Considerations for the use of biochemical laboratory registry data in clinical and public health research.

OBJECTIVES: To inform researchers of central considerations and limitations when applying biochemical laboratory-generated registry data in clinical and public health research. STUDY DESIGN AND SETTING: After review of literature on registry-based studies and the utilization of clinical laboratory registry data, relevant paragraphs and their applicability toward the creation of considerations for the use of biochemical registry data in research were evaluated. This led to the creation of an initial ten considerations. These were elaborated, edited, and merged after several read-throughs by all authors and discussed thoroughly under influence by the authors' personal experiences with laboratory databases and research registries in Denmark, leading to the formulation of five central considerations with corresponding items and illustrative examples. RESULTS: We recommend that the following considerations should be addressed in studies relying on biochemical laboratory-generated registry data: why are biochemical laboratory data relevant to examine the hypothesis, and how were the variable(s) utilized in the study? What were the primary indications for specimen collection in the study population of interest? Were there any pre-analytical circumstances that could influence the test results? Are data comparable between producing laboratories and within the single laboratory over time? Is the database representative in terms of completeness of study populations and key variables? CONCLUSION: It is crucial to address key errors in laboratory registry data and acknowledge potential limitations.

Risk and adverse clinical outcomes of thrombocytopenia among patients with solid tumors-a Danish population-based cohort study.

BACKGROUND: Knowledge about thrombocytopenia among patients with solid tumors is scarce. We examined the risk of thrombocytopenia among patients with solid tumors and its association with adverse outcomes. METHODS: Using Danish health registries, we identified all patients with incident solid tumors from 2015-2018 (n = 52,380) and a platelet count measurement within 2 weeks prior to or on their cancer diagnosis date. The risk of thrombocytopenia was categorized as grades 0 (any platelet count × 109/L): <150; 1: <100; 2: <75; 3: <50; 4: <25, and 5: <10. To study the outcomes, each patient with thrombocytopenia was matched with up to five cancer patients without thrombocytopenia by age, sex, cancer type, and stage. Cox regression was used to compute hazard ratios (HRs) of bleeding, transfusion, or death, adjusting for confounding factors. RESULTS: The 1-year risk of thrombocytopenia was 23%, increasing to 30% at 4 years. This risk was higher in patients receiving chemotherapy (43% at 1 year and 49% at 4 years). Overall, patients with thrombocytopenia had higher 30-days rates of bleeding (HR = 1.72 [95% confidence interval, CI: 1.41-2.11]). Thrombocytopenia was also associated with an increased rate of transfusion, and death, but some of the risk estimates were imprecise. CONCLUSIONS: The risk of thrombocytopenia was substantial among patients with solid tumors and associated with adverse outcomes.

Oral anticoagulant treatment and risk of kidney disease-a nationwide, population-based cohort study.

Background: Direct oral anticoagulants (DOACs) are recommended as first-line treatment of atrial fibrillation. Whether DOAC use is associated with lower risks of kidney complications compared with vitamin K antagonists (VKAs) remains unclear. We examined this association in a nationwide, population-based cohort study. Methods: We conducted a cohort study including patients initiating oral anticoagulant treatment within 3 months after an atrial fibrillation diagnosis in Denmark during 2012-18. Using routinely collected creatinine measurements from laboratory databases, we followed patients in an intention-to-treat approach for acute kidney injury (AKI) and chronic kidney disease (CKD) progression. We used propensity-score weighting to balance baseline confounders, computed weighted risks and weighted hazard ratios (HRs) with 95% confidence intervals (CIs) comparing DOACs with VKAs. We performed several subgroup analyses and a per-protocol analysis. Results: We included 32 781 persons with atrial fibrillation initiating oral anticoagulation (77% initiating DOACs). The median age was 75 years, 25% had a baseline estimated glomerular filtration rate <60 mL/min/1.73 m2, and median follow-up was 2.3 (interquartile range 1.1-3.9) years. The weighted 1-year risks of AKI were 13.6% in DOAC users and 15.0% in VKA users (HR 0.86, 95% CI 0.82; 0.91). The weighted 5-year risks of CKD progression were 13.9% in DOAC users and 15.4% in VKA users (HR 0.85, 95% CI 0.79; 0.92). Results were similar across subgroups and in the per-protocol analysis. Conclusions: Initiation of DOACs was associated with a decreased risk of AKI and CKD progression compared with VKAs. Despite the potential limitations of observational studies, our findings support the need for increased clinical awareness to prevent kidney complications among patients who initiate oral anticoagulants.

