Experience with sotrovimab treatment of SARS-CoV-2-infected patients in Denmark.

AIMS: To evaluate the experience with use of sotrovimab following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in high-risk groups. METHODS: In a nationwide, population-based cohort study, we identified all individuals treated with sotrovimab (N = 2933) and stratified them by 4 high-risk groups: (A) malignant haematological disease, (B) solid organ transplantation, (C) anti-CD20 therapy ≤1 year and (D) other risks. Cox regression analysis was used to calculate hazard ratios for hospitalization, death and associated prognostic factors. RESULTS: Of 2933 sotrovimab-treated individuals, 83% belonged to high-risk groups (37.6% haematological malignancy, 27.4% solid organ transplantation and 17.5% treatment with anti-CD20 ≤1 year). Only 17.8% had other risks (11.8% were pregnant, 10.7% primary immunodeficiency, 21.2% other malignancy, 4.3% received anti-CD20 >1 year and 52.0% other/unknown causes). Within 90 days of infusion, 30.2% were hospitalized and 5.3% died. The main prognostic factors were the predefined high-risk groups, mainly malignant haematological disease and age ≥65 years. Number of COVID-19 vaccines (≥3) was associated with a decreased risk of hospitalization. The Delta but not the Omicron BA.2 variant was associated with a higher risk of death compared to the BA.1 variant. CONCLUSION: More than 90% of the patients treated with sotrovimab belonged to the very high-risk groups as described in the Danish guidelines. Sotrovimab-treated individuals remained at a high risk of hospitalization and death which was strongly associated with the underlying immunocompromised state and age. Having received >3 COVID-19 vaccines was association with decreased risk of death and hospitalization.

Feasibility and early clinical impact of precision medicine for late-stage cancer patients in a regional public academic hospital.

AIM: Our goal was to describe a precision medicine program in a regional academic hospital, characterize features of included patients and present early data on clinical impact. MATERIALS AND METHODS: We prospectively included 163 eligible patients with late-stage cancer of any diagnosis from June 2020 to May 2022 in the Proseq Cancer trial. Molecular profiling of new or fresh frozen tumor biopsies was done by WES and RNAseq with parallel sequencing of non-tumoral DNA as individual reference. Cases were presented at a National Molecular Tumor Board (NMTB) for discussion of targeted treatment. Subsequently, patients were followed for at least 7 months. RESULTS: 80% (N = 131) of patients had a successful analysis done, disclosing at least one pathogenic or likely pathogenic variant in 96%. A strongly or potentially druggable variant was found in 19% and 73% of patients, respectively. A germline variant was identified in 2.5%. Median time from trial inclusion to NMTB decision was one month. One third (N = 44) of patients who underwent molecularly profiling were matched with a targeted treatment, however, only 16% were either treated (N = 16) or are waiting for treatment (N = 5), deteriorating performance status being the primary cause of failure. A history of cancer among 1st degree relatives, and a diagnosis of lung or prostate cancer correlated with greater chance of targeted treatment being available. The response rate of targeted treatments was 40%, the clinical benefit rate 53%, and the median time on treatment was 3.8 months. 23% of patients presented at NMTB were recommended clinical trial participation, not dependent on biomarkers. CONCLUSIONS: Precision medicine in end-stage cancer patients is feasible in a regional academic hospital but should continue within the frame of clinical protocols as few patients benefit. Close collaboration with comprehensive cancer centers ensures expert evaluations and equality in access to early clinical trials and modern treatment.

Improved Survival Among Hospitalized Patients With Coronavirus Disease 2019 (COVID-19) Treated With Remdesivir and Dexamethasone. A Nationwide Population-Based Cohort Study.

