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.

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.

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.

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.

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.