High-intensity versus moderate-intensity statin treatment for patients with ischemic stroke: Nationwide cohort study.

PURPOSE: Guidelines recommend high-intensity statin treatment after ischemic stroke, but evidence is sparse on the effectiveness and safety of different statin treatment intensities. We examined effectiveness and safety outcomes among patients initiating high-intensity versus moderate-intensity statins after ischemic stroke. METHODS: In this population-based new-user active-comparator cohort study, we used the Danish Stroke Registry, covering all Danish hospitals, to identify patients with a first-time ischemic stroke during 2012-2021. Using multiple Danish registries, patients who redeemed a statin prescription within 21 days after stroke admission were classified as high-intensity statin initiators or moderate-intensity statin initiators. Propensity score inverse probability of treatment weighting was used to balance patient characteristics. We used competing risk methods to compute 5 year risk differences (RDs) and Cox proportional hazards regression to compute 5 year hazard ratios (HRs) of stroke recurrence, myocardial infarction, heart failure, venous thromboembolism, and all-cause mortality (effectiveness outcomes) and diabetes, liver disease, and kidney disease (safety outcomes). RESULTS: High-intensity (n = 13,032) and moderate-intensity (n = 14,355) statin initiators were identified. Risks of most examined effectiveness outcomes were comparable between statin intensities. There was no clear association between statin intensity and stroke recurrence (RD: 0.8% [95% CI: 0.1, 1.4], HR: 1.08 [95% CI: 0.96, 1.22]). All-cause mortality was slightly reduced among high-intensity statin initiators (RD: -1.1% [95% CI: -0.1, -2.1], HR: 0.93 [95% CI: 0.85, 1.01]. Risks of most safety outcomes were comparable between statin intensities, but high-intensity statin use was associated with an increased risk of diabetes (RD: 1.2% [95% CI: 0.4, 1.9], HR: 1.10 [95% CI: 1.00, 1.21]). DISCUSSION AND CONCLUSION: Compared with initiation of moderate-intensity statins, initiation of high-intensity statins after ischemic stroke was associated with similar risks of most effectiveness and safety outcomes. However, mortality risk was reduced, and diabetes risk was increased.

Risk and Prognosis of Cancer in Patients With Cerebral Venous Thrombosis Compared With the Danish General Population.

BACKGROUND: Whether cerebral venous thrombosis (CVT) is a marker of cancer in clinical practice remains unknown. Little is known about the prognosis of cancer detected subsequent to CVT. METHODS: We used Danish nationwide registries (1996-2019) to identify patients with a first-time primary inpatient diagnosis of CVT without a history of cancer (N=811, 65% women, median age 42 years). We assessed the risk of an incident cancer diagnosis using standardized incidence ratios (SIRs). This measure contrasts the number of observed cancers among patients with CVT to the number of expected cancers where patients with CVT have the same cancer risk as the general population. We used Kaplan-Meier survival analysis and Cox regression to compare the survival of patients with both cancer and CVT with the survival of patients with cancer but without CVT, matched on cancer site, sex, age, and year of cancer diagnosis. RESULTS: Observing 43 incident cancer cases during follow-up, the overall SIR was unity (SIR, 1.04 [95% CI, 0.75-1.40]). However, the risk was ≈7-fold the expected level in the first 3 months following CVT diagnosis (SIR, 7.00 [95% CI, 3.02-13.80]) and ≈2-fold the expected level from 3 to 12 months following CVT diagnosis (SIR, 2.21 [95% CI, 0.89-4.56]). By 12 months following CVT diagnosis, the risk resembled the expected level (SIR, 0.76 [95% CI, 0.50-1.09]). Survival among cancer patients with prior CVT versus cancer patients without prior CVT was 91% versus 87% after 6 months and 65% versus 70% after 5 years. The adjusted hazard ratio of death was 0.78 (95% CI, 0.44-1.38). CONCLUSIONS: Patients with CVT were not at overall increased risk of a cancer diagnosis, except in the first 3 months after diagnosis during which period the risk was elevated ≈7-fold. The estimate from this early period, however, was based on only a few cancer diagnoses. Unlike other forms of venous thrombosis, a prior diagnosis of CVT did not negatively impact cancer survival.

