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BACKGROUND: Cladribine is a nucleoside analogue interfering with synthesis and repair of DNA. Treatment with cladribine leads to a preferential reduction in lymphocytes, resulting in profound depletion of B-cells with a rapid recovery of naïve B-cells, while T-cell show a lesser but long-lasting depletion It is approved for treatment of relapsing multiple sclerosis (MS). Cladribine tablets 3.5 mg/kg bodyweight are administered in two yearly treatment courses, each including two treatment series lasting 4 or 5 days, one at the start of the first month and the other at the start of the second month.OBJECTIVE: To describe treatment patterns of cladribine in a real-world setting.METHODS: Registry based observational cohort study with prospectively enrolled cases from December 2017 through June 2021. The data source is The Danish Multiple Sclerosis Registry, which is a near complete nationwide population-based registry. Outcomes were length of the treatment, preceding and following treatments, treatment response, and safety data.RESULTS: In total 268 patients had started therapy with cladribine tablets, 89 men and 179 women, with a median age of 40 years (interquartile range (IQR) 32-48. The disease course was relapsing-remitting MS in 97.8% of the patients, and at treatment start the median time from disease onset was 8.1 years (IQR 4.2-14.5) and EDSS 2.5 (IQR 1.5-3.5). Thirty-four patients (12.7%) were treatment naïve while 56 (20.9%) had received one previous disease-modifying therapy (DMT), 67 (25.0%) two, and 111 (41.4%) three or more previous DMTs. In total, 214 (80.0%) patients had completed the full treatment of two courses of cladribine, while 54 (20.0%) had received only one course of cladribine tablets. The median follow-up time after cladribine initiation was 34.7 months (IQR 23.3-43.7). Compared with an annualized relapse rate (ARR) of 0.67 (95% CI [0.56, 0.79]) in the year prior to start of cladribine, ARR was reduced to 0.11 (95% CI [0.08, 0.15]) in year 0-2 after 3-month re-baseline with cladribine (84.8% reduction). Adverse events, reported in 44 (16.4%) of the patients, were mild or moderate, and herpes zoster was only reported in 2 patients. In total, 30 (11.2%) patients discontinued cladribine treatment, of whom 7 (2.6%) discontinued because of adverse effects and 12 (4.5%) discontinued because of disease activity.CONCLUSION: In this nationwide review of all Danish patients starting therapy with cladribine tablets in a real-world setting, cladribine treatment was safe, and the therapeutic response was as expected from previous clinical trials. A prolonged observation period is necessary to assess the long-term benefit and risk of cladribine.

Exercise facilitates cerebral lactate uptake, likely by increasing arterial lactate concentration and hence the diffusion gradient across the blood brain barrier. However, non-specific β-adrenergic blockade by propranolol has previously reduced the arterio-jugular venous lactate difference (AVLac) during exercise, suggesting β-adrenergic control of cerebral lactate uptake. Alternatively, we hypothesize that propranolol reduces cerebral lactate uptake by decreasing arterial lactate concentration. To test that hypothesis, we evaluated cerebral lactate uptake taking changes in arterial concentration into account. Nine healthy males performed incremental cycling exercise to exhaustion with and without intravenous propranolol (18.7 ± 1.9 mg). Lactate concentration was determined in arterial and internal jugular venous blood at the end of each workload. To take changes in arterial lactate into account we calculated the fractional extraction (FELac) defined as AVLac divided by the arterial lactate concentration. Arterial lactate concentration was reduced by propranolol at any workload (p-1 during maximal exercise without and with propranolol, respectively. While AVLac and FELac increased during exercise (both P < 0.05), they were both unaffected by propranolol at any workload (P = 0.68 and P = 0.26) or for any given arterial lactate concentration (P = 0.78 and P = 0.22). These findings support that, while propranolol may reduce cerebral lactate uptake, this effect reflects the propranolol-induced reduction in arterial lactate concentration and not inhibition of a β-adrenergic mechanism within the brain. We hence conclude that cerebral lactate uptake during exercise is directly driven by the increasing arterial concentration with work rate.

BACKGROUND: Bleeding safety in relation to use of systemic fluconazole and topical azoles among patients with atrial fibrillation treated with apixaban, rivaroxaban, or dabigatran is insufficiently explored, despite clinical relevance and several reports suggesting associations.METHODS: Using nationwide Danish registers, we identified patients with atrial fibrillation initiated on apixaban, rivaroxaban, or dabigatran from 2012-2018. We investigated associations between bleeding incidents and systemic fluconazole or topical azole treatment using a case-crossover design with 30-day exposure windows and reported odds ratios (OR) with 95% confidence intervals (CI).RESULTS: We included 32,340 (36%), 32,409 (36%), and 24,940 (28%) patients initiated on apixaban, rivaroxaban, and dabigatran, respectively. Patients on apixaban were older (median age: 77 years; interquartile range [IQR] 70-84) compared with rivaroxaban users (median age: 75 years; IQR 68-82) and patients on dabigatran (median age: 73 years; IQR 66-80). Apixaban users had a significantly increased risk of bleeding following exposure to systemic fluconazole: odds ratio (OR) 3.5; 95% confidence interval (CI), 1.4-10.6. No increased risk was found among rivaroxaban and dabigatran users: ORs of 0.9 (95% CI, 0.2-3.0) and 1.7 (95% CI, 0.5-5.6), respectively. As to bleeding risk pertaining to topical azole exposure among apixaban, rivaroxaban, and dabigatran users, no association was found, with corresponding ORs of 0.8 (95% CI, 0.5-1.3); 1.3 (95% CI, 0.9-2.1); and 1.2 (95% CI 0.8-1.8), respectively.CONCLUSION: In patients with atrial fibrillation on either apixaban, rivaroxaban, or dabigatran, an association between an elevated bleeding risk and use of systemic fluconazole was found among patients on apixaban. We found no increased risk of bleeding following co-exposure to topical azoles.

ObjectiveGastrointestinal bleeding (GIB) risk in relation to concomitant treatment with non-vitamin K oral anticoagulants (NOAC) and oral glucocorticoids is insufficiently explored. We aimed to investigate the short-term risk following coexposure.MethodsThis is a register-based, nationwide Danish study including patients with atrial fibrillation on NOACs during 2012–2018. Patients were defined as exposed to oral glucocorticoids if they claimed a prescription within 60 days prior to GIB. We investigated the associations between GIB and oral glucocorticoid exposure, reporting HRs via a nested case–control design and absolute risk via a cohort design. Matching terms were age, sex, calendar year, follow-up time and NOAC agent.Results98 376 patients on NOACs (median age: 75 years (IQR: 68–82), 44% female) were included, and 16% redeemed at least one oral glucocorticoid prescription within 3 years. HRs of GIB were increased comparing exposed with non-exposed patients (ConclusionsConcomitant treatment with NOACs and oral glucocorticoids was associated with a short-term rate and risk increase of GIB compared with patients only on NOACs. This could have implications for clinical management, necessitating closer monitoring or other risk mitigation strategies during episodes of cotreatment with oral glucocorticoids.

