Healthcare fragmentation, multimorbidity, potentially inappropriate medication, and mortality: a Danish nationwide cohort study.

BACKGROUND: Patients with multimorbidity are frequent users of healthcare, but fragmented care may lead to suboptimal treatment. Yet, this has never been examined across healthcare sectors on a national scale. We aimed to quantify care fragmentation using various measures and to analyze the associations with patient outcomes. METHODS: We conducted a register-based nationwide cohort study with 4.7 million Danish adult citizens. All healthcare contacts to primary care and hospitals during 2018 were recorded. Clinical fragmentation indicators included number of healthcare contacts, involved providers, provider transitions, and hospital trajectories. Formal fragmentation indices assessed care concentration, dispersion, and contact sequence. The patient outcomes were potentially inappropriate medication and all-cause mortality adjusted for demographics, socioeconomic factors, and morbidity level. RESULTS: The number of involved healthcare providers, provider transitions, and hospital trajectories rose with increasing morbidity levels. Patients with 3 versus 6 conditions had a mean of 4.0 versus 6.9 involved providers and 6.6 versus 13.7 provider transitions. The proportion of contacts to the patient's own general practice remained stable across morbidity levels. High levels of care fragmentation were associated with higher rates of potentially inappropriate medication and increased mortality on all fragmentation measures after adjusting for demographic characteristics, socioeconomic factors, and morbidity. The strongest associations with potentially inappropriate medication and mortality were found for ≥ 20 contacts versus none (incidence rate ratio 2.83, 95% CI 2.77-2.90) and ≥ 20 hospital trajectories versus none (hazard ratio 10.8, 95% CI 9.48-12.4), respectively. Having less than 25% of contacts with your usual provider was associated with an incidence rate ratio of potentially inappropriate medication of 1.49 (95% CI 1.40-1.58) and a mortality hazard ratio of 2.59 (95% CI 2.36-2.84) compared with full continuity. For the associations between fragmentation measures and patient outcomes, there were no clear interactions with number of conditions. CONCLUSIONS: Several clinical indicators of care fragmentation were associated with morbidity level. Care fragmentation was associated with higher rates of potentially inappropriate medication and increased mortality even when adjusting for the most important confounders. Frequent contact to the usual provider, fewer transitions, and better coordination were associated with better patient outcomes regardless of morbidity level.

Chronic care services and variation between Danish general practices: a nationwide cohort study.

BACKGROUND: Little is known about variations in the provision of chronic care services in primary care. AIM: To describe the frequency of chronic care services provided by GPs and analyse the extent of non-random variation in service provision. DESIGN AND SETTING: Nationwide cohort study undertaken in Denmark using data from 2016. METHOD: Information on chronic care services was obtained from national health registers, including annual chronic care consultations, chronic care procedures, outreach home visits, and talk therapy. The associations between services provided, patient morbidity, and socioeconomic factors were estimated. Service variations were analysed, and excess variation related to practice-specific factors was estimated while accounting for random variation. RESULTS: Chronic care provision was associated with increasing patient age, increasing number of long-term conditions, and indicators of low socioeconomic status. Variation across practices ranged from 1.4 to 128 times more than expected after adjusting for differences in patient population and random variation. Variation related to practice-specific factors was present for all the chronic care services that were investigated. Older patients with lower socioeconomic status and multimorbidity were clustered in practices with low propensity to provide certain chronic care services. CONCLUSION: Chronic care was provided to patients typically in need of health care, that is, older adults, those with multimorbidity, and those with low socioeconomic status, but service provision varied more than expected across practices. GPs provided slightly fewer chronic care services than expected in practices where many patients with multimorbidity and low socioeconomic status were clustered, suggesting inverse care law mechanisms.

Quality of care and risk of incident atrial fibrillation in patients with newly diagnosed heart failure: a nationwide cohort study.

