Search

A framework for analysing incidence in pharmacoepidemiology and drug statistics is suggested using statins as an example. A new case of statin use (first-ever use or recurrence of treatment) can be defined as new on the group (NoG), new on substance whether new on the group or not (NoS), new on substance and new on the group (NoS_and_NoG), new on substance and not new on the group (NoS_not_NoG). MethodIndividual-level dispensations of statins 2006-2019 for 1 017 058 individuals with at least one dispensation 2019 in Sweden. ResultsWith 12-month run-in, corresponding to at least 8 months without treatment, the incidence proportion of NoG was 13.39 new cases per 1000 inhabitants and 8.40 with 10-year run-in. Thus, 37% had first been treated with any statin between 12 months and 10 years before the index date.For atorvastatin, NoS was 10.69, NoS_and_NoG 9.99, and NoS_not_NoG 0.70 per 1000 inhabitants. 0.70 per 1000 inhabitants or 6.6% of new cases of atorvastatin represented a change from another statin during the run-in. ConclusionIt is essential to separate new cases that are new both on the substance and on the group from those that represent a change of therapy during the run-in. Funding Agencies|NEPI Foundation [SE802400-2589]

The definition of a new case is a vital step in incidence studies in both epidemiology and pharmacoepidemiology, although with significant differences in methodology between the fields. We define and apply a framework for two different types of new cases of drug use, first-ever and recurrent, and show how the associated misclassifications related to length of run-in period can be expressed by the positive predictive value (PPV). In the study, we consider individual-level dispensations of statins 2006-2019 for 1,017,058 individuals with at least one dispensation in 2019 in Sweden. The incidence proportion for statins for both sexes of all ages in Sweden 2019 varied from 17.4/1000 with a run-in of 8 months, 9.45/1000 with 5 years and 8.4/1000 with 10 years. The PPV was 49% with 8 months and 89% for 5 years using 10 years as gold standard. We conclude that the interpretation of incidence and thus the selection of an appropriate run-in period, in pharmacoepidemiology, depends on whether first-ever use, recurrent treatment or both together (new cases) is the focus of the research question studied. At least five different misclassifications can be introduced depending on how incidence is defined. Funding Agencies|NEPI foundation [SE802400-2589]

IntroductionSafe and effective pharmacological treatment is of paramount importance for treating severe psoriasis. Brodalumab, a monoclonal antibody against interleukin (IL) 17 receptor A, was granted marketing authorisation in the EU in 2017. The European Medicines Agency requested a postauthorisation safety study of brodalumab to address potential safety issues raised during drug development regarding major adverse cardiovascular events, suicidal conduct, cancer and serious infections.Methods and analysisBRodalumab Assessment of Hazards: A Multinational Safety is a multicentre observational safety study of brodalumab running from 2017 to 2029 using population-based healthcare databases from Denmark, Sweden, Norway, Netherlands, Germany and three different centres in Italy. A distributed database network approach is used, such that only aggregate data are exchanged between sites.Two types of designs are used: a case-time-control design to study acute effects of transient treatment and a variation of the new user active comparator design to study the effects of transient or chronic treatment. As comparators, inhibitors of TNF-α, inhibitors of IL-12 and IL-23, and other inhibitors of cytokine IL-17A are included.In the self-controlled case-time-control design, the risk of developing the outcome of interest during periods of brodalumab use is compared within individuals to the risk in periods without use.In the active comparator cohort design, new users of brodalumab are identified and matched to new users of active comparators. Potential baseline confounders are adjusted for by using propensity score modelling. For outcomes that potentially require large cumulative exposure, an adapted active comparator design has been developed.Ethics and disseminationThe study is approved by relevant authorities in Denmark, Norway, Sweden, the Netherlands, Germany and Italy in line with the relevant legislation at each site. Data confidentiality is secured by the distributed network approach. Results will be published in peer-reviewed journals.Trial registration numberEUPAS30280.

Background In Denmark, the Cancer Patient Pathway for Non-Specific Signs and Symptoms (NSSC-CPP) has been implemented with variations: in some areas, general practitioners (GPs) do the initial diagnostic work-up (GP paradigm); in other areas, patients are referred directly to the hospital (hospital paradigm). There is no evidence to suggest the most beneficial organisation. Therefore, this study aims to compare the occurrence of colon cancer and the risk of non-localised cancer stage between the GP and hospital paradigms.Material and Methods In this registry-based case-control study, we applied multivariable binary logistic regression models to estimate the odds ratios (OR) of colon cancer and non-localised stage associated with the GP paradigm and hospital paradigm. All cases and controls were assigned to a paradigm based on their diagnostic activity (CT scan or CPP) six months before the index date. As not all CT scans in the control group were part of the cancer work-up as a sensitivity analysis, we investigated the impact of varying the fraction of these, which were randomly removed using a bootstrap approach for inference.Results The GP paradigm was more likely to result in a cancer diagnosis than the hospital paradigm; ORs ranged from 1.91–3.15 considering different fractions of CT scans as part of cancer work-up. No difference was found in the cancer stage between the two paradigms; ORs ranged from 1.08–1.10 and were not statistically significant.Conclusion Patients in the GP paradigm were diagnosed with colon cancer more often, but we cannot conclude that the distribution of respectively localised or non-localised extent of disease is different from that of patients in the hospital paradigm. Background In Denmark, the Cancer Patient Pathway for Non-Specific Signs and Symptoms (NSSC-CPP) has been implemented with variations: in some areas, general practitioners (GPs) do the initial diagnostic work-up (GP paradigm); in other areas, patients are referred directly to the hospital (hospital paradigm). There is no evidence to suggest the most beneficial organisation. Therefore, this study aims to compare the occurrence of colon cancer and the risk of non-localised cancer stage between the GP and hospital paradigms.Material and Methods In this registry-based case-control study, we applied multivariable binary logistic regression models to estimate the odds ratios (OR) of colon cancer and non-localised stage associated with the GP paradigm and hospital paradigm. All cases and controls were assigned to a paradigm based on their diagnostic activity (CT scan or CPP) six months before the index date. As not all CT scans in the control group were part of the cancer work-up as a sensitivity analysis, we investigated the impact of varying the fraction of these, which were randomly removed using a bootstrap approach for inference.Results The GP paradigm was more likely to result in a cancer diagnosis than the hospital paradigm; ORs ranged from 1.91-3.15 considering different fractions of CT scans as part of cancer work-up. No difference was found in the cancer stage between the two paradigms; ORs ranged from 1.08-1.10 and were not statistically significant.Conclusion Patients in the GP paradigm were diagnosed with colon cancer more often, but we cannot conclude that the distribution of respectively localised or non-localised extent of disease is different from that of patients in the hospital paradigm.