Aims Gastrointestinal bleeding (GI-bleeding) is frequent in patients with atrial fibrillation (AF) treated with oral anticoagulation (OAC) therapy. We sought to investigate to what extent lower GI-bleeding represents the unmasking of an occult colorectal cancer. Methods and results A total of 125 418 Danish AF patients initiating OAC therapy were identified using Danish administrative registers. Non-parametric estimation and semi-parametric absolute risk regression were used to estimate the absolute risks of colorectal cancer in patients with and without lower GI-bleeding. During a maximum of 3 years of follow-up, we identified 2576 patients with lower GI-bleeding of whom 140 patients were subsequently diagnosed with colorectal cancer within the first year of lower GI-bleeding. In all age groups, we observed high risks of colorectal cancer after lower GI-bleeding. The absolute 1-year risk ranged from 3.7% [95% confidence interval (CI) 2.2–6.2] to 8.1% (95% CI 6.1–10.6) in the age groups ≤65 and 76–80 years of age, respectively. When comparing patients with and without lower GI-bleeding, we found increased risk ratios of colorectal cancer across all age groups with a risk ratio of 24.2 (95% CI 14.5–40.4) and 12.3 (95% CI 7.9–19.0) for the youngest and oldest age group of ≤65 and >85 years, respectively. Conclusion In anticoagulated AF patients, lower GI-bleeding conferred high absolute risks of incident colorectal cancer. Lower GI-bleeding should not be dismissed as a benign consequence of OAC therapy but always examined for a potential underlying malignant cause.

Background and purpose: Real-world evidence regarding the effectiveness and safety of ocrelizumab for the treatment of multiple sclerosis (MS) is limited. The aim was to evaluate the effectiveness and safety of ocrelizumab treatment for MS in a real-world setting. Methods: A nationwide population-based cohort study was conducted where clinical and magnetic resonance imaging data of MS patients enrolled prospectively in the Danish Multiple Sclerosis Registry who initiated ocrelizumab treatment between January 2018 and November 2020 were analyzed. Results: A total of 1104 patients (85.7% relapsing–remitting MS [RRMS], 8.8% secondary progressive MS [SPMS], 5.5% primary progressive MS [PPMS]) were included, with a median follow-up period of 1.3 years. At baseline, the mean age was 41.4 years in the RRMS group, 44.5 years in the PPMS group and 50.3 years in the SPMS group. Median Expanded Disability Status Scale score was 2.5, 3.5 and 5.5, respectively. Most RRMS and SPMS patients had received previous disease-modifying therapies (87.5% and 91.8%, respectively), whereas PPMS patients were mostly treatment naïve (78.7%). After ocrelizumab initiation, 9.3% of the patients experienced a relapse and 8.7% a 24 weeks confirmed disability worsening. Conversely, 16.7% showed a 24 weeks confirmed disability improvement. After ~1 year of treatment, most patients (94.5%) were free of magnetic resonance imaging activity. Ocrelizumab was generally well tolerated, as side effects were only reported for 10% of patients, mostly consisting of infusion-related reactions and infections. Conclusions: It is shown that most MS patients treated with ocrelizumab are clinically stabilized and with an adverse event profile consistent with the experience from the pivotal clinical trials.

Aims Older patients with atrial fibrillation (AF) are at risk of adverse outcomes, which is accentuated by comorbidities. We sought to examine the association between morbidity burden and the treatment of older AF patients. Methods and results Using Danish nationwide registers we included patients ≥70 years of age between 2010 and 2017 at their first hospitalization due to AF. Using multiple logistic regression models we examined the association between morbidity burden and the odds of receiving oral anticoagulants (OACs), anti-arrhythmic drugs (AADs), and rhythm-control procedures (direct current cardioversions and catheter ablations). A total of 48 995 patients were included with a majority of women (54%), with a median age of 80 years [interquartile range (IQR) 75–85], and a median morbidity burden of 2 comorbidities (IQR 1–3). Increasing morbidity burden was associated with decreasing odds of OAC treatment with patients having >5 comorbidities having the lowest odds [odds ratio (OR) 0.38, 95% confidence interval (CI) 0.35–0.42] compared to patients with low morbidity burden (0–1 comorbidities). Having >5 comorbidities were associated with increased odds of AAD treatment (OR 1.90, 95% CI 1.64–2.21) and decreased odds of AF procedures (OR 0.39, 95% CI 0.31–0.48), compared to patients with a low morbidity burden (0–1 comorbidities). Examining morbidity burden continuously revealed similar results. Conclusions In older AF patients, multimorbidity was associated with lower odds of receiving OACs and rhythm-control procedures but increased odds of AADs. This presents a clinical conundrum as multimorbid patients potentially benefit the most from treatment with OACs.

Background: In observational studies, case reports, and animal studies, amiodarone has been associated with incident cancer. Objective: The purpose of this study was to examine whether a dose–response relationship between amiodarone use and the risk of cancer could be ascertained in a large nationwide study cohort. Methods: Using nationwide registers, we included all Danish patients with atrial fibrillation (AF) treated with amiodarone from 1996 to 2014. Exposure was defined both by categories and as a continuous variable of the cumulative defined daily doses (cDDDs) of amiodarone. The associations between amiodarone cDDD and incident cancer, as well as organ-specific types of cancer (skin, liver, lung), were estimated using multivariable Cox regression models and reported as hazard ratios (HR) with 95% confidence intervals (CI) and using cubic restricted spline plots. Results: We included 18,503 patients with a median follow-up time of 8.1 years (interquartile range [IQR] 4.3–12.4). Median age was 70 years (IQR 63–77). A total of 2974 individuals developed cancer during follow-up. We found no association between increasing amiodarone exposure (cDDD 181–400 and cDDD >400) and the hazard of incident cancer (HR 0.95; 95% CI 0.87–1.04; and HR 1.01; 95% CI 0.92–1.10) with reference to patients with cDDD

Background: Inpatient multidisciplinary rehabilitation (MDR) can improve health-related quality of life (HRQoL) in multiple sclerosis (MS) patients. However, the evidence of a long-term benefit is limited. Objectives: To investigate the long-term effectiveness of inpatient MDR on HRQoL in MS patients. Methods: We conducted a randomized controlled partial crossover trial with 427 MS patients. Results: Statistical significant long-term improvements in HRQoL were found in three of the six outcome measures at 12-month follow-up. Three in four suggested minimal clinically important differences (MCIDs) were unmet. Conclusion: These results indicate that the administration of inpatient MDR may lead to long-lasting improvements in HRQoL in MS patients.

Objective: To investigate clinical outcomes in a real-world setting in the complete population-based cohort of alemtuzumab-treated MS patients in Denmark. Methods: Data were retrieved from The Danish Multiple Sclerosis Registry between 2009 and 2019. Demographic and disease-specific patient parameters related to treatment history, efficacy, and safety outcomes were assessed at baseline and during follow-up visits. Results: A total of 209 patients (78% female) started treatment with alemtuzumab during the study period with 3.1 ± 1.4 years follow-up. After 2 years, 75% of patients were relapse-free compared to 48% the year before alemtuzumab ( p Conclusion: In a country with primarily escalation strategy, relapse rate reduction was maintained for 5 years, and EDSS stabilized/improved in majority of patients. Higher relapse rate 1 year before alemtuzumab increased the odds for additional courses. Novel serious AEs were not observed.