AIMS: Incident atrial fibrillation (AF) is an adverse prognostic indicator in heart failure (HF); identifying modifiable targets may be relevant to reduce the incidence and morbidity of AF. Therefore, we examined the association between quality of HF care and risk of AF. METHODS AND RESULTS: Using the Danish Heart Failure Registry, we conducted a nationwide registry-based cohort study of all incident HF patients diagnosed between 2008 and 2018 and without history of AF. Quality of HF care was assessed by seven process performance measures, including echocardiographic examination, New York Heart Association classification, treatment with angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, beta-blockers, and mineralocorticoid antagonists, physical training, and patient education. In the main analysis, we examined adherence with all measures in a cohort of 25 100 patients (mean age 68.5 ± 13.2 years; 33.6% women). The median follow-up was 3.1 years. Cox proportional hazard regressions estimated the hazard ratios (HRs) with 95% confidence intervals (95% CIs) between the number of fulfilled measures and incident AF. In a multivariable-adjusted analysis with 0 fulfilled performance measures as reference, the HRs (95% CIs) were 1: 0.78 (0.61-1.00), 2: 0.63 (0.49-0.80), 3: 0.53 (0.36-0.80), 4: 0.64 (0.44-0.94), 5: 0.56 (0.39-0.82), 6: 0.51 (0.35-0.74), and 7: 0.49 (0.33-0.73), with a significant decreasing linear trend (P < 0.001). CONCLUSION: In patients with incident HF, fulfilment of guideline-based process performance measures was associated with decreased long-term risk of AF. This study supports initiatives to improve the quality of care for patients with HF to prevent incident AF.

Potentially inappropriate medications (PIMs): frequency and extent of GP-related variation in PIMs: a register-based cohort study.

OBJECTIVES: Potentially inappropriate medications (PIMs) pose an increasing challenge in the ageing population. We aimed to assess the extent of PIMs and the prescriber-related variation in PIM prevalence. DESIGN: Nationwide register-based cohort study. SETTING: General practice. PARTICIPANTS: The 4.2 million adults listed with general practitioner (GP) clinics in Denmark (n=1906) in 2016. MAIN OUTCOME MEASURES: We estimated the patients' time with PIMs by using 29 register-operationalised STOPP criteria linking GP clinics and redeemed prescriptions. For each criterion and each GP clinic, we calculated ratios between the observed PIM time and that predicted by multivariate Poisson regressions on the patients. The observed variation was measured as the 90th/10th percentile ratios of these ratios. The extent of expectable random variation was assessed as the 90th/10th percentile ratios in randomly sampled GP populations (ie, the sampled variation). The GP-related excess variation was calculated as the ratio between the observed variation and sampled variation. The linear correlation between the observed/expected ratio for each of the criteria and the observed/expected ratio of total PIM time (for each clinic) was measured by Pearson's rho. RESULTS: Overall, 294 542 individuals were exposed to 1 44 117 years of PIMs. The two most prevalent PIMs were long-term use (>3 months) of non-steroidal anti-inflammatory drugs (51 074 years of PIMs) or benzodiazepines (48 723 years of PIMs). These two criteria showed considerable excess variation of 2.33 and 3.05, respectively; for total PIMs, this figure was 1.65. For more than half of the criteria, we observed a positive correlation between the specific PIM and the sum of remaining PIMs. CONCLUSIONS: This study documents considerable variations in the prescribing practice of GPs for certain PIMs. These findings highlight a need for exploring the causal explanations for such variations, which could be markers of suboptimal GP-prescribing strategies.

Association Between Bipolar Disorder or Schizophrenia and Oral Anticoagulation Use in Danish Adults With Incident or Prevalent Atrial Fibrillation.

