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.

Content and validation of the Electronic Patient Medication module (EPM)-the administrative in-hospital drug use database in the Capital Region of Denmark.

Aims: Registries on in-hospital drug use are sparse, especially those that can be linked to nationwide registries. In this study, we present and validate the Electronic Patient Medication module (EPM)-the electronic administrative database on in-hospital drug use covering the Capital Region of Denmark. Methods: The research database (EPM-research) is an adaptation of the database underlying the electronic administrative database for in-hospital drug use (EPM-clinic). The validation study was comprised of two sub-studies. Sub-study 1: Accordance of registration between EPM-clinic and EPM-research was investigated by analyzing randomly chosen retrospective patient records. Sub-study 2: Workflows and real-life registration practices were investigated through visits to three different (two medical and one emergency) departments. An observer followed a nurse while dispensing and administering drugs. This information was compared with EPM-research. The primary endpoint for both sub-studies was accordance of generic name between registrations. Secondary endpoints were exact brand name, dose, and time of each administration. Accordance (proportions) with 95% confidence intervals (CI) using the Clopper-Pearson method were calculated. The study was approved by the Danish Data Protection Agency (BFH-2016-058-04906) and the Danish Patient Safety Authority (3-3013-1884/1/). Results: In sub-study 1 227 retrospective drug administrations were reviewed. Accordance of generic name was 100.0% (CI 98.4%-100.0%). In sub-study 2 176 drug administrations were observed of which 173 were recorded with identical generic name, resulting in 98.3% (CI 95.1%-99.6%) accordance of data. Conclusions: Our validation of the EPM-research showed very high accordance. With detailed information on in-hospital drug use, the EPM-research may be a useful tool in pharmacoepidemiological research.

Prepregnancy obesity and associations with stroke and myocardial infarction in women in the years after childbirth: a nationwide cohort study.

BACKGROUND: Cardiovascular events (stroke or myocardial infarction) are often associated with poorer prognosis in younger, compared with older individuals. We examined the associations between prepregnancy obesity and the risks of myocardial infarction and stroke in young, healthy women. METHODS AND RESULTS: All Danish women giving birth during 2004-2009 without a history of renal disease or cardiovascular disease were identified from national registers and followed for a median time of 4.5 years (interquartile range, 2.8-5.8). They were grouped according to prepregnancy body mass index (BMI) in underweight (BMI<18.5 kg/m(2)), normal weight (BMI=18.5-<25 kg/m(2)), overweight (BMI=25-<30 kg/m(2)), and obese (BMI≥30 kg/m(2)). The hazard ratios of myocardial infarction, ischemic stroke, and a composite outcome (myocardial infarction, stroke, cardiovascular death) were assessed using multivariable Cox regression models. We included 273 101 women with a median age of 30.4 years (interquartile range, 27.2-33.8). A total of 68 women experienced a myocardial infarction, and 175 women experienced an ischemic stroke. The adjusted hazard ratios of myocardial infarction compared with normal weight were 2.50 (95% confidence interval [95% CI], 0.97-6.50) in underweight, 1.68 (95% CI, 0.92-3.06) in overweight, and 2.63 (95% CI, 1.41-4.91) in obese women. For ischemic stroke the adjusted hazard ratios were 1.06 (95% CI, 0.44-2.28) in underweight, 1.27 (95% CI, 0.87-1.85) in overweight, and 1.89 (95% CI, 1.25-2.84) in obese women, respectively. For the composite outcome, hazard ratios were 1.34 (95% CI, 0.81-2.20), 1.43 (95% CI, 1.11-1.84), and 1.76 (95% CI, 1.31-2.34) for underweight, overweight, and obese women. CONCLUSIONS: In apparently healthy women of fertile age, prepregnancy obesity was associated with increased risks of ischemic stroke and myocardial infarction in the years after childbirth.

Familial clustering of myocardial infarction in first-degree relatives: a nationwide study.

