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.

Bisphosphonate Use and Risk of Atypical Femoral Fractures: A Danish Case Cohort Study with Blinded Radiographic Review.

CONTEXT: Prolonged bisphosphonate (BP) treatment for osteoporosis prevents hip and other fractures but causes atypical femoral fractures (AFF). OBJECTIVE: To establish the relationship between patterns of BP use and the risk of AFF and hip fractures. Other potential risk factors for AFF were also examined. DESIGN: Population-based case-cohort study. SETTING: The Danish National Healthcare system maintains longitudinal records of medication use, healthcare utilization, and x-ray images. PARTICIPANTS: Among all 1.9 million Danish adults ≥50, those with subtrochanteric or femoral shaft fractures between 2010-2015 (n = 4,973) were identified and compared to a random sample (n = 37,021). PREDICTORS: Bisphosphonate use was collected from 1995-2015. MAIN OUTCOME MEASURES: Fracture radiographs (n = 4,769) were reviewed by blinded study radiologists to identify AFFs (n = 181) using established criteria. Traditional hip fractures in the random sample (n = 691) were identified by ICD-10. RESULTS: Compared to <1 year of BP use, 5-7 years of use was associated with a 7-fold increase in AFF [adjusted HR = 7.29 (CI: 3.07,17.30)]; the risk of AFF fell quickly after discontinuation. The 5-year number-needed-to-harm for one AFF was 1,424, while the 5-year number-needed-to-treat to prevent one hip fracture was 56. Glucocorticoid and proton pump inhibitor use were independently associated with increased AFF risk. Thirty-one percent of those with AFF had no BP exposure. CONCLUSIONS: The risk of AFF increases with duration of BP use but the beneficial effects of BP therapy in adults ≥50 dramatically exceed this increased risk. Nearly one-third of those with AFF have no BP exposure.

Prenatal antidepressant exposure and emotional disorders until age 22: a danish register study.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed antidepressants in pregnancy. Animal and some clinical studies have suggested potential increases in depression and anxiety following prenatal SSRI exposure, but the extent to which these are driven by the medication remains unclear. We used Danish population data to test associations between maternal SSRI use during pregnancy and children outcomes up to age 22. METHODS: We prospectively followed 1,094,202 single-birth Danish children born 1997-2015. The primary exposure was ≥ 1 SSRI prescription filled during pregnancy; the primary outcome, first diagnosis of a depressive, anxiety, or adjustment disorder, or redeemed prescription for an antidepressant medication. We used propensity score weights to adjust potential confounders, and incorporated data from the Danish National Birth Cohort (1997-2003) to further quantify potential residual confounding by subclinical factors. RESULTS: The final dataset included 15,651 exposed and 896,818 unexposed, children. After adjustments, SSRI-exposed had higher rates of the primary outcome than those of mothers who either did not use an SSRI (HR = 1.55 [95%CI:1.44,1.67] or discontinued the SSRI use ≥ 3 months prior to conception (HR = 1.23 [1.13,1.34]). Age of onset was earlier among exposed (9 [IQR:7-13] years) versus unexposed (12 [IQR:12-17] years) children (p < 0.01). Paternal SSRI use in the absence of maternal use during the index pregnancy (HR = 1.46 [1.35,1.58]) and maternal SSRI use only after pregnancy (HR = 1.42 [1.35,1.49]) were each also associated with these outcomes. CONCLUSIONS: While SSRI exposure was associated with increased risk in the children, this risk may be driven at least partly by underlying severity of maternal illness or other confounding factors.

Use of low-dose quetiapine increases the risk of major adverse cardiovascular events: results from a nationwide active comparator-controlled cohort study.