Importance: Individuals with bipolar disorder or schizophrenia have a higher risk of adverse outcomes from cardiovascular diseases. Oral anticoagulation therapy (OAT) for patients with atrial fibrillation (AF) is needed for stroke prevention, but whether patients with bipolar disorder or schizophrenia face disparities in receiving this therapy is unknown. Objective: To assess whether bipolar disorder or schizophrenia is associated with a lower rate of OAT initiation in patients with incident AF and lower prevalence of OAT in those with prevalent AF. Design, Setting, and Participants: A nationwide cohort study of Danish patients with AF was conducted from January 1, 2005, to December 31, 2016, and data were analyzed from January 1 to June 15, 2020. Data from national registries included information on all redeemed prescriptions and all hospital contacts of all patients with incident or prevalent AF (age, 18-100 years) and increased risk status, defined by a CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes, stroke or transient ischemic attack, vascular disease, age 65-74 years, sex category) risk score greater than or equal to 2. Exposures: Hospital diagnosis of bipolar disorder or schizophrenia. Main Outcomes and Measures: Adjusted proportion differences for OAT initiation and OAT prevalence, comparing individuals with and without bipolar disorder or schizophrenia. Results: Patients included with incident AF (n = 147 810) had a mean (SD) age of 76.9 (10.1) years, 78 577 (53.2%) were women, 1208 (0.8%) had bipolar disorder, and 572 (0.4%) had schizophrenia. Accounting for age, sex, and calendar time, bipolar disorder and schizophrenia were associated with significantly lower frequency of OAT initiation within 90 days after incident AF (bipolar disorder: -12.7%; 95% CI, -15.3% to -10.0%; schizophrenia: -24.5%; 95% CI, -28.3% to -20.7%) and lower OAT prevalence in patients with prevalent AF (bipolar disorder: -11.6%; 95% CI, -13.9% to -9.3% schizophrenia: -21.6%; 95% CI, -24.8% to -18.4%). Adjusting for socioeconomic factors and other comorbid conditions attenuated these associations, particularly for patients with bipolar disorder. However, schizophrenia continued to be associated with a with a lower rate of OAT initiation (-15.5%, 95% CI, -19.3% to -11.7%) and a -12.8% (95% CI, -15.9% to -9.7%) lower OAT prevalence. These associations were also present after the introduction of non-vitamin K antagonists (adjusted proportion difference in 2013-2016: -12.4%; 95% CI, -18.7% to -6.1% for initiation and -10.1%; 95% CI, -13.8% to -6.4% for prevalence). Conclusions and Relevance: In this study, patients with bipolar disorder or schizophrenia were less likely to receive OAT in the setting of AF. For patients with bipolar disorder, this deficit was largely associated with socioeconomic factors and comorbidities, especially toward the end of the study period. For patients with schizophrenia, disparities in this stroke prevention therapy persistently exceeded what could be explained by other patient characteristics.

Death of a Partner and Risks of Ischemic Stroke and Intracerebral Hemorrhage: A Nationwide Danish Matched Cohort Study.

Background Stress has been reported to trigger stroke, and the death of a loved one is a potentially extremely stressful experience. Yet, previous studies have yielded conflicting findings of whether bereavement is associated with stroke risk, possibly because of insufficient distinction between ischemic stroke (IS) and intracerebral hemorrhage (ICH). We therefore examined the associations between bereavement and IS and ICH separately in contemporary care settings using nationwide high-quality register resources. Methods and Results The study cohort included all Danish individuals whose partner died between 2002 and 2016 and a reference group of cohabiting individuals matched 1:2 on sex, age, and calendar time. Cox proportional hazards regression was used to estimate adjusted hazard ratios (aHRs) and corresponding 95% CIs during up to 5 years follow-up. During the study period, 278 758 individuals experienced partner bereavement, of whom 7684 had an IS within the subsequent 5 years (aHR, 1.11; CI, 1.08-1.14 when compared with nonbereaved referents) and 1139 experienced an ICH (aHR, 1.13; CI, 1.04-1.23). For ICH, the estimated association tended to be stronger within the initial 30 days after partner death (aHR, 1.66; CI, 1.06-2.61), especially in women (aHR, 1.99; CI, 1.06-3.75), but the statistical precision was low. In absolute numbers, the cumulative incidence of IS at 30 days was 0.73 per 1000 in bereaved individuals versus 0.63 in their referents, and the corresponding figures for ICH were 0.13 versus 0.08. Conclusions Statistically significant positive associations with partner bereavement were documented for both IS and ICH risk, for ICH particularly in the short term. However, absolute risk differences were small.

Trends in excess mortality associated with atrial fibrillation over 45 years (Framingham Heart Study): community based cohort study.