BACKGROUND: There are limited data on outcomes of moderate to severe coronavirus disease 2019 (COVID-19) among patients treated with remdesivir and dexamethasone in a real-world setting. We sought to compare the effectiveness of standard of care (SOC) alone versus SOC plus remdesivir and dexamethasone. METHODS: Two population-based nationwide cohorts of individuals hospitalized with COVID-19 during February through December 2020 were studied. Death within 30 days and need of mechanical ventilation (MV) were compared by inverse probability of treatment weighted (ITPW) logistic regression analysis and shown as odds ratio (OR) with 95% confidence interval (CI). RESULTS: The 30-days mortality rate of 1694 individuals treated with remdesivir and dexamethasone in addition to SOC was 12.6% compared to 19.7% for 1053 individuals receiving SOC alone. This corresponded to a weighted OR of 30-day mortality of 0.47 (95% CI: .38-.57) for patients treated with remdesivir and dexamethasone compared to patients receiving SOC alone. Similarly, progression to MV was reduced (OR 0.36; 95% CI: .29-.46). CONCLUSIONS: Treatment of moderate to severe COVID-19 during June through December that included remdesivir and dexamethasone was associated with reduced 30-day mortality and need of MV compared to treatment in February through May.

Uptake of biosimilar trastuzumab in Denmark compared with other European countries: a comparative study and discussion of factors influencing implementation and uptake of biosimilars.

PURPOSE: The aim of this study was to describe the implementation and uptake of biosimilar trastuzumab in Denmark compared with other European countries. METHODS: European data for usage of trastuzumab was supplied by IQVIA™, using the MIDAS® dataset. A comparison was performed based on market share estimated in sales volume. A separate comparison was undertaken between countries with a full two-fold switch between different biosimilars. Data was collected spanning the time from first registered sales of biosimilar trastuzumab until the 1st quarter of 2020. RESULTS: Denmark had the fastest and most thorough uptake of biosimilar trastuzumab compared with other EU countries. After 3 months, the market share of biosimilar trastuzumab had increased to 90% while the second fastest country had a 50% market share after 3 months. Only two other countries had undergone a full second switch between biosimilars, Hungary and Norway. All of the three countries made near complete switches between biosimilars while only Denmark had reduced the use of biooriginator below 10%. CONCLUSION: The implementation of biosimilar trastuzumab in Denmark was rapid and achieved high overall uptake compared with other EU countries. The switch from one biosimilar to another was also achieved quickly and thoroughly. We believe that the rapid dissemination of information and involvement of all stakeholders - administrators, pharmacies, prescribers, nurses, and patients - constitute the backbone of the Danish success. A similar strategy is recommend for biosimilar implementation in other countries.

The Danish model for the quick and safe implementation of infliximab and etanercept biosimilars.

PURPOSE: A rapidly increasing use of biological drugs has led to substantial costs. Shift to biosimilars enables considerable reduction of these costs without jeopardizing the treatment of patients, but most countries have extensive possibilities of untapped cost-savings. The aim of this study was to describe the Danish quick and near-complete implementation of the two first TNF inhibitor biosimilars (infliximab and etanercept). METHODS: We shed light on the considerations and experiences made during the implementation, and present key figures from the implementation. RESULTS: The infliximab biosimilar constituted 90.6% of the total amount of infliximab four months following patent expiration of the biooriginator. Similar results were seen for etanercept biosimilar. Substantial cost reductions were experienced in the way that e.g. the infliximab-shift reduced cost by two thirds. CONCLUSION: We believe that a thorough preparation and an organizational setting supporting the implementation is crucial for the successful implementation. This same implementation model will be used for future biosimilars.

Clinical events preceding switching and discontinuation of oral anticoagulant treatment in patients with atrial fibrillation.

AIMS: Switching between oral anticoagulants and treatment discontinuation are common events related to therapy with non-vitamin K antagonist oral anticoagulants (NOACs). However, knowledge on the reasons leading to these treatment changes is scarce. The aim of this study was to identify clinical events preceding anticoagulant switching and NOAC discontinuation during oral anticoagulant therapy in patients with atrial fibrillation. METHODS AND RESULTS: We performed a nationwide register-based study including Danish atrial fibrillation patients initiating a NOAC between August 2011 and February 2016 (n = 50 623). We explored potential reasons leading to changes in anticoagulant treatment by identifying clinical events preceding switches from vitamin K antagonists (VKA) to NOAC, switches from NOAC to VKA, and discontinuations of NOACs. Among 23 531 anticoagulant users changing treatment, we identified 13 295 switches from VKA to NOAC, 5206 switches from NOAC to VKA, and 8995 discontinuations of NOACs. Approximately half of all treatment changes were preceded by a hospitalization. A relevant specific clinical event or procedure was identified prior to 18.3% of switches from VKA to NOAC, prior to 23.0% of switches from NOAC to VKA, and prior to 26.6% of discontinuations. Switches from VKA to NOAC were most often preceded by thromboembolic events (7.0%), whereas cardioversion was the most common specific event prior to a switch from NOAC to VKA (11.4%). Discontinuations were most often preceded by bleeding events (7.6%). CONCLUSION: For about one in five patients, treatment changes during anticoagulant therapy were preceded by a major clinical event. However, the majority of patients changed treatment for reasons not recorded in health registries.

