Validation of algorithms in studies based on routinely collected health data: general principles.

Clinicians, researchers, regulators, and other decision-makers increasingly rely on evidence from real-world data (RWD), including data routinely accumulating in health and administrative databases. RWD studies often rely on algorithms to operationalize variable definitions. An algorithm is a combination of codes or concepts used to identify persons with a specific health condition or characteristic. Establishing the validity of algorithms is a prerequisite for generating valid study findings that can ultimately inform evidence-based health care. This paper aims to systematize terminology, methods, and practical considerations relevant to the conduct of validation studies of RWD-based algorithms. We discuss measures of algorithm accuracy; gold/reference standard; study size; prioritizing accuracy measures; algorithm portability; and implication for interpretation. Information bias is common in epidemiologic studies, underscoring the importance of transparency in decisions regarding choice and prioritizing measures of algorithm validity. The validity of an algorithm should be judged in the context of a data source, and one size does not fit all. Prioritizing validity measures within a given data source depends on the role of a given variable in the analysis (eligibility criterion, exposure, outcome or covariate). Validation work should be part of routine maintenance of RWD sources.

Risk of progression of cervical intraepithelial neoplasia grade 2 in human papillomavirus-vaccinated and unvaccinated women: a population-based cohort study.

BACKGROUND: Many countries have implemented active surveillance (ie, leaving the lesion untreated) as an option among younger women with cervical intraepithelial neoplasia grade 2 because regression rates are high and excisional treatment increases the risk for preterm birth in subsequent pregnancies. However, early identification of women at increased risk for progression to cervical intraepithelial neoplasia grade 3 or worse is important to ensure timely treatment. Because women who have received a human papillomavirus vaccine have a lower risk for cervical cancer, they may have a lower risk for progression of untreated cervical intraepithelial neoplasia grade 2 to cervical intraepithelial neoplasia grade 3 or worse. OBJECTIVE: This study aimed to investigate if women who received a human papillomavirus vaccine and who are undergoing active surveillance for cervical intraepithelial neoplasia grade 2 are less likely to progress to cervical intraepithelial neoplasia grade 3 or worse when compared with women who did not receive the vaccine. STUDY DESIGN: We conducted a population-based cohort study in Denmark using data from national health registers. We identified all women aged 18 to 40 years who were undergoing active surveillance for cervical intraepithelial neoplasia grade 2 from January 1, 2007, to December 31, 2020. Women with a previous record of cervical intraepithelial neoplasia grade 2 or worse, hysterectomy, or a loop electrosurgical excision procedure were excluded. Exposure was defined as having received ≥1 dose of a human papillomavirus vaccine at least 1 year before the cervical intraepithelial neoplasia grade 2 diagnosis. We used cumulative incidence functions to estimate the risk for progression to cervical intraepithelial neoplasia grade 3 or worse within 28 months using hysterectomy, emigration, and death as competing events. We used modified Poisson regression to calculate crude and adjusted relative risks of progression during the 28-month surveillance period. Results were stratified by age at vaccination and adjusted for index cytology, disposable income, and educational level. RESULTS: The study population consisted of 7904 women of whom 3867 (48.9%) were vaccinated at least 1 year before a diagnosis of cervical intraepithelial neoplasia grade 2. At the time of cervical intraepithelial neoplasia grade 2 diagnosis, women who were vaccinated were younger (median age, 25 years; interquartile range, 23-27 years) than those who were not (median age, 29 years; interquartile range, 25-33 years). The 28-month cumulative risk for cervical intraepithelial neoplasia grade 3 or worse was significantly lower among women who were vaccinated before the age of 15 years (22.9%; 95% confidence interval, 19.8-26.1) and between the ages of 15 and 20 years (31.5%; 95% confidence interval, 28.8-34.3) when compared with women who were not vaccinated (37.6%; 95% confidence interval, 36.1-39.1). Thus, when compared with women who were not vaccinated, those who were vaccinated before the age of 15 years had a 35% lower risk for progression to cervical intraepithelial neoplasia grade 3 or worse (adjusted relative risk, 0.65; 95% confidence interval, 0.57-0.75), whereas women who were vaccinated between the ages of 15 and 20 years had a 14% lower risk (adjusted relative risk, 0.86; 95% confidence interval, 0.79-0.95). For women who were vaccinated after the age of 20 years, the risk was comparable with that among women who were not vaccinated (adjusted relative risk, 1.02; 95% confidence interval, 0.96-1.09). CONCLUSION: Women who were vaccinated and who were undergoing active surveillance for cervical intraepithelial neoplasia grade 2 had a lower risk for progression to cervical intraepithelial neoplasia grade 3 or worse during 28 months of follow-up when compared with women who were not vaccinated but only if the vaccine was administered by the age of 20 years. These findings may suggest that the human papillomavirus vaccination status can be used for risk stratification in clinical management of cervical intraepithelial neoplasia grade 2.

Preterm Birth Following Active Surveillance vs Loop Excision for Cervical Intraepithelial Neoplasia Grade 2.

