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Annemarie Voss,1 Bianca Kollhorst,2 Katharina Platzbecker,1 Ute Amann,1 Ulrike Haug1,3 1Department of Clinical Epidemiology, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany; 2Department of Biometry and Data Management, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany; 3Faculty of Human and Health Sciences, University of Bremen, Bremen, GermanyCorrespondence: Ulrike Haug, Department of Clinical Epidemiology, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany, Tel +49 421 218 56862, Email haug@leibniz-bips.dePurpose: Over the last decade, the use of direct oral anticoagulants (DOACs) has strongly increased. We aimed to describe and compare risk profiles including potential changes over time among persons with non-valvular atrial fibrillation initiating treatment with different DOACs or phenprocoumon (vitamin K antagonist) between 2011 and 2019 in Germany.Patients and Methods: Using the German Pharmacoepidemiological Research Database (GePaRD; claims data of ~20% of the German population), we identified persons with a first dispensing of phenprocoumon or a DOAC and a diagnosis of non-valvular atrial fibrillation between August 2011 and December 2019. We described the morbidity of included patients prior to treatment initiation, stratified by year of treatment initiation.Results: Overall, we included 448,028 new users (phenprocoumon: N = 118,117, rivaroxaban: N = 130,997, apixaban: N = 130,300, edoxaban: N = 38,128, dabigatran: N = 30,486). Comparing new DOAC users in 2019, the proportion with prior ischemic stroke was highest for dabigatran (17%) and lowest for rivaroxaban (8%). The proportion with prior major bleeding was also highest for dabigatran (25%) and lowest for edoxaban (20%). New users of apixaban were oldest and, eg, showed the highest prevalence of congestive heart failure. Changes over time were most pronounced for phenprocoumon. For example, among persons initiating phenprocoumon in 2012 vs 2019, the proportion with prior major bleeding increased from 18% to 35%; the proportion with renal disease increased from 20% to 36% and the proportion with liver disease from 18% to 24%.Conclusion: This study demonstrated differences in risk profiles between new users of different oral anticoagulants and substantial changes over time among new phenprocoumon users. These differences have to be considered in head-to-head comparisons of these drugs based on observational data, especially regarding potential unmeasured confounding.Keywords: atrial fibrillation, oral anticoagulants, direct oral anticoagulants, DOACs, risk profiles

Katharina Platzbecker,1 Annemarie Voss,1 Jonas Reinold,1 Anne Elbrecht,2 Wolfgang Biewener,2 Daniel Prieto-Alhambra,3,4 Annika M Jödicke,3 Tania Schink1 1Department of Clinical Epidemiology, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany; 2Department of Epidemiological Methods and Etiological Research, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany; 3Pharmaco- and Device Epidemiology, Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK; 4Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, NetherlandsCorrespondence: Tania Schink, Department of Clinical Epidemiology, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Achterstrasse 30, Bremen, 28359, Germany, Tel +4942121856865, Email schink@leibniz-bips.dePurpose: Validation of outcomes allows measurement of and correction for potential misclassification and targeted adjustment of algorithms for case definition. The purpose of our study was to validate algorithms for identifying cases of acute myocardial infarction (AMI), stroke, and cardiovascular (CV) death using patient profiles, ie, chronological tabular summaries of relevant available information on a patient, extracted from pseudonymized German claims data.Patients and Methods: Based on the German Pharmacoepidemiological Research Database (GePaRD), 250 cases were randomly selected (50% males) for each outcome between 2016 and 2017 based on the inclusion criteria age ≥ 50 years and continuous insurance ≥ 1 year and applying the following algorithms: hospitalization with a main diagnosis of AMI (ICD-10-GM codes I21.- and I22.