Potentially inappropriate prescriptions in patients admitted to a psychiatric hospital.

Background Very little is known about the general appropriateness of prescribing for psychiatric patients. Aims To identify prevalence and types of potentially inappropriate prescribing (PIP) of psychotropic and somatic medications, to assess the severity of potential clinical consequences and to identify possible predictive factors of PIP in a sample of adult psychiatric in-patients. Methods A descriptive, cross-sectional design using medication reviews by clinical pharmacologists to identify PIP during a 3-month period. The setting was in-patient units in a psychiatric department of a Danish university hospital during a 3-month period (September 2013-November 2013). Patients medication lists (n = 207) were reviewed at the time of admission and all identified PIPs were assessed for potential consequences by clinical pharmacologists. Results There were 349 PIP identified in 1291 prescriptions. The proportion of patients found to have at least one PIP was 123/207 (59%) and the proportions of patients with at least one PIP assessed to be potentially serious or fatal was 69/207 (33%) and 24/207 (12%), respectively. Interactions between drugs 125/207 (36%) and too high doses of drugs 56/207 (16%) were the most frequent PIP. Predictive factors for PIP were polypharmacy (>5 prescriptions) and having one or more somatic diagnoses. Conclusion PIP is common in psychiatric patients and potentially fatal. Particularly polypharmacy (>5 prescriptions) and concomitant somatic illness were associated with the probability of PIP. Improving the quality of prescribing might benefit from an interprofessional approach and thus better training of physicians and nurses is needed in order to minimize PIP.

Treatment with enzyme replacement therapy during pregnancy in a patient with Pompe disease.

Pregnancy is in general physically demanding, even more so for women with hereditary muscular diseases (HMDs). With increasing numbers of women with HMD reaching reproductive age, there is a growing need for research into what impact pregnancy can have on their clinical condition. A 25-year-old woman was diagnosed with Pompe disease at the age of 22 and began enzyme replacement therapy (ERT) right away. At the age of 25 she became pregnant. ERT was paused during the first trimester and recommenced throughout the second and third trimesters. Her clinical condition throughout the pregnancy remained stable. Delivery was uneventful, but prolonged and physically demanding. After delivery, cystitis further compromised her health, leaving her bedridden during early postpartum. In this case, continuing ERT during pregnancy resulted in a healthy outcome, with an uneventful pregnancy and delivery of a normal and healthy baby. However, data on pregnancy in women with Pompe disease are rare.

Medication errors involving anticoagulants: Data from the Danish patient safety database.

Reporting of adverse incidents is mandatory in Denmark. All reported adverse incidents are made anonymously, and stored in an encrypted database. It is the purpose of this descriptive study to describe the severity of adverse medication incidents caused by oral anticoagulants in hospitals. All moderate, severe and fatal reports concerning non-vitamin K antagonist oral anticoagulants were analyzed from date of marketing until July 8 2014. The data collection for warfarin was from January 1 2014 until July 8 2014. Three independent specialists in clinical pharmacology evaluated the severity of incident outcomes. A total of 147 adverse medication incidents were analyzed, and showed that de facto or potentially fatal and serious incidents were most frequently associated with sector change (admission to or discharge from hospital, or undergoing surgery) and resulted from insufficient or excess dosing. Physicians should be aware when prescribing and changing anticoagulant therapy to avoid severe or fatal incidents.

Treatment Changes among Users of Non-Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation.