Background Oral glucocorticoids and direct-acting oral anticoagulants (DOAC) have both been associated with a risk of gastrointestinal (GI) bleeding. However, drug safety, especially regarding the risk of bleeding, in relation to concomitant treatment with oral glucocorticoids and DOACs is insufficiently explored. Purpose We aimed to investigate the short-term risk of GI bleeding in patients with atrial fibrillation (AF) following concomitant treatment with DOACs and oral glucocorticoids. Methods Register-based, retrospective and nationwide Danish study including patients with AF and on DOAC treatment during 2012–2018. Patients were defined as exposed to oral glucocorticoids from the date of a redeemed prescription and 60 days forward. We associated concomitant treatment with GI bleeding and reported hazard ratios (HR) via a nested case-control design and standardized 60-day absolute risk adjusted for comorbidities using a cohort design. In both analyses, exposed were compared to non-exposed controls matched on age, sex, calendar year, follow-up time and DOAC agent. Results We included 98,376 patients (age [interquartile range]: 75 [68– 82], 44% females) with AF on DOAC treatment. The use of oral glucocorticoids among included patients was widespread with 16% redeeming at least one prescription within three years, 4% redeeming at least five (Figure 1A). Lung disease was the most frequent indication (Figure 1B). Concomitant treatment with DOACs and oral glucocorticoids was associated with an increased incidence of GI bleeding (total n=4,946) compared with only DOAC treatment, including a dose-response trend ( Conclusion Caution should be exercised when prescribing even short-term oral glucocorticoid treatment for DOAC treated patients, most notably in high doses and for patients with elevated bleeding risk. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Ib Mogens Kristiansens Almene FondandHelsefonden

Background Atrial fibrillation (AF) and chronic obstructive pulmonary disease (COPD) often coexist. Beta-blockers are a mainstay of treatment in AF and are considered safe in COPD patients after myocardial infarction, though real-life studies have demonstrated significant under-use. Little is known on the utilization patterns in patients with AF and COPD. Purpose To investigate the temporal trends of beta-blocker utilization in patients following first diagnosis of AF in a hospital setting, with and without concomitant COPD, and determine clinical factors associated with beta-blocker use. Methods A nationwide study from 1995 to 2015 using data from the comprehensive Danish health registers. All patients with first registered AF diagnosis in a hospital setting were included. Beta-blocker use was identified by claimed prescriptions within 90 days following AF diagnosis. Factors associated with beta-blocker use or non-use in COPD patients during the most recent period (2010–2015) was examined using multivariable logistic regression and presented as odds ratios (OR) with 95% confidence intervals (95% CI). Results A total of 264 180 patients were included, of these 31 981 (12.1%) had COPD. Patients with concurrent COPD were older than those without COPD (median age 76 vs. 74 years), the proportion of males was similar (54%) and patients with COPD had more comorbidities, particularly cardiovascular disease. Across the 21-year study period, fewer patients with COPD used beta-blockers after AF diagnosis, than those without COPD (38.8% vs. 53.2%, p Predictors for decreased beta-blocker use included high age, COPD severity represented by use of triple inhaled therapy (OR 0.84 [95% CI 0.77–0.92]), and a history of frequent COPD exacerbations (OR 0.80 [95% CI 0.74–0.86]) (Figure 2). In a subgroup of COPD patients with complete clinical data from the Danish Register of COPD, severe airflow limitation (Forced Expiratory Volume in 1 second Conclusions Beta-blocker use in patients with AF and concurrent COPD have increased considerably over a 21-year period yet remained less used than in patients without COPD. The severity of COPD was a strong negative predictor for beta-blocker use following AF diagnosis, suggesting a fear for adverse effects. The lower use of beta-blocker treatment in patients with severe COPD and AF might suggest underuse and warrants further evaluation. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Naestved - Slagelse - Ringsted Hospitals, Region Sjaelland, Denmark Figure 1. Temporal trends of beta-blocker useFigure 2. Factors associated with beta-blocker use

Disease or acquired damage to the central nervous system frequently causes disabling spasticity and central neuropathic pain (NP), both of which are frequent in multiple sclerosis (MS) and spinal cord injury (SCI). Patients with MS and SCI often request treatment with cannabis-based medicine (CBM). However, knowledge about effects, side effects, choice of active cannabinoids (Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) alone or in combination), and doses of CBM remains limited. Using a double-blind, parallel design in a national multicenter cohort, this study examines the effect of CBM on spasticity and NP. Patients are randomized to treatment with capsules containing either THC, CBD, THC and CBD, or placebo. Primary endpoints are patient-reported pain and spasticity on a numerical rating scale. Other endpoints include quality of life and sleep, depression and anxiety, and relief of pain and spasticity. Side-effects of CBM are described. In a sub-study, the pharmacodynamics (PD) and pharmacokinetics (PK) of oral capsule CBM are examined. We expect that the study will contribute to the literature by providing information on the effects and side-effects of CBD, THC, and the combination of the two for central neuropathic pain and spasticity. Furthermore, we will describe the PD/PK of THC and CBD in a patient population.

Importance: Treatment strategies for relapsing-remitting multiple sclerosis (RRMS) vary markedly between Denmark and Sweden. The difference in the association of these national strategies with clinical outcomes is unknown. Objective: To investigate the association of national differences in disease-modifying treatment (DMT) strategies for RRMS with disability outcomes. Design, Setting, and Participants: This cohort study used data on 4861 patients from the Danish and Swedish national multiple sclerosis (MS) registries from the date of index DMT initiation (between January 1, 2013, and December 31, 2016) until the last recorded visit at time of data extraction (October 2, 2019). Exposures: All MS-specific DMTs initiated during the observation period were included in the analysis. Main Outcomes and Measures: The primary study outcome was time to 24-week confirmed disability worsening. Secondary outcomes were 24-week confirmed disability improvement, milestone Expanded Disability Status Scale scores of 3 and 4, annualized relapse rate, time to first relapse, and treatment switching. Data were analyzed using inverse probability of treatment weighting-based models using a propensity score to weight and correct the comparison for the imbalance of confounders observed at baseline between the 2 countries. Results: A total of 2700 patients from the Swedish MS registry (1867 women [69.2%]; mean [SD] age, 36.1 [9.5] years) and 2161 patients from the Danish MS registry (1472 women [68.1%]; mean [SD] age, 37.3 [9.4 years]) started a first DMT between 2013 and 2016, were included in the analysis, and were observed for a mean (SD) of 4.1 (1.5) years. A total of 1994 Danish patients (92.3%) initiated a low to moderately effective DMT (teriflunomide, 907 [42.0%]) and 165 (7.6%) initiated a highly effective DMT, whereas a total of 1769 Swedish patients (65.5%) initiated a low to moderately effective DMT (teriflunomide, 64 [2.4%]) and 931 (34.5%) initiated a highly effective DMT. The Swedish treatment strategy was associated with a 29% reduction in the rate of postbaseline 24-week confirmed disability worsening relative to the Danish treatment strategy (hazard ratio, 0.71; 95% CI, 0.57-0.90; P =.004). The Swedish treatment strategy was also associated with a 24% reduction in the rate of reaching an expanded disability status scale score of 3 (hazard ratio, 0.76; 95% CI, 0.60-0.97; P =.03) and a 25% reduction in the rate of reaching an expanded disability status scale score of 4 (hazard ratio, 0.75; 95% CI, 0.61-0.96; P =.01) relative to Danish patients. Conclusions and Relevance: The findings of this study suggest that there is an association between differences in treatment strategies for RRMS and disability outcomes at a national level. Escalation of treatment efficacy was inferior to using more efficacious DMT as initial treatment..