Introduction Informed decision making is recommended in breast cancer screening. Decision aids with balanced information on harms and benefits are recommended to support informed decision making. However, informed screening decision making may be challenged by overly positive attitudes toward cancer screening. We hypothesized that a substantial proportion of Danish women would want to participate in screening regardless of the presented information. Therefore, we aimed to estimate the prevalence of Danish women wanting to participate in a hypothetical breast cancer screening offering no reduction in breast cancer mortality but potential harms related to unnecessary treatment. Methods In a cross-sectional study, we invited a random sample of 751 women in the nonscreening population aged 44 to 49 y in the Central Denmark Region to an online questionnaire using the official digital mailbox system. The questionnaire included a description of a hypothetical screening and questions about thoughts on breast cancer, health literacy, and questions on the assessment of the hypothetical screening including intended participation, understanding, and belief in information. Data were linked to register data on sociodemographic factors. Results In total, 43.0% (323/751) responded to the questionnaire. Of these, 247 (82.3% [95% confidence interval: 77.5–86.5]) wanted to participate in the hypothetical breast cancer screening (participation group). More than two-thirds in both the participation group and nonparticipation group seemed to understand the presented information. Half of the women who understood the information disbelieved it. Conclusions Exceeding our expectations, a majority of women wanted to participate in a hypothetical screening with potential harms but no reduction in breast cancer mortality. A large proportion understood but disbelieved the screening information. This could indicate that Danish women make their screening decisions based on beliefs rather than presented screening information. This study was registered at ClinicalTrials.gov (Identifier: NCT04509063) Highlights The majority of Danish women wanted to participate in a hypothetical breast cancer screening with potential harms related to unnecessary treatment but no reduction in mortality. A large proportion of women understood but disbelieved the hypothetical screening information. Informed decision making may be challenging when women disbelieve the information they receive. Enthusiasm for cancer screening and potential disbelief in information are important factors when developing and improving screening information and invitation.

Background: Observational studies on corona virus disease 2019 (COVID-19) vaccines compare event rates in vaccinated and unvaccinated person time using Poisson or Cox regression. In Cox regression, the chosen time scale needs to account for the time-varying incidence of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection and COVID-19 vaccination.We aimed to quantify bias in person-time based methods, with and without adjustment for calendar time, using simulations and empirical data analysis. Methods: We simulated 500,000 individuals who were followed for 365 days, and a point exposure resembling COVID-19 vaccination (cumulative incidence 80%). We generated an effectiveness outcome, emulating the incidence of severe acute respiratory syndrome corona virus 2 infection in Denmark during 2021 (risk 10%), and a safety outcome with seasonal variation (myocarditis, risk 1/5,000). Incidence rate ratios (IRRs) were set to 0.1 for effectiveness and 5.0 for safety outcomes. IRRs and hazard ratios (HRs) were estimated using Poisson and Cox regression with a time under observation scale, and a calendar time scale. Bias was defined as estimated IRR or HR−true IRR. Further, we obtained estimates for both outcomes using data from the Danish health registries. Results: Unadjusted IRRs (biaseffectivenes +0.16; biassafety −2.09) and HRs estimated using a time-under-observation scale (+0.28;-2.15) were biased. Adjustment for calendar time reduced bias in Cox (+0.03; +0.33) and Poisson regression (0.00; −0.28). Cox regression using a calendar time scale was least biased (0.00, +0.12). When analyzing empirical data, adjusted Poisson and Cox regression using a calendar time scale yielded estimates in accordance with existing evidence. Conclusion: Lack of adjustment for the time-varying incidence of COVID-19 related outcomes may severely bias estimates.

In November 2013, the Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease was published, recommending statins for all individuals 50 years or older with an estimated glomerular filtration rate below 60 ml/min/1.73 m2 to lower the risk of major cardiovascular events. We quantified the prevalence of statin use among the target population before and after the guideline publication in a large Danish cohort of individuals with an estimated glomerular filtration rate below 60 ml/min/1.73 m2, to investigate the effect of the guideline, but found no difference in the prevalence of statin use prior to and after the guideline publication.

Aims In clinical practice, many patients do not reach the recommended treatment targets for LDL-cholesterol levels. We aimed to examine treatment patterns and adherence for patients on lipid lowering drugs in Norway to inform future strategies to improve therapies. Methods and results We obtained information on all dispensed statins, ezetimibe, and proprotein convertase subtilisin/-kexin 9 (PCSK9) inhibitors 2010–2019 from the Norwegian Prescription Database. Treatment gaps were assessed assuming patients take one tablet per day and were defined to occur if a patient did not refill a prescription when the previous one should have been depleted. Treatment was defined as discontinued when the preceding prescription would have been used and no new subsequent prescription was filled. The mean proportion of days covered (PDC) was calculated by aggregating the total number of tablets dispensed during each calendar year and dividing by 365. Patients 80 years were excluded. A considerable proportion of statin users in Norway had long treatment gaps or discontinuation in treatment. The 19.6% of the patients had treatment gaps of 180 days or more, and 10.8% had gaps or greater than 365 days. Similar results were found for patients on antidiabetics and hypertensives. PDC ranged from 84.9% for simvastatin to 72.2% for ezetimibe (2019). The most common lipid lowering drugs in 2019 were atorvastatin, simvastatin, and ezetimibe. Conclusion There is a great potential for improving drug adherence and optimizing lipid lowering therapy by switching to more effective statins in greater doses, and more often add ezetimibe and PCSK9 inhibitors to treatment.

PURPOSE: In pharmacoepidemiology, correctly defining the exposure period of pharmacological treatment is a challenging step when information on the time in treatment is missing or incomplete.METHODS: In this review, we describe several methods for defining exposure to pharmacological treatments using secondary data sources that lack such information.RESULTS AND CONCLUSION: Several methods for assessing the duration of redeemed prescriptions and combining them into temporal sequences are available. We present a set of considerations to make researchers aware of the potentials and pitfalls of these methods that may aid in minimizing biases in research using these methods. Additionally, we highlight that, to date, there is no one-size-fits-all solution. Thus, the choice of method should be based on their area of applicability combined with a careful mapping to the research scenario under investigation.