AIMS: Family history is an established risk factor for myocardial infarction (MI), but it is not clear how this risk changes with number and gender of first-degree relatives with MI. We used the entire Danish population to examine the importance of MI in siblings and parents. METHODS AND RESULTS: This study is a retrospective nationwide register-based cohort study including registered relatives to all Danish citizens diagnosed with MI in the period 1978-2010. In the entire Danish population we identified siblings to 7552 patients with a first-time MI. The rate ratios (RR) calculated by Poisson models showed an RR of 4.30 (95% confidence interval 3.53-5.23) for siblings of a patient with MI. Children of parents with MI also showed high risk: for children of a maternal case RR 2.40 (2.20-2.60), and of a paternal case RR 1.98 (1.98-2.09), respectively; P value for gender interaction <0.0001. A paternal case with MI at an age <50 years was associated with an RR of 3.30 (2.92-3.72) while a case >50 years was associated with a risk of 1.83 (1.73-1.93). For maternal cases below and above 50 years of age the risks were 3.23 (2.56-4.10) and 2.31 (2.11-2.52), respectively. CONCLUSION: First-degree relatives of a patient with myocardial infarction themselves have a substantial higher risk of myocardial infarction. The risk is particularly elevated when the MI case is the mother or a sibling, and when the MI case has the infarction before the age of 50 years.

Risk factors for venous thromboembolism during pregnancy.

BACKGROUND: Pregnant women are at an increased risk of venous thromboembolism (VTE). Risk factors for VTE among pregnant women are not sufficiently investigated. PURPOSE: To examine pharmacological and non-pharmacological VTE risk factors during pregnancy (antepartum). METHODS: The population comprised all pregnant women in Denmark aged 15-50 giving birth 2003-2010. Pregnancies were linked on an individual level with national registers for hospital admissions and drug dispenses from pharmacies. Risk of first occurring VTE antepartum was examined with Cox regression models. RESULTS: Out of 299 810 pregnancies, 337 experienced a VTE, incidence rate 1.1 (95% confidence interval [CI] 1.0-1.3) per 1000 pregnancies. Being underweight (body mass index [BMI] < 18.5 kg/m(2) ) was associated with a decreased risk of VTE (hazard ratio [HR] 0.53 [CI 0.29-0.98]) compared to normal weight (18.5 ≤ BMI < 25 kg/m(2) ). Overweight (25 ≤ BMI < 30 kg/m(2) ) increased VTE risk (HR 1.30 [CI 1.01-1.67]) but obesity (BMI ≥ 30 kg/m(2) ) was insignificant (HR 1.14 [CI 0.82-1.58]). A history of VTE was highly significant (HR 72.65 [CI 51.17-103.15]). The youngest (<20 years) and oldest (≥35 years) had insignificantly increased risks (HR 1.45 [CI 0.80-2.62] and HR 1.31 [CI 0.98-1.75], respectively) compared to those aged 20-30 years. Sixteen groups of medications, including anti-infectious medications, hormones, aminosalicylic acid, insulin, and benzodiazepine derivatives, were associated with VTE. CONCLUSION: The risk of antepartum VTE was increased in women with prior VTE. Compared to normal weight women, being underweight decreased the risk of VTE whereas being overweight increased the risk. Also, the use of several medications was associated with increased risk of VTE.

Efficacy and safety of oral semaglutide in Japanese patients with type 2 diabetes: A subgroup analysis by baseline variables in the PIONEER 9 and PIONEER 10 trials.