International audience; Background: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.Methods: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.Results: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P

Background Electrical cardioversion (ECV) is a common procedure for terminating atrial fibrillation (AF). ECV is associated with brady-arrhythmic events, however, the age-specific risks of clinically significant brady-arrhythmic events are unknown. Methods Using Danish nationwide registers, we identified patients with AF at their first non-emergent ECV between 2005 and 2018 and estimated their 30-day risk of brady-arrhythmic events. Moreover, factors associated with increased risks of brady-arrhythmias were identified. Absolute risks were estimated using logistic regression models fitted with natural splines as well as standardization (G-formula). Results We identified 20,725 eligible patients with a median age of 66 years (IQR 60-72) and most males (73%). The 30-day risks of brady-arrhythmic events after ECV were highly dependent on age with estimated risks ranging from 0.5% (95% CI 0.2-1.7) and 1.2% (95% CI 0.99-1.5) to 2.7% (95% CI 2.1-3.3) and 5.1% (95% CI 2.6-9.7) in patients aged 40, 65, 80, and 90 years, respectively. Factors associated with brady-arrhythmias were generally related to cardiovascular disease (eg, ischemic heart disease, heart failure, valvular AF) or a history of syncope. We found no indications that pre-treatment with anti-arrhythmic drugs conferred increased risks of brady-arrhythmic events (standardized absolute risk difference -0.25% [95% CI -0.67 to 0.17]). Conclusions ECV conferred clinically relevant 30-day risks of brady-arrhythmic events, especially in older patients. Anti-arrhythmic drug treatment was not found to increase the risk of brady-arrhythmias. Given the widespread use of ECV, these data should provide insights regarding the potential risks of brady-arrhythmic events.

Objective Teriflunomide is a once-daily, oral disease-modifying therapy (DMT) for relapsing forms of multiple sclerosis (MS). We studied clinical outcomes in a real-world setting involving a population-based large cohort of unselected patients enrolled in The Danish Multiple Sclerosis Registry (DMSR) who started teriflunomide treatment between 2013–2019. Methods This was a complete nationwide population-based cohort study with prospectively enrolled unselected cases. Demographic and disease-specific patient parameters related to treatment history, efficacy outcomes, and discontinuation and switching rates among other clinical variables were assessed at baseline and during follow-up visits. Results A total of 3239 patients (65.4% female) started treatment with teriflunomide during the study period, 56% of whom were treatment-naïve. Compared to previously treated patients, treatment-naïve patients were older on average at disease onset, had a shorter disease duration, a lower Expanded Disability Status Scale score at teriflunomide treatment start and more frequently experienced a relapse in the 12 months prior to teriflunomide initiation. In the 3001 patients initiating teriflunomide treatment at least 12 months before the cut-off date, 72.7% were still on treatment one year after treatment start. Discontinuations in the first year were due mainly to adverse events (15.6%). Over the full follow-up period, 47.5% of patients discontinued teriflunomide treatment. Sixty-three percent of the patients treated with teriflunomide for 5 years were relapse-free, while significantly more treatment-naïve versus previously treated patients experienced a relapse during the follow-up (p Conclusions Solid efficacy and treatment persistence data consistent with other real-world studies were obtained over the treatment period. Treatment outcomes in this real-world scenario of the population-based cohort support previous findings that teriflunomide is an effective and generally well-tolerated DMT for relapsing MS patients with mild to moderate disease activity.

ObjectiveTo compare on-treatment efficacy and discontinuation outcomes in teriflunomide (TFL) and dimethyl fumarate (DMF) in the treatment of relapsing-remitting multiple sclerosis (RRMS) in a real-world setting.MethodsWe identified all patients starting TFL or DMF from the Danish Multiple Sclerosis Registry and compared on-treatment efficacy outcomes between DMF using TFL, adjusted for clinical baseline variables and propensity score-based methods.ResultsWe included 2,236 patients in the study: 1,469 patients on TFL and 767 on DMF. Annualized relapse rates (ARRs) in TFL and DMF were 0.16 (95% confidence interval [CI] 0.13–0.20) and 0.09 (95% CI 0.07–0.12), respectively. Relapse rate ratio for DMF/TFL was 0.58 (95% CI 0.46–0.73, p < 0.001). DMF had a higher relapse-free survival proportion at 48 months of follow-up (p < 0.05). We observed no difference in Expanded Disability Status Scale score worsening. Discontinuations due to disease breakthrough were 10.2% (95% CI 7.6%–12.8%) and 22.1% (95% CI 19.2%–25.0%) for DMF and TFL, respectively. A subgroup analysis of ARRs in 708 patients with available baseline MRI T2 lesion amount reported similar results after adjustment.ConclusionWe found lower ARR, higher relapse-free survival, and lower incidence of discontinuation due to disease breakthrough on treatment with DMF compared with TFL.Classification of evidenceThis study provides Class II evidence that for patients with RRMS, DMF is more effective in preventing relapses and has lower discontinuation due to disease breakthrough compared with TFL.

Background: Time matters in multiple sclerosis (MS). Irreversible neural damage and cell loss occur from disease onset. The MS community has endorsed a management strategy of prompt diagnosis, timely intervention and regular proactive monitoring of treatment effectiveness and disease activity to improve outcomes in people with MS. Objectives: We sought to develop internationally applicable quality standards for timely, brain health–focused MS care. Methods: A panel of MS specialist neurologists participated in an iterative, online, modified Delphi process to define ‘core’, ‘achievable’ and ‘aspirational’ time frames reflecting minimum, good and high care standards, respectively. A multidisciplinary Reviewing Group (MS nurses, people with MS, allied healthcare professionals) provided insights ensuring recommendations reflected perspectives from multiple stakeholders. Results: Twenty-one MS neurologists from 19 countries reached consensus on most core (25/27), achievable (25/27) and aspirational (22/27) time frames at the end of five rounds. Agreed standards cover six aspects of the care pathway: symptom onset, referral and diagnosis, treatment decisions, lifestyle, disease monitoring and managing new symptoms. Conclusion: These quality standards for core, achievable and aspirational care provide MS teams with a three-level framework for service evaluation, benchmarking and improvement. They have the potential to produce a profound change in the care of people with MS.

Background Fascicular heart blocks can progress to complete heart blocks, but this risk has not been evaluated in a large general population. Objective The purpose of this study was to investigate the association between various types of fascicular blocks diagnosed by electrocardiographic (ECG) readings and the risk of incident higher degree atrioventricular block (AVB), syncope, pacemaker implantation, and death. Methods We studied primary care patients referred for ECG recording between 2001 and 2015. Cox regression models were used to estimate hazard ratios (HRs) as well as absolute risks of cardiovascular outcomes. Results Of 358,958 primary care patients (median age 54 years; 55% women), 13,636 (3.8%) had any type of fascicular block. Patients were followed up to 15.9 years. We found increasing HRs of incident syncope, pacemaker implantation, and third-degree AVB with increasing complexity of fascicular block. Compared with no block, isolated left anterior fascicular block (LAFB) was associated with 0%–2% increased 10-year risk of developing third-degree AVB (HR 1.6; 95% confidence interval [CI] 1.25–2.05), whereas right bundle branch block combined with LAFB and first-degree AVB was associated with up to 23% increased 10-year risk (HR 11.0; 95% CI 7.7–15.7), depending on age and sex group. Except for left posterior fascicular block (HR 2.09; 95% CI 1.87–2.32), we did not find any relevant associations between fascicular block and death. Conclusion We found that higher degrees of fascicular blocks were associated with increasing risk of syncope, pacemaker implantation, and complete heart block, but the association with death was negligible.

