User-defined outcomes of the Danish cardiovascular screening (DANCAVAS) trial: A post hoc analyses of a population-based, randomised controlled trial.

BACKGROUND: The Danish cardiovascular screening (DANCAVAS) trial, a nationwide trial designed to investigate the impact of cardiovascular screening in men, did not decrease all-cause mortality, an outcome decided by the investigators. However, the target group may have varied preferences. In this study, we aimed to evaluate whether men aged 65 to 74 years requested a CT-based cardiovascular screening examination and to assess its impact on outcomes determined by their preferences. METHODS AND FINDINGS: This is a post hoc study of the randomised DANCAVAS trial. All men 65 to 74 years of age residing in specific areas of Denmark were randomised (1:2) to invitation-to-screening (16,736 men, of which 10,471 underwent screening) or usual-care (29,790 men). The examination included among others a non-contrast CT scan (to assess the coronary artery calcium score and aortic aneurysms). Positive findings prompted preventive treatment with atorvastatin, aspirin, and surveillance/surgical evaluation. The usual-care group remained unaware of the trial and the assignments. The user-defined outcome was based on patient preferences and determined through a survey sent in January 2023 to a random sample of 9,095 men from the target group, with a 68.0% response rate (6,182 respondents). Safety outcomes included severe bleeding and mortality within 30 days after cardiovascular surgery. Analyses were performed on an intention-to-screen basis. Prevention of stroke and myocardial infarction was the primary motivation for participating in the screening examination. After a median follow-up of 6.4 years, 1,800 of 16,736 men (10.8%) in the invited-to-screening group and 3,420 of 29,790 (11.5%) in the usual-care group experienced an event (hazard ratio (HR), 0.93 (95% confidence interval (CI), 0.88 to 0.98; p = 0.010); number needed to invite at 6 years, 148 (95% CI, 80 to 986)). A total of 324 men (1.9%) in the invited-to-screening group and 491 (1.7%) in the usual-care group had an intracranial bleeding (HR, 1.17; 95% CI, 1.02 to 1.35; p = 0.029). Additionally, 994 (5.9%) in the invited-to-screening group and 1,722 (5.8%) in the usual-care group experienced severe gastrointestinal bleeding (HR, 1.02; 95% CI, 0.95 to 1.11; p = 0.583). No differences were found in mortality after cardiovascular surgery. The primary limitation of the study is that exclusive enrolment of men aged 65 to 74 renders the findings non-generalisable to women or men of other age groups. CONCLUSION: In this comprehensive population-based cardiovascular screening and intervention program, we observed a reduction in the user-defined outcome, stroke and myocardial infarction, but entail a small increased risk of intracranial bleeding. TRIAL REGISTRATION: ISRCTN Registry number, ISRCTN12157806 https://www.isrctn.com/ISRCTN12157806.

Association of Antithrombotic Drug Use With Incident Intracerebral Hemorrhage Location.

