001). Left ventricular ejection fraction was lower at discharge (40% (30-50%) vs. 50% (45-55%), p<0.001), and more had an anterior infarction (61% vs. 38%, p<0.001) compared to ‘low’ risk patients. Moreover, median peak troponin was higher (5010 ng/L (2195-9930) vs. 2820 ng/L (1138-5805), p<0.001). Aside from hypertension (52% vs. 39%, p<0.001), there were no differences in factors not covered by the ORBI score. In patients with ‘intermediate-high’ risk, both median acute and final infarct size were larger compared to those with ‘low’ risk (21% (12-28%) vs. 15% (7-24%), p=0.004, and 15% (10-26%) vs. 10% (4-17%), p<0.001). Median final salvage index was lower (0.66 (0.47-0.76) vs. 0.69 (0.55-0.87), p=0.048). ‘Intermediate-high’ risk was associated with higher odds of an above-median acute infarct size (odds ratio (OR) 2.02 (95% confidence interval (CI) 1.13-3.68) p=0.019), final infarct size (OR 3.00 (1.65-5.37), p<0.001), and lower odds of an above-median final salvage index (OR 0.52 (0.29-0.91), p=0.026). One-year mortality was higher in patients with ‘intermediate-high’ (9.7% (95%CI 5.9-13)) compared to "low" risk patients (1.9% (1.1-2.7), p<0.001). In univariate analyses, ‘intermediate-high’ risk was associated with a higher mortality risk (hazard ratio 5.31 (95%CI 2.98-9.48), p<0.001). Conclusions In patients with STEMI, an intermediate-high ORBI risk score of >=8 was associated with larger infarct size and less myocardial salvage, and a 5-time higher mortality risk relative to the overall favorable outcomes in those with a low-risk score.Kaplan-Meier Plot, one-year survival

Two-year outcomes of primary prophylactic use of defibrillators with ischemic and non-ischemic cardiomyopathy: propensity score-matched analysis from NIPPON STORM Study

Abstract Background In 2016, the DANISH study showed negative results regarding the efficacy of implantable cardioverter defibrillators (ICDs) for patients with non-ischemic cardiomyopathy (NICM) and reduced left ventricular ejection fraction (LVEF). Thus, the ESC guidelines downgraded the indication for primary ICD prophylaxis for NICM patients with reduced LVEF from Class I to IIa. However, the change might be felt somewhat improper in the real wolrd ICD therapy and decided to use the Nippon storm study, a prospective registry study in Japan, to determine whether the DANISH results are of equal value in the clinical setting. Objective To determine the efficacy of ICDs as primary prevention in patients with NICM, the incidence of ICD appropriate therapy in patients with NICM was compared with that in patients with ischemic cardiomyopathy (ICM) for which primary ICD efficacy is generally recognized as a Class I indication. Methods We selected 1274 patients with underlying cardiac disease from a total of 1548 patients enrolled in the Nippon storm study. We analyzed data of 451 patients with LVEF ≤35% owing to NICM or ICM who underwent ICD implantation of primary prophylaxis (men, 78%; age, 65±12 years; LVEF, 25±1.4%; cardiac resynchronization therapy, 20%; ICM, 33%). All patients were followed up for at least 2 years. Patient selection was performed by employing the propensity score matching method with a digit-matching algorithm for clinical factors, ie, age, sex, cardiac resynchronization therapy with a defibrillator, LVEF. After all propensity score matches had been performed, we compared baseline covariates between the 2 groups: 132 patients with NICM and 132 with ICM. The cumulative incidences of ICD therapies (including both anti-tachycardia pacing and shock therapies) were calculated using competing risk analysis, because death is a competing risk for loss to follow-up. Results In the matched cohort, the 2-year appropriate ICD therapy risks were 27.7% and 12.2% in NICM and ICM groups, respectively (HR = 0.390 [95% CI, 0.218–0.701; P = 0.002) (Figure A). Two-year appropriate ATP therapy risks were 25.5% and 11.4% in NICM and ICM groups, respectively (HR = 0.417 [95% CI, 0.226– 0.776; P = .005]) (Figure B), and appropriate shock therapy risks were 6.3% and 1.6% in NICM and ICM groups, respectively (HR = 0.230 [95% CI, 0.049–1.085; P = .063]) (Figure C). Conclusion The present subanalysis of the Nippon Storm Study revealed that the risk for appropriate ICD therapy was significantly higher in the patients with NICM than in those with ICM based on our propensity score–matching method.