Preadmission Opioid Use and 1-Year Mortality Following Incident Myocardial Infarction: A Danish Population-Based Cohort Study (1997-2016).

Background Opioid use has been linked to an increased risk of myocardial infarction and cardiovascular mortality, but the prognostic impact of opioid use before an incident myocardial infarction is largely unknown. Methods and Results We conducted a nationwide population-based cohort study including all patients hospitalized for an incident myocardial infarction in Denmark (1997-2016). Based on their last redeemed opioid prescription before admission, patients were categorized as current users (0-30 days), recent users (31-365 days), former users (>365 days), and nonusers. One-year all-cause mortality was calculated using the Kaplan-Meier method. Hazard ratios (HRs) were computed using Cox proportional hazards regression analyses, adjusting for age, sex, comorbidity, any preceding surgery within 6 months before the myocardial infarction admission, and medication use before the myocardial infarction admission. We identified 162 861 patients with an incident myocardial infarction. Of these, 8% were current opioid users, 10% were recent opioid users, 24% were former opioid users, and 58% were nonusers of opioids. One-year mortality was highest among current users (42.5% [95% CI, 41.7%-43.3%]) and lowest among nonusers (20.5% [95% CI, 20.2%-20.7%]). Compared with nonusers, current users had an elevated 1-year all-cause mortality risk (adjusted HR, 1.26 [95% CI, 1.22-1.30]). Following adjustment, neither recent users nor former users of opioids were at elevated risk. Conclusions Preadmission opioid use was associated with an increased 1-year all-cause mortality risk following an incident myocardial infarction. Opioid users thus represent a high-risk subgroup of patients with myocardial infarction.

In vitro Effect of Dalteparin and Argatroban on Hemostasis in Critically Ill Sepsis Patients with New-Onset Thrombocytopenia.

Thrombocytopenia is common among critically ill sepsis patients, while they also hold an increased risk for thromboembolic events. Thus, the choice of anticoagulant prophylaxis for this patient population is challenging. We investigated the in vitro effect of low-molecular-weight heparin (dalteparin) and direct thrombin inhibitor (argatroban) on the hemostasis in blood from sepsis patients with new-onset thrombocytopenia. Thrombocytopenia was defined as a platelet count drop of ≥30% and/or from >100 × 10 9 /L to 30 to 100 × 10 9 /L within 24 hours prior to inclusion. We included five healthy individuals and ten patients. Analyses of thrombin generation (Calibrated Automated Thrombogram), thrombin-antithrombin (TAT) complex levels, prothrombin fragment 1+2 (F1+2), and rotational thromboelastometry (ROTEM) were performed. Based on dose-response relationships investigated in healthy blood, patient samples were spiked with prophylactic (0.25 IU/mL) and therapeutic (0.75 IU/mL) dalteparin and low (0.25 µg/mL) and high (0.50 µg/mL) argatroban concentrations, each with a sample without anticoagulant. In patients, the endogenous thrombin potential was markedly lower in therapeutic dalteparin samples than in samples without anticoagulant [median (range): 29 (0-388) vs. 795 (98-2121) nM × min]. In high argatroban concentration samples, thrombin lag time was longer than in samples without anticoagulant [median (range): 15.5 (10.5-20.2) versus 5.3 (2.8-7.3) min]. Dalteparin and argatroban both increased clotting time but did not affect maximum clot firmness in the ROTEM INTEM assay. Six patients had elevated TAT and eight patients had elevated F1 + 2. In conclusion, dalteparin mainly affected the amount of thrombin generated and argatroban delayed clot initiation in critically ill sepsis patients with new-onset thrombocytopenia. Neither anticoagulant affected clot strength.

Labour market participation and retirement after stroke in Denmark: registry based cohort study.