BACKGROUND AND OBJECTIVES: Few population-based studies have assessed associations between the use of antithrombotic (platelet antiaggregant or anticoagulant) drugs and location-specific risks of spontaneous intracerebral hemorrhage (s-ICH). In this study, we estimated associations between antithrombotic drug use and the risk of lobar vs nonlobar incident s-ICH. METHODS: Using Danish nationwide registries, we identified cases in the Southern Denmark Region of first-ever s-ICH in patients aged 50 years or older between 2009 and 2018. Each verified case was classified as lobar or nonlobar s-ICH and matched to controls in the general population by age, sex, and calendar year. Prior antithrombotic use was ascertained from a nationwide prescription registry. We calculated odds ratios (aORs) for associations between the use of clopidogrel, aspirin, direct oral anticoagulants (DOACs) or vitamin K antagonists (VKA), and lobar and nonlobar ICH in conditional logistic regression analyses that were adjusted for potential confounders. RESULTS: A total of 1,040 cases of lobar (47.9% men, mean age [SD] 75.2 [10.7] years) and 1,263 cases of nonlobar s-ICH (54.2% men, mean age 73.6 [11.4] years) were matched to 41,651 and 50,574 controls, respectively. A stronger association with lobar s-ICH was found for clopidogrel (cases: 7.6%, controls: 3.5%; aOR 3.46 [95% CI 2.45-4.89]) vs aspirin (cases: 22.9%, controls: 20.4%; aOR 2.14 [1.74-2.63; p = 0.019). Corresponding estimates for nonlobar s-ICH were not different between clopidogrel (cases: 5.4%, controls: 3.4%; aOR 2.44 [1.71-3.49]) and aspirin (cases: 20.7%, controls: 19.2%; aOR 1.77 [1.47-2.15]; p = 0.12). VKA use was associated with higher odds of both lobar (cases: 14.3%, controls: 6.1%; aOR 3.66 [2.78-4.80]) and nonlobar (cases: 15.4%, controls: 5.5%; aOR 4.62 [3.67-5.82]) s-ICH. The association of DOAC use with lobar s-ICH (cases: 3.5%, controls: 2.7%; aOR 1.66 [1.02-2.70]) was weaker than that of VKA use (p = 0.006). Corresponding estimates for nonlobar s-ICH were not different between DOACs (cases: 5.1%, controls: 2.4%; aOR 3.44 [2.33-5.08]) and VKAs (p = 0.20). DISCUSSION: Antithrombotics were associated with higher risks of s-ICH, but the strength of the associations varied by s-ICH location and drug, which may reflect differences in the cerebral microangiopathies associated with lobar vs nonlobar hemorrhages and the mechanisms of drug action.

Postmenopausal hormone therapy and cognition in twins.

OBJECTIVE: Mild cognitive impairment may be caused by pathophysiological changes occurring decades prior to symptom development. It has been hypothesised that oestrogen can prevent such changes. We aimed to investigate the association between postmenopausal hormone therapy and cognition in Danish female twins and to examine differences in this association before and after publication of the findings from the Women's Health Initiative study in 2002. STUDY DESIGN: This study includes cognitive assessment of 4510 twins aged 50+ years. Information on hormone therapy was obtained through Danish health registries. The association between current hormone therapy use and cognition was analysed in twins aged 50+ using both cross-sectional, intrapair and longitudinal analysis, adjusting for age, education, social class, and unobserved familial confounding. RESULTS: Cross-sectionally, systemic HT users aged 70+ had a significantly lower cognitive function than non-users, whereas systemic HT users aged 50-69 did not differ from non-users before 2002. Longitudinal data in younger twins aged 50-69 showed a significantly lower cognitive function in systemic HT users after 2002 compared to non-users. Systemic HT users aged 70+ showed that the lower cognitive function was most explicit before 2002, whereas after 2002 the cognitive function was closer to non-users. Twins aged 50-69 who changed from systemic HT to local HT after 2002, or dropped it altogether, performed cognitively better. CONCLUSIONS: Our findings cautiously indicate a change in the association between cognition and hormone therapy use after 2002, which suggests an alteration in the hormone therapy user profile in the wake of the 2002 WHI publication.

Lessons learned from a multi-data source research collaboration: The mirabegron post-authorization safety study program.

BACKGROUND: Many factors contribute to developing and conducting a successful multi-data source, non-interventional, post-authorization safety study (NI-PASS) for submission to multiple health authorities. Such studies are often large undertakings; evaluating and sharing lessons learned can provide useful insights to others considering similar studies. OBJECTIVES: We discuss challenges and key methodological and organizational factors that led to the delivery of a successful post-marketing requirement (PMR)/PASS program investigating the risk of cardiovascular and cancer events among users of mirabegron, an oral medication for the treatment of overactive bladder. RESULTS: We provide context and share learnings, including sections on research program collaboration, scientific transparency, organizational approach, mitigation of uncertainty around potential delays, validity of study outcomes, selection of data sources and optimizing patient numbers, choice of comparator groups and enhancing precision of estimates of associations, potential confounding and generalizability of study findings, and interpretation of results. CONCLUSIONS: This large PMR/PASS program was a long-term commitment from all parties and benefited from an effective coordinating center and extensive scientific interactions across research partners, scientific advisory board, study sponsor, and health authorities, and delivered useful learnings related to the design and organization of multi-data source NI-PASS.