Importance: Active surveillance for cervical intraepithelial neoplasia grade 2 (CIN2) is being implemented in many high-income countries due to the association of excisional treatment with preterm birth. However, it is unknown whether active surveillance results in lower risk of preterm birth given that cervical dysplasia itself is associated with higher risk of preterm birth. Objective: To compare the preterm birth risk between women with CIN2 undergoing active surveillance or immediate loop electrosurgical excision procedure (LEEP). Design, Setting, and Participants: This historical population-based cohort study included women with a first-time diagnosis of CIN2 and a subsequent singleton birth from 1998 to 2018 in Denmark. Women with prior CIN grade 3 or greater or LEEP were excluded. Data were collected from 4 Danish health care registries. Analyses were conducted from October 2022 to June 2023. Exposure: Women were categorized into active surveillance (cervical biopsy and/or cytology) or immediate LEEP based on their first cervical sample after CIN2 diagnosis. The active surveillance group was further subdivided based on whether a delayed LEEP was performed within 28 months from CIN2 diagnosis. Main Outcomes and Measures: Risk of preterm birth (<37 + 0 weeks) was assessed and relative risks (RRs) were calculated using modified Poisson regression. Analyses used inverse probability treatment weighting of the propensity scores to adjust for age, parity, calendar year, index cytology, and smoking. Results: A total of 10 537 women with CIN2 and a singleton birth were identified; 4430 (42%) underwent active surveillance and 6107 (58%) were treated with immediate LEEP. For both groups, most were aged 23 to 29 years at CIN2 diagnosis (3125 [70%] and 3907 [64%], respectively). Overall, 869 births (8.2%) were preterm. The risk of preterm birth was comparable between active surveillance and immediate LEEP (RR, 1.03; 95% CI, 0.90-1.18). However, for women undergoing delayed LEEP after active surveillance (1539 of the active surveillance group [35%]), the risk of preterm birth was higher than for women treated with immediate LEEP (RR, 1.29; 95% CI, 1.08-1.55). Conclusions and relevance: In this cohort study of women with CIN2, the risk of preterm birth was comparable between active surveillance and immediate LEEP. However, delayed LEEP was associated with 30% higher risk of preterm birth than immediate LEEP. Thus, risk stratification at CIN2 diagnosis is important to identify women with increased risk of delayed LEEP.

Human papillomavirus genotypes and risk of persistence and progression in women undergoing active surveillance for cervical intraepithelial neoplasia grade 2.

BACKGROUND: In recent years, active surveillance has been introduced as an alternative to excisional treatment in younger women with cervical intraepithelial neoplasia grade 2 because regression rates are high and excisional treatment is associated with increased risk of preterm birth. However, early identification of women at increased risk of persistence/progression is important to ensure timely treatment. Evidence is limited on biomarkers that may be used to identify women at increased risk of persistence/progression. OBJECTIVE: This study aimed to describe human papillomavirus HPV type-specific persistence/progression in women undergoing active surveillance for cervical intraepithelial neoplasia grade 2. STUDY DESIGN: We conducted a historical cohort study of women aged 23 to 40 years diagnosed with cervical intraepithelial neoplasia grade 2 at Aarhus University Hospital from 2000 to 2010. Women were identified through the Danish Pathology Data Bank (DPDB) and were considered as undergoing active surveillance if they had a first record of a cervical biopsy within 2 years after index diagnosis and no loop electrosurgical excision procedure before this. Human papillomavirus genotyping was performed on archived tissue samples using the HPV SPF10-DEIA-LiPA25 system (DNA ELISA [enzyme-linked immunosorbent assay] HPV SPF10 kit and RHA HPV SPF10-LiPA25 kit). Persistence/progression was defined as having a record of cervical intraepithelial neoplasia grade ≥2 in the DPDB determined on the last and worst diagnosis on a biopsy or loop electrosurgical excision procedure specimen during follow-up. We estimated the relative risk (95% confidence interval) of persistence/progression using a modified Poisson model. RESULTS: A total of 455 women were included. Two-thirds were aged ≤30 years (73.8%) at index diagnosis, and nearly half had a high-grade index cytology (48.8%). Overall, 52.2% of all women had cervical intraepithelial neoplasia grade ≥2 during follow-up; 70.5% were human papillomavirus-16-positive and 29.5% were positive for other human papillomavirus types. Human papillomavirus-16 was associated with a significantly higher risk of persistence/progression (relative risk, 1.64; 95% confidence interval, 1.37-1.95) compared with non-human papillomavirus-16. The risk of persistence/progression was highest in human papillomavirus-16-positive women with a high-grade index cytology compared with human papillomavirus-16-positive women with a low-grade cytology (relative risk, 1.29; 95% confidence interval, 1.03-1.61), whereas no differences were observed across age groups. CONCLUSION: The highest risk of persistence/progression was observed among human papillomavirus-16-positive women, particularly those with associated high-grade cytology. These findings suggest that early excisional treatment should be considered in this group of women.

Long-term outcomes after coronary intervention with biodegradable polymer stents in patients with acute coronary syndromes.