Machine learning applied in patient-reported outcome research-exploring symptoms in adjuvant treatment of breast cancer.

Patient-reported outcome (PRO) data may help us better understand the life of breast cancer patients. We have previously collected PRO data in a national Danish breast cancer study in patients undergoing adjuvant chemotherapy. The aim of the present post-hoc explorative study is to apply Machine Learning (ML) algorithms using permutation importance to explore how specific PRO symptoms influence nonadherence to six cycles of planned adjuvant chemotherapy in breast cancer patients. We here investigate ePRO-data from the 347 patients. The ePRO presented 42 PROCTCAE questions on 25 symptoms. Patients completed the ePRO before each cycle of chemotherapy. Number of patients with completion of the scheduled six cycles of chemotherapy were registered. Two ML models were applied. One aimed at discovering the individual relative importance of the different questions in the dataset while the second aimed at discovering the relationships between the questions. Permutation importance was used. Out of 347 patients 238 patients remained in the final dataset, 15 patients dropped out. Two symptoms: aching joints and numbness/tingling, were the most important for dropout in the final dataset, each with an importance value of about 0.04. Model's average ROC-AUC-score being 0.706. In the second model a low performance score made the results very unreliable. In conclusion, this explorative data analysis using ML methodologies in an ePRO dataset from a population of women with breast cancer treated with adjuvant chemotherapy unravels that the symptoms aching joints and numbness/tingling could be important for drop out of planned adjuvant chemotherapy.

Invasive Aspergillosis among Lung Transplant Recipients during Time Periods with Universal and Targeted Antifungal Prophylaxis-A Nationwide Cohort Study.

The optimal prevention strategy for invasive aspergillosis (IA) in lung transplant recipients (LTXr) is unknown. In 2016, the Danish guidelines were changed from universal to targeted IA prophylaxis. Previously, we found higher rates of adverse events in the universal prophylaxis period. In a Danish nationwide study including LTXr, for 2010-2019, we compared IA rates in time periods with universal vs. targeted prophylaxis and during person-time with vs. person-time without antifungal prophylaxis. IA hazard rates were analyzed in multivariable Cox models with adjustment for time after LTX. Among 295 LTXr, antifungal prophylaxis was initiated in 183/193 and 6/102 during the universal and targeted period, respectively. During the universal period, 62% discontinued prophylaxis prematurely. The median time on prophylaxis was 37 days (IQR 11-84). IA was diagnosed in 27/193 (14%) vs. 15/102 (15%) LTXr in the universal vs. targeted period, with an adjusted hazard ratio (aHR) of 0.94 (95% CI 0.49-1.82). The aHR of IA during person-time with vs. person-time without antifungal prophylaxis was 0.36 (95% CI 0.12-1.02). No difference in IA was found during periods with universal vs. targeted prophylaxis. Prophylaxis was protective of IA when taken. Targeted prophylaxis may be preferred over universal due to comparable IA rates and lower rates of adverse events.

Arts and culture engagement for health: a Danish population-based study

ObjectivesGlobal health challenges are complex and new approaches are pivotal. Engagement in arts and cultural activities is commonplace across different cultures, and research shows associations with benefits for health and wellbeing. Using the arts for health promotion and prevention of illness has increased worldwide. Study designA population-based study. MethodsData were obtained from the Danish Health and Wellbeing Survey in 2019. A self-administered questionnaire was sent to 14,000 randomly selected adults (aged ≥15 years). The questionnaire included items on self-rated health and frequency of participation in various cultural activities (concerts or musical events; participation in a choir, band, or orchestra; theatre show or other performing arts; cinema; art museum or exhibition; library). A cultural participation index was calculated based on the six questions on cultural activities. Logistic regression models were fitted to examine the associations between the index and good self-rated health, adjusting for relevant covariates. ResultsIn total, 6629 individuals completed the questionnaire (47.4%). The most frequent activity, used at least once a month, was visiting a library. A strong association between the cultural participation index and self-reported health was observed. A one-point-higher index score was associated with a 10% higher likelihood of having good self-reported health (adjusted odds ratio: 1.10; 95% confidence interval: 1.08–1.12). ConclusionsThis study supports the understanding that engagement in arts and cultural activities is beneficial for self-rated good health. Individuals with higher frequency of arts and culture engagement were more likely to report good health than those with lower engagement.