At standard doses used for schizophrenia or bipolar disorder, quetiapine has been associated with weight gain and increased levels of triglycerides, to-tal cholesterol and low-density lipoprotein (LDL) cholesterol, which are risk factors for cardiovascular morbidity and mortality. However, this drug is also commonly used off-label at low doses for anxiolytic or hypnotic purposes, and its cardiovascular safety at these doses is unknown. We aimed to assess the risk of major adverse cardiovascular events with use of low-dose quetiapine compared to use of Z-drug hypnotics in a nationwide, active comparator-controlled cohort study. The cohort included new users of either drugs in Denmark from 2003 to 2017, aged 18-85 years, without history of ischemic stroke, myocardial infarction, cancer, and severe mental illness. The main outcome was the occurrence of major adverse cardiovascular events, defined as non-fatal myocardial infarction or ischemic stroke, or death from cardiovascular causes. Selective serotonin reuptake inhibitors (SSRIs) were used as an alternative comparator in sensitivity analyses. Altogether, we compared 60,566 low-dose quetiapine users with 454,567 Z-drug users, followed for 890,198 person-years in intent-to-treat analysis, and 330,334 person-years in as-treated analysis. In intention-to-treat analysis, low-dose quetiapine was associated with an increased risk of major adverse cardiovascular events (adjusted hazard ratio, aHR=1.13, 95% CI: 1.02-1.24, p=0.014) and cardiovascular death (aHR=1.26, 95% CI: 1.11-1.43, p<0.001). In as-treated analysis, continuous low-dose quetiapine use was associated with increased risk of major adverse cardiovascular events (aHR=1.52, 95% CI: 1.35-1.70, p<0.001), non-fatal ischemic stroke (aHR=1.37, 95% CI: 1.13-1.68, p=0.002) and cardiovascular death (aHR=1.90, 95% CI: 1.64-2.19, p<0.001). The risk of major adverse cardiovascular events was greater in women (aHR=1.28, p=0.02) and those aged ≥65 years at initiation (aHR=1.24, p<0.001). Compared to SSRIs, low-dose quetiapine use was associated with an increased risk of major adverse cardiovascular events (aHR=1.42, p<0.001), non-fatal ischemic stroke (aHR=1.27, p=0.0028) and cardiovascular death (aHR=1.72, p<0.001). So, we conclude that the use of low-dose quetiapine is associated with an increased risk of major adverse cardiovascular events, especially in women and the elderly. On the basis of these findings, we suggest that use of off-label low-dose quetiapine for sedative or hypnotic purposes should be discouraged.

Changing characteristics over time of individuals receiving COVID-19 vaccines in Denmark: A population-based descriptive study of vaccine uptake.

AIMS: The 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 and characteristics of COVID-19 vaccine recipients in Denmark. METHODS: Using nationwide healthcare registries, we identified all Danish residents ⩾5 years of age who received at least one dose of a COVID-19 vaccine from 27 December 2020-29 January 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, and described characteristics of vaccine recipients during two-month-intervals and in vaccination priority groups. RESULTS: By 29 January 2022, 88%, 86% and 64% of Danish residents ⩾5 years (n=5,562,008) had received a first, second and third dose, respectively, of a COVID-19 vaccine, most commonly the BNT162b2 vaccine (84%). Uptake ranged from 48% in 5-11-year-olds 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). CONCLUSIONS: We document substantial changes over time in, for example, age, sex and medical history of COVID-19 vaccine recipients. Though these results are related to the differential vaccine rollout in Denmark, similar findings are probable in other countries and should be considered when designing and interpreting studies on the effectiveness and safety of COVID-19 vaccines.

Agreement Between Self-Reported Information and Administrative Data on Comorbidities, Imaging and Treatment in Denmark - A Validation Study of 38,745 Patients with Knee or Hip Osteoarthritis.

PURPOSE: To validate self-reported information obtained from patients with knee or hip osteoarthritis (OA) in primary care against administrative data from the three national Danish registries. PATIENTS AND METHODS: We compared the baseline and 12-month follow-up data from 38,745 patients with knee or hip OA participating in the Good Life with osteoArthritis in Denmark (GLA:D®) program with registry-based data on joint surgeries, pain medication dispensing, radiographs, and hospital diagnoses. Agreement was calculated using Cohen's Kappa (k) and percentage agreement, both with 95% CI. RESULTS: There was a moderate agreement between self-report and registry-based data for previous knee surgery (k=0.58, 84.99%) and a substantial agreement for previous hip surgery (k=0.73, 97.05%). Agreement varied from 0.05 to 0.95 and 84.99% to 99.94% for different types of surgeries with lowest agreement for collateral ligament surgery (k=0.05, 99.82%) and highest agreement for joint replacement (k=0.95, 99.54% for knee; k=0.95, 99.48% for hip). There was a moderate agreement (k=0.41, 81.59%) for knee and a slight agreement (k=0.20, 64.79%) for hip radiographs. Agreement varied from 0.01 to 0.53 and 65.39% to 99.90% for pain medication with lowest agreement for topical NSAID (k=0.01, 95.00%) and highest agreement for opioids (k=0.53, 92.56%). For comorbidities, agreement varied from 0.14 to 0.90 and 78.07% to 98.91%, with lowest agreement for anemia or other blood disease (k=0.14, 97.63%) and highest agreement for diabetes (k=0.90, 98.73%). CONCLUSION: As the most common types of pain medication used by patients with OA can be bought over-the-counter and as most OA patients are treated in primary care, which is often not covered by national registries, self-report of pain medication use and comorbidities is preferred but cannot be sufficiently validated against registry-based data. Future studies collecting self-reported information on joint surgery and pain medication from patients with OA should use a less detailed categorization to improve accuracy.