BACKGROUND: Patients with acute coronary syndromes (ACS) may have worse outcomes after percutaneous coronary intervention compared to patients without ACS. AIMS: To compare 5-year efficacy and safety outcomes in patients with and without ACS treated with biodegradable polymers, the ultrathin strut sirolimus-eluting Orsiro stent (O-SES) or the biolimus-eluting Nobori stent (N-BES). METHODS: The Scandinavian Organisation for Randomized Trials with Clinical Outcome VII is a randomized trial comparing O-SES and N-BES in an all-comer setting. Of 2525 patients, 1329 (53%) patients had ACS and 1196 (47%) patients were without ACS. Endpoints were target lesion failure (TLF) (a composite of cardiac death, target lesion myocardial infarction, or target lesion revascularization) and definite stent thrombosis within 5 years. RESULTS: At 5-year follow-up, TLF did not differ significantly between patients with and without ACS (12.3% vs. 13.2%; rate ratio (RR) 1.00; 95% confidence interval (CI): 0.70-1.44), whereas the risk of definite stent thrombosis was increased in patients with ACS (2.3% vs. 1.3; RR: 2.01 [95% CI: 1.01-3.98]). In patients with ACS, the rate of TLF was similar between O-SES and N-BES (12.4% vs. 12.3%; RR: 1.02; 95% CI: 0.74-1.40). The reduced risk of definite stent thrombosis in O-SES treated ACS patients within the first year (0.2% vs. 1.6%; RR: 0.12; 95% CI: 0.02-0.93) was not maintained after 5 years (1.8% vs. 2.7%; RR: 0.77; 95% CI: 0.37-1.63). CONCLUSION: Patients with ACS had an increased risk of stent thrombosis regardless of the stent type used. Long-term outcomes were similar for ACS patients treated with O-SES or N-BES at 5 years.

Untreated cervical intraepithelial neoplasia grade 2 and subsequent risk of cervical cancer: population based cohort study.

OBJECTIVE: To describe the long term risk of cervical cancer in women with untreated (that is, undergoing active surveillance) or immediately treated cervical intraepithelial neoplasia grade 2 (CIN2). DESIGN: Nationwide population based historical cohort study. SETTING: Danish healthcare registries. PARTICIPANTS: Women with CIN2 diagnosed in 1998-2020 and aged 18-40 years at diagnosis, who had either active surveillance or immediate treatment with large loop excision of the transformation zone (LLETZ). Women with a previous record of CIN2 or worse or LLETZ were excluded. MAIN OUTCOME MEASURE: A Weibull survival model for interval censored time-to-event data was used to estimate the cumulative risk of cervical cancer. Inverse probability treatment weighting was used to adjust estimates for age, index cytology, calendar year, and region of residence. RESULTS: The cohort included 27 524 women with CIN2, of whom 12 483 (45%) had active surveillance and 15 041 (55%) had immediate LLETZ. During follow-up, 104 cases of cervical cancer were identified-56 (54%) in the active surveillance group and 48 (46%) in the LLETZ group. The cumulative risk of cervical cancer was comparable across the two groups during the active surveillance period of two years. Thereafter, the risk increased in the active surveillance group, reaching 2.65% (95% confidence interval 2.07% to 3.23%) after 20 years, whereas it remained stable in the LLETZ group at 0.76% (0.58% to 0.95%). CONCLUSIONS: Undergoing active surveillance for CIN2, thereby leaving the lesion untreated, was associated with increased long term risk of cervical cancer compared with immediate LLETZ. These findings show the importance of continued follow-up of women having active surveillance.

10-Year Cardiovascular Risk in Patients With Newly Diagnosed Type 2 Diabetes Mellitus.

BACKGROUND: Contemporary data on cardiovascular disease (CVD) risk in patients with newly diagnosed type 2 diabetes mellitus (T2DM) is needed to guide appropriate preventive management. OBJECTIVES: The authors sought to investigate sex- and age-specific 10-year CVD risk in patients with newly diagnosed T2DM compared with the general population. METHODS: A cohort study was conducted of all Danish patients with T2DM diagnosed between 2006 and 2013 (n = 142,587) and sex- and age-matched individuals from the general population (n = 388,410), all without prior atherosclerotic CVD. Ten-year CVD risk (myocardial infarction, stroke, and fatal CVD) was estimated. RESULTS: A total of 52,471 CVD events were recorded. Compared with the general population, the 10-year CVD risks were higher in patients with T2DM in both sexes and across all age groups, especially among younger individuals. For example, patients aged 40 to 49 years had the largest 10-year CVD risk difference (T2DM 6.1% vs general population 3.3%; risk difference: 2.8%, subdistribution HR: 1.91; 95% CI: 1.76-2.07). The age when a given CVD risk was reached differed substantially between the cohorts. Thus, a 10-year CVD risk of 5% was reached at age 43 in men with T2DM compared with 12 years later, at age 55, in men without T2DM. A 10-year CVD risk of 5% was reached at age 51 in women with T2DM and 10 years later, at age 61, in women without T2DM. CONCLUSIONS: Newly diagnosed T2DM increased 10-year CVD risk across both sexes and all age groups, especially among younger patients, with CVD occurring ≤12 years earlier than in general population individuals.