Critical evaluation of cohort study results.

Being able to critically evaluate modern cohort studies is important when being presented with claims based on observational evidence. In this review article, key aspects of the cohort design are presented using an example of a cohort study investigating the association between the use of SGLT2 inhibitors and gout. We describe the active comparator, new user design, modern methods used to address confounding, how to identify the most common sources of bias, and how to interpret study results appropriately.

Critical evaluation of articles on case-control studies.

The case-control design is one of the key designs used in observational research. In this review, we discuss common pitfalls of case-control studies and describe how case-control studies can be critically evaluated. We further assert that a well-conducted case-control study provides the same results, precision, and level of evidence as a corresponding cohort study.

Is the sequence ratio an unbiased estimate of the incidence rate ratio? A simulation study.

PURPOSE: We aimed to evaluate the conditions under which the sequence ratio (SR) obtained from a sequence symmetry analysis is an unbiased estimate of the true incidence rate ratio (IRR). METHODS: We simulated cohorts of 1 million individuals who could initiate an exposure drug and experience a very rare, rare, common, or frequent outcome of interest. The outcome rate among exposed individuals was modified by a true incidence rate ratio of 0.2, 0.5, 1.0, 2.0, and 5.0. We further evaluated scenarios where the outcome was fatal and led to immediate censoring or the outcome reduced the rate of initiation of the exposure drug. RESULTS: We found the SR to be close to unbiased for rare, common, and frequent events, except when the true IRR was 5.0 (mean SR 4.94 and 3.74 for common and frequent events). The SR was slightly biased when the outcome was very rare. When the outcome was potentially fatal, the SR was increasingly biased with an increasing probability of death. Likewise, when the outcome reduced the probability of future exposure, the SR was upwards biased. CONCLUSION: The SR is a biased estimate of the incidence rate ratio, when the true IRR is high, the outcome has a high mortality, or when the outcome reduces the probability of future exposure.

Screening of dermatology drugs for aberrant use-patterns: An application of epidemiologic estimates and measures of inequality in drug use.

AIMS: Dermatology treatments require adherence for safe and effective use. Real-world healthcare databases can reveal drug utilization patterns and uncover inappropriate or unexpected use. This study aimed to analyse dermatology drug utilization patterns using epidemiological and inequality measures, leveraging Danish nationwide registries. It also assessed the feasibility of this method for detecting aberrant drug use. METHODS: We formed a 2019 cohort of all patients treated for skin conditions through Danish healthcare registries. We calculated prevalence, incidence rates and treatment duration for dermatological drugs. Inequality in drug utilization was assessed using Lorenz curves, Gini coefficients and other measures. RESULTS: The study encompassed 1 021 255 patients using 94 dermatology drugs. Most usage aligned with 'expected clinical use', but we detected inequality, with some drugs having high Gini coefficients and disproportionate consumption by the top percentile of users. Notable findings included potential inappropriate antibiotic use, excessive topical corticosteroid use and unexpected drug use duration. CONCLUSIONS: In Denmark, dermatology drugs are used primarily as anticipated, with minimal unexpected patterns. Specific follow-up is required to draw conclusions about inappropriate use. This approach demonstrates broad applicability for screening aberrant drug utilization.

Identifying high-risk medications and error types in Danish patient safety database using disproportionality analysis.

BACKGROUND: Medication error (ME) surveillance in Danish healthcare relies on the mandatory national incident reporting system, the Danish Patient Safety Database (DPSD). Individual case reviews and descriptive statistics with frequency counts are the most often used approaches when analyzing MEs in incident reporting systems, including the DPSD. However, incident reporting systems often generate a large number of reports and may suffer from underreporting; consequently, additional approaches are needed to overcome these challenges. Disproportionality analysis (DPA) is a statistical tool used for signal detection of adverse drug reactions in pharmacovigilance reports, but the evidence for using DPA on ME analysis in safety reporting systems is limited. OBJECTIVES: We aimed to test the feasibility of DPA by analysing harmful MEs reported to DPSD 2014-2018. METHODS: We utilized proportional reporting ratios (PRR) to identify signals of diproportionality. RESULTS: We identified well-known high-risk medicines, including anticoagulants, opioids, insulins, antiepileptic, and antipsychotic drugs, and their association with several ME types and stages in a medication process. CONCLUSION: DPA might be suggested as an additional tool for screening MEs and identifying priority areas for further investigation in safety reporting systems.