AIMS/INTRODUCTION: To assess the impact of baseline characteristics on the efficacy and safety of oral semaglutide in Japanese patients with type 2 diabetes. MATERIALS AND METHODS: In the Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) 9 and 10 trials, Japanese patients were randomized to once-daily oral semaglutide (3, 7, or 14 mg) or a comparator (placebo or once-daily subcutaneous liraglutide 0.9 mg in PIONEER 9; once-weekly subcutaneous dulaglutide 0.75 mg in PIONEER 10) for 52 weeks, with 5 weeks of follow up. An exploratory analysis grouped patients in each trial according to baseline glycated hemoglobin (HbA1c ; ≤8.0, >8.0-≤9.0, or >9.0%), body mass index (<25, ≥25-<30, or ≥30 kg/m2 ) and, for PIONEER 10 only, by background medication (sulfonylurea, glinide, thiazolidinedione, α-glucosidase inhibitor, sodium-glucose cotransporter 2 inhibitor). Efficacy (changes from baseline to week 26 in HbA1c and bodyweight) and safety were assessed. RESULTS: Seven hundred and one patients were included (PIONEER 9: N = 243; PIONEER 10: N = 458). In both trials, HbA1c reductions increased as baseline HbA1c increased; there were no other apparent patterns between the variables investigated and HbA1c or bodyweight changes. There was one statistically significant subgroup interaction between baseline HbA1c and estimated treatment differences in bodyweight change for oral semaglutide 14 mg versus placebo in PIONEER 9 (P = 0.0286). Baseline HbA1c , baseline body mass index and background medication did not appear to affect the proportions of patients reporting adverse events. CONCLUSIONS: Oral semaglutide is effective across a range of baseline subgroups of Japanese patients with type 2 diabetes, with no unexpected safety findings.

Reinforcement of the abdominal wall with acellular dermal matrix or synthetic mesh after breast reconstruction with the pedicled transverse rectus abdominis musculocutaneous flap. A prospective double-blind randomized study.

INTRODUCTION: The pedicled transverse rectus abdominis musculocutaneous flap (p-TRAM) is a well-established option for autologous breast reconstruction (BR) but donor-site morbidity is still reported. The aim of the present study was to compare donor-site morbidity after reinforcement of the abdominal wall regarding development of bulging or hernia, abdominal muscle strength, complications, and abdominal pain hypothesizing, that reinforcement with acellular dermal matrix (Strattice™) is superior to reinforcement with synthetic mesh (Prolene®). MATERIALS AND METHODS: A randomized, prospective, double-blind study was conducted with 29 patients admitted for BR with the p-TRAM flap at Department of Plastic Surgery, AUH, Denmark, 2014-2016. Allocation rate 1:1. Follow-up at 4, 12, and 24 months. RESULTS: 24 months postoperatively the computerized tomography verified bulging frequency was 35.7% in the ADM group and 6.7% in the synthetic mesh group (p = 0.11). Two patients (14.3%) in the ADM group and no patients in the synthetic mesh group developed hernia. No significant difference between baseline and 2-year measurement of abdominal muscle strength was observed. CONCLUSION: The present study did not demonstrate any statistically significant differences between treatment groups regarding risk of bulging or hernia, abdominal muscle strength, complications, pain or pain related QoL within two years of follow-up. Although the small sample size sets limitations for drawing wide conclusions the hypothesis that reinforcement with ADM is superior to synthetic mesh cannot be confirmed. Further research into methods for decreasing donor-side morbidity related to the TRAM flap or other rectus abdominis muscle-based flaps is needed.

Comparison of one-stage direct-to-implant with acellular dermal matrix and two-stage immediate implant-based breast reconstruction-a cohort study.

BACKGROUND: The use of acellular dermal matrix (ADM) in one-stage immediate implant-based breast reconstruction (BR) may offer advantages over the two-stage expander-to-implant technique, but literature shows conflicting results. The aim of the present study was to compare these two techniques for immediate implant-based BR regarding postoperative complications, aesthetic correction procedures and aesthetic outcome. METHODS: The study was designed as an observational cohort study with 44 participants admitted for immediate implant-based BR at Department of Plastic Surgery, Aarhus University Hospital, Denmark. 21 patients underwent BR with a one-stage direct-to-implant technique using ADM and 23 patients underwent BR with a two-stage expander-to-implant technique. Follow-up time was 2 years. RESULTS: The risk of implant loss was equal between groups; one-stage group 16% and two-stage group 17% whereas the risk of implant exchange (but not loss of BR) was 13% in the one-stage group compared to 7% in the two-stage group. The risk of at least one major complication were equal between groups; 28% and 24% but the risk of at least one minor complication was significantly higher in the two-stage group (41%) compared to the one-stage group (3%). Number of aesthetic corrections were equally frequent in the two treatment groups (one-stage group 1.8, two-stage group 1.5). Patient and investigator assessed aesthetic outcome was very high in both groups as well as the degree of symmetry between breasts. No capsular contracture Baker grade 3 or 4 was observed. CONCLUSIONS: The present study design sets limitations for drawing wide conclusions. This study did not reveal any significant differences between the two breast reconstructive techniques besides a higher risk of minor complications in the two-stage group, that did, however, not lead to a higher risk of implant loss. With equally high satisfaction with the aesthetic result and no significant difference in number of aesthetic corrections between the two groups we suggest, that the one-stage approach using ADM may be feasible and allows the patient to achieve an implant-based BR with a minimum of surgeries and outpatient visits. The study was registered in ClinicalTrials.gov (NCT04209010).