OBJECTIVE: To assess temporal trends in the association between newly diagnosed atrial fibrillation and death. DESIGN: Community based cohort study. SETTING: Framingham Heart Study cohort, in 1972-85, 1986-2000, and 2001-15 (periods 1-3, respectively), in Framingham, MA, USA. PARTICIPANTS: Participants with no atrial fibrillation, aged 45-95 in each time period, and identified with newly diagnosed atrial fibrillation (or atrial flutter) during each time period. MAIN OUTCOME MEASURES: The main outcome was all cause mortality. Hazard ratios for the association between time varying atrial fibrillation and all cause mortality were calculated with adjustment for time varying confounding factors. The difference in restricted mean survival times, adjusted for confounders, between participants with atrial fibrillation and matched referents at 10 years after a diagnosis of atrial fibrillation was estimated. Meta-regression was used to test for linear trends in hazard ratios and restricted mean survival times over the different time periods. RESULTS: 5671 participants were selected in time period 1, 6177 in period 2, and 6174 in period 3. Adjusted hazard ratios for all cause mortality between participants with and without atrial fibrillation were 1.9 (95% confidence interval 1.7 to 2.2) in time period 1, 1.4 (1.3 to 1.6) in period 2, and 1.7 (1.5 to 2.0) in period 3 (Ptrend=0.70). Ten years after diagnosis of atrial fibrillation, the adjusted difference in restricted mean survival times between participants with atrial fibrillation and matched referents decreased by 31%, from -2.9 years (95% confidence interval -3.2 to -2.5) in period 1, to -2.1 years (-2.4 to -1.8) in period 2, to -2.0 years (-2.3 to -1.7) in period 3 (Ptrend=0.03). CONCLUSIONS: No evidence of a temporal trend in hazard ratios for the association between atrial fibrillation and all cause mortality was found. The mean number of life years lost to atrial fibrillation at 10 years had improved significantly, but a two year gap compared with individuals without atrial fibrillation still remained.

Role for machine learning in sex-specific prediction of successful electrical cardioversion in atrial fibrillation?

OBJECTIVE: Electrical cardioversion is frequently performed to restore sinus rhythm in patients with persistent atrial fibrillation (AF). However, AF recurs in many patients and identifying the patients who benefit from electrical cardioversion is difficult. The objective was to develop sex-specific prediction models for successful electrical cardioversion and assess the potential of machine learning methods in comparison with traditional logistic regression. METHODS: In a retrospective cohort study, we examined several candidate predictors, including comorbidities, biochemistry, echocardiographic data, and medication. The outcome was successful cardioversion, defined as normal sinus rhythm immediately after the electrical cardioversion and no documented recurrence of AF within 3 months after. We used random forest and logistic regression models for sex-specific prediction. RESULTS: The cohort comprised 332 female and 790 male patients with persistent AF who underwent electrical cardioversion. Cardioversion was successful in 44.9% of the women and 49.9% of the men. The prediction errors of the models were high for both women (41.0% for machine learning and 48.8% for logistic regression) and men (46.0% for machine learning and 44.8% for logistic regression). Discrimination was modest for both machine learning (0.59 for women and 0.56 for men) and logistic regression models (0.60 for women and 0.59 for men), although the models were well calibrated. CONCLUSIONS: Sex-specific machine learning and logistic regression models showed modest predictive performance for successful electrical cardioversion. Identifying patients who will benefit from cardioversion remains challenging in clinical practice. The high recurrence rate calls for thoroughly informed shared decision-making for electrical cardioversion.

Association between Mental Disorders and Subsequent Medical Conditions.

BACKGROUND: Persons with mental disorders are at a higher risk than the general population for the subsequent development of certain medical conditions. METHODS: We used a population-based cohort from Danish national registries that included data on more than 5.9 million persons born in Denmark from 1900 through 2015 and followed them from 2000 through 2016, for a total of 83.9 million person-years. We assessed 10 broad types of mental disorders and 9 broad categories of medical conditions (which encompassed 31 specific conditions). We used Cox regression models to calculate overall hazard ratios and time-dependent hazard ratios for pairs of mental disorders and medical conditions, after adjustment for age, sex, calendar time, and previous mental disorders. Absolute risks were estimated with the use of competing-risks survival analyses. RESULTS: A total of 698,874 of 5,940,299 persons (11.8%) were identified as having a mental disorder. The median age of the total population was 32.1 years at entry into the cohort and 48.7 years at the time of the last follow-up. Persons with a mental disorder had a higher risk than those without such disorders with respect to 76 of 90 pairs of mental disorders and medical conditions. The median hazard ratio for an association between a mental disorder and a medical condition was 1.37. The lowest hazard ratio was 0.82 for organic mental disorders and the broad category of cancer (95% confidence interval [CI], 0.80 to 0.84), and the highest was 3.62 for eating disorders and urogenital conditions (95% CI, 3.11 to 4.22). Several specific pairs showed a reduced risk (e.g., schizophrenia and musculoskeletal conditions). Risks varied according to the time since the diagnosis of a mental disorder. The absolute risk of a medical condition within 15 years after a mental disorder was diagnosed varied from 0.6% for a urogenital condition among persons with a developmental disorder to 54.1% for a circulatory disorder among those with an organic mental disorder. CONCLUSIONS: Most mental disorders were associated with an increased risk of a subsequent medical condition; hazard ratios ranged from 0.82 to 3.62 and varied according to the time since the diagnosis of the mental disorder. (Funded by the Danish National Research Foundation and others; COMO-GMC ClinicalTrials.gov number, NCT03847753.).