Impact of immunosuppressive therapy on SARS-CoV-2 mRNA vaccine effectiveness in patients with immune-mediated inflammatory diseases: a Danish nationwide cohort study.

OBJECTIVE: Patients receiving immunosuppressives have been excluded from trials for SARS-CoV-2 vaccine efficacy. Investigation of immunosuppressants' impact on effectiveness of vaccines, particularly in patients with immune-mediated inflammatory diseases (IMID), is therefore required. DESIGN: We performed a nationwide cohort study to assess the risk of COVID-19 infection in vaccinated patients with IMID exposed to immunosuppressives compared with IMID unexposed to immunosuppressives. Exposure to immunosuppressives in the 120 days before receiving the second SARS-CoV-2 mRNA vaccination was assessed. Patients were followed from date of second vaccination and weighted Cox models were used to estimate the risk of infection associated with immunosuppressives. Secondary outcomes included hospitalisation and death associated with a positive SARS-CoV-2 test. Risk of infection by immunosuppressant drug class was also analysed. SETTING: This study used population-representative data from Danish national health registries in the period from 1 January to 30 November 2021. RESULTS: Overall, 152 440 patients were followed over 19 341 person years. Immunosuppressants were associated with a significantly increased risk of infection across IMID (HR: 1.4, 95% CI 1.2 to 1.5), in inflammatory bowel disease (IBD) (HR: 1.6, 95% CI 1.4 to 1.9) and arthropathy (HR: 1.3, 95% CI 1.1 to 1.4) but not psoriasis (HR: 1.1, 95% CI 0.9 to 1.4). Immunosuppressants were also associated with an increased risk of hospitalisation across IMID (HR: 1.4, 95% CI 1.1 to 2.0), particularly in IBD (HR: 2.1, 95% CI 1.0 to 4.1). No significantly increased risk of death in immunosuppressant exposed patients was identified. Analyses by immunosuppressant drug class showed increased COVID-19 infection and hospitalisation with anti-tumour necrosis factor (TNF), systemic corticosteroid, and rituximab and other immunosuppressants in vaccinated patients with IMID. CONCLUSION: Immunosuppressive therapies reduced effectiveness of mRNA SARS-CoV-2 vaccination against infection and hospitalisation in patients with IMID. Anti-TNF, systemic corticosteroids, and rituximab and other immunosuppressants were particularly associated with these risks.

Risk of Stroke and Myocardial Infarction Among Initiators of Triptans.

Importance: Triptans are contraindicated in patients with ischemic heart disease or previous myocardial infarction, and caution is advised when prescribing these drugs to patients with vascular risk factors. However, controlled observational studies have either shown no association or an apparent lower risk, possibly owing to a channeling of triptans to individuals at low risk of cardiovascular outcomes, and it remains unclear whether avoiding triptan treatment for these patients is meaningful. Objective: To establish whether an association between triptans and ischemic events could be demonstrated using a self-controlled design because this type of design is robust to the previously mentioned type of confounding. Design, Setting, and Participants: All people in nationwide Danish registries who were initiating triptans and all the ischemic events that they experienced were identified. A case-crossover design was used to estimate odds ratios (OR) for associations between first-ever triptan use and ischemic outcomes, comparing triptan exposure in the 2-week period up to the event with four 2-week reference periods. Data were obtained for the period January 1995 to August 2022. Included from the population of Denmark were individuals redeeming a prescription for any triptan and experiencing at least 1 of 3 predefined ischemic outcomes. No one was excluded. Exposure: Initiation of any triptan. Main Outcomes and Measures: Acute myocardial infarction, ischemic stroke, or nonspecified stroke. Results: Identified were a total of 429 612 individuals (median [IQR] age, 38 [28-48] years; 325 687 female [75.8%]) who redeemed a first prescription for a triptan in the study period. Of these patients, 11 (0.003%) had a myocardial infarction with the first triptan prescription in either a focal or referent window (odds ratio [OR], 3.3; 95% CI, 1.0-10.9), 18 (0.004%) had ischemic stroke (OR, 3.2; 95% CI, 1.3-8.1), and 35 (0.008%) had ischemic/nonspecified stroke (OR, 3.0; 95% CI, 1.5-5.9). Case patients had a median age of approximately 60 years and had a high-risk cardiovascular profile. Conclusions and Relevance: Results of this case-crossover study suggest that triptan initiation was associated with higher risk of ischemic stroke and myocardial infarction. For the individual patient with low background cardiovascular risk, the risk of an ischemic event after triptan initiation was very low.