AimsThe Danish authorities implemented a differential rollout of the COVID-19 vaccines where individuals at high risk of COVID-19 were prioritized. We describe the temporal uptake of COVID-19 vaccines and changing characteristics of vaccine recipients in Denmark.MethodsUsing the Danish national health care registries, we identified all Danish residents ≥5 years of age who received at least one dose of a COVID-19 vaccine from December 27th, 2020, to January 29th, 2022. We charted the daily number of newly vaccinated individuals and the cumulative vaccine coverage over time, stratified by vaccine type, age groups, and vaccination priority groups. In addition, we described characteristics of vaccine recipients during 2-months-intervals and in vaccination priority groups.ResultsBy January 29th, 2022, 86%, 84% and 63% of Danish residents ≥5 years had received a first, second, and third dose, respectively, of a COVID-19 vaccine, most commonly the BNT162b2 vaccine (84% of vaccinated individuals). Vaccine uptake ranged from 48% in 5-11-year-olds up to 98% in 65-74-year-olds. Individuals vaccinated before June 2021 were older (median age 61-70 years vs. 10-35 years in later periods) and had more comorbidities such as hypertension (22-28% vs. 0.77-2.8% in later periods), chronic lung disease (9.4-15% vs. 3.7-4.6% in later periods), and diabetes (9.3-12% vs. 0.91-2.4% in later periods).ConclusionsThe uptake of the COVID-19 vaccines is high in Denmark. We document substantial changes over time in characteristics of vaccine recipients which should be considered when designing and interpreting studies on the effectiveness and safety of COVID-19 vaccines.

Aim:To investigate the association between women’s health literacy and attendance in the Danish national breast cancer screening programme.Methods:In a population-based cross-sectional study, information on two health literacy subscales, measured using the Health Literacy Questionnaire (HLQ), and sociodemographic factors was obtained from the ‘How are you? 2017’ survey in the Central Denmark Region. Information on screening attendance was obtained from register data from 2016–2017. Data were linked based on individual civil registration numbers. To account for missing data, multiple imputation by chained equations was implemented to fill in missing values on all variables. Unadjusted and adjusted logistic regression analyses were performed separately for two HLQ subscales to estimate odds ratio (OR) of screening attendance. Both multiple imputation analyses and complete case analyses were performed.Results:A total of 6012 women were included in multiple imputed statistical analyses. Generally, women had high health literacy levels. In multiple imputed analyses, the unadjusted OR of the primary HLQ subscale, understanding, was 1.32 (95% confidence interval (CI): 1.10–1.59), indicating higher odds for screening attendance with higher health literacy level. However, after adjustment no significant association between the HLQ subscale of understanding and screening attendance was found (OR 1.09 (95% CI: 0.90–1.33)). Similar results were found for the secondary HLQ subscale of engaging (insignificant association in adjusted analysis). No effect modification from sociodemographic characteristics was found. Similar results were found in complete case analyses.Conclusions:No significant association was found between health literacy and attendance in the Danish breast cancer screening programme. Aim:To investigate the association between women’s health literacy and attendance in the Danish national breast cancer screening programme.Methods:In a population-based cross-sectional study, information on two health literacy subscales, measured using the Health Literacy Questionnaire (HLQ), and sociodemographic factors was obtained from the ‘How are you? 2017’ survey in the Central Denmark Region. Information on screening attendance was obtained from register data from 2016–2017. Data were linked based on individual civil registration numbers. To account for missing data, multiple imputation by chained equations was implemented to fill in missing values on all variables. Unadjusted and adjusted logistic regression analyses were performed separately for two HLQ subscales to estimate odds ratio (OR) of screening attendance. Both multiple imputation analyses and complete case analyses were performed.Results:A total of 6012 women were included in multiple imputed statistical analyses. Generally, women had high health literacy levels. In multiple imputed analyses, the unadjusted OR of the primary HLQ subscale, understanding, was 1.32 (95% confidence interval (CI): 1.10–1.59), indicating higher odds for screening attendance with higher health literacy level. However, after adjustment no significant association between the HLQ subscale of understanding and screening attendance was found (OR 1.09 (95% CI: 0.90–1.33)). Similar results were found for the secondary HLQ subscale of engaging (insignificant association in adjusted analysis). No effect modification from sociodemographic characteristics was found. Similar results were found in complete case analyses.Conclusions:No significant association was found between health literacy and attendance in the Danish breast cancer screening programme.

The E value method deals with unmeasured confounding, a key source of bias in observational studies. The E value method is described and its use is shown in a worked example of a meta-analysis examining the association between the use of antidepressants in pregnancy and the risk of miscarriage.

Purpose: In pharmacoepidemiological studies, the precision of effect estimates usually depends on the lowest number in the underlying two by two table. We denote this the “bottleneck count” (BNC). We describe how to translate the BNC into an achievable precision and provide empirical examples. Methods: First, we derive a theoretical prediction of the precision in a study where only the BNC determines precision. As an illustration, we calculated the expected precision of a null-effect study on retinoids and peptic ulcer bleeding, expressed as the upper/lower confidence limit ratio (ULCLR). Finally, we reviewed 126 effect estimates from the literature, analyzing the relationship between the predicted and achieved precision. Results: The log–log transformed ULCLR was shown to be a simple linear function of log(BNC). The expected annual number of retinoid-users experiencing a peptic ulcer bleeding was 9.8, yielding an estimated ULCLR for a 1-year study of 3.84. The literature review showed an inverse linear relationship between the logarithmic BNC and the log–log transformed ULCLR, which was largely independent of study design, effect measure and category of BNC. Achieved precision deviated little from predictions but was usually lower than predicted, particularly with low BNC. Conclusion: The precision of a study can be predicted simply and with good accuracy from the BNC, which is useful for determining whether a study is worth pursuing or not.

Background Reductions in breast cancer mortality observed over the last three decades are partly due to improved patient management, which may erode the benefit-harm balance of mammography screening. Methods We estimated the numbers of women needed to invite (NNI) to prevent one breast cancer death within 10 years. Four scenarios of screening effectiveness (5–20% mortality reduction) were applied on 10,580 breast cancer deaths among Norwegian women aged 50–75 years from 1986 to 2016. We used three scenarios of overdiagnosis (10–40% excess breast cancers during screening period) for estimating ratios of numbers of overdiagnosed breast cancers for each breast cancer death prevented. Results Under the base case scenario of 20% breast cancer mortality reduction and 20% overdiagnosis, the NNI rose from 731 (95% CI: 644–830) women in 1996 to 1364 (95% CI: 1181–1577) women in 2016, while the number of women with overdiagnosed cancer for each breast cancer death prevented rose from 3.2 in 1996 to 5.4 in 2016. For a mortality reduction of 8.7%, the ratio of overdiagnosed breast cancers per breast cancer death prevented rose from 7.4 in 1996 to 14.0 in 2016. For a mortality reduction of 5%, the ratio rose from 12.8 in 1996 to 25.2 in 2016. Conclusions Due to increasingly potent therapeutic modalities, the benefit in terms of reduced breast cancer mortality declines while the harms, including overdiagnosis, are unaffected. Future improvements in breast cancer patient management will further deteriorate the benefit–harm ratio of screening.