OBJECTIVE: To examine labour market participation and retirement among patients with stroke and matched people in the general population according to stroke subtype. DESIGN: Nationwide, population based, matched cohort study. SETTING: Danish Stroke Registry, covering all Danish hospitals, and other nationwide registries (2005-18). PARTICIPANTS: Patients (aged 18-60 years and active in the labour market) with a first time diagnosis of ischaemic stroke (n=16 577), intracerebral haemorrhage (n=2025), or subarachnoid haemorrhage (n=4305), and individuals from the general population, matched on age, sex, and calendar year (n=134 428). The median Scandinavian stroke scale score was 55. MAIN OUTCOME MEASURES: Unweighted prevalences of labour market participation, receipt of sick leave benefits, receipt of disability pension, voluntary early retirement, state pension, and death were computed for each week and up to five years after stroke diagnosis. A log-linear Poisson model was used to obtain exact prevalence estimates as well as propensity score weighted prevalence differences and prevalence ratios at six months, one year, two years, and five years after stroke diagnosis. RESULTS: Most patients (62% of those with ischaemic stroke, 69% of those with intracerebral haemorrhage, and 52% of those with subarachnoid haemorrhage) went on sick leave within three weeks of diagnosis. Prevalence of labour market participation among patients with ischaemic stroke compared with matched individuals from the general population was 56.6% versus 96.6% at six months, and 63.9% versus 91.6% at two years. Prevalence of sick leave was 39.8% versus 2.6% at six months, and 15.8% versus 3.8% at two years. Prevalence of receipt of a disability pension was 0.9% versus 0.2% at six months, and 12.2% versus 0.6% at two years. Adjusting for socioeconomic and comorbidity differences between patients and matched individuals from the general population using propensity score weighting methods had little impact on contrasts. Patients with intracerebral haemorrhage had higher prevalences of sick leave and receipt of a disability pension and thus a lower prevalence of labour market participation, while prevalences for patients with subarachnoid haemorrhage were similar in magnitude to those for patients with ischaemic stroke. CONCLUSIONS: In a highly resourced country, about two thirds of working age adults with ischaemic stroke of primarily mild severity participated in the labour market two years after diagnosis. Sick leave and receipt of a disability pension were the most common reasons for non-participation. Patients with intracerebral haemorrhage were less likely to return to the labour market than patients with ischaemic stroke and subarachnoid haemorrhage.

Thromboembolic events, bleeding, and mortality in patients with cerebral venous thrombosis: a nationwide cohort study.

Cerebral venous thrombosis (CVT) predominantly affects young to middle-aged women. Scarce data exist regarding the long-term prognosis. We examined the clinical course of patients with CVT overall and according to their age and sex. Using Danish registries, we identified all patients with a first-time primary inpatient diagnosis of CVT from 1996-2018 (N = 653; median age, 41 years; 67% women) and individuals from the general population matched for age, sex, and calendar year (N = 65 300). Patients with CVT were at an increased risk of venous thromboembolism (VTE) at other sites, ischemic stroke, major bleeding, and mortality. For both sexes, the increased risks of VTE at other sites were most prominent among younger patients (18-54 years), whereas the increased risks of ischemic stroke, major bleeding, and mortality were most prominent among older patients (≥55 years). Among young women, the 10-year risks of VTE at other sites for patients with CVT compared with members of the matched cohort were 2.2% vs 0.4% (risk difference, 1.8%; 95% confidence interval [CI], 0.0-3.6). Among older women, compared with members of the matched cohort, the 10-year risks were 12.8% vs 3.1% (risk difference, 9.7%; 95% CI, 1.6-17.9) for ischemic stroke, 11.1% vs 4.6% (risk difference, 6.5%; 95% CI, -1.0 to 14.1) for major bleeding, and 43.1% vs 26.7% (risk difference, 16.4%; 95% CI, 3.7-29.1) for all-cause mortality. The risk of myocardial infarction was not elevated. Clinicians should be aware of the importance of age and sex heterogeneity in the prognosis of CVT.

Exploring the epidemiology of disseminated intravascular coagulation: protocol for the DANish Disseminated Intravascular Coagulation (DANDIC) Cohort Study.