Use of molnupiravir: A Danish nationwide drug utilization study.

PURPOSE: To describe utilization patterns, characteristics of users and prescribers of the new oral antiviral medication, molnupiravir, indicated for mild-to-moderate COVID-19. METHODS: Using nationwide registries, we identified all Danish adults who filled a prescription for molnupiravir from December 16th, 2021, to August 31st, 2022. We described weekly incidence rates and patient characteristics over time, prescriber characteristics as well as time between molnupiravir initiation and a positive SARs-CoV-2 test. Patient characteristics were compared to matched, untreated SARS-CoV-2 positive reference groups. RESULTS: By August 31st, 2022, 5847 individuals had filled a prescription for molnupiravir. The incidence rate gradually increased to 16 weekly prescriptions per 1000 RT-PCR SARS-CoV-2 positives. Users of molnupiravir were most often men (55% vs. 45% women). The majority (81%) had a positive RT-PCR SARS-CoV-2 test and few (2.9%) redeemed molnupiravir outside the recommended window of 5 days from the positive test result. Compared to matched, untreated SARS-CoV-2 positive reference groups, users of molnupiravir had a median age of 74 years versus 49 years, a higher proportion resided in a nursing home (12% vs. 1.5%) and had a higher number of comorbidities (median of 3 vs. 0); most commonly hypertension (38%), chronic lung disease (35%), diabetes (20%) and mood disorders (20%). General practitioners were the primary prescribers of molnupiravir (91%). CONCLUSIONS: Molnupiravir was mainly prescribed by general practitioners to RT-PCR SARS-CoV-2 positive individuals who had a potentially increased risk of severe COVID-19. Though some off-label prescribing occurred, our study indicates a high level of adherence to contemporary guidelines.

A case for screening real-world data for collateral drug benefits: Glucagon-like peptide 1 receptor agonists and bile acid diarrhea.

PURPOSE: Collateral drug benefits are hitherto unknown beneficial effects that might lead to repurposing of already marketed drugs. A randomized controlled trial has found liraglutide to be non-inferior to colesevelam in reducing bile acid diarrhea. We hypothesized that this collateral drug benefit of liraglutide could have been detected using observational data. METHODS: We performed a sequence symmetry analysis (SSA). In the SSA, we indexed individuals on the date of the first prescription of GLP1-RA and restricted the analysis to all individuals who had a first prescription of bile acid sequestrants between 365 days prior to until 365 days after the index date. Sequence ratios (SR), that is, the ratio between counts of persons initiating GLP1-RA first versus last, were calculated, and 95% confidence intervals were obtained. We adjusted for prescribing trends using null-effect SR adjustment. RESULTS: We included 158 individuals, with a median age of 58 years. The trend-adjusted SR was 0.96 (95% confidence interval 0.70-1.31). When stratifying on the type of GLP1-RA (liraglutide or semaglutide), we found results compatible with the previous trial (SRliraglutide 0.75, 0.51-1.10 and SRsemagltuide 1.23, 0.80-1.89). Since BAS also can be used as a cholesterol lowering drug, we repeated the main analysis while excluded statin users, resulting in a stronger association (SR 0.56, 0.33-0.96). CONCLUSION: Using the SSA methodology, we obtained estimates of a collateral drug benefit that were compatible with trial results. These results support the use of epidemiological analyses of observational data as instrument for detecting collateral drug benefits.