STUDY QUESTIONDo maternal hypertensive disorders affect pubertal development in daughters and sons?SUMMARY ANSWERPubertal development tended to occur earlier in daughters of mothers with ‘preeclampsia, eclampsia or HELLP syndrome’ (hemolysis, elevated liver enzymes and low blood platelets) or hypertension in pregnancy compared to daughters born of normotensive mothers.WHAT IS KNOWN ALREADYThe existing literature suggests some or no association between preeclampsia and pubertal development in daughters, but not in sons. None of the previous studies has investigated the possible association between other types of hypertensive disorders (hypertension, eclampsia or HELLP syndrome) and pubertal timing in children.STUDY DESIGN, SIZE, DURATIONLongitudinal cohort study consisting of 15 819 mother–child pairs with information on maternal hypertensive disorders collected during pregnancy and information on pubertal development collected half-yearly from the age of 11 years and until fully developed or 18 years of age.PARTICIPANTS/MATERIALS, SETTING, METHODSParticipants are children from the Puberty Cohort nested within the Danish National Birth Cohort. The exposure was register-based and self-reported information on maternal hypertensive disorders during pregnancy. The outcomes were children’s self-reported information on pubertal development, including Tanner stage 1–5 (pubic hair (both daughters and sons) and breast development (daughters) or genital development (sons)), first menstrual bleeding (daughters) or first ejaculation (sons), voice break episode (sons), axillary hair development and acne occurrence (both daughters and sons). The main outcome was mean difference in age at attaining each pubertal milestone and a combined pubertal marker in children of mothers with hypertensive disorders in pregnancy (either hypertension (n = 490), ‘preeclampsia, eclampsia or HELLP syndrome’ (n = 419) or ‘unspecific hypertensive disorders’ (n = 334) with unexposed children as reference (n = 14 576)).MAIN RESULTS AND THE ROLE OF CHANCEIn daughters of mothers with ‘preeclampsia, eclampsia or HELLP syndrome’, we observed tendencies of earlier pubertal timing (combined marker: −2.0 (95% CI: −3.9; 0.0) months). In daughters of mothers with hypertension, several pubertal milestones tended to occur earlier than in daughters of normotensive mothers; however, all 95% CIs overlapped the null resulting in a combined pubertal marker of −1.0 (95% CI: −3.2; 1.1) months. In sons of mothers with any of the hypertensive disorders, we observed no difference in pubertal timing (combined markers: ‘preeclampsia, eclampsia or HELLP syndrome’: 0.1 (95% CI: −2.0; 2.1) months; hypertension: −0.6 (95% CI: −2.3; 1.1) months; ‘unspecific hypertensive disorders’: 0.2 (95% CI: −1.9; 2.2) months).LIMITATIONS, REASONS FOR CAUTIONThe study is subject to non-differential misclassification of self-reported information on maternal hypertensive disorders in pregnancy and current pubertal status; possibly causing bias toward the null.WIDER IMPLICATIONS OF THE FINDINGSHypertensive disorders in pregnancy might accelerate pubertal timing in daughters; however, more studies are needed for causal conclusions.STUDY FUNDING/COMPETING INTEREST(S)The study was funded by the Faculty of Health at Aarhus University. The authors have no financial relationships or competing interests to disclose.TRIAL REGISTRATION NUMBERN/A.

Background To facilitate research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a prospective cohort of all Danish residents tested for SARS-CoV-2 in Denmark is established. Data structure All Danish residents tested by reverse transcriptase polymerase chain reactions (RT-PCR) for SARS-CoV-2 in Denmark are included. The cohort is identified using the Danish Microbiology Database. Individual-level record linkage between administrative and health-care registries is facilitated by the Danish Civil Registration System. Information on outcomes related to SARS-CoV-2 infection includes hospital admission, intensive care unit admission, mechanical ventilation, and death and is retrieved from the five administrative Danish regions, the Danish National Patient Registry, and the Danish Register of Causes of Death. The Patient Registry further provides a complete hospital contact history of somatic and psychiatric conditions and procedures. Data on all prescriptions filled at community pharmacies are available from the Danish National Prescription Registry. Health-care authorization status is obtained from the Danish Register of Healthcare Professionals. Finally, selected laboratory values are obtained from the Register of Laboratory Results for Research. The cohort is governed by a steering committee with representatives from the Danish Medicines Agency, Statens Serum Institut, the Danish Health Authority, the Danish Health Data Authority, Danish Patients, the Faculties of Health Sciences at the Danish universities, and Danish regions. The steering committee welcomes suggestions for research studies and collaborations. Research proposals will be prioritized based on timeliness and potential clinical and public health implications. All research protocols assessing specific hypotheses for medicines will be made publicly available using the European Union electronic Register of Post-Authorisation Studies. Conclusion The Danish COVID-19 cohort includes all Danish residents with an RT-PCR test for SARS-CoV-2. Through individual-level linkage with existing Danish health and administrative registries, this is a valuable data source for epidemiological research on SARS-CoV-2.