Statins and Risk of Intracerebral Hemorrhage in Individuals With a History of Stroke.

Background and Purpose- It has been suggested that statins increase the risk of intracerebral hemorrhage in individuals with a history of stroke, which has led to a precautionary principle of avoiding statins in patients with prior intracerebral hemorrhage. However, such prescribing reticence may be unfounded and potentially harmful when considering the well-established benefits of statins. This study is so far the largest to explore the statin-associated risk of intracerebral hemorrhage in individuals with prior stroke. Methods- We conducted a population-based, propensity score-matched cohort study using information from Danish national registers. We included all individuals initiating statin treatment after a first-time stroke diagnosis (intracerebral hemorrhage, N=2728 or ischemic stroke, N=52 964) during 2002 to 2016. For up to 10 years of follow-up, they were compared with a 1:5 propensity score-matched group of statin nonusers with the same type of first-time stroke. The difference between groups was measured by adjusted hazard ratios for intracerebral hemorrhage calculated by type of first-time stroke as a function of time since statin initiation. Results- Within the study period, 118 new intracerebral hemorrhages occurred among statin users with prior intracerebral hemorrhage and 319 new intracerebral hemorrhages in users with prior ischemic stroke. The risk of intracerebral hemorrhage was similar for statin users and nonusers when evaluated among those with prior intracerebral hemorrhage, and it was reduced by half in those with prior ischemic stroke. These findings were consistent over time since statin initiation and could not be explained by concomitant initiation of other medications, by dilution of treatment effect (due to changes in exposure status over time), or by healthy initiator bias. Conclusions- This large study found no evidence that statins increase the risk of intracerebral hemorrhage in individuals with prior stroke; perhaps the risk is even lower in the subgroup of individuals with prior ischemic stroke.

Body mass and atrial fibrillation risk: Status of the epidemiology concerning the influence of fat versus lean body mass.

Obesity is repeatedly proclaimed an important risk factor for atrial fibrillation (AF) and considered one of the most promising targets for prevention. This widely held view has been questioned by recent findings, which suggest that AF risk is associated with a high lean (aka fat-free) body mass, whereas fat carries little or no independent risk of AF. Focusing on these recent results, the present overview summarizes and interprets the evidence underlying this apparent controversy and discusses whether a change of paradigm is warranted in AF research or in clinical practice. The overall conclusion is that the excess AF risk in obese persons seems primarily associated with other characteristics than the amount of adipose tissue per se.

Depression and Uptake of Oral Anticoagulation Therapy in Patients With Atrial Fibrillation: A Danish Nationwide Cohort Study.

BACKGROUND: Oral anticoagulation therapy (OAT) in patients with atrial fibrillation (AF) is a highly important preventive intervention, perhaps especially in those with comorbid depression, who have a worse prognosis. However, OAT may pose particular challenges in depressed patients. OBJECTIVES: To assess whether AF patients with depression have lower OAT uptake. METHODS: This nationwide register-based 2005-2016 cohort study of all Danes with AF and OAT indication (CHA2DS2VASc stroke risk score ≥2) assessed OAT initiation within 90 days in those with incident AF (N=147,162) and OAT prevalence in those with prevalent AF (N=192,656). The associations of depression with both outcomes were estimated in regression analyses with successive adjustment for socioeconomic characteristics and somatic and psychiatric comorbidity. RESULTS: Comorbid depression was significantly associated with lower frequency of OAT initiation in incident AF patients {adjusted proportion differences (aPDs): -6.6% [95% confidence interval (CI), -7.4 to -5.9]} and lower prevalence of OAT [aPD: -4.2% (95% CI, -4.7 to -3.8)] in prevalent AF patients. Yet, the OAT uptake increased substantially during the period, particularly in depressed patients [aPD for OAT prevalence in 2016: -0.8% (95% CI, -1.6 to -0.0)]. CONCLUSIONS: Comorbid depression was associated with a significantly lower OAT uptake in patients with AF, which questions whether depressed patients receive sufficient support to manage this consequential cardiac condition. However, a substantial increase in the overall OAT uptake and a decrease of the depression-associated deficit in OAT were seen over the period during which OAT was developed through the introduction of new oral anticoagulation therapy.