Low-dose aspirin for primary and secondary prevention of cardiovascular events in Denmark 1998-2018.

Randomised controlled trials have shown a neutral or even unfavourable risk-benefit balance of aspirin for primary prevention of cardiovascular events. Using Danish nationwide registries, we investigated aspirin use and associated risks during the past two decades (1998-2018). We linked individual patient data on repeated aspirin redemptions with registered hospital ICD-10 diagnoses of atherosclerotic cardiovascular disease and bleedings. The prevalence of aspirin use among 1.1 million Danish adults fluctuated over the 20-year study period peaking in 2008 with 8.5% (5.4% primary prevention) and dropping to 5.1% (3.1% primary prevention) in 2018. Aspirin use showed strong age dependency, and 21% of individuals > 80 years were treated with aspirin for primary prevention in 2018. Medication adding to bleeding risk was used concurrently by 21% of all aspirin users in 2018. The incidence of major bleedings were similar with primary and secondary prevention aspirin use and highest in elderly (2 per 100 patient years among individuals > 80 years in 2018). In conclusion, low-dose aspirin use for primary prevention of cardiovascular events remains prevalent. The widespread use of aspirin, especially among older adults, and substantial concomitant use of medications adding to bleeding risk warrant increased focus on discontinuation of inappropriate aspirin use.

Oral Bisphosphonate use Reduces Cardiovascular Events in a Cohort of Danish Patients Referred for Bone Mineral Density.

CONTEXT: The cardiovascular (CV) safety of oral bisphosphonates (oBPs) is uncertain. OBJECTIVE: Determine the risk of CV events in oBP users referred for bone mineral density (BMD) testing compared with matched controls. DESIGN: Cohort study. SETTING: Danish national prescription registry enriched with local hospital data from Odense. PARTICIPANTS: Individuals aged ≥45 years referred for BMD testing. EXPOSURE: oBP. OUTCOMES: Hospitalization for any CV event. Secondary study outcomes were specific CV events. Negative (inguinal hernia surgery and ingrown toenail) and positive (fragility fracture) control outcomes assessed systemic bias. Cox proportional hazards models were fitted to estimate hazard ratio (HR) and 95% confidence intervals. RESULTS: There were 2565 oBP users (82.6% women) and 4568 (82.3% women) propensity score-matched controls. Alendronate accounted for 96% of oBP prescription. A total of 406 (15.8%) CV events occurred in oBP users (rate = 73.48 [66.67-80.98]); rate = events divided by person-time; and 837 (18.3%) events in controls (rate = 104.73 [97.87-112.07]) with an adjusted HR of 0.68 (95% CI 0.60-0.77). Additional adjustment for BMD did not attenuate estimates (HR 0.67; 95% CI 0.58-0.78]. Similar results were seen for secondary outcomes where risk reductions were seen regarding atrial fibrillation, stroke, heart failure, and aneurysms. Positive and negative control outcome analyses identified minimal residual confounding. CONCLUSION: Oral BP users experienced a 33% reduced risk of CV events. This observational real-world study adds to a growing body of evidence for cardioprotection by oBP that warrants testing in a randomized setting.

The association between renal function and BMD response to bisphosphonate treatment: Real-world cohort study using linked national registers.