Background: Natalizumab and fingolimod were the first preparations recommended for disease breakthrough in priorly treated relapsing-remitting multiple sclerosis. Of three published head-to-head studies two showed that natalizumab is the more effective to prevent relapses and EDSS worsening. Methods: By re-analyzing original published results from MSBase, France, and Denmark using uniform meth-odologies, we aimed at identifying the effects of differences in methodology, in the MS-populations, and at re-evaluating the differences in effectiveness between the two drugs. We gained access to copies of the individual amended databases and pooled all data. We used uniform inclusion/ exclusion criteria and statistical methods with Inverse Probability Treatment Weighting. Results: The pooled analyses comprised 968 natalizumab-and 1479 fingolimod treated patients. The on-treatment natalizumab/fingolimod relapse rate ratio was 0.77 (p=0.004). The hazard ratio (HR) for a first relapse was 0.82 (p=0.030), and the HR for sustained EDSS improvement was 1.4 (p=0.009). There were modest differences between each of the original published studies and the replication study, but the conclusions of the three original studies remained unchanged: in two of them natalizumab was more effective, but in the third there was no difference between natalizumab and fingolimod. Conclusion: The results were largely invariant to the epidemiological and statistical methods but differed between the MS populations. Generally, the advantage of natalizumab was confirmed. BiogenBiogen; NovartisNovartis; MerckMerck & Company; RocheRoche Holding; Teva; Sanofi GenzymeSanofi-AventisGenzyme Corporation; NHMRCNational Health and Medical Research Council of Australia [1140766,1129789, 1157717]; French State; Agence Nationale de la Recherche-French National Research Agency (ANR)European Commission [ANR-10-COHO-002]; Eugene Devic EDMUS Foundation; ARSEP Foundation

Introduction: Natalizumab has proved to be more effective than fingolimod in reducing disease activity in relapsing-remitting multiple sclerosis (RRMS). Whether this association is universal for all patient groups remains to be determined. Objective: The aim of this study was to compare the relative effectiveness of natalizumab and fingolimod in RRMS subgroups defined by the baseline demographic and clinical characteristics of interest. Methods: Patients with RRMS who were given natalizumab or fingolimod were identified in a merged cohort from three international registries. Efficacy outcomes were compared across subgroups based on patients’ sex, age, disease duration, Expanded Disability Status Scale (EDSS) score, and disease and magnetic resonance imaging (MRI) activity 12 months prior to treatment initiation. Study endpoints were number of relapses (analyzed withweighted negative binomial generalized linear model) and 6-month confirmed disability worsening and improvement events (weighted Cox proportional hazards model), recorded during study therapy. Each patient was weighted using inverse probability of treatment weighting based on propensity score. Results: A total of 5148 patients (natalizumab 1989; fingolimod 3159) were included, with a mean ± standard deviation age at baseline of 38 ± 10 years, and the majority (72%) were women. The median on-treatment follow-up was 25 (quartiles 15–41) months. Natalizumab was associated with fewer relapses than fingolimod (incidence rate ratio [IRR]; 95% confidence interval [CI]) in women (0.76; 0.65–0.88); in those aged ≤38 years (0.64; 0.54–0.76); in those withdisease duration ≤7 years (0.63; 0.53–0.76); in those with EDSS score 38 years (1.34; 1.04–1.73); those with disease duration >7 years (1.33; 1.01–1.74); those with EDSS score

Background Knowledge is scarce regarding how multimorbidity is associated with therapeutic decisions regarding oral anticoagulants (OACs) in patients with atrial fibrillation. Methods and Results We conducted a cross‐sectional study of hospitalized patients with atrial fibrillation using the Get With The Guidelines‐Atrial Fibrillation registry from 2013 to 2019. We identified patients ≥65 years and eligible for OAC therapy. Using 16 available comorbidity categories, patients were stratified by morbidity burden. A multivariable logistic regression model was used to determine the odds of receiving OAC prescription at discharge by morbidity burden. We included 34 174 patients with a median (interquartile range) age of 76 (71–83) years, 56.6% women, and 41.9% were not anticoagulated at admission. Of these patients, 38.6% had 0 to 2 comorbidities, 50.7% had 3 to 5 comorbidities, and 10.7% had ≥6 comorbidities. The overall discharge OAC prescription was high (85.6%). The prevalence of patients with multimorbidity increased from 59.7% in 2014 to 64.3% in 2019 ( P trend=0.002). Using 0 to 2 comorbidities as the reference, the adjusted odds ratio (95% CI) of OAC prescription were 0.93 (0.82, 1.05) for patients with 3 to 5 comorbidities and 0.72 (0.60, 0.86) for patients with ≥6 comorbidities. In those with ≥6 comorbidities, the most common reason for nonprescription of OACs were frequent falls/frailty (31.0%). Conclusions In a contemporary quality‐of‐care database of hospitalized patients with atrial fibrillation eligible for OAC therapy, multimorbidity was common. A higher morbidity burden was associated with a lower odds of OAC prescription. This highlights the need for interventions to improve adherence to guideline‐recommended anticoagulation in multimorbid patients with atrial fibrillation.

Background Bradyarrhythmia is a known complication to direct current cardioversion (DC-cardioversion) in patients with atrial fibrillation (AF). However, whether concomitant treatment with anti-arrhythmic drugs (AADs) is associated with an increased risk of bradyarrhythmia in relation to the procedure is unknown. Purpose To investigate the short-term risk of bradyarrhythmia associated with AAD treatment in AF patients undergoing DC-cardioversion. Methods Using Danish nationwide registers, all AF patients treated with either an AAD (amiodarone, sotalol, dronedarone, flecainide, or propafenone) or rate-lowering drugs (beta-blocker, non- dihydropyridine calcium-antagonist, or digoxin) were identified at their first DC-cardioversion between 2001 and 2016. Patients were excluded if they were under 18 or above 100 years of age or had a pacemaker or implantable cardioverter defibrillator. The event of interest was a composite outcome of either a diagnosis of bradyarrhythmia (sinoatrial arrest, atrioventricular block, or unspecified bradycardia) or a procedure of pacemaker implantation. Patients were followed from the date of DC-cardioversion until event of interest, 90 days after the procedure, or at study end. Absolute risks of bradyarrhythmic events were estimated using the Aalen-Johansen estimator taking the competing risk of death into account. Hazard ratios (HR) with 95% confidence intervals (95% CI) of bradyarrhythmic events were computed using multivariable Cox models adjusted for age, sex, calendar year, as well as relevant comorbidity and concomitant medication. Results A total of 22,344 patients were included in the study with 3,224 (14%) individuals treated with an AAD. The median age was 67 years (interquartile range [IQR] 59–73) and most were males (69%). Patients treated with AADs were younger and had more ischemic heart disease, heart failure, and valvular disease. During follow-up we identified 601 cases of bradyarrhythmia. We found an absolute risk of bradyarrhythmic events at 90 days after cardioversion of 3.7% (95% CI 3.1–4.4) for patients treated with an AAD and 2.5% (95% CI 2.3–2.7) for patients treated with rate-lowering drugs (P Conclusion Using a large nationwide study population of patients with AF undergoing DC-cardioversion, concomitant treatment with AADs was associated with an increased risk of bradyarrhythmic events. Moreover, the absolute risks of bradyarrhythmic events after DC-cardioversion were higher than what has previously been reported. These data provide valuable insights aiding physicians in clinical decision making as well as informing patients prior to the procedure. Figure 1. Absolute risk and adjusted hazard ratio (HR) of bradyarrythmia. AAD: Anti-arrhythmic drugs. CI: Confidence Interval. Funding Acknowledgement Type of funding source: None

Background Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulin G-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT. Methods In the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity. Results The significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder. Conclusion Across a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate. Trial registration NCT01892345 (ClinicalTrials.gov).