-) or stroke (I63, I61, I64) or death with a hospitalization in the 60 days before with a main diagnosis of CV disease. Patient profiles were built including (i) age and sex, (ii) hospitalizations incl. diagnoses, procedures, discharge reasons, (iii) outpatient diagnoses incl. diagnostic certainty, physician specialty, (iv) outpatient encounters, and (v) outpatient dispensings. Using adjudication criteria based on clinical guidelines and risk factors, two trained physicians independently classified cases as “certain”, “probable”, “unlikely” or “not assessable”. Positive predictive values (PPVs) were calculated as percentage of confirmed cases among all assessable cases.Results: For AMI, the overall PPV was 97.6% [95% confidence interval 94.8– 99.1]. The PPV for any stroke was 94.8% [91.3– 97.2] and higher for ischemic (98.3% [95.0– 99.6]) than for hemorrhagic stroke (86.5% [76.5– 93.3]). The PPV for CV death was 79.9% [74.4– 84.4]. It increased to 91.7% [87.2– 95.0] after excluding 32 cases with data insufficient for a decision.Conclusion: Algorithms based on hospital diagnoses can identify AMI, stroke, and CV death from German claims data with high PPV. This was the first study to show that German claims data contain information suitable for outcome validation.Keywords: claims data, algorithm validation, patient profiles, positive predictive value

Background: Exposure to isotretinoin during pregnancy must be avoided due to its teratogenicity, but real-world data on its use are scarce. We aimed to describe (i) isotretinoin use in women of childbearing age in Germany; (ii) the occurrence of isotretinoin-exposed pregnancies; and (iii) malformations among children exposed in utero., Methods and Findings: Using observational data from the German Pharmacoepidemiological Research Database (GePaRD, claims data from approximately 20% of the German population), we conducted annual cross-sectional analyses to determine age-standardized prevalence of isotretinoin use between 2004 and 2019 among girls and women aged 13 to 49 years. In cohort analyses, we estimated the number of exposed pregnancies by assessing whether there was prescription supply overlapping the beginning of pregnancy (estimated supply was varied in sensitivity analyses) or a dispensation within the first 8 weeks of pregnancy. Data of live-born children classified as exposed in a critical period according to these criteria were reviewed to assess the presence of congenital malformations. The age-standardized prevalence of isotretinoin use per 1,000 girls and women increased from 1.20 (95% confidence interval [CI]: 1.16, 1.24) in 2004 to 1.96 (95% CI: 1.92, 2.01) in 2019. In the base case analysis, we identified 178 pregnancies exposed to isotretinoin, with the number per year doubling during the study period, and at least 45% of exposed pregnancies ended in an induced abortion. In sensitivity analyses, the number of exposed pregnancies ranged between 172 and 375. Among live-born children, 6 had major congenital malformations. The main limitation of this study was the lack of information on the prescribed dose, i.e., the supply had to be estimated based on the dispensed amount of isotretinoin., Conclusions: Isotretinoin use among girls and women of childbearing age increased in Germany between 2004 and 2019, and there was a considerable number of pregnancies likely exposed to isotretinoin in a critical period. This highlights the importance of monitoring compliance with the existing risk minimization measures for isotretinoin in Germany., Competing Interests: The authors have declared that no competing interests exist. JR, NW, KP, BK, and UH are working at an independent, non-profit research institute, the Leibniz Institute for Prevention Research and Epidemiology – BIPS. Unrelated to this study, BIPS occasionally conducts studies financed by the pharmaceutical industry. These are post-authorization safety studies (PASS) requested by health authorities. The design and conduct of these studies as well as the interpretation and publication are not influenced by the pharmaceutical industry. The study presented was not funded by the pharmaceutical industry., (Copyright: © 2024 Reinold et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims: Atrial fibrillation (AF) is a risk factor for brain infarction, which can lead to epilepsy. We aimed to investigate whether treatment of AF with direct oral anticoagulants (DOACs) affects the risk of epilepsy in comparison to treatment with the vitamin K antagonist phenprocoumon (PPC)., Methods and Results: We performed an active comparator, nested case-control study based on the German Pharmacoepidemiological Research Database that includes claims data from statutory health insurance providers of about 25 million persons since 2004. In 2011-17, 227 707 AF patients initiated treatment with a DOAC or PPC, of which 1828 cases developed epilepsy on current treatment with an oral anticoagulant. They were matched to 19 084 controls without epilepsy. Patients with DOAC treatment for AF had an overall higher risk of epilepsy with an odds ratio of 1.39, 95% CI (1.24; 1.55) compared to current PPC treatment. Cases had higher baseline CHA2DS2-VASc scores and more frequently a history of stroke than controls. After excluding patients with ischaemic stroke prior to the diagnosis of epilepsy, the risk of epilepsy was still higher on DOACs than on PPC. In