Attempts to reduce the human immunodeficiency virus type 1 (HIV-1) reservoir and induce antiretroviral therapy (ART)-free virologic control have largely been unsuccessful. In this phase 1b/2a, open-label, randomized controlled trial using a four-group factorial design, we investigated whether early intervention in newly diagnosed people with HIV-1 with a monoclonal anti-HIV-1 antibody with a CD4-binding site, 3BNC117, followed by a histone deacetylase inhibitor, romidepsin, shortly after ART initiation altered the course of HIV-1 infection (NCT03041012). The trial was undertaken in five hospitals in Denmark and two hospitals in the United Kingdom. The coprimary endpoints were analysis of initial virus decay kinetics and changes in the frequency of CD4+ T cells containing intact HIV-1 provirus from baseline to day 365. Secondary endpoints included changes in the frequency of infected CD4+ T cells and virus-specific CD8+ T cell immunity from baseline to day 365, pre-ART plasma HIV-1 3BNC117 sensitivity, safety and tolerability, and time to loss of virologic control during a 12-week analytical ART interruption that started at day 400. In 55 newly diagnosed people (5 females and 50 males) with HIV-1 who received random allocation treatment, we found that early 3BNC117 treatment with or without romidepsin enhanced plasma HIV-1 RNA decay rates compared to ART only. Furthermore, 3BNC117 treatment accelerated clearance of infected cells compared to ART only. All groups had significant reductions in the frequency of CD4+ T cells containing intact HIV-1 provirus. At day 365, early 3BNC117 + romidepsin was associated with enhanced HIV-1 Gag-specific CD8+ T cell immunity compared to ART only. The observed virological and immunological effects of 3BNC117 were most pronounced in individuals whose pre-ART plasma HIV-1 envelope sequences were antibody sensitive. The results were not disaggregated by sex. Adverse events were mild to moderate and similar between the groups. During a 12-week analytical ART interruption among 20 participants, 3BNC117-treated individuals harboring sensitive viruses were significantly more likely to maintain ART-free virologic control than other participants. We conclude that 3BNC117 at ART initiation enhanced elimination of plasma viruses and infected cells, enhanced HIV-1-specific CD8+ immunity and was associated with sustained ART-free virologic control among persons with 3BNC117-sensitive virus. These findings strongly support interventions administered at the time of ART initiation as a strategy to limit long-term HIV-1 persistence. Attempts to reduce the human immunodeficiency virus type 1 (HIV-1) reservoir and induce antiretroviral therapy (ART)-free virologic control have largely been unsuccessful. In this phase 1b/2a, open-label, randomized controlled trial using a four-group factorial design, we investigated whether early intervention in newly diagnosed people with HIV-1 with a monoclonal anti-HIV-1 antibody with a CD4-binding site, 3BNC117, followed by a histone deacetylase inhibitor, romidepsin, shortly after ART initiation altered the course of HIV-1 infection (NCT03041012). The trial was undertaken in five hospitals in Denmark and two hospitals in the United Kingdom. The coprimary endpoints were analysis of initial virus decay kinetics and changes in the frequency of CD4+ T cells containing intact HIV-1 provirus from baseline to day 365. Secondary endpoints included changes in the frequency of infected CD4+ T cells and virus-specific CD8+ T cell immunity from baseline to day 365, pre-ART plasma HIV-1 3BNC117 sensitivity, safety and tolerability, and time to loss of virologic control during a 12-week analytical ART interruption that started at day 400. In 55 newly diagnosed people (5 females and 50 males) with HIV-1 who received random allocation treatment, we found that early 3BNC117 treatment with or without romidepsin enhanced plasma HIV-1 RNA decay rates compared to ART only. Furthermore, 3BNC117 treatment accelerated clearance of infected cells compared to ART only. All groups had significant reductions in the frequency of CD4+ T cells containing intact HIV-1 provirus. At day 365, early 3BNC117 + romidepsin was associated with enhanced HIV-1 Gag-specific CD8+ T cell immunity compared to ART only. The observed virological and immunological effects of 3BNC117 were most pronounced in individuals whose pre-ART plasma HIV-1 envelope sequences were antibody sensitive. The results were not disaggregated by sex. Adverse events were mild to moderate and similar between the groups. During a 12-week analytical ART interruption among 20 participants, 3BNC117-treated individuals harboring sensitive viruses were significantly more likely to maintain ART-free virologic control than other participants. We conclude that 3BNC117 at ART initiation enhanced elimination of plasma viruses and infected cells, enhanced HIV-1-specific CD8+ immunity and was associated with sustained ART-free virologic control among persons with 3BNC117-sensitive virus. These findings strongly support interventions administered at the time of ART initiation as a strategy to limit long-term HIV-1 persistence.

Background: There is ample evidence for several pharmaceutical treatments that adherence in terms of treatment duration and dose is suboptimal. The actual drug intake cannot be observed directly in prescription databases, which only register drug redeemed and a limited number of patient characteristics. Consequently, the actual dose and duration of treatment must be inferred from observed redemptions. Persistence can then be expressed as treatment duration (also referred to as drug survival). Method: We used data from the Norwegian Prescription Database (NorPD) on redemptions of statins (ATC-code C10AA) for the period 2010-2019 to explore three methods for determining prescription durations and in turn persistence (treatment duration): (i) The DDD-method using the number of DDD redeemed; (ii) The dose-unit approach using the number of tablets redeemed; (iii) The reverse waiting time distribution method (WTD), which estimates prescription duration as the 90th percentile of the distribution within which patients in ongoing treatment will have a new subsequent redemption. The three methods for estimating prescription duration were then used to estimate treatment duration using Kaplan Meier (KM) survival functions. For the DDD-method and the dose-unit approach we conducted sensitivity analyses assuming that one DDD or one tablet would last for 1.00, 1.25 or 2.00 days. We also tested the impact of grace periods in sensitivity analyses. Results: Treatment duration and drug survival varied substantially for the same patients depending on the chosen method, duration of a DDD or a tablet, and inclusion of grace periods. The 25th percentile of treatment duration was 100 days for the DDD approach with one DDD per day, 100 days with the dose-unit approach with one tablet per day and 453 days with the WTD approach. Conclusion: When estimating treatment duration from prescription databases one should be aware that these measures of persistence are highly influenced by the chosen methodology. The choice of method should be informed by the clinical context with a preference for use of methods based on a formal model.

Background Case–control studies based on pharmaco-epidemiological databases typically use decision rules to determine exposure status from information on dates of prescription redemptions, although this induces misclassification. The reverse Waiting Time Distribution has been suggested as a likelihood based model to estimate the latent exposure status, and we therefore suggest to extend this into a joint likelihood based model, which incorporates both the latent exposure status and the exposure-outcome association. This will achieve consistency and efficiency of the estimates, i.e. they can be expected to be asymptotically unbiased and have optimal precision. Methods We established a joint likelihood for the observed case–control status and last prescription redemption before the index date. The likelihood combines the ordinary logistic regression likelihood and the reverse Waiting Time Distribution, and allows inclusion of covariates in both parts to adjust for observed confounders. We conducted a simulation study of the new model and standard models based on decision rules for exposure and the probability of being exposed, respectively, to assess the relative bias and variability of estimates. Lastly, we applied the models to a case–control study on use of nonsteroidal anti-inflammatory drugs and risk of upper-gastrointestinal bleeding. Results In simulation studies the new model had low relative bias ( Conclusions Unlike standard methods, the proposed model gave nearly unbiased estimates with adequate coverage probabilities in simulation studies. The developed model demonstrates the potential for the reverse Waiting Time Distribution to be integrated with existing likelihood based analyses in pharmacoepidemiological studies.