A Randomised Trial Examining Cardiovascular Morbidity and All-Cause Mortality 24 years Following General Health Checks: the Ebeltoft Health Promotion Project (EHPP).

INTRODUCTION: Global prevalence of risk factors for cardiovascular disease (CVD) and all-cause mortality is increasing. Treatments are available but can only be implemented if individuals at risk are identified. General health checks have been suggested to facilitate this process. OBJECTIVES: To examine the long-term effect of population-based general health checks on CVD and all-cause mortality. DESIGN AND SETTING: The Ebeltoft Health Promotion Project (EHPP) is a parallel randomised controlled trial in a Danish primary care setting. PARTICIPANTS: The EHPP enrolled individuals registered in the Civil Registration System as (1) inhabitants of Ebeltoft municipality, (2) registered with a general practitioner (GP) participating in the study and (3) aged 30-49 on 1 January 1991. A total of 3464 individuals were randomised as invitees (n=2000) or non-invitees (n=1464). Of the invitees, 493 declined. As an external control group, we included 1 511 498 Danes living outside the municipality of Ebeltoft. INTERVENTIONS: Invitees were offered a general health check and, if test-results were abnormal, recommended a 15-45 min consultation with their GP. Non-invitees in Ebeltoft received a questionnaire at baseline and were offered a general health check at year 5. The external control group, that is, the remaining Danish population, received routine care only. OUTCOME MEASURES: HRs for CVD and all-cause mortality. RESULTS: Every individual randomised was analysed. When comparing invitees to non-invitees within the municipality of Ebeltoft, we found no significant effect of general health checks on CVD (HR=1.11 (0.88; 1.41)) or all-cause mortality (HR=0.93 (0.75; 1.16)). When comparing invitees to the remaining Danish population, we found similar results for CVD (adjusted HR=0.99 (0.86; 1.13)) and all-cause mortality (adjusted HR=0.96 (0.85; 1.09)). CONCLUSION: We found no effect of general health checks offered to the general population on CVD or all-cause mortality. TRIAL REGISTRATION NUMBER: NCT00145782; 2015-57-0002; 62908, 187.

Selective serotonin reuptake inhibitors and risk of epilepsy after traumatic brain injury - A population based cohort study.

OBJECTIVE: Traumatic brain injury (TBI) is common and associated with a marked increased risk of developing epilepsy. Animal studies indicate that treatment with selective serotonin reuptake inhibitors (SSRIs) may increase the risk of epilepsy after TBI. The aim of this study was to investigate whether use of SSRIs modifies the risk of epilepsy after TBI. METHODS: This was a cohort study of 205,715 persons, who suffered a TBI in Denmark from 1996 to 2013. For each person with TBI, we matched 10 reference persons (N = 2,057,150) who were alive on the day of TBI and who had the same age and gender but had no history of TBI. We used a stratified Cox regression to calculate the relative risk of epilepsy after TBI for persons exposed to TBI, SSRI or both after adjustment for income, civil status, medical and neurological comorbidities, severe mental disease, and substance abuse. RESULTS: The risk of epilepsy was 5.61 times higher for persons who used SSRI at time of TBI (adjusted Hazard Ratio (aHR): 5.61 (95% CI: 4.88; 6.45)), 3.23 times higher for persons who had a TBI but did not use SSRI at time of TBI (aHR: 3.23 (95% CI: 3.12;3.35)), and 1.31 times higher for persons who used SSRI but had no TBI (aHR: 1.31 (95% CI: 1.18; 1.45)) compared to persons unexposed to both TBI and SSRI. CONCLUSIONS: This large population based cohort study showed that people using SSRI at the time of a TBI had higher risk of developing epilepsy compared to people not using SSRI at the time of TBI. The results are in line with those of animal studies and calls for further studies to evaluate whether the association is due to SSRIs or to the underlying disease (e.g. depression or anxiety).