contrast, within a cohort of patients with venous thromboembolism, the risk of epilepsy on treatment with DOACs was less elevated [adjusted odds ratio 1.15, 95% CI (0.98; 1.34)]., Conclusion: In patients with AF initiating oral anticoagulation, treatment with a DOAC was associated with an increased risk of epilepsy compared to the vitamin K antagonist PPC. Covert brain infarction may explain the observed elevated risk of epilepsy., Competing Interests: Conflict of interest: The funder of the study, Federal Joint Committee in Germany, had no influence on the design and conduct of the study, the interpretation of the data, or the decision to publish. K.P., R.F., A.V., I.P., and T.S. are working at an independent, non-profit research institute, the Leibniz Institute for Prevention Research and Epidemiology—BIPS. Unrelated to this study, BIPS occasionally conducts studies financed by the pharmaceutical industry. Almost exclusively, these are post-authorization safety studies requested by health authorities. The design and conduct of these studies as well as the interpretation and publication are not influenced by the pharmaceutical industry. No financial relationships with any organizations that might have an interest in the submitted work in the previous three years; No other relationships or activities that could appear to have influenced the submitted work., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: There is an under-recognised patient cohort at elevated risk of postoperative ischaemic stroke. We aimed to develop and validate a prognostic model for the identification of such patients at high risk of ischaemic stroke within 1 yr after noncardiac surgery., Methods: This was a hospital registry study of adult patients undergoing noncardiac surgery between 2005 and 2017 at two independent healthcare networks in Massachusetts, USA without a preoperative indication for therapeutic anticoagulation. Logistic regression was used to fit a model from a priori defined candidate predictors for the outcome 1 yr postoperative ischaemic stroke. To enhance clinical applicability, the model was simplified to a scoring system and externally validated., Results: In the development (n=107 756) and validation (n=141 724) cohorts, 1.4% and 0.5% of patients had an ischaemic stroke up to 1 yr postoperatively. The final model included 13 variables (patient characteristics, comorbidities, procedural factors), considering sub-models conditional on a previous history of ischaemic stroke. Areas under the curve were 0.89 (95% confidence interval 0.89-0.90) and 0.88 (95% confidence interval 0.86-0.89) in the development and validation cohorts. Decision curve analysis indicated positive net benefits superior to other prediction instruments., Conclusions: Stroke after surgery (STRAS) screening can reliably identify patients with a high risk for ischaemic stroke during the first year after surgery. A STRAS-guided risk stratification may inform the recruitment to future randomised trials testing the efficacy of treatments for the prevention of postoperative ischaemic stroke., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Adverse discharge disposition, which is discharge to a long-term nursing home or skilled nursing facility is frequent and devastating in older patients after lower-extremity orthopaedic surgery. Predicting individual patient risk allows for preventive interventions to address modifiable risk factors and helps managing expectations. Despite a variety of risk prediction tools for perioperative morbidity in older patients, there is no tool available to predict successful recovery of a patient's ability to live independently in this highly vulnerable population., Questions/purposes: In this study, we asked: (1) What factors predict adverse discharge disposition in patients older than 60 years after lower-extremity surgery? (2) Can a prediction instrument incorporating these factors be applied to another patient population with reasonable accuracy? (3) How does the instrument compare with other predictions scores that account for frailty, comorbidities, or procedural risk alone?, Methods: In this retrospective study at two competing New England university hospitals and Level 1 trauma centers with 673 and 1017 beds, respectively; 83% (19,961 of 24,095) of patients 60 years or older undergoing lower-extremity orthopaedic surgery were included. In all, 5% (1316 of 24,095) patients not living at home and 12% (2797 of 24,095) patients with missing data were excluded. All patients were living at home before surgery. The mean age was 72 ± 9 years, 60% (11,981 of 19,961) patients were female, 21% (4155 of 19,961) underwent fracture care, and 34% (6882 of 19,961) underwent elective joint replacements. Candidate predictors were tested in a multivariable logistic