INTRODUCTION: Since disseminated intravascular coagulation (DIC) was first described, it has been considered a serious disease of the coagulation system and a major challenge to clinicians. Currently, several important knowledge gaps remain. The DANish Disseminated Intravascular Coagulation (DANDIC) Cohort Study will aim to answer questions regarding the incidence and mortality of patients with DIC including time trends. The study will also identify prognostic factors that may guide personalised prevention and treatment. Furthermore, the study will describe treatment patterns and the safety and effectiveness of various treatment modalities. METHODS AND ANALYSIS: We will establish the DANDIC Cohort using data collected in daily clinical practice from the Central Denmark Region, which covers approximately 1.3 million residents. The study period will encompass 1 January 2011 through 1 July 2021. Potential DIC cases will be identified from the hospital laboratory database, based on coagulation biomarkers, and diagnoses will be adjudicated by medical experts. The dataset will be enriched with detailed clinical data from electronic medical charts on aetiologies, bleeding, microthrombus formation, organ failure, thrombosis, treatments and comorbidities. The dataset will also take advantage of in-hospital data with longitudinal information on laboratory records, transfusions, microbiology and treatments. It will be possible to merge this dataset with other unique Danish health registries with more than 10 years of virtually complete follow-up. The project will use state-of-the-art epidemiological and biostatistical methods. ETHICS AND DISSEMINATION: The project has been approved by the Danish Patient Safety Authority (31-1521-452), the Central Denmark Region (1-45-70-83-21), the Danish Data Protection Agency (1-16-02-258-21) and all the hospital chairs. Register-based studies require no ethical approval in Denmark. The results will be disseminated in international peer-reviewed journals.

Evaluation of Neurologic and Psychiatric Outcomes After Hospital Discharge Among Adult Survivors of Cardiac Arrest.

Importance: Long-term risks of neurologic and psychiatric disease after cardiac arrest are largely unknown. Objective: To examine the short-term and long-term risks of common neurologic outcomes (stroke, epilepsy, Parkinson disease, and dementia) and psychiatric outcomes (depression and anxiety) in patients after hospitalization for cardiac arrest. Design, Setting, and Participants: This nationwide population-based cohort study with 21 years of follow-up included data on 250 838 adults from all Danish hospitals between January 1, 1996, and December 31, 2016. Danish medical registries were used to identify all patients with a first-time diagnosis of cardiac arrest and 2 matched comparison cohorts. The first comparison cohort included patients with a first-time diagnosis of myocardial infarction; the second comprised people from the general population. Data analysis was performed from November 1, 2020, to June 30, 2021. Exposures: In-hospital or out-of-hospital cardiac arrest. Main Outcomes and Measures: Neurologic and psychiatric outcomes after hospital discharge were ascertained using medical registries. Twenty-one-year hazard ratios (HRs) and 95% CIs were computed based on Cox regression analysis, controlled for matching factors, and adjusted for comorbidity and socioeconomic status. Results: Among the 250 838 individuals included in this study (median age, 67 years [IQR, 57-76 years]; 173 946 [69.3%] male), 3 groups were identified: 12 046 patients with cardiac arrest, 118 332 patients with myocardial infarction, and 120 460 people from the general population. Compared with patients with myocardial infarction, patients with cardiac arrest had an increased rate of ischemic stroke (10 per 1000 persons; HR, 1.30; 95% CI, 1.02-1.64) and hemorrhagic stroke (2 per 1000 persons; HR, 2.03; 95% CI, 1.12-3.67) in the first year after discharge. During the full follow-up period, rates were as follows: for epilepsy, 28 per 1000 persons (HR, 2.01; 95% CI, 1.66-2.44); for dementia, 73 per 1000 persons (HR, 1.23; 95% CI, 1.09-1.38); for mood disorders including depression, 270 per 1000 persons (HR, 1.78; 95% CI, 1.68-1.89); and for anxiety, 187 per 1000 persons (HR, 1.98; 95% CI, 1.85-2.12). The rate of Parkinson disease was similar in the 2 cohorts (8 per 1000 persons; HR, 0.96; 95% CI, 0.65-1.42). The rates of the aforementioned outcomes were highest during the first year after cardiac arrest and then declined over time. Comparisons between the cohort of patients with cardiac arrest and the general population cohort showed higher rates of epilepsy, dementia, depression, and anxiety in the cardiac arrest group. Conclusions and Relevance: In this cohort study, patients discharged after cardiac arrest had an increased rate of subsequent stroke, epilepsy, dementia, depression, and anxiety compared with patients with myocardial infarction and people from the general population, with declining rates over time. These findings suggest the need for preventive strategies and close follow-up of cardiac arrest survivors.