Clinical course of cervical intraepithelial neoplasia grade 2: a population-based cohort study.

BACKGROUND: Cervical intraepithelial neoplasia grade 2 has historically been the threshold for surgical excision, but because of high regression rates, many countries are transitioning to active surveillance. However, estimates for regression rates are based on small studies with heterogeneous definitions of regression and progression. OBJECTIVE: This study aimed to describe regression and progression rates of cervical intraepithelial neoplasia grade 2 using nationwide healthcare registry data. STUDY DESIGN: This was a nationwide population-based cohort study on women aged 18 to 40 years who had undergone active surveillance for cervical intraepithelial neoplasia grade 2 in Denmark from 1998 to 2020. This study excluded women with a previous record of cervical intraepithelial neoplasia grade 2 or worse or surgical excision. Cumulative incidence functions were used to estimate the rates of regression and progression at 6, 12, 18, and 24 months after diagnosis. In addition, a modified Poisson regression was used to estimate the crude and adjusted relative risks of progression within 24 months stratified by index cytology and age. RESULTS: During the study period, 11,056 women underwent active surveillance, 6767 of whom regressed and 3580 of whom progressed within 24 months. This corresponded to regression rates of 62.9% (95% confidence interval, 61.9-63.8) and progression rates of 33.3% (95% confidence interval, 32.4-34.2) at 24 months of follow-up. Most women regressed (90%) or progressed (90%) within the first 12 months. Women with high-grade index cytology had a higher risk of progression than women with normal index cytology (adjusted relative, 1.58; 95% confidence interval, 1.43-1.76), whereas there was no difference in the risk of progression between women aged 30 and 40 years and women aged 23 to 29 years (adjusted relative risk, 0.98; 95% confidence interval, 0.88-1.10). CONCLUSION: The observed high regression rates of cervical intraepithelial neoplasia grade 2 supported the transition in clinical management from surgical excision to active surveillance, particularly among women with low-grade or normal index cytology.

Dual-therapy CD34 antibody-covered sirolimus-eluting COMBO stents versus sirolimus-eluting Orsiro stents in patients treated with percutaneous coronary intervention: the three-year outcomes of the SORT OUT X randomised clinical trial.

BACKGROUND: Target lesion failure (TLF) remains an issue with contemporary drug-eluting stents. The dual-therapy sirolimus-eluting and CD34 antibody-coated COMBO stent (DTS) was designed to improve early healing. AIMS: We aimed to compare the 3-year outcomes of the DTS and the sirolimus-eluting Orsiro stent (SES) in all-comer patients treated with percutaneous coronary intervention. METHODS: The SORT OUT X trial is a prospective multicentre randomised clinical trial with a registry-based follow-up comparing DTS and SES. The primary endpoint, TLF, is a composite of cardiac death, myocardial infarction or target lesion revascularisation (TLR). RESULTS: A total of 3,146 patients were randomised to treatment with the DTS (1,578 patients) or the SES (1,568 patients). At 3 years, an intention-to-treat analysis showed that 155 patients (9.8%) who were assigned the DTS and 118 patients (7.5%) who were assigned the SES met the primary endpoint (incidence rate ratio for TLF=1.33, 95% confidence interval: 1.04-1.70; p=0.02). This difference was caused by a significantly higher TLF rate in the DTS group compared to the SES group within the first year, which was mainly explained by a higher incidence of TLR in the DTS group compared to the SES group. Of note, the TLF rates were almost identical from 1 year to 3 years in both stent groups. CONCLUSIONS: At 3 years, the SES was superior to the DTS, mainly because the DTS was associated with an increased risk of TLF within the first year but not from 1 to 3 years. CLINICALTRIALS: gov: NCT03216733.

Triglycerides and risk of cardiovascular events in statin-treated patients with newly diagnosed type 2 diabetes: a Danish cohort study.