BACKGROUND: Management of osteoporosis given reduced renal function is one of the largest challenges in the bone clinic. OBJECTIVES: Identify the cut-off for renal function below which there would be no overall BMD benefit associated with bisphosphonate use. Track safety outcomes resulting in hospital encounters. METHODS: Population-based, observational register-linked study of BMD trajectories in adults from the island of Funen (pop 465,000) as a function of estimated creatinine clearance (CKD-epi), treatment and adherence to oBP. One laboratory performed all the biochemical analyses for the area while all DXA scans were in a central facility. For inclusion, patients were required to have both a DXA scan and an eGFR measurement (CKD-EPI) within 1 year prior to their study index date. Medication Possession Ratio (MPR) was calculated from national data. RESULTS: Out of 6176 incident BP users, 1789 had eGFR and DXA measurements at appropriate timepoints for the planned analysis, while this was the case for 3908 of 29,336 non-users. Users of oBPs exhibited progressively smaller gains in BMD with decreasing renal function. However, for CKD stage 3A and better, the annual change in BMD was significantly more positive than in the non-user group at similar levels of renal function. In non-users, the average annual change in BMD was negative but largely unaffected by renal function down to stage 3B. There were no new cases of acute renal injury, glomerulonephritis or dialysis. The rate of new kidney transplantation was zero in non-users and 0.26 per 1000 PY in the BP user population. Hypocalcaemia encounters did not differ significantly from that seen in non-users. CONCLUSIONS: The BMD changes observed in real-world users of oBP in this population based single-clinic are consistent with those observed in the original RCTs of alendronate. We noted a gradual decrease in the absolute gains in BMD in oBP users with decreasing renal function though there was no significant interaction - largely explained by low numbers of treated patients with poor renal function - between CKD stage and adherence driven BMD change. There were no cases of acute renal injury resulting in hospital encounters. More data is needed on the efficacy and safety of bisphosphonates in CKD stage 3B to 5 and prescribers should reconsider the low use of DXA in patients with renal function impairment now that a wider range of treatment options are available.

Tramadol prescribed use in general and chronic noncancer pain: a nationwide register-based cohort study of all patients above 16 years.

Background and aims In the Western world, it has become clear that we are facing a crisis of overuse, abuse and improperly prescribed use of opioids. As part of the ongoing discussion on opioid use, the use and prescription of tramadol have been addressed in recent years. A significant portion of this discussion should adequately address the risk factors for the use of weak opioid products such as tramadol. The risk factors which characterise the long-term tramadol use are still incompletely understood. Thus, we aimed to describe the characteristics of Danish patients using tramadol in more detail, under different scenarios and determinants of subsequent usage patterns. Methods We conducted a nationwide cohort study to identify individuals purchasing tramadol from 01/01/2004 to 31/12/2015 who are age 16 + years old by using data from The Danish National Databases; these databases consist of unique information for all citizens in Denmark. Logistic regression analyses were used to assess the potential risk factors for repeated tramadol use. Results The final cancer-free cohort consisted of N = 941,839 tramadol users: 54.4% women, with a mean age of 53.2 years. The number of chronic noncancer pain (CNCP) was 430,641 individuals, and 56% of the total third who repeated the use of tramadol with two + purchased prescriptions were CNCP patients. The increased risk of repeated use for CNCP was, among others, associated with: male sex (HR 1.21), age 69-110 (HR 1.72), back/spine pain men (HR 1.47), women (HR 1.46), spondylopathies (HR 1.24), male osteoporosis (HR 1.22), multimorbid ulcer/skin (HR 1.28), region of municipality Northern Jutland (HR 1.74), Central Jutland (HR 1.75), number of co-medication 4-9 (HR 1.33), dementia (HR 1.27). Factors associated with decreased risk: co-medication ischemic heart disease (HR 0.85), diagnosis headache (HR 0.70), household income highest tertile (HR 0.81), unknown (HR 0.70), single women (HR 0.96). Conclusions This study proved a widespread prescribed use of tramadol in Denmark, and, as know from the literature, weak opioid use may lead to long-term use of high potent opioids, this usage is inappropriate, in general, but especially for the treatment of CNCP. Implications When striving to reduce the overuse of opioids, focus on the extensive use of tramadol may be essential. The current study indicates an excessive and not appropriately prescribed use of tramadol among Danish CNCP patients. In addition to being inappropriate, such use may also have an impact on the growing problem of an illicit Internet market for this drug. Thus, the situation must be taken seriously. The current study confirms the recent clinical guideline and the National Recommendations in Denmark, which emphasises the risks of problematic use of tramadol. The research may also be relevant in other comparable countries. Caution must especially be taken with CNCP patients with comorbidities like diabetes, lung disease, dementia, and osteoporosis.