Application of the waiting time distribution in a nationwide screening of real-world dermatology drug utilization for aberrant use patterns.

BACKGROUND: Inappropriate use of medicines may have critical consequences from individual, public health, and economic perspectives. Discovering wrongful medicine use may require intentional surveillance or screening. OBJECTIVES: The objectives of this study were to: (i) apply and evaluate the waiting time distribution (WTD) method as a screening tool for identifying aberrant drug use and (ii) evaluate the nationwide use of Dermatology drugs in Denmark for signals of aberrant drug use. METHOD: Dermatology drug use data from the Danish nationwide healthcare registries from 2018 to 2020 were used to produce WTDs that were analyzed for drug use patterns. The method provides estimates of the prevalence and incidence and enables estimation of mean treatment duration, drug relapse, and unexpected drug prescribing. RESULTS: The study included 2 027 889 individual drug users and analyzed 6 141 449 prescriptions. The analysis included approximately 100 dermatology drugs and drug categories and produced 56 WTD drug curves. The WTD patterns and epidemiological estimates confirmed that most drugs are used as intended and revealed few unexpected patterns for further investigation. Three unexpected findings were identified concerning (i) short-term use that would entail suboptimal clinical efficiency for minoxidil, (ii) sub-optimal use of topical tacrolimus, and (iii) potential undesirable increase in short-course doxycycline treatments. CONCLUSION: In Denmark, dermatology drugs are predominantly used as expected, with few unexpected use patterns identified. Targeted specific follow-up on the identified signals is necessary for conclusions about inappropriate use. The findings suggest that the WTD method is applicable for screening for aberrant drug use.

Mortality and clinical outcomes following SARS-CoV-2 infection among individuals with haematological malignancies: A Danish population-based cohort study.

OBJECTIVES: We aimed to quantify the risk of death following a positive test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among individuals with haematological malignancies, stratified by virus variants and type of malignancy. METHODS: Using the Danish nationwide registries, we conducted a population-based cohort study among individuals who received a discharge diagnosis of haematological malignancies during the 5 years prior to testing positive for SARS-CoV-2 (February 2020-April 2023). All individuals were followed for 30 days after a positive test, and overall and time-stratified case fatality risks (CFR) were estimated. RESULTS: We identified 7154 individuals with a history of haematological malignancies who tested positive for SARS-CoV-2. Among these, we observed 223 deaths, yielding a CFR of 3.1%. The CFR was highest at the beginning of the pandemic (10%) and gradually declined to 1.9% during the period of Omicron BA1/BA2 predominance. The highest CFR was observed among individuals with acute leukaemia (CFR 6.2%, adjusted relative risk 1.95, 95% confidence interval 1.33-2.88) compared to individuals with lymphoma (CFR 3%). CONCLUSIONS: We observed a reduction in the CFR over time, which may be attributed to new treatments, COVID-19 vaccination and the emergence of less aggressive variants.

Effect of single versus multiple prophylactic antibiotic doses on prosthetic joint infections following primary total hip arthroplasty in patients with osteoarthritis at public and private hospitals in Denmark: protocol for a nationwide cross-over, cluster randomised, non-inferiority trial [The Pro-Hip-Quality Trial].