BACKGROUND: Elevated triglyceride levels are a clinically useful marker of remnant cholesterol. It is unknown whether triglycerides are associated with residual cardiovascular risk in CVD-naïve patients with newly diagnosed type 2 diabetes mellitus (T2DM), who are already on statin therapy. We aimed to assess the association between triglyceride levels and risk of major cardiovascular events (MACE) in statin-treated patients with newly diagnosed T2DM managed in routine clinical care. METHODS: This cohort study included newly diagnosed T2DM patients without a previous diagnosis of cardiovascular disease in Northern Denmark during 2005-2017. Individual triglyceride levels while on statin treatment were assessed within 1 year after T2DM diagnosis. The primary outcome was a composite of myocardial infarction, ischemic stroke, or cardiac death (MACE). Patients were followed from one year after T2DM diagnosis until 30 April 2021, MACE, emigration, or death. We used Cox regression to compute hazard ratios (HRs) controlling for confounding factors. RESULTS: Among 27,080 statin-treated patients with T2DM (median age 63 years; 53% males), triglyceride levels were < 1.0 mmol/L in 17%, 1.0-1.9 mmol/L in 52%, 2.0-2.9 mmol/L in 20%, and ≥ 3.0 mmol/L in 11%. During follow-up, 1,957 incident MACE events occurred (11.0 per 1000 person-years). Compared with triglyceride levels < 1.0 mmol/L, confounder-adjusted HRs for incident MACE were 1.14 (95% CI 1.00-1.29) for levels between 1.0 and 1.9 mmol/L, 1.30 (95% CI 1.12-1.51) for levels between 2.0 and 2.9 mmol/L, and 1.44 (95% CI 1.20-1.73) for levels ≥ 3.0 mmol/L. This association was primarily driven by higher rates of myocardial infarction and cardiac death and attenuated only slightly after additional adjustment for LDL cholesterol. Spline analyses confirmed a linearly increasing risk of MACE with higher triglyceride levels. Stratified analyses showed that the associations between triglyceride levels and MACE were stronger among women. CONCLUSIONS: In statin-treated patients with newly diagnosed T2DM, triglyceride levels are associated with MACE already from 1.0 mmol/L. This suggests that high triglyceride levels are a predictor of residual cardiovascular risk in early T2DM and could be used to guide allocation of additional lipid-lowering therapies for CVD prevention.

Five-Year Clinical Outcome of the Biodegradable Polymer Ultrathin Strut Sirolimus-Eluting Stent Compared to the Biodegradable Polymer Biolimus-Eluting Stent in Patients Treated With Percutaneous Coronary Intervention: From the SORT OUT VII Trial.

BACKGROUND: Biodegradable polymer drug-eluting stents were developed to improve safety and efficacy outcomes for patients undergoing percutaneous coronary intervention. However, few long-term follow-up efficacy studies are available. The study sought to investigate 5-year results from the SORT OUT VII trial (Scandinavian Organization for Randomized Trials With Clinical Outcome) comparing the biodegradable polymer ultrathin-strut sirolimus-eluting Orsiro stent (O-SES) versus the biodegradable polymer biolimus-eluting Nobori stent (N-BES). METHODS: This registry-based, randomized, multicenter, single-blinded, noninferiority trial compared O-SES and N-BES in an all-comer population. The composite primary end point, target lesion failure, consisted of cardiac death, myocardial infarction related to the target lesion, or target lesion revascularization within 1 year. Follow-up was extended to 5 years. RESULTS: Five-year follow-up was completed for 2521 patients (99.8%). Five-year target lesion failure did not differ between O-SES (12.4%) and N-BES (13.1%; rate ratio [RR], 0.94 [95% CI, 0.75-1.18]). Cardiac death (RR, 0.95 [95% CI, 0.67-1.34]), target myocardial infarction (RR, 1.14 [95% CI, 0.76-1.71]), target lesion revascularization (RR, 0.90 [95% CI, 0.67-1.21]), and definite stent thrombosis rates (RR, 0.73 [95% CI, 0.41-1.33]) did not differ significantly between the 2 stents. Within the first year, definite ST was significantly lower for O-SES (0.4%) compared to N-BES (1.2%; RR, 0.33 [95% CI, 0.12-0.92]), but no difference was from 1 through 5 years: O-SES 1.2% and N-BES 0.9% (RR, 1.28 [95% CI, 0.58-2.82]). CONCLUSIONS: Five years after treatment with biodegradable polymer stents, target lesion failure did not differ among O-SES and N-BES. Definite stent thrombosis was less often seen within the first year in the O-SES but the difference was not maintained after 5 years. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT01879358.

Impact of acute coronary syndrome on clinical outcomes after revascularization with the dual-therapy CD34 antibody-covered sirolimus-eluting Combo stent and the sirolimus-eluting Orsiro stent.

OBJECTIVES: To compare the efficacy and safety of the dual-therapy CD34 antibody-covered sirolimus-eluting Combo stent (DTS) and the sirolimus-eluting Orsiro stent (O-SES) in patients with and without acute coronary syndrome (ACS) included in the SORT OUT X study. BACKGROUND: The incidence of target lesion failure (TLF) after treatment with modern drug-eluting stents has been reported to be significantly higher in patients with ACS when compared to patients without ACS. Whether the results from the SORT OUT X study apply to patients with and without ACS remains unknown. METHODS: In total, 3146 patients were randomized to stent implantation with DTS (n = 1578; ACS: n = 856) or O-SES (n = 1568; ACS: n = 854). The primary end point, TLF, was a composite of cardiac death, target-lesion myocardial infarction (MI), or target lesion revascularization (TLR) within 1 year. RESULTS: At 1 year, the rate of TLF was higher in the DTS group compared to the O-SES group, both among patients with ACS (6.7% vs. 4.1%; incidence rate ratio: 1.65 [95% confidence interval, CI: 1.08-2.52]) and without ACS (6.0% vs. 3.2%; incidence rate ratio: 1.88 [95% CI: 1.13-3.14]). The differences were mainly explained by higher rates of TLR, whereas rates of cardiac death and target lesion MI did not differ significantly between the two stent groups in patients with or without ACS CONCLUSION: Compared to the O-SES, the DTS was associated with a higher risk of TLF at 12 months in patients with and without ACS. The differences were mainly explained by higher rates of TLR.