Statins and Risk of Intracerebral Haemorrhage in a Stroke-Free Population: A Nationwide Danish Propensity Score Matched Cohort Study.

BACKGROUND: Statins may increase the risk of intracerebral haemorrhage (ICH) in individuals with previous stroke. It remains unclear whether this applies to individuals with no history of stroke. This study is the first to explore the statin-associated risk of ICH in stroke-free individuals while considering the timing of statin initiation. METHODS: We conducted a population-based, propensity score matched cohort study using information from five Danish national registers. We included all stroke-free individuals initiating statins in 2004-2013 and a propensity score matched group of non-users. Adjusted hazard ratios (aHRs) for ICH risk among statin users compared to non-users were calculated as a function of time since statin initiation. FINDINGS: 519,894 stroke-free individuals initiating statins and their 1:5 matched stroke-free reference subjects were included and followed for up to ten years. During this period, 1409 ICHs occurred in statin users. Statin users had an overall aHR of 0.85 (95% confidence interval: 0.80-0.90) compared to non-users, but this risk was modified by time since statin initiation. Statin users and non-users had similar ICH risk during the first six months after statin initiation. Hereafter, statin users had a 22-35% lower risk throughout the study period. INTERPRETATION: Statin users had lower ICH risk than non-users from six months after statin initiation. This finding could not be explained by healthy initiator bias or differences between users and non-users in terms of sociodemographic characteristics, comorbidity, or parallel treatment regimens. Our study suggests that statin use in stroke-free populations is associated with reduced ICH risk. FUNDING: The Novo Nordisk Foundation.

Frequency of health care utilization in the year prior to completed suicide: A Danish nationwide matched comparative study.

BACKGROUND: Suicide accounts for more than 800,000 annual deaths worldwide. Some of these deaths may be preventable by timely identification of individuals at risk and effective intervention. General practitioners (GPs) may have the potential to play an important role in this process. AIM: The present study aimed to assess the frequency of primary health care utilization in the year preceding suicide. METHODS: Using Danish national registers, we identified all persons who died by suicide in Denmark from 1997 through 2013 and assessed the frequency of their primary care utilization and compared it with that of an age- and sex-matched reference group sampled from the background population. RESULTS: We identified 11,191 persons who died by suicide (males: 8,095, females: 3,096). Compared with the reference group (N = 55,955), a greater proportion attended general practice in the year before index date (83% vs. 76%). In the last month before index date, these figures were 32.0% and 19.4%, respectively, corresponding to a difference of 12.0 95% CI: (11.1; 12.9) percentage points after adjustment for demographic characteristics and physical comorbidity. Suicide cases had a higher GP attendance in every week in the year before suicide, but the difference increased specifically in the last four months. CONCLUSION: More than 30% attended the GP in the month before the suicide. This indicates that general practice could be a possible place to identify suicide cases and offer intervention. However, although this proportion represents a markedly higher GP attendance than seen in the reference group, almost 70% of those who died by suicide did not attend primary care in the month before the suicide. Our study suggests that it is important that the GPs have easy access to effective suicide prevention programs for patients at risk of suicide, and that persons with suicidal thoughts are encouraged to contact their GP.

Depression, antidepressants, and the risk of non-valvular atrial fibrillation: A nationwide Danish matched cohort study.

BACKGROUND: Depression is associated with an increased risk of a series of cardiovascular diseases and with increased symptom burden in patients with atrial fibrillation. The aim of this study was to determine the association between depression as well as antidepressant treatment and the risk of incident atrial fibrillation. DESIGN: A nationwide register-based study comparing the atrial fibrillation risk in all Danes initiating antidepressant treatment from 2000 to 2013 ( N = 785,254) with that in a 1:5-matched sample from the general population. METHODS: Cox regression was used to estimate adjusted hazard ratios (aHRs) and associated 95% confidence intervals (95% CIs), both after initiation of treatment and in the month before when patients were assumed to have medically untreated depression. RESULTS: Antidepressant treatment was associated with a three-fold higher risk of atrial fibrillation during the first month (aHR = 3.18 (95% CI: 2.98-3.39)). This association gradually attenuated over the following year (aHR = 1.37 (95% CI: 1.31-1.44) 2-6 months after antidepressant therapy initiation, and aHR = 1.11 (95% CI: 1.06-1.16) 6-12 months after). However, the associated atrial fibrillation risk was even higher in the month before starting antidepressant treatment (aHR = 7.65 (95% CI: 7.05-8.30) from 30 to 15 days before, and aHR = 4.29 (95% CI: 3.94-4.67) the last 15 days before). Overall, 0.4% of patients were diagnosed with atrial fibrillation from 30 days before to 30 days after antidepressant treatment. CONCLUSIONS: Antidepressant users had a substantially increased atrial fibrillation risk, particularly before treatment initiation. Whether this mirrors a causal relation between depression and atrial fibrillation may have large consequences for public health and should be discussed.