INTRODUCTION: A feared complication after total hip arthroplasty (THA) is prosthetic joint infection (PJI), associated with high morbidity and mortality. Prophylactic antibiotics can reduce the risk of PJI. However, there is no consensus on the dosages and current recommendations are based on a low evidence level. The objective is to compare the effect of a single versus multiple doses of prophylactic antibiotics administered within 24 hours on PJI. METHODS AND ANALYSIS: The study is designed as a cross-over, cluster randomised, non-inferiority trial. All clinical centres use both antibiotic practices (1 year of each intervention). All Danish orthopaedic surgery departments will be involved: Based on quality databases, 2-year cohorts of approximately 20 000 primary THAs conducted at 39 public and private hospitals, will be included. INCLUSION CRITERIA: age ≥18 years, all indications for THA except patients operated due to acute or sequelae from proximal femoral or pelvic fractures or bone tumour or metastasis. The primary outcome is PJI within 90 days after primary THA. Secondary outcomes include (1) serious adverse events, (2) potential PJI, (3) length of hospitalisation stay, (4) cardiovascular events, (5) hospital-treated infections, (6) community-based antibiotic use, (7) opioid use and (8) use of acetaminophen and non-steroidal anti-inflammatory drugs. All outcome measures will be extracted from national databases. Analyses will be based on the intention-to-treat population. Non-inferiority will be shown if the upper limit of the two-sided 95% CI for the OR is less than 1.32 for the single dose as compared with multiple doses. The results will establish best practice on antibiotic prophylaxis dosages in the future. ETHICS AND DISSEMINATION: This study has been approved by Committees on Health Research Ethics for The Capital Region of Denmark (21069108) and The Danish Medicines Agency (2021091723). All results will be presented in peer-reviewed medical journals and international conferences. TRIAL REGISTRATION NUMBER: NCT05530551.

Harnessing patient complaints to systematically monitoring healthcare concerns through disproportionality analysis.

Staff observations are the most common source of data for driving improvements in care. However, the patient perspective should also be considered, and healthcare complaints offer concrete details that health organizations might otherwise overlook and that can highlight areas for learning and improvement in the healthcare system. However, because of the diverse nature of patient complaints, systematic analyses can be challenging. This study aimed to identify and prioritize areas for improvement using a data-driven approach to analysing patient complaints. The Danish version of the Healthcare Complaints Analysis Tool was used to categorize the content of complaint letters. All complaints managed by the national complaints authority, compensation claims to the Patient Compensation Association, and locally managed complaints that were filed directly at Odense University Hospital from 2017 to 2021 were included. Proportional reporting ratios (PRRs) were used to measure and display the top five signals of disproportionality and rank them by excess complaints at the hospital level and when divided into department types. The study included 6366 complaints containing 13 156 problems (on average, 2.1 problems mentioned per complaint letter). Surgical departments had the highest number of complaints (3818), followed by medical (1059), service (439), and emergency departments (239). Signal 1 of disproportionality, relating to quality problems during ward procedures, had the highest excess reporting of 1043 complaints at the hospital level and a PRR of 1.61 and was present in all department types. Signal 2, relating to safety problems during the examination and diagnosis stage, had an excess reporting of 699 problems and a PRR of 1.86 and was also present in all department types. Signal 3, relating to institutional problems during admission, had the highest PRR of 3.54 and was found in most department types. Signals 4 and 5, relating to environmental problems during ward procedures and care on the ward, respectively, had PRRs of 1.5 and 1.84 and were present in most department types. The study found that analysing patient complaints can identify potential areas for hospital improvement. The study identified recurring issues in multiple departments, including quality problems during ward procedures, safety problems during the examination, institutional problems during admission, and environmental problems on the ward. The study highlights disproportionality analysis of complaints as a valuable tool to monitor patient concerns systematically.

Association of Statin Use With Risk of Stroke Recurrence After Intracerebral Hemorrhage.