Background: The combination of organized cervical cancer screening and childhood HPV vaccination programs has the potential to eliminate cervical cancer in the future. However, only women participating in both programs gain the full protection, and combined non-attenders remain at high risk of developing cervical cancer. Our aim was to analyze the association between non-adherence to HPV vaccination and non-participation in cervical cancer screening for the total population and stratified by native background and parental education. Participants: Women born in 1993 eligible for both childhood HPV vaccination and first cervical cancer screening. Analysis: Logistic regression models were used to estimate the odds ratio (OR) of non-participation in cervical cancer screening with 95% confidence intervals (CI). Stratified and adjusted logistic regression models were used along with the Wald test in order to test for interaction. Results: 24,828 women were included in the study. Among vaccinated women, 61.4% participated in cervical cancer screening; only 39.0% of unvaccinated women participated in cervical cancer screening. Unvaccinated and unscreened women were often non-native and had the lowest socio-economic status, whereas vaccinated and screened women were often native and had the highest socio-economic status. The adjusted OR for non-participation in cervical cancer screening was 2.07 [95% CI: 1.88–2.28] for unvaccinated compared to vaccinated women. After stratifying by country of origin, unvaccinated natives had the highest adjusted OR of not participating in cervical cancer screening compared to non-native women from both western and non-western countries (adjusted ORs of 2.2 [95% CI: 2.0– 2.4], 1.3 [95% CI: 0.6–2.8], and 1.5 [95% CI: 1.1–2.0], respectively) (Wald test p=0.019). Conclusion: Among natives, non-adherence to HPV vaccination and non-participation in screening seem to be signs of generally poor health-preventive behavior, whereas among non-natives from non-western countries, non-attendance in HPV vaccination and cervical cancer screening seem to be influenced by unrelated factors. Therefore, a differentiated and culturally sensitive approach is needed to enhance overall cervical cancer preventive behavior across different nativities.

Purpose Socioeconomic inequality in stroke care occurs even in countries with free access to health care. We aimed to investigate the association between socioeconomic status and guideline-recommended acute care in Denmark during the last decade. Design We conducted a nationwide, population-based study. We used household income, employment status, and education as markers of socioeconomic status and adjusted the results for relevant clinical covariates. We used weighted linear regression models to analyse empirical log odds of performance measure fulfillment at patient level. Setting Public hospitals in Denmark. Participants A total of 110,848 consecutive stroke patients discharged between 2004 and 2014. Interventions Acute stroke care according to clinical guidelines. Main outcome measures Guideline-recommended care was defined in two ways based on clinical performance measures: the percentage of fulfilled measures used throughout the study period (m=8) (model 1) and the percentage of fulfilled measures used at the time of discharge (m=8 to 16) (model 2). Results Compared with high family income, low income was negatively associated with the guideline-recommended care; odds ratios (95% CI) were 0.89 (0.85-0.93) in model 1 and 0.81 (0.77-0.85) in model 2. Low family income was negatively associated with fulfillment of 14 of the 16 performance measures. In general, the percentage of performance measures fulfilled increased over time from 70% (95% CI 63-76) to 85% (95% CI 83-87). Conclusion Socioeconomic inequality in guideline-recommended stroke care remains despite overall improvements in a setting with free access to care and systematic monitoring of health care quality.

BACKGROUND: Gain in mean survival time from new cancer treatments is a core component of cost-effectiveness analyses frequently used by payers for reimbursement decisions. Due to limited follow-up time, clinical trials rarely report this measure, whereas they often report hazard ratios comparing treatment groups.AIM: We aimed to explore the empirical relationship between gain in mean survival time and the hazard ratio for cancer patients.METHODS: We included all patients in Norway diagnosed from 1965 through 2004 with late-stage cancer at the point of diagnosis and with one of the following cancers: stomach, colon, rectal, pancreas, lung and trachea, kidney excluding renal pelvis, and metastasized breast and prostate. Patients were followed until emigration, death, or June 30, 2016, whichever came first. Observed mean survival times and hazard ratios were obtained in subcohorts defined by patients' sex, age, cancer type, and time period of diagnosis, which had nearly complete follow-up. Based on theoretical considerations, we fitted a linear relationship between observed differences in mean survival and logarithmic hazard ratios. For validation, we estimated differences in mean survival from hazard ratios of bootstrap samples with artificially induced censoring and compared with fitting a Weibull distribution.RESULTS: The relationship between differences in mean survival time and corresponding logarithmic hazard ratios was linear for each of the included cancers. The predicted differences in mean survival of the empirical approach generally had smaller bias than the Weibull approach.CONCLUSION: For cancer diagnoses with poor prognosis, differences in mean survival times could be predicted from corresponding hazard ratios. This hazard ratio-based approach outperforms or is similar to fitting Weibull models to data with incomplete follow-up, while making fewer assumptions.

Background Relative reduction in breast cancer mortality is the preferred outcome measure for evaluation of mammography screening. However, mean survival time has been advocated as a better and more intuitive outcome for risk communication. We have previously introduced a method to predict difference in mean survival time from empirical hazard ratios for all-cause mortality. In this article, we aim to investigate the association between hazard ratios for breast cancer mortality and the difference in mean survival time for women diagnosed with breast cancer. Methods We retrieved data on all women diagnosed with first-time invasive breast cancer in Norway from 1960 through 2004. Women were followed until emigration or end of follow-up on 31 December 2015, whichever came first. Observed differences in mean survival times and hazard ratios for both breast cancer death and death from causes other than breast cancer were obtained for neighbouring time periods defined by women’s age and year of diagnosis. Based on previously developed methods, we fitted a linear relationship between observed differences in mean survival and logarithmic hazard ratios. Results A linear association was found between breast cancer-specific hazard ratios and difference in mean survival time for women diagnosed with breast cancer. This association was also estimated with adjustment for other causes of death than breast cancer. Conclusions The change in mean survival time could be predicted from an estimated reduction in breast cancer mortality. This outcome measure can contribute to better and more understandable risk information about the effect of mammography screening programmes.

PURPOSE: To improve the precision of prescription duration estimates when using the reverse waiting time distribution (rWTD).METHODS: For each patient we uniformly sampled multiple random index dates within a sampling window of length δ . For each index date, we identified the last preceding prescription redemption, if any, within distance δ . Based on all pairs of last prescription and index date, we estimated prescription durations using the rWTD with robust variance estimation. In simulation studies with increasing misspecification we investigated bias, root mean square error (RMSE) and coverage probability of the rWTD using multiple index dates (1, 5, 10, and 20). We applied the method to Danish data on warfarin prescriptions from 2013 to 2014 stratifying by and adjusting for sex and age. RESULTS: In simulation scenarios without misspecification, the relative bias was negligible (-0.04% to 0.01%) and nominal coverage probabilities almost retained (93.8%-95.4%). RMSE decreased with the number of random index dates (e.g., from 1.3 with 1 index date to 0.6 days with 5). With misspecification, the relative bias was higher irrespective of the number of index dates. Precision increased with the number of index dates, and hence coverage probabilities decreased. When estimating durations of warfarin prescriptions in Denmark, precision increased with number of index dates, in particular in strata with few patients (e.g., men 90+ years: width of 95% confidence interval was 16.2 days with 5 index dates versus 35.4 with 1).CONCLUSIONS: Increasing the number of random index dates used with the rWTD improved precision without affecting bias.