Patients with atrial fibrillation discontinuing anticoagulant therapy are left unprotected against ischaemic stroke. Further, switching between oral anticoagulants may be associated with a transiently increased risk of bleeding or thromboembolism. However, there is a paucity of real-life data on pattern of switching and discontinuation of oral anticoagulants. To address this, we conducted a nationwide drug utilization study including all registered Danish atrial fibrillation patients initiating a non-VKA oral anticoagulant (NOAC) between August 2011 and February 2016. We assessed changes in anticoagulant treatment, including switching between oral anticoagulants and discontinuation of NOACs, and explored patient characteristics predicting these changes. We identified 50,632 patients with atrial fibrillation initiating NOAC therapy within the study period. The majority initiated dabigatran (49.9%) and one-third had previously used VKA. Within 1 year, 10.1% switched to VKA, 4.8% switched to another NOAC and 14.4% discontinued treatment. The frequencies of switching to VKA and discontinuation were highest among NOAC users of young age (<55 years) and with low CHA2 DS2 -VASc score (=0). However, the majority of patients (87.3%) stopping NOAC treatment had a CHA2 DS2 -VASc score ≥1. We conclude that switching from VKA to NOAC, and to a lesser extent from NOAC to VKA, is common, as is early treatment discontinuation. The majority of treatment changes are observed in patients at increased risk of stroke. More research is warranted on the risks of bleeding and thromboembolism associated with switching and discontinuation of NOACs as well as the underlying reasons why these treatment changes occur.

Clinical Pharmacology in Denmark in 2016 - 40 Years with the Danish Society of Clinical Pharmacology and 20 Years as a Medical Speciality.

The Danish Society of Clinical Pharmacology was founded in 1976, and mainly thanks to the persistent efforts of the society, clinical pharmacology became an independent medical speciality in Denmark in 1996. Since then, clinical pharmacology has gone from strength to strength. In the Danish healthcare system, clinical pharmacology has established itself as an indispensible part of the efforts to promote the rational, safe and economic use of drugs. Clinical pharmacologists are active in drug committees both in hospitals and in the primary sector. All clinical pharmacology centres offer a local medicines information service. Some centres have established an adverse drug effect manager function. Only one centre offers a therapeutic drug monitoring service. Clinical pharmacologists are responsible for the toxicological advice at the Danish Poison Information Centre at Bispebjerg University Hospital in the Capital Region. The Department of Clinical Pharmacology at Aarhus University Hospital works closely together with forensic toxicologists and pathologists, covering issues regarding illicit substances, forensic pharmacology, post-mortem toxicology, expert testimony and research. Therapeutic geriatric and psychiatric teach-inns for specialist and junior doctors are among the newest initiatives organized by clinical pharmacologists. Clinical pharmacologists work also in the Danish Medicines Agency and in the Danish pharmaceutical industry, and the latter has in particular a great growth potential for creating new jobs and career opportunities for clinical pharmacologists. As of July 2016, the Danish Society of Clinical Pharmacology has 175 members, and 70 of these are specialists in clinical pharmacology corresponding to approximately 2.5 specialists per 1000 doctors (Denmark has in total 28,000 doctors) or approximately 12 specialists per one million inhabitants.

[Serious bleeding complications caused by warfarin with international normalized ratio 2.1]. / Alvorlige blødningskomplikationer udløst af warfarinbehandling med international normalized ratio 2,1.

The risk of bleeding due to anticoagulation therapy with warfarin rises exponentially, when the international normalized ratio (INR) exceeds 4.5. We present a 52-year-old male admitted to the hospital with severe bleeding in the lower limbs caused by warfarin. Laboratory tests showed therapeutic INR (2.1), however the activated partial tromboplastin time was unusually prolonged (135 sec.) and a severe, reversible reduction in factor IX was detected. These findings were suggestive of a mutation in the factor IX propeptide, but thrombocytopathy induced by selective serotonin re-uptake inhibitors could have worsened the bleeding.

[Gastrointestinal bleeding after treatment with ticagrelor]. / Gastrointestinal blødning ved behandling med ticagrelor.

Ticagrelor is a reversible inhibitor of platelet-aggregation, and is used instead of clopidogrel in the treatment of acute coronary syndrome (ACS). Ticagrelor has documented better outcomes as shown in the PLATO-study, when compared to clopidogrel. However, more major non-CABG bleedings are observed with ticagrelor. Treatment of ACS with platelet-inhibitors is the standard, but there is no antidote for ticagrelor or clopidogrel, making haemostasis problematic in the case of a major bleeding. The following case describes a 76-year-old woman, who after admission for chronic obstructive pulmonary disease and ACS, was treated with ticagrelor and developed a major gastrointestinal bleeding.