Thromboembolic and bleeding complications following primary total knee arthroplasty : a Danish nationwide cohort study.

AIMS: The aim of this study is to compare the effectiveness and safety of thromboprophylactic treatments in patients undergoing primary total knee arthroplasty (TKA). METHODS: Using nationwide medical registries, we identified patients with a primary TKA performed in Denmark between 1 January 2013 and 31 December 2018 who received thromboprophylactic treatment. We examined the 90-day risk of venous thromboembolism (VTE), major bleeding, and all-cause mortality following surgery. We used a Cox regression model to compute hazard ratios (HRs) with 95% confidence intervals (CIs) for each outcome, pairwise comparing treatment with dalteparin or dabigatran with rivaroxaban as the reference. The HRs were both computed using a multivariable and a propensity score matched analysis. RESULTS: We identified 27,736 primary TKA patients who received thromboprophylactic treatment (rivaroxaban (n = 18,846); dalteparin (n = 5,767); dabigatran (n = 1,443); tinzaparin (n = 1,372); and enoxaparin (n = 308)). In the adjusted multivariable analysis and compared with rivaroxaban, treatment with dalteparin (HR 0.68 (95% CI 0.49 to 0.92)) or dabigatran (HR 0.31 (95% CI 0.13 to 0.70)) was associated with a decreased risk of VTE. No statistically significant differences were observed for major bleeding or all-cause mortality. The propensity score matched analysis yielded similar results. CONCLUSION: Treatment with dalteparin or dabigatran was associated with a decreased 90-day risk of VTE following primary TKA surgery compared with treatment with rivaroxaban. Cite this article: Bone Joint J 2021;103-B(10):1571-1577.

Validation of registration of pharmacological treatment in the Danish Hip and Knee Arthroplasty Registers.

The aim of this study was to validate registration of pharmacological treatment in the Danish Hip Arthroplasty Register (DHR) and Danish Knee Arthroplasty Register (DKR). We conducted a population-based study in the Capital Region of Denmark, January 2012 to April 2016. Positive predictive value (PPV) and sensitivity were calculated with 95% confidence intervals (CI) for antithrombotic, antihemorrhagic and antibiotic treatment registered in the DHR and DKR using electronic health records as the reference standard. For the DHR, the PPV and sensitivity were 77.9% (95% CI: 77.2-78.6) and 99.6% (95% CI: 99.4-99.7) for antithrombotic treatment, 70.9% (95% CI: 70.1-71.7) and 97.4% (95% CI: 97.1-97.7) for antihemorrhagic treatment, and 82.9% (95% CI: 82.2-83.5) and 99.4% (95% CI: 99.3-99.5) for antibiotic treatment, respectively. For the DKR, the PPV and sensitivity were 80.6% (95% CI: 79.8-81.4) and 99.6% (95% CI: 99.4-99.7) for antithrombotic treatment, and 84.4% (95% CI: 83.7-85.1) and 100.0% (95% CI: 99.9-100.0) for antibiotic treatment, respectively. The PPV and sensitivity for overall pharmacological treatment registered in the DHR and DKR were generally high and acceptable for use in research.

No effect of autologous growth factors (AGF) around ungrafted loaded implants in dogs.