Healthcare Resource Utilization and Costs for Empagliflozin Versus Glucagon-Like Peptide-1 Receptor Agonists in Routine Clinical Care in Denmark.

INTRODUCTION: The sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin has shown reductions in major adverse cardiac events similar to glucagon-like peptide-1 receptor agonists (GLP-1RAs). However, evidence is limited about how these therapies compare regarding overall healthcare resource utilization and costs in routine clinical care. METHODS: We conducted a comparative cohort study based on linked prospective healthcare databases for the entire population of Denmark during 2015-2018. We included 13,747 new users of empagliflozin and 13,249 new users of GLP-1RAs. Propensity scores were applied to balance potential confounders across the two treatment groups through inverse probability treatment weighting (IPTW). We assessed directly referable costs per person-year associated with healthcare resource utilization (inpatient, emergency room, and outpatient clinic hospital care, primary care health services, and prescription medication costs at pharmacies) among drug initiators while on-treatment. RESULTS: The two IPTW cohorts were well balanced at baseline (median age 61 years, 60% men, diabetes duration 6.7 years, 19% with pre-existing ischemic heart disease, 8% with pre-existing cerebrovascular disease), with similar healthcare costs in the previous year. During follow-up, average on-treatment costs per person-year were very similar among empagliflozin and GLP-1 RA initiators for the following services: inpatient hospitalizations (13,565 DKK versus 13,275 DKK), hospital outpatient clinic visits (12,007 DKK versus 12,152 DKK), emergency room visits (370 DKK versus 399 DKK), and primary care services (4108 DKK versus 4302 DKK). Total costs for any prescription drugs were clearly lower for empagliflozin initiators than for GLP-1 RA initiators (8946 DKK versus 14,029 DKK). In sum, overall healthcare costs on-treatment were lower for empagliflozin initiators (38,995 DKK per person-year) than for GLP-1RA initiators (44,157 DKK per person-year). CONCLUSIONS: In this nationwide population-based cohort study, average healthcare costs after drug initiation and while on treatment were lower for empagliflozin initiators than for GLP-1RAs initiators, driven by lower drug costs. REGISTRATION: The study protocol and analysis plan have been registered on the website of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) ( http://www.encepp.eu/encepp/viewResource.htm?id=37726 , first protocol registration 4 June 2019), and on clinicaltrials.gov ( https://clinicaltrials.gov/ct2/show/NCT03993132 , first posted 20 June 2019).

Performance of HPV E4 and p16INK4a biomarkers in predicting regression of cervical intraepithelial neoplasia grade 2 (CIN2): protocol for a historical cohort study.

INTRODUCTION: Cervical intraepithelial neoplasia grade 2 (CIN2) represents a spectrum of lesions with variable progression and regression. Pathological diagnosis of CIN2 is subjective and poorly reproducible. Accurate diagnosis and identification of different patterns of CIN2 related to outcome are essential to reduce the risks of overtreatment or undertreatment. It is important to explore novel methods for risk stratification of CIN2 to enable targeted treatment of women at high risk of progression or persistent disease and follow-up of women at low risk. The combination of the novel biomarker human papillomavirus (HPV) E4 with p16INK4a targets steps in the transition from a productive oncogenic HPV infection (CIN1) to a transformed lesion (CIN3) within CIN2. Previous cross-sectional studies suggest that HPV E4 combined with p16INK4a may be valuable for risk assessment of CIN2. However, data on HPV E4/p16INK4a as a predictor for CIN2 regression is lacking. METHODS AND ANALYSIS: We will conduct a historical cohort study including 500 women aged 23-40 years with a first CIN2 diagnosis in Aarhus, Denmark during 2000-2010. Women will be eligible if they have undergone active surveillance and have no previous record of hysterectomy, cone biopsy, and CIN2 or worse. Women will be randomly selected through the Danish Pathology Databank. Tissue samples from women included will be sectioned for p16INK4a and HPV E4 immunohistochemical staining in addition to conventional hematoxylin and eosin (H&E) staining. A positive result will be defined as HPV E4 positive. Through the Danish Pathology Databank, we will collect results on all subsequent cervical biopsies. Regression will be used as the primary outcome. ETHICS AND DISSEMINATION: The study has been approved by the Ethical Committee in Central Denmark Region (1-10-72-60-20) and registered at the Faculty of Health, Aarhus University. Results will be published in a peer-reviewed journal and presented at scientific meetings. TRIAL REGISTRATION NUMBER: NCT05049252.

Twenty-Year Temporal Trends in Risk of Ischemic Stroke in Incident Type 2 Diabetes: A Danish Population-Based Cohort Study.