Atrial Fibrillation and Risk of Cancer: A Danish Population-Based Cohort Study.

Background Atrial fibrillation ( AF ) and cancer are frequent diseases worldwide. The timewise association between the diagnosis of AF and a subsequent diagnosis of cancer may clarify whether a mutual cause exists, and may also guide clinicians about time windows of high risk of cancer occurrence. Methods and Results We conducted a population-based cohort study among 26 222 men and 28 879 women free of AF and cancer at baseline based on the Danish Diet, Cancer and Health study. The participants were followed for the development of AF (the Danish National Patient Registry) and subsequent cancer (the Danish Cancer Registry) until 2013. We used Cox proportional hazard models with new-onset AF as time-dependent exposure. The men (median age 56 years) and women (median age 56 years) were followed for medians of 16.7 and 19.6 years, respectively. AF was associated with higher risks of any type of cancer (men: hazard ratio [ HR ] 1.41, 95% confidence interval [ CI ], 1.26-1.58; women: HR 1.15, 95% CI , 1.02-1.32), and for men only, lung ( HR 1.66, 95% CI , 1.19-2.30), and colorectal cancer ( HR 1.37, 95% CI , 1.02-1.85). Within the initial 90 days following the diagnosis of AF , the risks of any type of cancer (men: HR 2.89, 95% CI , 2.10-3.98; women: HR 3.72, 95% CI , 2.49-5.56), lung (men: HR 7.70, 95% CI , 4.34-13.68; women: HR 7.98, 95% CI , 3.96-16.09), and colorectal cancer (men: HR 3.35, 95% CI , 1.03-10.90; women: HR 5.91, 95% CI , 2.44-14.29) were higher for men and women. Conclusions A diagnosis of AF is associated with a higher incidence rate of cancer among men and women. The cancer incidence rate is particularly elevated within 90 days after the diagnosis of AF .

Early treatment with talk therapy or antidepressants in severely bereaved people and risk of suicidal behavior and psychiatric illness: an instrumental variable analysis.

PURPOSE: Losing a loved one to death is a common and natural life-course experience. Still, bereavement has been associated with an increased risk of suicidal behavior and psychiatric hospitalization and little is known of how to counter these adverse events. We aimed to study the effect of early treatment in primary care with talk therapy (TT) or antidepressants (AD) in severely bereaved people. METHODS: We conducted a population-based cohort study including 207,435 adult Danes who experienced a severe loss in 1996-2013. We compared treatment and no treatment with either of the two treatment regimens within 6 months after the loss. The main outcome was a serious mental health condition (defined as suicide, deliberate self-harm, or psychiatric hospitalization) occurring >6 months after bereavement. Adjusted risk differences (RDs) 2 years after bereavement were calculated using both standard regression analysis and instrumental variable analysis (IVA) in which estimated physician preferences for treatment served as instruments. RESULTS: The standard adjusted regression analysis showed a higher risk of developing a serious mental health condition associated with both TT (RD, 7.1; 95% CI, 5.0 to 9.1 per 1000 people) and AD (RD, 30.1; 95% CI, 25.7 to 34.6 per 1000 people). The IVA, which was used to control for unmeasured confounding, showed that TT was associated with a lower risk of a serious mental health condition (RD, -17.1; 95% CI, -30.7 to -3.5 per 1000 people), whereas the results were inconclusive for AD (RD, -8.6; 95% CI, -62.6 to 45.4 per 1000 people). CONCLUSION: This study suggests that early treatment with TT is associated with reduced long-term risk of serious mental health conditions in severely bereaved people. No clear benefit or harm of treatment with AD after bereavement was ascertained since the statistical precision was low.