Purpose Evidence of the effects of inpatient multidisciplinary rehabilitation (MDR) on physical function in patients with multiple sclerosis (MS) is limited, particularly whether clinically relevant improvements can be achieved. The aim of this study, therefore, was to investigate the effects of personalised inpatient MDR on the physical function of MS patients. Methods Embedded in the Danish MS Hospitals Rehabilitation Study, a pragmatic study was performed in MS patients undergoing four weeks of inpatient MDR specifically targeting physical function. Outcomes were assessed at baseline (n = 142), at discharge (n = 137) and at six months follow-up (n = 126) using the six-minute walk test (6MWT), six-spot step test (SSST), five times sit to stand test (5STS), nine-hole peg test (NHPT), dynamic gait index (DGI) and 12-item MS walking scale (MSWS). Results From Baseline-to-Discharge, significant and clinically relevant improvements were found in all measures of walking capacity (6MWT, SSST, 5STS, DGI and MSWS; p 2.5–5.5] vs. severe [EDSS6.0–7.5]) and age (young/middle-aged [Age24–59] vs. old [Age60–65]), an attenuated adaptation was nevertheless observed for 6MWT in the most affected and vulnerable subgroups (i.e. SP + PP, EDSS6.0–7.5 and Age60–65). The significant improvements in walking capacity and upper extremity function persisted at six months follow-up but did not exceed anymore the thresholds regarded as clinically relevant. Conclusion The results provide novel evidence that personalised inpatient MDR targeting physical function in MS patients elicits significant and clinically relevant improvements in physical function.

ObjectiveTo determine the effectiveness of high-efficacy disease-modifying therapies (heDMTs) vs medium-efficacy disease-modifying therapies (meDMT) as the first treatment choice in treatment-naive patients with multiple sclerosis (MS) on disability worsening and relapses. We assessed this using a nationwide population-based MS registry.MethodsWe identified all patients starting a heDMT as first-time treatment from the Danish Multiple Sclerosis Registry and compared treatment outcomes with a propensity score matched sample of patients starting meDMT.ResultsWe included 388 patients in the study: 194 starting initial therapy with heDMT matched to 194 patients starting meDMT. At 4 years of follow-up, the probabilities of a 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening were 16.7% (95% confidence interval [CI] 10.4%–23.0%) and 30.1% (95% CI 23.1%–37.1%) for heDMT and meDMT initiators, respectively (hazard ratio [HR] 0.53, 95% CI 0.33–0.83,p= 0.006). Patients initiating heDMT also had a lower probability of a first relapse (HR 0.50, 95% CI 0.37–0.67). Results were similar after pairwise censoring and in subgroups with high baseline activity, diagnosis after 2006, or information on baseline T2 lesion load.ConclusionWe found a lower probability of 6-month confirmed EDSS score worsening and lower probability of a first relapse in patients starting a heDMT as first therapy, compared to a matched sample starting meDMT.Classification of evidenceThis study provides Class III evidence that for patients with MS, starting heDMT lowers the risk of EDSS worsening and relapses compared to starting meDMT.

Key pointsAcclimatization to hypoxia leads to a reduction in plasma volume (PV) that restores arterial O-2 content.Findings from studies investigating the mechanisms underlying this PV contraction have been controversial, possibly as experimental conditions were inadequately controlled.We examined the mechanisms underlying the PV contraction evoked by 4 days of exposure to hypobaric hypoxia (HH) in 11 healthy lowlanders, while strictly controlling water intake, diet, temperature and physical activity.Exposure to HH-induced an similar to 10% PV contraction that was accompanied by a reduction in total circulating protein mass, whereas diuretic fluid loss and total body water remained unchanged.Our data support an oncotically driven fluid redistribution from the intra- to the extravascular space, rather than fluid loss, as the mechanism underlying HH-induced PV contraction.Extended hypoxic exposure reduces plasma volume (PV). The mechanisms underlying this effect are controversial, possibly as previous studies have been confounded by inconsistent experimental conditions. Here, we investigated the effect of hypobaric hypoxia (HH) on PV in a cross-over study that strictly controlled for diet, water intake, physical activity and temperature. Eleven males completed two 4-day sojourns in a hypobaric chamber, one in normoxia (NX) and one in HH equivalent to 3500 m altitude. PV, urine output, volume-regulating hormones and plasma protein concentration were determined daily. Total body water (TBW) was determined at the end of both sojourns by deuterium dilution. Although PV was 8.1 +/- 5.8% lower in HH than in NX after 24 h and remained similar to 10% lower thereafter (all P 0.23). Plasma renin activity and circulating aldosterone were suppressed in HH during the first half of the sojourn (all P 0.05). Markers for atrial natriuretic peptide were higher in HH than NX after 30 min (P = 0.001) but lower during the last 2 days (P

Aims The study aimed to estimate the risk of cardiac events in immune checkpoint inhibitor (ICI)-treated patients with lung cancer or malignant melanoma. Methods and results The study included consecutive patients with lung cancer or malignant melanoma in 2011–17 nationwide in Denmark. The main composite outcome was cardiac events (arrhythmia, peri- or myocarditis, heart failure) or cardiovascular death. Absolute risks were estimated and the association of ICI and cardiac events was analysed in multivariable Cox models. We included 25 573 patients with lung cancer. Of these, 743 were treated with programmed cell death-1 inhibitor (PD1i) and their 1-year absolute risk of cardiac events was 9.7% [95% confidence interval (CI) 6.8–12.5]. Of the 13 568 patients with malignant melanoma, 145 had PD1i and 212 had cytotoxic T-lymphocyte-associated protein-4 inhibitor (CTLA-4i) treatment. Their 1-year risks were 6.6% (1.8–11.3) and 7.5% (3.7–11.3). The hazard rates of cardiac events were higher in patients with vs. without ICI treatment. Within 6 months from 1st ICI administration, the hazard ratios were 2.14 (95% CI 1.50–3.05) in patients with lung cancer and 4.30 (1.38–13.42) and 4.93 (2.45–9.94) in patients with malignant melanoma with PD1i and CTLA-4i, respectively. After 6 months, HRs were 2.26 (1.27–4.02) for patients with lung cancer and 3.48 (1.91–6.35) for patients with malignant melanoma and CTLA-4i. Conclusions Among patients with lung cancer and malignant melanoma, ICI treated had increased rates of cardiac events. The absolute risks were higher in these data compared with previous pharmacovigilance studies (e.g. 1.8% peri-/myocarditis 1-year risk).

Aims Patients with atrial fibrillation (AF) treated with oral anticoagulants (OACs) have an increased risk of bleeding including haematuria. In the general population, gross haematuria is associated with urinary tract cancer. Consequently, we aimed to investigate the potential association between gross haematuria and urinary tract cancer in anticoagulated patients with AF. Methods and results Using Danish nationwide registers, we included Danish AF patients treated with OACs between 2001 and 2015. Non-parametric estimation and semi-parametric absolute risk regression were used to estimate the absolute risk of urinary tract cancer in patients with and without gross haematuria. We included 125 063 AF patients with a median age of 74 years (interquartile range 65–80) and a majority of males (57%). The absolute risk of gross haematuria 12 months after treatment initiation increased with age ranging from 0.37% [95% confidence interval (CI) 0.31–0.42] to 0.85% (95% CI 0.75–0.96) in the youngest and oldest age groups of ≤70 and >80 years of age, respectively. The 1-year risk of urinary tract cancer after haematuria ranged from 4.2% (95% CI 2.6–6.6) to 6.5% (95% CI 4.6–9.0) for patients in age group >80 and 71–80 years, respectively. Gross haematuria conferred large risk ratios of urinary tract cancer when comparing patients with and without haematuria across all age groups. Conclusion Gross haematuria was associated with clinically relevant risks of urinary tract cancer in anticoagulated patients with AF. These findings underline the importance of meticulously examining anticoagulated patients with haematuria.