Age-Based Validation of the Advanced-Stage Hodgkin Lymphoma International Prognostic Index (A-HIPI) in a Real-World Danish Study: Suboptimal Performance in Older Patients

Purpose: Improved predictive tools are desired in classic Hodgkin lymphoma (cHL) to improve prognostication and to better risk stratify patients (pts) for clinical trials. In younger pts who tolerate intensive therapies, focus has been on limiting late treatment toxicity through risk-adapted, PET-guided treatment strategy. In older pts, acute treatment toxicities are limiting factors for optimal disease control. Due to these fundamental differences, predictive tools may perform differently in younger and older pts. In particular, tools developed in younger pts may be suboptimal in older populations and vice versa. The primary objective of this study was to assess the performance of the A-HIPI (development was limited to 18-65 years of age) against the international prognostic score (IPS) for modelling overall survival (OS) and progression-free survival (PFS) in younger and older pts with cHL. Methods: This study utilized data from the population-based, nationwide Danish National Lymphoma registry. Pts with advanced-stage cHL (Ann Arbor stage III-IV or IIB with extra nodal disease) were included and categorized by age in two groups: ages ≤65 years vs. >65 years. In the primary analysis, all pts regardless of therapy were included. A sensitivity analysis restricting to pts starting on BEACOPP or ABVD was performed (Only ABVD in the >65 cohort). Concordance index (C-index) and calibration were used to assess model performance and generalizability. Calibration was visualized using calibration plots and quantified by calibration in the large (CITL) and calibration slope (CS) at 5-years post diagnosis. Results: A total of 893 advanced-stage HL pts fulfilled the inclusion criteria (634 in the ≤65 cohort and 259 in the >65 cohort). The 5-year OS and PFS in the >65-year cohort were 44% (Confidence intervals (CI); 37-51%) and 35% (CI; 30-42%), respectively. Fifty-six pts in the >65 cohort were classified as low-intermediate-risk (IPS; 1-2), 128 intermediate-risk (IPS; 3-4), and 75 high-risk (IPS; 5-7). For the ≤65 cohort, the 5-year OS and PFS was 88% (CI; 85-90%) and 76% (CI; 73-80%), respectively. Twenty-three pts were classified as low-risk (IPS; 0), 244 low-intermediate-risk, 286 intermediate-risk, and 81 high-risk. The A-HIPI had a C-index of 0.74 and 0.63 for OS and PFS, respectively in the ≤65 years cohort vs. 0.65 and 0.64 for OS and PFS, respectively, in the >65 cohort. The IPS had a C-index in the ≤65 cohort of 0.66 and 0.60 for OS and PFS, respectively, vs. 0.58 and 0.59 for OS and PFS, respectively, in the >65 cohort (i.e., the IPS performed better in the ≤65 cohort in terms of OS and PFS but was inferior to the A-HIPI). When restricting to pts treated with ABVD or BEACOPP, the A-HIPI C-index in the >65 cohort (116 pts) were reduced to 0.55 for OS and 0.54 for PFS. For the ≤65 cohort (595 pts), the A-HIPI C-index was stable at 0.75 and 0.62 for OS and PFS, respectively. In terms of A-HIPI calibration in the >65 cohort, CITL and CS were -0.78 and 0.39 for OS vs. -0.98 and 0.80 for PFS. In the ≤65 cohort, CITL and CS were -0.06 and 0.99 for OS vs. 0.21 and 1.18 for PFS. Visual inspection of the calibration plot (Figure 1) for the >65 cohort showed that the A-HIPI underestimated the observed proportion for both OS and PFS (i.e., the observed events were higher than the predicted). Calibration plot for the ≤65 cohort (Figure 2) indicated that the A-HIPI accurately modelled the observed proportion for both OS and PFS (i.e., the predicted probability was consistent with the observed proportion). Conclusion: The newly developed A-HIPI was validated in a large population-based cohort of Danish pts with advanced-stage cHL. Performance of the A-HIPI was high in the ≤65 cohort and superior to the IPS for OS prediction. Calibration of A-HIPI was excellent in pts ages ≤65 years. However, A-HIPI performed significantly worse among pts >65 years and attained poor performance in pts receiving ABVD or BEACOPP, which is not surprising since patients older than 65 were not included in the development. This study emphasizes the importance of further efforts to develop or update models that apply specifically in older individuals. The inclusion of additional variables reflecting comorbidities and pts fitness into a prognostic model may be necessary to effectively deliver accurate prognoses and risk assessments for the older pt.