High-sensitivity troponin T and I in patients suspected of acute myocardial infarction.

Measurement of cardiac troponin (cTn) is the cornerstone in the diagnosis of myocardial infarction (MI). Potential disparities in concentrations of cTn, trajectories and mortality, following initial measurement warrant further investigation. Such data may guide clinicians treating patients suspected of MI. Plasma concentrations of cTnT and cTnI were measured in 503 consecutive patients at Aarhus University Hospital between June 13th and June 27th, 2019. cTnT was measured with the Roche cobas® E602 hs-cTnT assay, while cTnI was measured with the Siemens ADVIA Centaur® XPT hs-cTnI assay. Analytical agreement was determined based on assay-specific 99th percentiles. Medical records were reviewed for adjudication of the MI diagnosis. MI was the final diagnosis in 65 patients (12.9%) and the analytical agreement between cTnT and cTnI assays was 95.2%. For patients diagnosed with MI, cTnI reached higher peak concentrations in shorter time, compared to cTnT. All-cause mortality risk increased with increasing levels of both biomarkers. In this study, the analytical agreement of two cTn assays was high. However, some disparities in troponin trajectories were observed.

Stroke and Risk of Mental Disorders Compared With Matched General Population and Myocardial Infarction Comparators.

BACKGROUND: Accurate estimates of risks of poststroke outcomes from large population-based studies can provide a basis for public health policy decisions. We examined the absolute and relative risks of a spectrum of incident mental disorders following ischemic stroke and intracerebral hemorrhage. METHODS: During 2004 to 2018, we used Danish registries to identify patients (≥18 years and with no hospital history of mental disorders), with a first-time ischemic stroke (n=76 767) or intracerebral hemorrhage (n=9344), as well as age-,sex-, and calendar year-matched general population (n=464 840) and myocardial infarction (n=92 968) comparators. We computed risk differences, considering death a competing event, and hazard ratios adjusted for income, occupation, education, and history of cardiovascular and noncardiovascular comorbidity. RESULTS: Compared with the general population, following ischemic stroke, the 1-year risk difference was 7.3% (95% CI, 7.0-7.5) for mood disorders (driven by depression), 1.4% (95% CI, 1.3-1.5) for organic brain disorders (driven by dementia and delirium), 0.8% (95% CI, 0.7-0.8) for substance abuse disorders (driven by alcohol and tobacco abuse), and 0.5% (95% CI, 0.4-0.5) for neurotic disorders (driven by anxiety and stress disorders). For suicide, risk differences were near null. Hazard ratios were particularly elevated in the first year of follow-up, ranging from a 2- to a 4-fold increased hazard, decreasing thereafter. Compared with myocardial infarction patients, the 1-year risk difference was 4.9% (95% CI, 4.6 to 5.3) for mood disorders, 1.0% (95% CI, 0.8 to 1.1) for organic brain disorders, 0.1% (95% CI, 0.0 to 0.2) for substance abuse disorders, but -0.2% (95% CI, -0.2 to -0.1) for neurotic disorders. Hazard ratios during the first year of follow-up were elevated 1.1- to 1.8-fold for mood, organic brain, and neurotic disorders, while decreased 0.8-fold for neurotic disorders. CONCLUSIONS: The considerably greater risks of mental disorders following a stroke, particularly mood disorders, underline the importance of mental health evaluation after stroke.

Atrial fibrillation, liver cirrhosis, thrombosis, and bleeding: A Danish population-based cohort study.