Background: In multiple sclerosis (MS), the Expanded Disability Status Scale (EDSS) reflects disease severity. Although parts of the EDSS are dependent on actual walking distance, self-reported statements are often applied. Objectives: The purpose of the present study was, therefore, to compare self-reported walking distance to actual walking distance to outline how this influences EDSS scoring. Methods: MS patients with EDSS 4.0–7.5 ( n = 273) were included from the Danish MS hospitals rehabilitation study ( n = 427). All patients subjectively classified their maximal walking distance according to one of seven categories (>500; 300–499; 200–299; 100–199; 20–99; 5–19; 0–4 m). Subsequently, actual maximal walking distance was assessed and EDSS was determined from both self-reported walking distance (EDSSself-report) and actual walking distance (EDSSactual). Results: In 145 patients (53%), self-reported walking distance was misclassified when compared to the actual walking distance. Misclassification was more frequent in patients using walking aids (64% vs. 44%, p self-report vs EDSSactual) of ⩾0.5 point in 24%. Conclusion: In MS patients with EDSS 4.0–7.5, 53% misclassified their walking distance yielding incorrect EDSS scores in 24%. Therefore, correct EDSS determination must be based on measurement of actual walking distance.

Background Older patients with atrial fibrillation (AF) often have multiple chronic conditions adding complexity to treatment decisions. However, regarding older AF patients, the association between multimorbidity and quality of care has not been explored previously in a non-selected nationwide cohort. Purpose To investigate the association between morbidity burden and the treatment with oral anticoagulation therapy (OAC) and rhythm-control strategies in patients >65 years of age with incident AF in Denmark. Methods Using Danish nationwide registers, we identified all Danish AF patients >65 years of age hospitalized for incident AF between 2010 and 2016. Using logistic regression models, we estimated the association between morbidity burden (5 comorbidities) and the likelihood of receiving AF specific treatments. Estimates were reported as odds ratios with 95% confidence intervals (OR, 95% CI) with Results A total of 49,802 AF patients were eligible for inclusion, with a median age of 77.5 years (Interquartile range [IQR] 71.8–83.8) and 24,983 (50.2%) were male. A total of 25,181 (50.6%) patients had 5 comorbidities. The median CHA2DS2-VASc score ranged from 3 (IQR 2–3) to 5 (IQR 4–5) in patients with 5 comorbidities, respectively. Increasing morbidity burden was associated with decreasing odds of being treated with OAC therapy with the lowest odds in patients with >5 comorbidities (OR 0.39, 95% CI 0.34–0.45) compared with AF patients with Morbidity burden was associated with increased odds of being prescribed anti-arrhythmic medication with the highest odds in patients with >5 comorbidities (OR 2.50 95% CI 2.08–2.99). In contrast, having >5 comorbidities was associated with decreased odds of AF related procedures (OR 0.32, 95% CI 0.23–0.43) compared to patients with Forest plot of OAC initiation factors Conclusion Morbidity burden is strongly associated with OAC initiation and rhythm-control strategies in older patients with incident AF. Older AF patients with multimorbidity are less likely to be treated with OAC although these are the patients who benefit most from treatment. Therefore, initiatives and quality improvement programs should be done to close this important gap between clinical trials and clinical practice.

Background The number of patients with relapsing remitting multiple sclerosis (RRMS) who convert to secondary progressive (SP) MS is uncertain, and with emerging treatment options for SPMS, it is important to identify RRMS patients in transition to the SP phase. The objective of the present study was to characterize clinical parameters and use of disease modifying therapies in patients diagnosed with SPMS and RRMS patients already entered the SP phase by use of the Danish Multiple Sclerosis Registry (DMSR). Methods We used a cross-sectional design, including all living patients with MS as of June 30, 2020 from DMSR. First, we applied the MSBase definition of SPMS on all RRMS patients. Second, we applied the slightly modified inclusion criteria from the EXPAND clinical trial on patients with clinically confirmed SPMS and patients with RRMS fulfilling the MSBase definition of SPMS to identify SPMS patients recently progressed who may benefit from treatment with disease modifying therapy. We compared clinical characteristics and disease-modifying therapy use in the different patient groups. Results Among patients with clinically confirmed SPMS, application of a slightly modified EXPAND trial inclusion criteria for SPMS (m-EXPAND) captured patients who had converted to SPMS more recently and who had relapsed and initiated high-efficacy treatment more frequently. Moreover, our RRMS patients fulfilling the “SPMS”-criteria according to MSBase and recently progression according to m-EXPAND had similar characteristics and remarkably resembled the SPMS population in the EXPAND trial. Conclusion Our results indicate that data-driven diagnostic definitions might help identify RRMS patients at risk for SPMS and we highlight the challenges and reluctance in diagnosing SPMS in clinical practice.

Background: There is insufficient evidence to support the effectiveness of multidisciplinary rehabilitation on the health-related quality of life (HRQoL) of MS patients. Objectives: To evaluate the longer term effectiveness of inpatient multidisciplinary rehabilitation on the HRQoL of MS patients. Methods: The study was a two-hospital, pragmatic, randomized controlled trial with a 6-month follow-up. Patients aged 18–65 years with MS and Expanded Disability Status Scale scores ≤7.5 were randomly assigned (1:1) to 4 weeks of inpatient multidisciplinary rehabilitation (20 days of scheduled rehabilitation) or 6 months on a wait list. The outcome measures were Functional Assessment in Multiple Sclerosis (FAMS), Multiple Sclerosis Impact Scale-29 (MSIS-29), EQ-5D-5L and 15D. Results: We randomized 213 patients to the wait-list control group and 214 patients to the treatment group. Trends in favour of the treatment group were observed across all measures. However, the difference was significant in only two of the six measures. The treatment effect was −2.7 (95% CI: −5.6 to (−0.1)), p = 0.046) for the MSIS-29 Psychological and 0.017 (95% CI: 0.005–0.030, p = 0.008) for the 15D. FAMS, which we used to calculate the sample size, was not significant. Conclusion: The results indicated that inpatient multidisciplinary rehabilitation is effective in improving the HRQoL of MS patients after 6 months.

Aims: During the last decade, ablation has increasingly been used in rhythm control management of patients with atrial fibrillation (AF). Over time, experience and techniques have improved and indications for ablation have expanded. The purpose of this study was to investigate whether the recurrence rate of AF following ablation has improved during last decade.Methods and results: Through Danish nationwide registers, all patients with first-time AF ablation, between 2005 and 2014 in Denmark were identified. Recurrent AF after ablation was identified with 1 year follow-up. A total of 5425 patients undergoing first-time ablation were included. While patient median age increased over time the median AF duration prior to ablation decreased. The rates of recurrent AF decreased from 45% in 2005-2006 to 31% 2013-2014 with the relative risk of recurrent AF almost halved with an odds ratio of 0.57 [95% confidence intervals (95% CI) 0.47-0.68] in 2013-2014 compared with patients undergoing ablation in 2005-2006. Female gender, hypertension, AF duration >2 years, and cardioversion within 1 year prior to ablation were all associated with an increased risk of recurrent AF.Conclusion: One year risk of recurrent AF following first-time ablation has almost halved from 2006 to 2014. Hypertension, female sex, cardioversion 1 year prior to ablation, and AF duration for more than 2 years all increased the associated risk of recurrent AF.