OBJECTIVE: We examined temporal trends in risk of first-time ischemic stroke in patients with incident type 2 diabetes mellitus (T2DM) and no prior atherosclerotic cardiovascular disease (ASCVD). RESEARCH DESIGN AND METHODS: Using nationwide health registries, we identified all patients with incident T2DM without a prior hospital diagnosis of ASCVD from 1996 to 2015 in Denmark. Patients were assigned to 5-year periods based on the date of T2DM diagnosis and were followed for 5 years. Each patient was matched by sex and age with up to three individuals from the general population. Temporal trends in ischemic stroke were examined using Cox regression to compute hazard ratios (HRs). Temporal use of prophylactic cardiovascular medications was also assessed. RESULTS: The study comprised 288,825 patients with incident T2DM and 782,232 general population individuals. From 1996-2000 to 2011-2015, the 5-year risk of first-time ischemic stroke was approximately halved in the T2DM cohort (5.2% vs. 2.7%; sex- and age-adjusted HR 0.52 [95% CI 0.49-0.55]). Patients diagnosed in 2011-2015 had increased risk of ischemic stroke compared with individuals in the general population; however, the risk difference narrowed over time (5.2% vs. 2.9% in 1996-1999 [difference 2.3%]; 2.7% vs. 2.0% in 2011-2015 [difference 0.7%]). Use of prophylactic cardiovascular medications increased markedly during the overall study period, especially use of statins (from 5% to 50%) and multiple antihypertensive drugs (from 18% to 33%). CONCLUSIONS: From 1996 to 2015, the 5-year risk of first-time ischemic stroke was approximately halved in patients with incident T2DM and no prior ASCVD, coinciding with markedly increased use of prophylactic cardiovascular medications.

Impact of diabetes on clinical outcomes after revascularization with the dual therapy CD34 antibody-covered sirolimus-eluting Combo stent and the sirolimus-eluting Orsiro stent.

OBJECTIVES: To compare the efficacy and safety of the dual therapy CD34 antibody-covered sirolimus-eluting Combo stent (DTS) and the sirolimus-eluting Orsiro stent (SES) in patients with and without diabetes mellitus (DM) included in the Scandinavian Organization for Randomized Trials with Clinical Outcome (SORT OUT) X study. BACKGROUND: The incidence of target lesion failure (TLF) after treatment with modern drug-eluting stents has been reported to be significantly higher in patients with DM when compared to patients without DM. Thus, whether the results from the SORT OUT X study apply to patients with and without DM remains unknown. METHODS: In total 3146 patients were randomized to stent implantation with DTS (n = 1578; DM: n = 279) or SES (n = 1568; DM: n = 271). The primary end point, TLF, was a composite of cardiac death, target-lesion myocardial infarction (MI), or target lesion revascularization (TLR) within 1 year. RESULTS: At 1 year, the rate of TLF was increased in the DTS group compared to the SES group, both among patients with DM (9.3% vs. 4.8%; risk difference: 4.5%; incidence rate ratio: 1.99, 95% confidence interval [CI]: 1.02-3.90) and without DM (5.7% vs. 3.5%; incidence rate ratio: 1.67, 95% CI: 1.15-2.42). The differences were mainly explained by higher rates of TLR. CONCLUSION: Compared to the SES, the DTS was associated with an increased risk of TLF at 12 months in patients with and without DM. The differences were mainly explained by higher rates of TLR, whereas rates of cardiac death and target lesion MI did not differ significantly between the two stent groups in patients with or without DM.

Impact of diabetes on 1-year clinical outcome in patients undergoing revascularization with the BioFreedom stents or the Orsiro stents from the SORT OUT IX trial.

This sub-study of the SORT OUT IX trial sought to compare clinical outcomes between patients with diabetes randomized to implantation of either the polymer-free biolimus A9-coated BioFreedom stent (BF-BES) or the ultra-thin strut, biodegradable polymer sirolimus-eluting Orsiro stent (O-SES). Patients with diabetes have an increased risk of target lesion failure (TLF) after percutaneous coronary intervention (PCI). The impact of different stent types in patients with diabetes is still discussed. A total of 607 of the 3151 patients (19.3%) enrolled in the SORT OUT IX study had diabetes. Randomization was stratified by patients with/without diabetes; 304 received BF-BES and 303 O-SES. The primary endpoint was TLF, which was a composite of cardiac death, myocardial infarction (not related to other than the index lesion) and target lesion revascularization (TLR) within 1 year. After 1 year, patients with diabetes had higher TLF (7.2% vs. 3.7%, incidence rate ratio [IRR]: 1.65; 95% confidence interval [CI]: 1.08-2.50), than patients without diabetes. TLF did not differ significantly between BF-BES and O-SES in patients with diabetes (8.2% vs. 6.3%, IRR: 1.17; 95% CI: 0.63-2.20). In patients with diabetes, cardiac death occurred in 2.3% of BF-BES and in 3.6% of O-SES (IRR: 0.58; 95% CI: 0.23-1.45) and TLR occurred in 5.3% and 2.3% of BF-BES and O-SES, respectively (IRR: 2.12; 95% CI: 0.81-5.56). Definite stent thrombosis rates of 1.3% were found in both stent types. Patients with diabetes had higher 1-year TLF rate after PCI compared to patients without diabetes, whereas TLF did not differ significantly between the two stent types BF-BES and O-SES in patients with diabetes.