Background One-fourth of women experience substantially higher weight years after childbirth. We examined weight change from prepregnancy to 18 months postpartum according to subsequent maternal risk of hypertension and cardiovascular disease (CVD). Methods and findings We conducted a cohort study of 47,966 women with a live-born singleton within the Danish National Birth Cohort (DNBC; 1997–2002). Interviews during pregnancy and 6 and 18 months postpartum provided information on height, gestational weight gain (GWG), postpartum weights, and maternal characteristics. Information on pregnancy complications, incident hypertension, and CVD was obtained from the National Patient Register. Using Cox regression, we estimated adjusted hazard ratios (HRs; 95% confidence interval [CI]) for hypertension and CVD through 16 years of follow-up. During this period, 2,011 women were diagnosed at the hospital with hypertension and 1,321 with CVD. The women were on average 32.3 years old (range 18.0–49.2) at start of follow-up, 73% had a prepregnancy BMI 1–2 and >2 BMI units were associated with 25% (10%–42%), P = 0.001 and 31% (14%–52%), P < 0.001 higher risks of hypertension, respectively. These risks were similar whether weight gain presented postpartum weight retention or a new gain from 6 months to 18 months postpartum and whether GWG was below, within, or above the recommendations. For CVD, findings differed according to prepregnancy BMI. In women with normal-/underweight, weight gain >2 BMI units and weight loss >1 BMI unit were associated with 48% (17%–87%), P = 0.001 and 28% (6%–55%), P = 0.01 higher risks of CVD, respectively. Further, weight loss >1 BMI unit combined with a GWG below recommended was associated with a 70% (24%–135%), P = 0.001 higher risk of CVD. No such increased risks were observed among women with overweight/obesity (interaction by prepregnancy BMI, P = 0.01, 0.03, and 0.03, respectively). The limitations of this observational study include potential confounding by prepregnancy metabolic health and self-reported maternal weights, which may lead to some misclassification. Conclusions Postpartum weight retention/new gain in all mothers and postpartum weight loss in mothers with normal-/underweight may be associated with later adverse cardiovascular health., Helene Kirkegaard and co-workers study maternal weight changes and cardiovascular risk over 16 years of follow-up., Author summary Why was this study done? Many women experience persistent weight gain from childbearing. This pregnancy-related weight change may be associated with worse long-term cardiovascular health. What did the researchers do and find? We used data from 47,966 mothers who participated in the Danish National Birth Cohort (DNBC). Self-reported weights were used to define their weight change patterns from prepregnancy to 6 and 18 months postpartum. We examined how these patterns were related to their risk of hypertension and cardiovascular disease (CVD) the following 16 years. We found that weight gain from before pregnancy to 18 months postpartum was positively associated with the risk of hypertension regardless of whether the women retained weight from pregnancy or gained weight from 6 to 18 months postpartum. In women with normal-/underweight, risk of CVD increased with a weight gain from before pregnancy to 18 months postpartum, but also with a weight loss in this period, especially if they had gained below recommended during pregnancy. No such increased risks of CVD were observed in women with overweight/obesity. What do these findings mean? Our findings suggest that health professionals should also focus on the mother’s weight change patterns after given birth to improve their cardiovascular health. While women with overweight should avoid weight gain, both weight gain and loss should be of concern among women with normal-/underweight.

Many consider inequality in health unfair if it is caused by inequality within the healthcare system but less unfair when caused by individuals’ health behaviour. However, healthcare systems are challenged when it comes to ensuring equal care for equal need. In Roemer’s equality of opportunity theory, people have equal opportunity for obtaining something if obtaining it reflects their effort instead of their circumstances. Very little is known about how responsibility exerted by patients prior to illness affects the healthcare they are provided by the healthcare system. We aimed to apply Roemer’s theory to an acute care setting where healthcare is most directly in the hands of the healthcare system in order to study the role of patient-exerted responsibility for their opportunities in the healthcare system. We operationalised the responsibility patients exert as Body Mass Index (BMI), smoking and alcohol habits, and their circumstances as demographics, socioeconomics, prognostic factors and year of discharge. Opportunity in healthcare was defined as patients’ attainment of clinical guideline-recommended acute hospital care. In Roemer’s theory, we detected inequality of opportunity as restricted attainment of healthcare was mainly associated with patients’ circumstances, such as lower education, old age or living alone. We also identified a strong association with BMI; being underweight negatively affected patients’ opportunities as it led to suboptimal healthcare, while the opposite was found for being overweight and, in particular, obese. Hence, patient-exerted responsibility affected patients’ opportunities in healthcare, though perhaps in an unexpected way. This improved understanding of inequality may help to focus future research and, in the long term, support clinical and political efforts to achieve equal care for equal needs. Published: Online March 2021.

Identification of risk factors for contracting and developing serious illness following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of paramount interest. Here, we performed a retrospective cohort analysis of all Danish individuals tested for SARS-CoV-2 between 27 February 2020 and 30 July 2020, with a known ABO and RhD blood group, to determine the influence of common blood groups on virus susceptibility. Distribution of blood groups was compared with data from nontested individuals. Participants (29% of whom were male) included 473 654 individuals tested for SARS-CoV-2 using real-time polymerase chain reaction (7422 positive and 466 232 negative) and 2 204 742 nontested individuals, accounting for ∼38% of the total Danish population. Hospitalization and death from COVID-19, age, cardiovascular comorbidities, and job status were also collected for confirmed infected cases. ABO blood groups varied significantly between patients and the reference group, with only 38.41% (95% confidence interval [CI], 37.30-39.50) of the patients belonging to blood group O compared with 41.70% (95% CI, 41.60-41.80) in the controls, corresponding to a relative risk of 0.87 (95% CI, 0.83-0.91) for acquiring COVID-19. This study identifies ABO blood group as a risk factor for SARS-CoV-2 infection but not for hospitalization or death from COVID-19.