Background: To estimate the value of treatments in multiple sclerosis (MS) – where lifetime costs and outcomes cannot be observed – outcome data have to be combined with cost data. This, in turn, requires that cost data be regularly updated. Objectives and Methods: This study is part of a cross-sectional retrospective study in 16 countries collecting current data on resource consumption, work capacity, health-related quality of life (HRQoL) and prevalent symptoms for patients with MS. Descriptive analyses are presented by level of severity, from the societal perspective, in 2015 Danish Kronor (DKK). Results: A total of 830 patients (mean age of 54 years) participated; 78% were below retirement age and of these, 43% were employed. Employment was related to disease severity, and MS was felt to affect productivity at work by 73% of patients, most often through fatigue. Overall, 95% and 65% of patients felt that fatigue and cognition, respectively, were a problem. Mean utility and costs were 0.770 and 196,900DKK at Expanded Disability Status Scale (EDSS) 0–3, 0.619 and 287,300DKK at EDSS 4–6.5, and 0.302 and 533,250DKK at EDSS 7–9. The average cost of a relapse was estimated at 19,000DKK. Conclusion: This study illustrates the burden of MS on Danish patients and provides current data that are important for the development of health policies.

Chronic hypoxia increases resting heart rate (HR), but the underlying mechanism remains incompletely understood. We investigated the relative contributions of the sympathetic and parasympathetic ne ...

Matthias Peter Hilty, Andrea Mueller, Daniela Flück, Christoph Siebenmann, Peter Rasmussen, Stefanie Keiser, Katja Auinger, Carsten Lundby, and Marco Maggiorini. Effect of increased blood flow on the pulmonary circulation before and during high altitude acclimatization. High Alt Med Biol. 17:305-314, 2016.-Introduction and Methods: Acute exposure to high altitude increases pulmonary artery pressure (Ppa) and pulmonary vascular resistance (PVR). The evolution of Ppa and PVR with continuous hypoxic exposure remains, however, elusive. To test the hypothesis that altitude exposure leads to a persistent elevation in Ppa and PVR throughout acclimatization in seven healthy male subjects, echocardiography was performed at sea level (SL; 488 m) weekly during a 4-week sojourn at 3454 m (HA1-HA4) and upon return (SL2). Pulmonary artery catheterization and bilateral thigh cuff release maneuver were performed at SL and HA3 to study the properties of pulmonary circulation after 3 weeks of acclimatization.Pulmonary artery catheter determined that systolic Ppa (mean ± SEM) was increased from 20 ± 1 at SL to 27 ± 2 mmHg at HA3 (p 0.01). Echocardiography assessed that systolic Ppa remained equally increased throughout acclimatization (26 ± 2, 25 ± 2, 25 ± 2, and 24 ± 2 mmHg at HA1-HA4; p = 0.93) and returned to baseline upon return (17 ± 2, 18 ± 1 mmHg at SL, SL2; p = 0.3). The same was shown for PVR. Right heart function remained unaffected. Thigh cuff release maneuvers at SL and HA3 resulted in similar increase in cardiac output (2.5 ± 0.5 and 2.2 ± 0.4 L/min; p = 0.61) without affecting mean Ppa.Prolonged altitude exposure leads to a persistent increase in Ppa and PVR without affecting right heart function and is fully reversible within 1 week after return to SL. The thigh cuff release maneuver-induced increase in cardiac output suggests a preserved ability of pulmonary circulation to cope with sudden remarkable increase in pulmonary blood flow throughout acclimatization.

Siebenmann C, Ryrsø CK, Oberholzer L, Fisher JP, Hilsted LM, Rasmussen P, Secher NH, Lundby C. Hypoxia-induced vagal withdrawal is independent of the hypoxic ventilatory response in men. J Appl Physiol 126: 124 –131, 2019. First published November 29, 2018; doi:10.1152/japplphysiol.00701.2018.—Hypoxia increases heart rate (HR) in humans by sympathetic activation and vagal withdrawal. However, in anaesthetized dogs hypoxia increases vagal activity and reduces HR if pulmonary ventilation does not increase and we evaluated whether that observation applies to awake humans. Ten healthy males were exposed to 15 min of normoxia and hypoxia (10.5% O2), while respiratory rate and tidal volume were volitionally controlled at values identified during spontaneous breathing in hypoxia. End-tidal CO2 tension was clamped at 40 mmHg by CO2 supplementation. -Adrenergic blockade by intravenous propranolol isolated vagal regulation of HR. During spontaneous breathing, hypoxia increased ventilation by 3.2 2.1 l/min (P 0.0033) and HR by 8.9 5.5 beats/min (P 0.001). During controlled breathing, respiratory rate (16.3 3.2 vs. 16.4 3.3 breaths/min) and tidal volume (1.05 0.27 vs. 1.06 0.24 l) were similar for normoxia and hypoxia, whereas the HR increase in hypoxia persisted without (8.6 10.2 beats/min) and with (6.6 5.6 beats/min) propranolol. Neither controlled breathing (P 0.80), propranolol (P 0.64), nor their combination (P 0.89) affected the HR increase in hypoxia. Arterial pressure was unaffected (P 0.48) by hypoxia across conditions. The hypoxia-induced increase in HR during controlled breathing and -adrenergic blockade indicates that hypoxia reduces vagal activity in humans even when ventilation does not increase. Vagal withdrawal in hypoxia seems to be governed by the arterial chemoreflex rather than a pulmonary inflation reflex in humans. NEW & NOTEWORTHY Hypoxia accelerates the heart rate of humans by increasing sympathetic activity and reducing vagal activity. Animal studies have indicated that hypoxia-induced vagal withdrawal is governed by a pulmonary inflation reflex that is activated by the increased pulmonary ventilation in hypoxia. The present findings, however, indicate that humans experience vagal withdrawal in hypoxia even if ventilation does not increase, indicating that vagal withdrawal is governed by the arterial chemoreflex rather than a pulmonary inflation reflex.

ObjectivesTo externally validate the accuracy of the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) model against existing risk scores for stroke and major bleeding risk in patients with non-valvular AF in a population-based cohort.DesignRetrospective cohort study.SettingDanish nationwide registries.Participants90 693 patients with newly diagnosed non-valvular AF were included between 2010 and 2016, with follow-up censored at 1 year.Primary and secondary outcome measuresExternal validation was performed using discrimination and calibration plots. C-statistics were compared with CHA2DS2VASc score for ischaemic stroke/systemic embolism (SE) and HAS-BLED score for major bleeding/haemorrhagic stroke outcomes.ResultsOf the 90 693 included, 51 180 patients received oral anticoagulants (OAC). Overall median age (Q1, Q3) were 75 (66–83) years and 48 486 (53.5%) were male. At 1-year follow-up, a total of 2094 (2.3%) strokes/SE, 2642 (2.9%) major bleedings and 10 915 (12.0%) deaths occurred. The GARFIELD-AF model was well calibrated with the predicted risk for stroke/SE and major bleeding. The discriminatory value of GARFIELD-AF risk model was superior to CHA2DS2VASc for predicting stroke in the overall cohort (C-index: 0.71, 95% CI: 0.70 to 0.72 vs C-index: 0.67, 95% CI: 0.66 to 0.68, pConclusionIn a nationwide Danish cohort with non-valvular AF, the GARFIELD-AF model adequately predicted the risk of ischaemic stroke/SE and major bleeding. Our external validation confirms that the GARFIELD-AF model was superior to CHA2DS2VASc in predicting stroke/SE and comparable with HAS-BLED for predicting major bleeding.