OBJECTIVES: We examined the impact of liver cirrhosis on the risk of thromboembolic events and bleeding complications in patients with atrial fibrillation or flutter (AFF). METHODS: This population-based cohort study used data from Danish health registries. We identified all patients with a first-time diagnosis of AFF during 1995 to 2015, and followed them from their AFF diagnosis until the end of 2016. Patients were categorized according to the presence or absence of liver cirrhosis. We computed incidence rates per 1000 person-years and hazard ratios (HRs) with 95% confidence intervals (CIs) based on Cox regression analyses, adjusting for age, CHA2DS2VASc score, and Charlson Comorbidity Index score. RESULTS: We identified 273 225 patients with AFF. Of these, 1463 (0.54%) had liver cirrhosis. During 0 to 5 years of follow-up, compared to patients without liver cirrhosis, patients with liver cirrhosis had higher incidence rates and hazards of ischemic stroke (29.7 vs 21.6; HR, 1.3; 95% CI, 1.1-1.6), venous thromboembolism (9.2 vs 5.5; HR, 1.5; 95% CI, 1.2-2.3), but not myocardial infarction (10.2 vs 11.2; HR, 0.9; 95% CI, 0.7-1.2). Patients with liver cirrhosis also had higher rates of hemorrhagic stroke (5.8 vs 3.3; HR, 1.7; 95% CI, 1.1-2.6), subdural hemorrhage (5.3 vs 1.6; HR, 3.2; 95% CI, 2.1-4.9), hemorrhage of the lung or urinary tract (24.6 vs 15.2; HR, 1.6; 95% CI, 1.3-2.0), and gastrointestinal hemorrhage (34.5 vs 10.4; HR, 3.3; 95% CI, 2.7-3.9). CONCLUSION: In patients with AFF, liver cirrhosis was associated with an elevated risk of ischemic stroke, venous thromboembolism, and all evaluated bleeding complications.

Risk of Parkinson Disease and Secondary Parkinsonism in Myocardial Infarction Survivors.

Background In addition to primary neurodegenerative processes, vascular disorders, such as stroke, can lead to parkinsonism. However, some cardiovascular risk factors, such as smoking and elevated cholesterol levels, are associated with reduced risk of Parkinson disease. We examined the risk of Parkinson disease and secondary parkinsonism in 1-year survivors of myocardial infarction (MI). Methods and Results We conducted a nationwide population-based matched cohort study using Danish medical registries from 1995 to 2016. We identified all patients with a first-time MI diagnosis and sampled a sex-, age-, and calendar year-matched general population comparison cohort without MI. Cox regression analysis was used to compute adjusted hazard ratios (aHRs) for Parkinson disease and secondary parkinsonism, controlled for matching factors and adjusted for relevant comorbidities and socioeconomic factors. We identified 181 994 patients with MI and 909 970 matched comparison cohort members (median age, 71 years; 62% men). After 21 years of follow-up, the cumulative incidence was 0.9% for Parkinson disease and 0.1% for secondary parkinsonism in the MI cohort. Compared with the general population cohort, MI was associated with a decreased risk of Parkinson disease (aHR, 0.80; 95% CI, 0.73-0.87) and secondary parkinsonism (aHR, 0.72; 95% CI, 0.54-0.94). Conclusions MI was associated with a 20% decreased risk of Parkinson disease and 28% decreased risk of secondary parkinsonism. Reduced risk may reflect an inverse relationship between cardiovascular risk factors and Parkinson disease.

Dynamic Hemostasis and Fibrinolysis Assays in Intensive Care COVID-19 Patients and Association with Thrombosis and Bleeding-A Systematic Review and a Cohort Study.