BACKGROUND AND OBJECTIVES: Survivors of spontaneous intracerebral hemorrhage (ICH) may have indications for statin therapy. The effect of statins on the risk of subsequent hemorrhagic and ischemic stroke (IS) in this setting is uncertain. We sought to determine the risk of any stroke (ischemic stroke, IS or recurrent ICH), IS, and recurrent ICH associated with statin use among ICH survivors. METHODS: Using the Danish Stroke Registry, we identified all patients admitted to a hospital in Denmark (population 5.8 million) with a first-ever ICH between January 2003 and December 2021 who were aged 50 years or older and survived >30 days. Patients were followed up until August 2022. Within this cohort, we conducted 3 nested case-control analyses for any stroke, IS, and recurrent ICH. We matched controls for age, sex, time since first-ever ICH, and history of prior IS. The primary exposure was statin use before or on the date of subsequent stroke or the equivalent date in matched controls. Using conditional logistic regression, we calculated adjusted odds ratios (aORs) and corresponding 95% confidence intervals (CIs) for any stroke, IS, and recurrent ICH associated with statin exposure. RESULTS: We identified 1,959 patients with any stroke (women 45.3%; mean [SD] age, 72.6 [9.7] years) who were matched to 7,400 controls; 1,073 patients with IS (women 42.0%; mean [SD] age, 72.4 [10.0] years) who were matched to 4,035 controls and 984 patients with recurrent ICH (women 48.7%; mean [SD] age, 72.7 [9.2] years) who were matched to 3,755 controls. Statin exposure was associated with a lower risk of both any stroke (cases 38.6%, controls 41.1%; aOR 0.88; 95% CI 0.78-0.99) and IS (cases 39.8%, controls 41.8%, aOR 0.79; 95% CI 0.67-0.92), but was not associated with recurrent ICH risk (cases 39.1%, controls 40.8%, aOR 1.05; 95% CI 0.88-1.24). DISCUSSION: Exposure to statins was not associated with an increased risk of recurrent ICH but was associated with a lower risk of any stroke, largely due to a lower risk of IS. Confirmation of these findings in randomized trials is needed. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that statin use in patients with ICH is associated with a lower risk of any stroke and IS and not with increased risk of recurrent ICH.

Comparative effectiveness of heterologous third dose vaccine schedules against severe covid-19 during omicron predominance in Nordic countries: population based cohort analyses.

OBJECTIVE: To investigate the comparative vaccine effectiveness of heterologous booster schedules (ie, three vaccine doses) compared with primary schedules (two vaccine doses) and with homologous mRNA vaccine booster schedules (three vaccine doses) during a period of omicron predominance. DESIGN: Population based cohort analyses. SETTING: Denmark, Finland, Norway, and Sweden, 27 December 2020 to 31 December 2022. PARTICIPANTS: All adults aged ≥18 years who had received at least a primary vaccination schedule of AZD1222 (Oxford-AstraZeneca) or monovalent SARS-CoV-2 wild type (ancestral) strain based mRNA vaccines BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna), in any combination. MAIN OUTCOME MEASURES: The main outcome measure was country combined risks of covid-19 related hospital admission and death with covid-19 and additional outcomes of covid-19 related admission to an intensive care unit and SARS-CoV-2 infection. During a period of omicron predominance, these outcomes were compared in those who received a heterologous booster versus primary schedule (matched analyses) and versus those who received a homologous mRNA vaccine booster (weighted analyses). Follow-up was for 75 days from day 14 after the booster dose; comparative vaccine effectiveness was calculated as 1-risk ratio. RESULTS: Across the four Nordic countries, 1 086 418 participants had received a heterologous booster schedule of AZD1222+BNT162b2 or mRNA-1273 and 2 505 093 had received a heterologous booster schedule of BNT162b2+mRNA-1273. Compared with the primary schedule only (two doses), the vaccine effectiveness of heterologous booster schedules comprising AZD1222+BNT162b2 or mRNA-1273 and BNT162b2+mRNA-1273 was 82.7% (95% confidence interval 77.1% to 88.2%) and 81.5% (78.9% to 84.2%) for covid-19 related hospital admission and 95.9% (91.6% to 100.0%) and 87.5% (82.5% to 92.6%) for death with covid-19, respectively. Homologous mRNA booster schedules were similarly associated with increased protection against covid-19 related hospital admission (≥76.5%) and death with covid-19 (≥84.1%) compared with previous primary course vaccination only. When a heterologous booster schedule was compared with the homologous booster schedule, vaccine effectiveness was 27.2% (3.7% to 50.6%) for AZD1222+BNT162b2 or mRNA-1273 and 23.3% (15.8% to 30.8%) for BNT162b2+mRNA-1273 schedules against covid-19 related hospital admission and 21.7% (-8.3% to 51.7%) and 18.4% (-15.7% to 52.5%) against death with covid-19, respectively. CONCLUSION: Heterologous booster schedules are associated with increased protection against severe, omicron related covid-19 outcomes compared with primary course schedules and homologous booster schedules.