Key Points Question Is exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) associated with increased risk of intensive care unit admission or death among patients hospitalized with influenza? Findings In this Danish nationwide cohort study that included 7747 adults aged 40 years or older, no association of NSAID use with intensive care unit admission or 30-day mortality was found. Meaning The findings of this study suggest that among patients hospitalized with influenza, those who use NSAIDs do not have worse prognosis than those with no NSAID use., This cohort study examines the association of nonsteroidal anti-inflammatory drugs (NSAIDs) with adverse outcomes in patients hospitalized with influenza or influenza pneumonia., Importance During the ongoing coronavirus disease 2019 pandemic, case reports have suggested that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may lead to adverse outcomes. Objective To study the association of NSAID use with adverse outcomes in patients hospitalized with influenza or influenza pneumonia. Design, Setting, and Participants This cohort study used propensity score matching among 7747 individuals aged 40 years or older who were hospitalized with influenza, confirmed by polymerase chain reaction or antigen testing, between 2010 and 2018. Data were collected using Danish nationwide registers. All analyses reported were performed on May 29, 2020. Exposures Prescription fill of an NSAID within 60 days before admission. Main Outcomes and Measures Risk ratio (RR) and risk difference (RD) with 95% CIs for intensive care unit admission and death within 30 days of admission. Results A total of 7747 patients (median [interquartile range] age, 71 [59-80] years, 3980 [51.4%] men) with confirmed influenza were identified. Of these, 520 (6.7%) were exposed to NSAIDs. In the unmatched cohorts, 104 of 520 patients (20.0%) who used NSAIDs and 958 of 7227 patients (13.3%) who did not use NSAIDs were admitted to the intensive care unit. For death within 30 days of admission, we observed 37 events (7.1%) among those who used NSAIDs compared with 563 events (7.8%) among those who did not. Current NSAID use was associated with intensive care unit admission (RR, 1.51; 95% CI, 1.26 to 1.81; RD, 6.7%; 95% CI, 3.2% to 10.3%), while NSAID use was not associated with death (RR, 0.91; 95% CI, 0.66 to 1.26; RD, –0.7%; 95% CI, –3.0% to 1.6%). In the matched cohorts, risks were unchanged for patients who used NSAIDs, while 83 ICU admissions (16.0%) and 36 deaths (6.9%) were observed among matched individuals who did not use NSAIDs. Matched (ie, adjusted) analyses yielded attenuated risk estimates for intensive care unit admission (RR, 1.25; 95% CI, 0.95 to 1.63; RD, 4.0%; 95% CI, –0.6% to 8.7%) and death (RR, 1.03; 95% CI, 0.66 to 1.60; RD, 0.2%; 95% CI, –2.9% to 3.3%). Associations were more pronounced among patients who used NSAIDs for a longer period (eg, for intensive care unit admission: RR, 1.90; 95% CI, 1.19 to 3.06; RD, 13.4%; 95% CI, 4.0% to 22.8%). Conclusions and Relevance In this cohort study of adult patients hospitalized with influenza, the use of NSAIDs was not associated with 30-day intensive care unit admission or death in adjusted analyses. There was an association between long-term use of NSAIDs and intensive care unit admission.

Background Concerns over the safety of non-steroidal anti-inflammatory drug (NSAID) use during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been raised. We studied whether use of NSAIDs was associated with adverse outcomes and mortality during SARS-CoV-2 infection. Methods and findings We conducted a population-based cohort study using Danish administrative and health registries. We included individuals who tested positive for SARS-CoV-2 during the period 27 February 2020 to 29 April 2020. NSAID users (defined as individuals having filled a prescription for NSAIDs up to 30 days before the SARS-CoV-2 test) were matched to up to 4 non-users on calendar week of the test date and propensity scores based on age, sex, relevant comorbidities, and use of selected prescription drugs. The main outcome was 30-day mortality, and NSAID users were compared to non-users using risk ratios (RRs) and risk differences (RDs). Secondary outcomes included hospitalization, intensive care unit (ICU) admission, mechanical ventilation, and acute renal replacement therapy. A total of 9,236 SARS-CoV-2 PCR-positive individuals were eligible for inclusion. The median age in the study cohort was 50 years, and 58% were female. Of these, 248 (2.7%) had filled a prescription for NSAIDs, and 535 (5.8%) died within 30 days. In the matched analyses, treatment with NSAIDs was not associated with 30-day mortality (RR 1.02, 95% CI 0.57 to 1.82, p = 0.95; RD 0.1%, 95% CI −3.5% to 3.7%, p = 0.95), risk of hospitalization (RR 1.16, 95% CI 0.87 to 1.53, p = 0.31; RD 3.3%, 95% CI −3.4% to 10%, p = 0.33), ICU admission (RR 1.04, 95% CI 0.54 to 2.02, p = 0.90; RD 0.2%, 95% CI −3.0% to 3.4%, p = 0.90), mechanical ventilation (RR 1.14, 95% CI 0.56 to 2.30, p = 0.72; RD 0.5%, 95% CI −2.5% to 3.6%, p = 0.73), or renal replacement therapy (RR 0.86, 95% CI 0.24 to 3.09, p = 0.81; RD −0.2%, 95% CI −2.0% to 1.6%, p = 0.81). The main limitations of the study are possible exposure misclassification, as not all individuals who fill an NSAID prescription use the drug continuously, and possible residual confounding by indication, as NSAIDs may generally be prescribed to healthier individuals due to their side effects, but on the other hand may also be prescribed for early symptoms of severe COVID-19. Conclusions Use of NSAIDs was not associated with 30-day mortality, hospitalization, ICU admission, mechanical ventilation, or renal replacement therapy in Danish individuals who tested positive for SARS-CoV-2. Trial registration The European Union electronic Register of Post-Authorisation Studies EUPAS34734, In a nationwide cohort study, Lars C. Lund, Kasper B. Kristensen, and colleagues investigate the association of NSAID use and outcomes in COVID-19 patients., Author summary Why was this study done? During the early phases of the pandemic of coronavirus disease 2019 (COVID-19), concerns were raised that ibuprofen, a drug commonly used to treat weak pain and fevers, may lead to a more severe course of coronavirus disease. If this risk is verified, it would be important to reduce the use of ibuprofen and ibuprofen-like drugs, commonly referred to as non-steroidal anti-inflammatory drugs (NSAIDs), among patients at risk of COVID-19. What did the researchers do and find? We identified all Danish residents who tested positive for the infectious agent of COVID-19 and grouped them into users and non-users of NSAIDs. The risks of being hospitalized, admitted to the intensive care unit, or dying were compared between the 2 groups. Overall, risks for all studied outcomes were similar between users and non-users of ibuprofen and other NSAIDs. What do these findings mean? NSAIDs do not lead to more severe coronavirus disease according to this study.