regression model for adverse discharge disposition in a development cohort of all 14,123 patients from the first hospital, and then included in a prediction instrument that was validated in all 5838 patients from the second hospital by calculating the area under the receiver operating characteristics curve (ROC-AUC).Thirty-eight percent (5360 of 14,262) of patients in the development cohort and 37% (2184 of 5910) of patients in the validation cohort had adverse discharge disposition. Score performance in predicting adverse discharge disposition was then compared with prediction scores considering frailty (modified Frailty Index-5 or mFI-5), comorbidities (Charlson Comorbidity Index or CCI), and procedural risks (Procedural Severity Scores for Morbidity and Mortality or PSS)., Results: After controlling for potential confounders like BMI, cardiac, renal and pulmonary disease, we found that the most prominent factors were age older than 90 years (10 points), hip or knee surgery (7 or 8 points), fracture management (6 points), dementia (5 points), unmarried status (3 points), federally provided insurance (2 points), and low estimated household income based on ZIP code (1 point). Higher score values indicate a higher risk of adverse discharge disposition. The score comprised 19 variables, including socioeconomic characteristics, surgical management, and comorbidities with a cutoff value of ≥ 23 points. Score performance yielded an ROC-AUC of 0.85 (95% confidence interval 0.84 to 0.85) in the development and 0.72 (95% CI 0.71 to 0.73) in the independent validation cohort, indicating excellent and good discriminative ability. Performance of the instrument in predicting adverse discharge in the validation cohort was superior to the mFI-5, CCI, and PSS (ROC-AUC 0.72 versus 0.58, 0.57, and 0.57, respectively)., Conclusion: The Adverse Discharge in Older Patients after Lower Extremity Surgery (ADELES) score predicts adverse discharge disposition after lower-extremity surgery, reflecting loss of the ability to live independently. Its discriminative ability is better than instruments that consider frailty, comorbidities, or procedural risk alone. The ADELES score identifies modifiable risk factors, including general anesthesia and prolonged preoperative hospitalization, and should be used to streamline patient and family expectation management and improve shared decision making. Future studies need to evaluate the score in community hospitals and in institutions with different rates of adverse discharge disposition and lower income. A non-commercial calculator can be accessed at www.adeles-score.org., Level of Evidence: Level III, diagnostic study., Competing Interests: All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request. Each remaining author certifies that neither he or she, nor any member of his or her immediate family, has funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article., (Copyright © 2020 by the Association of Bone and Joint Surgeons.)

Background Preclinical studies suggest that volatile anesthetics decrease infarct volume and improve the outcome of ischemic stroke. This study aims to determine their effect during noncardiac surgery on postoperative ischemic stroke incidence. Methods and Results This was a retrospective cohort study of surgical patients undergoing general anesthesia at 2 tertiary care centers in Boston, MA, between October 2005 and September 2017. Exclusion criteria comprised brain death, age <18 years, cardiac surgery, and missing covariate data. The exposure was defined as median age-adjusted minimum alveolar concentration of all intraoperative measurements of desflurane, sevoflurane, and isoflurane. The primary outcome was postoperative ischemic stroke within 30 days. Among 314 932 patients, 1957 (0.6%) experienced the primary outcome. Higher doses of volatile anesthetics had a protective effect on postoperative ischemic stroke incidence (adjusted odds ratio per 1 minimum alveolar concentration increase 0.49, 95% CI, 0.40-0.59, P <0.001). In Cox proportional hazards regression, the effect was observed for 17 postoperative days (postoperative day 1: hazard ratio (HR), 0.56; 95% CI, 0.48-0.65; versus day 17: HR, 0.85; 95% CI, 0.74-0.99). Volatile anesthetics were also associated with lower stroke severity: Every 1-unit increase in minimum alveolar concentration was associated with a 0.006-unit decrease in the National Institutes of Health Stroke Scale (95% CI, -0.01 to -0.002, P =0.002). The effects were robust throughout various sensitivity analyses including adjustment for anesthesia providers as random effect. Conclusions Among patients undergoing noncardiac surgery, volatile anesthetics showed a dose-dependent protective effect on the incidence and severity of early postoperative ischemic stroke.