Autologous growth factors (AGF) is a growth-factor-rich concentrate of platelets, white blood cells and fibrinogen. Application of AGF was presumed to improve implant fixation and gap healing of non-grafted, loaded implants. We inserted one loaded titanium implant intra-articularly in each medial femoral condyle of eight dogs. Each implant was surrounded by a 0.75 mm gap. One implant in each dog was coated with AGF prior to implantation whereas the contralateral implant served as a control. AGF was prepared by isolating the buffy-coat from blood and further concentrated using an Interpore Cross UltraConcentrator. Platelet counts were increased from a median baseline of 168x10(3)/microl to 1003x10(3)/microl in AGF. However, AGF had no significant effect on implant fixation or bone formation. Even though AGF increased ultimate shear strength and energy absorption by approximately 50%, these differences had a p-value less than 0.05. The sample size in this study was small and any negative conclusions should be taken with caution due to low statistical power. We have previously demonstrated that AGF significantly improves fixation and incorporation of grafted implants. AGF might require mixing with an osteoconductive grafting material in order to provide a scaffold on which to foster bone growth and to keep the growth factors on location for a prolonged period.

Real-world effectiveness and safety of pharmacological thromboprophylaxis in patients undergoing primary total hip and knee arthroplasty: A narrative review.

In this narrative review of the real-world effectiveness and safety of pharmacological thromboprophylaxis following primary total hip and knee arthroplasty, a total of 12 non-interventional observational studies were included. Pharmacological thromboprophylaxis included warfarin, heparins, dabigatran, rivaroxaban, apixaban, acetylsalicylic acid, and fondaparinux. The absolute risks varied across the included studies. These variations can be explained by differences in patient populations, drug exposure, follow-up time, and definition of outcomes, which makes it a challenge to compare the risk estimates. These findings emphasize the need for a large population-based real-world study to provide comparable risk estimates associated with different pharmacological thromboprophylaxis.

Glycemic control and use of glucose-lowering medications in hospital-admitted type 2 diabetes patients over 80 years.

Treatment guidelines for type 2 diabetes (T2D) recommend avoidance of hypoglycemia and less stringent glycemic control in older patients. We examined the relation of glycemic control to glucose-lowering medications use in a cohort of patients aged>80 years with a diagnosis of T2D and a hospital admission in the Capital Region of Denmark in 2012-2016. We extracted data on medication use, diagnoses, and biochemistry from the hospitals' records. We identified 5,172 T2D patients with high degree of co-morbidity and where 17% had an HbA1c in the range recommended for frail, comorbid, older patients with type 2 diabetes (58-75 mmol/mol (7.5-9%)). Half of the patients (n = 2,575) had an HbA1c <48 mmol/mol (<6.5%), and a majority of these (36% of all patients) did not meet the diagnostic criteria for T2D. Of patients treated with one or more glucose-lowering medications (n = 1,758), 20% had HbA1c-values <42 mmol/mol (<6%), and 1% had critically low Hba1c values <30 mmol/mol (<4.9%), In conclusion, among these hospitalized T2D patients, few had an HbA1c within the generally recommended glycemic targets. One third of patients did not meet the diagnostic criteria for T2D, and of the patients who were treated with glucose-lowering medications, one-fifth had HbA1c-values suggesting overtreatment.

Hemodynamic Effects of Intravenous, High-Dose Lipid Emulsion With and Without Metoprolol Infusion in Healthy Volunteers: A Randomized Clinical Trial.

In a double-blinded, randomized, crossover trial, we investigated the hemodynamic effects of high-dose intravenous lipid emulsion (ILE) with/without metoprolol. Ten healthy volunteers each completed 4 trial days (placebo + ILE; metoprolol + placebo; metoprolol + ILE; placebo + placebo) in random order. Metoprolol was administered as an initial bolus (10 mg), followed by an infusion (50 mg) from 5 to 30 minutes. ILE was administered as a bolus at 12.5 minutes (2.5 mL/kg), followed by a 15-minute infusion (0.25 mL/kg per minute). On metoprolol + ILE days (compared with metoprolol + placebo) after 120 minutes, mean heart rates were significantly higher (difference, 5.5 beats per minute (bpm); 95% confidence interval (CI), 3.0-8.1 bpm; P < 0.001), and average relative cardiac output was higher (difference, 10 percentage points; 95% CI, 5-15 percentage points; P < 0.001). The hemodynamic effect of ILE developed gradually. ILE had no effect on plasma metoprolol or major adverse events. In conclusion, high-dose ILE has relatively marginal and delayed hemodynamic effects that may have limited clinical relevance in the short-term clinical toxicological setting.