Patients admitted to the intensive care unit (ICU) with coronavirus disease 2019 (COVID-19), the infectious pathology caused by severe acute respiratory syndrome coronavirus 2, have a high risk of thrombosis, though the precise mechanisms behind this remain unclarified. A systematic literature search in PubMed and EMBASE identified 18 prospective studies applying dynamic coagulation assays in ICU COVID-19 patients. Overall, these studies revealed normal or slightly reduced primary hemostasis, prolonged clot initiation, but increased clot firmness. Thrombin generation assay parameters generally were equivalent to the control groups or within reference range. Fibrinolysis assays showed increased clot resistance. Only six studies related their findings to clinical outcome. We also prospectively included 51 COVID-19 patients admitted to the ICU. Blood samples were examined on day 1, 3-4, and 7-8 with platelet function tests, rotational thromboelastometry (ROTEM), in vivo and ex vivo thrombin generation, and clot lysis assay. Data on thrombosis, bleeding, and mortality were recorded during 30 days. Primary hemostasis was comparable to healthy controls, but COVID-19 patients had longer ROTEM-clotting times and higher maximum clot firmness than healthy controls. Ex vivo thrombin generation was similar to that of healthy controls while in vivo thrombin generation markers, thrombin-antithrombin (TAT) complex, and prothrombin fragment 1 + 2 (F1 + 2) were higher in ICU COVID-19 patients than in healthy controls. Impaired fibrinolysis was present at all time points. TAT complex and F1 + 2 levels were significantly higher in patients developing thrombosis (n = 16) than in those without. In conclusion, only few previous studies employed dynamic hemostasis assays in COVID-19 ICU-patients and failed to reveal a clear association with development of thrombosis. In ICU COVID-19 patients, we confirmed normal platelet aggregation, while in vivo thrombin generation was increased and fibrinolysis decreased. Thrombosis may be driven by increased thrombin formation in vivo.

Biotin interference in routine IDS-iSYS immunoassays for aldosterone, renin, insulin-like growth factor 1, growth hormone and bone alkaline phosphatase.

Biotin is increasingly used as dietary supplement. As many immunoassays rely on a binding between biotin and streptavidin, intake of biotin may interfere with laboratory tests, leading to spurious test results. We examined the extent to which levels of aldosterone, renin, insulin-like growth factor 1 (IGF-1), growth hormone (GH) and bone alkaline phosphatase (BAP) were affected by biotin. In an experimental study performed at Aarhus University Hospital, Denmark, patient samples (plasma or serum) were pooled and spiked with biotin in increasing concentrations (0, 20, 50, 100 and 500 ng/mL). All biomarkers were analyzed using Immunodiagnostic Systems (IDS-iSYS) Multi-Discipline Automated System assays. The average bias (%) was calculated, as the difference in concentrations between the sample without biotin (reference) and the samples with increasing concentrations of biotin. Both aldosterone and renin assays showed substantial biotin interference in a dose-dependent manner, with biases up to +3484% for aldosterone and -98% for renin in the highest concentrations of biotin (100-500 ng/mL). IGF-1, GH and BAP results were generally less affected by added biotin and significant bias (>10%) was observed only when the biotin concentration was 100 ng/mL (IGF-1 and GH) or 500 ng/mL (BAP). In conclusion, biotin interfered with the IDS-iSYS immunoassays, particularly for aldosterone and renin. The assays for GH, IGF-1 and BAP were less sensitive and only with high concentrations of biotin.

Disseminated intravascular coagulation diagnosis: Positive predictive value of the ISTH score in a Danish population.

BACKGROUND: The diagnostic accuracy of the ISTH's disseminated intravascular coagulation (DIC) score remains to be investigated in contemporary patient populations. OBJECTIVE: To examine the positive predictive value (PPV) of an ISTH DIC score ≥5 for identifying patients with overt DIC in a Danish hospital laboratory information system database. MATERIALS AND METHODS: A population-based cross-sectional validation study in the Central Denmark Region (2015-2018). Patients with a DIC score ≥5 were identified from the hospital laboratory information system database. Only patients with a potential underlying cause of DIC were included in the analyses. Cases were adjudicated by the authors as the gold standard for DIC diagnosis. The diagnosis of overt DIC was assigned on the basis of clinical signs of microthrombosis and/or bleeding and available laboratory records. PPVs with 95% confidence intervals (CIs) were computed. RESULTS: Medical records of 225 patients were included. The overall PPV for overt DIC was 68% (95% CI, 61-74) and for overt + subclinical DIC, 83% (95% CI, 77%-88%) and increased with higher scores from 47% (95% CI, 35-59) for DIC score 5 to 88 (95% CI, 79-94) for DIC score ≥7. PPV was higher among intensive care patients and patient with sepsis, low antithrombin activity, prolonged activated partial thromboplastin time, or high Sequential Organ Failure Assessment score. CONCLUSION: The accuracy of ISTH DIC score ≥5 was moderate for overt DIC but increased with increasing scores and depended on the underlying cause of DIC. This new knowledge provides guidance to physicians and enables DIC research using laboratory-based data.