Introduction: Insomnia frequently occurs in patients admitted to an intensive care unit (ICU). Sleep-promoting agents may reduce rapid eye movement sleep and have deliriogenic effects. Suvorexant (Belsomra) is an orexin receptor antagonist with Food and Drug Administration (FDA) approval for the treatment of adult insomnia, which improves sleep onset and maintenance as well as subjective measures of quality of sleep. This trial will evaluate the efficacy of postoperative oral suvorexant treatment on night-time wakefulness after persistent sleep onset as well as the incidence and duration of delirium among adult cardiac surgical patients., Methods and Analysis: In this single-centre, randomised, double-blind, placebo-controlled trial, we will enrol 120 patients, aged 60 years or older, undergoing elective cardiac surgery with planned postoperative admission to the ICU. Participants will be randomised to receive oral suvorexant (20 mg) or placebo one time a day starting the night after extubation. The primary outcome will be wakefulness after persistent sleep onset. The secondary outcome will be total sleep time. Exploratory outcomes will include time to sleep onset, incidence of postoperative in-hospital delirium, number of delirium-free days and subjective sleep quality., Ethics and Dissemination: Ethics approval was obtained through the 'Committee on Clinical Investigations' at Beth Israel Deaconess Medical Center (protocol number 2019P000759). The findings will be published in peer-reviewed journals., Trial Registration Number: This trial has been registered at clinicaltrials.gov on 17 September 2019 (NCT04092894)., Competing Interests: Competing interests: ME also received compensation for serving on the advisory board for Suvorexant in 2018., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We developed and implemented a perioperative guideline for obstructive sleep apnea (OSA), comprising a preoperative screening tool (BOSTN) and clinical management pathways. OSA was suspected with 2 or more of the following: body mass index ≥30 kg/m, observed apnea, loud snoring, daytime tiredness, and neck circumference ≥16.5 inches in women or ≥ 17.5 inches in men. The primary objective of this study was to assess the association between high BOSTN scores and the requirement of invasive mechanical ventilation after surgery., Methods: In this hospital registry study, 169,662 noncardiac surgical cases performed at Beth Israel Deaconess Medical Center (BIDMC), Boston, MA, between May 2008 and September 2017 were analyzed. We assessed the association between a high BOSTN Score (score ≥2) and the primary outcome of requirement of invasive mechanical ventilation within 7 days after surgery using multivariable logistic regression adjusted for patient-specific factors and case-specific surgical and anesthesiological confounders. Patients with a BOSTN Score ≥2 were assumed to have a high likelihood of suffering from OSA. Key secondary outcome was postoperative desaturation, defined as a peripheral oxygen saturation measurement <90% within 10 minutes of extubation., Results: Invasive mechanical ventilation within 7 days of surgery was necessary in 3170 (2.3%) low-risk cases (BOSTN Score <2) and 664 (2.1%) high-risk cases (BOSTN Score ≥2). A score ≥2 was associated with significantly lower odds of requiring postoperative invasive ventilation (adjusted odds ratio [aOR], 0.89; 95% confidence interval [CI], 0.80-0.98; P = .017), but with an increased risk of postextubation desaturation (aOR, 1.34; 99.3% CI, 1.21-1.48; P < .001). Patients with a score ≥2 were hospitalized for an average of 3.71 days after surgery, compared to 4.27 days with a score <2 (adjusted incidence rate ratio [aIRR], 0.87; 99.3% CI, 0.84-0.91; P < .001)., Conclusions: Patients at high risk of OSA required postoperative mechanical ventilation less frequently, had higher odds of postoperative desaturation, and were hospitalized for shorter periods of time.

Aims: Pre-operatively diagnosed patent foramen ovale (PFO) is associated with an increased risk of ischaemic stroke within 30 days after surgery. This study aimed to assess the PFO-attributable ischaemic stroke risk beyond the perioperative period., Methods and Results: This observational study of adult patients without history of stroke undergoing non-cardiac surgery with general anaesthesia examined the association of PFO with ischaemic stroke 1 and 2 years after surgery using multivariable logistic regression. Of the 144 563 patients included, a total of 1642 (1.1%) and 2376 (1.6%) ischaemic strokes occurred within 1 and 2 years after surgery, 54 (4.7%) and 76 (6.6%) among patients with PFO, and 1588 (1.1%) and 2300 (1.6%) among patients without PFO, respectively. The odds of ischaemic stroke within 1 and 2 years after surgery were increased in patients with PFO: adjusted odds ratio (aOR) 2.01, 95% confidence interval (CI) 1.51-2.69; P < 0.001 and aOR 2.10, 95% CI 1.64-2.68; P < 0.001, respectively. Among patients who underwent contrast transoesophageal echocardiography, the frequency of PFO was 27%, and the increased stroke risk in patients with PFO was robust (aOR 3.80, 95% CI 1.76-8.23; P = 0.001 for year 1). The PFO-attributable risk was mitigated by post-operative prescription of combination antithrombotic therapy (odds ratio 0.41, 95% CI 0.22-0.75; P for interaction = 0.004)., Conclusion: Patients with PFO are vulnerable to ischaemic stroke for an extended period of time after surgery. Physicians should consider implementing PFO screening protocols in patients scheduled for major non-cardiac surgery., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)