[Fourth generation oral contraceptives are associated with a higher risk of venous thromboembolism compared to second generation]. / Fjerdegenerations-p-piller medfører større risiko for venøs tromboemboli end andengenerations-p-piller.

It has been widely discussed whether fourth generation oral contraceptives (OC) are associated with a higher risk of venous thromboembolism (VTE) compared to second generation. Lack of randomized controlled trials, methodological problems and inconsistent criteria for the VTE event has led to conflicting results. Three newly published studies utilising improved methodology show that fourth generation OC are associated with an increased risk of VTE compared to second generation OC. This knowledge has led to a change in recommendation of the first drug of choice, which is now second generation OC.

The medication process in a psychiatric hospital: are errors a potential threat to patient safety?

PURPOSE: To investigate the frequency, type, and potential severity of errors in several stages of the medication process in an inpatient psychiatric setting. METHODS: A cross-sectional study using three methods for detecting errors: (1) direct observation; (2) unannounced control visits in the wards collecting dispensed drugs; and (3) chart reviews. All errors, except errors in discharge summaries, were assessed for potential consequences by two clinical pharmacologists. SETTING: Three psychiatric wards with adult patients at Aalborg University Hospital, Denmark, from January 2010-April 2010. THE OBSERVATIONAL UNIT: The individual handling of medication (prescribing, dispensing, and administering). RESULTS: In total, 189 errors were detected in 1,082 opportunities for error (17%) of which 84/998 (8%) were assessed as potentially harmful. The frequency of errors was: prescribing, 10/189 (5%); dispensing, 18/189 (10%); administration, 142/189 (75%); and discharge summaries, 19/189 (10%). The most common errors were omission of pro re nata dosing regime in computerized physician order entry, omission of dose, lack of identity control, and omission of drug. CONCLUSION: Errors throughout the medication process are common in psychiatric wards to an extent which resembles error rates in somatic care. Despite a substantial proportion of errors with potential to harm patients, very few errors were considered potentially fatal. Medical staff needs greater awareness of medication safety and guidelines related to the medication process. Many errors in this study might potentially be prevented by nursing staff when handling medication and observing patients for effect and side effects of medication. The nurses' role in psychiatric medication safety should be further explored as nurses appear to be in the unique position to intercept errors before they reach the patient.

[Methods for systematic listing of medication in the elderly]. / Metoder til systematisk gennemgang af ældres medicin.

To improve medication in the elderly several screening tools have been developed. The most used tool is the Beers 2003 criteria; however, the newer STOPP/START criteria have proven more effective and easier to use. Based on the literature we aim to compare these tools according to a list of desired properties and to suggest the best template for a Danish tool, though it is still to be determined, whether the identification and correction of potentially inappropriate medication leads to a better outcome in terms of decreased morbidity and mortality and improved health economics.

New oral anticoagulants: a review of the literature with particular emphasis on patients with impaired renal function.

Oral anticoagulant therapy (OAT) is widely used to prevent and treat thromboembolic events. Traditionally, warfarin has been the drug of choice and, indeed, this drug is effective and provides a more than 60% reduction in stroke risk in patients with atrial fibrillation. However, OAT entails an increased bleeding risk, and management of this is challenging. Among other things, new oral anticoagulant drugs offer fixed dosing, more predictable pharmacokinetics and fewer interactions with drugs and food. Moreover, these drugs seem to provide an improved benefit-risk ratio with respect to thromboembolic events and bleeding complications in a broad patient population. The new drugs differ from traditional OAT with respect to their mechanism of action and pharmacokinetics, especially with respect to elimination through the kidneys. These drugs may potentially cause bleeding complications in patients with reduced drug excretion due to impaired renal function. Dabigatran etexilate and rivaroxaban carry the highest risk due to a high degree of renal excretion, whereas the risk for apixaban, edoxaban and betrixaban seems lower. Pharmacokinetic studies and data from clinical studies have provided information on how to guide dosing in patients with renal impairment. However, the risk of drug accumulation and bleeding may be amplified by several drug-drug interactions. This article provides a review of the literature on the pharmacology of new anticoagulant drugs with particular focus on the impact of impaired renal function.