Changing Infliximab Prescription Patterns in Inflammatory Bowel Disease: A Population-Based Cohort Study, 1999-2014.

Background: Long-term data on real life use of infliximab (IFX) for inflammatory bowel disease (IBD) are lacking. We studied prescription patterns during the first 16 years following marketing authorization. Methods: In a population-based cohort from the North Denmark Region, all IBD patients exposed to IFX during 1999 to 2014 were identified. Results: A total of 623 patients (210 with ulcerative colitis [UC] and 413 with Crohn's disease [CD]) were exposed to IFX. In patients with UC, age at first exposure decreased by 10 months per calendar year (P < 0.05) during the study period. In patients with CD, disease duration at time of first IFX exposure decreased by 7 months per calendar year (P < 0.001). From 2005-2009 to 2010-2014, the proportion of IFX-exposed patients with pancolitis (40% vs 24%, P = 0.04) and the proportion of patients with extensive CD (P = 0.002) decreased. The mean time to discontinuation of IFX remained stable in patients with CD during the study period (2.5-3.0 years) and increased from 0.34 years (2005-2009) to 1.11 years (2010-2015) in patients with UC (P = 0.04). Conclusion: During the first 16 years postmarketing, age at first exposure to IFX decreased in patients with UC, whereas disease duration at time of first exposure decreased in patients with CD. Also, a significant change toward less extensive disease in both UC and CD patients exposed to IFX was observed. Treatment duration in patients with UC increased during the study period, but did not reach the more constant and longer duration of treatment observed in patients with CD.

Risk of Adverse Pregnancy Outcome After Paternal Exposure to Methotrexate Within 90 Days Before Pregnancy.

OBJECTIVE: To study the association between paternal exposure to methotrexate within the 90-day period before pregnancy and congenital malformations and stillbirth in the offspring. METHODS: We conducted a nationwide register study. Our cohort consisted of all live births in Denmark between 1997 and 2011 identified from the Medical Birth Registry. Methotrexate-exposed fathers were identified from the National Prescription Registry. From the national Hospital Registry we identified paternity, live births, and stillbirths as well as discharge diagnoses on congenital malformations. RESULTS: We identified 849,676 live births with known paternity. There were 127 live births of methotrexate-exposed fathers. Of these, four (3.2%) had major malformations compared with 28,814 (3.4%) of the unexposed. The odds ratio (OR) for major congenital malformation among exposed fathers compared with unexposed was 0.93 (95% confidence interval [CI] 0.34-2.51) and when adjusted for year of birth, maternal age, educational length, household income, and parity, the adjusted OR was 1.01 (95% CI 0.37-2.74). There were no stillbirths in the methotrexate-exposed group compared with 2,541 (0.3%) in the unexposed group and no increased risk of preterm birth (adjusted OR 1.31, 95% CI 0.66-2.59) among the children from exposed fathers. CONCLUSION: We found no association between paternal exposure to methotrexate within 90 days before pregnancy and congenital malformations, stillbirths, or preterm birth. Available data suggest that prepregnancy paternal methotrexate exposure should not be of major concern. Multinational recommendations should be changed accordingly.

Delayed total breast reconstruction with brava.

Several surgical procedures exist in regard to reconstruction of the breast after mastectomy. The use of Brava a vacuum-based external soft-tissue expansion system in combination with fat transplantation is a less documented but viable option in treating patients after mastectomy. We share our experience in treating a 57-year-old patient with mastectomy, describing the complications and pitfalls we experienced when using the Brava system in combination with fat transplantation.