Polymer-free biolimus-coated stents versus ultrathin-strut biodegradable polymer sirolimus-eluting stents: two-year outcomes of the randomised SORT OUT IX trial.

BACKGROUND: For patients with high bleeding risk, the BioFreedom stent is safer and more effective than a bare metal stent. However, at the one-year follow-up of the SORT OUT IX trial, the BioFreedom stent did not meet the criteria for non-inferiority for target lesion failure (TLF) when compared with the Orsiro stent and had a higher incidence of target lesion revascularisation (TLR). AIMS: The aim of the study was to compare the two-year outcomes following coronary implantation of the BioFreedom or the Orsiro stents in all-comer patients. METHODS: The Scandinavian Organization for Randomized Trials with Clinical Outcome (SORT OUT) IX trial is a prospective, multicentre, randomised clinical trial comparing the BioFreedom and the Orsiro stents. The primary endpoint, TLF, was a composite of cardiac death, myocardial infarction (MI; not related to other lesions) and TLR. RESULTS: A total of 1,572 patients were randomised to treatment with the BioFreedom stent and 1,579 patients with the Orsiro stent. At two-year follow-up, TLF was 7.8% in the BioFreedom and 6.3% in the Orsiro stent groups (rate ratio [RR] 1.23, 95% confidence interval [CI]: 0.94-1.61). Risks of cardiac death, MI and definite stent thrombosis did not differ significantly between the groups, whereas more patients in the BioFreedom group had TLR (5.1% vs 2.6%; RR 1.98, 95% CI: 1.26-2.89) attributable to a higher risk of TLR within the first year (3.5% vs 1.3%; RR 2.77, 95% CI: 1.66-4.62). CONCLUSIONS: At two years, there were no significant differences between the BioFreedom and Orsiro stents for TLF. TLR was significantly higher with the BioFreedom stent due to higher risk of TLR within the first year.

Trends in Hysterectomy Incidence Rates During 2000-2015 in Denmark: Shifting from Abdominal to Minimally Invasive Surgical Procedures.

BACKGROUND: Hysterectomy (removal of the uterus) is a common surgical procedure in gynecology. Although minimally invasive surgical procedures have been introduced, hysterectomy is still associated with risk of short- and long-term complications. Given that hysterectomized women are no longer at risk of either hysterectomy or being diagnosed with endometrial or cervical cancer, it is important to describe trends in hysterectomy rates. OBJECTIVE: To describe trends in hysterectomy incidence rates overall and stratified by age, indication, and procedure. METHODS: Nationwide population-based cohort study using Danish national registries, 2000-2015, was conducted. We calculated the overall hysterectomy-corrected and age-standardized incidence rates of hysterectomy among women ≥20 years old. Incidence rates were stratified by age group, indication, and surgical procedure. We performed trend analyses using Joinpoint regression, thereby estimating the average annual percentage change (AAPC). RESULTS: A total of 98,484 women had a hysterectomy during the study period, corresponding to an overall age-standardized, hysterectomy-corrected hysterectomy incidence rate (SIR) of 351.1 per 100,000 person-years (95% CI 348.9;353.3). SIR of hysterectomy declined over time (AAPC -1.4; 95% CI -1.9;-1.0), which was driven by a decline in rates of benign hysterectomy (AAPC -2.1; 95% CI -2.7;-1.6). Irrespective of indication, rates of abdominal hysterectomy declined substantially during the study period and were surpassed by rates of minimally invasive procedures (ie, laparoscopy and robot-assisted laparoscopy) in 2013. CONCLUSION: Hysterectomy-corrected incidence rates of benign hysterectomy declined over time. Irrespective of indication, we observed a shift in surgical procedure over time, from abdominal hysterectomy to minimally invasive surgical procedures.

Cardiovascular Events, Acute Hospitalizations, and Mortality in Patients With Type 2 Diabetes Mellitus Who Initiate Empagliflozin Versus Liraglutide: A Comparative Effectiveness Study.

Background In cardiovascular outcome trials, the sodium glucose cotransporter 2 inhibitor empagliflozin and glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide caused similar reductions in major adverse cardiac events (MACE). We compared clinical outcomes in routine clinical care. Methods and Results EMPLACE (Cardiovascular and Renal Outcomes, and Mortality in Danish Patients with Type 2 Diabetes Who Initiate Empagliflozin Versus GLP-1RA: A Danish Nationwide Comparative Effectiveness Study) is an ongoing nationwide population-based comparative effectiveness cohort study in Denmark. For the present study, we included 14 498 new users of empagliflozin and 12 706 new users of liraglutide, 2015 to 2018. Co-primary outcomes were expanded major adverse cardiac events (stroke, myocardial infarction, unstable angina, coronary revascularization, hospitalization for heart failure [HHF], or all-cause death); HHF or all-cause death; and first HHF or first initiation of loop-diuretic therapy. Secondary outcomes included all-cause hospitalization or death. We applied propensity score balancing and Cox regression to compute adjusted hazard ratios (aHRs) in on-treatment (OT) and intention-to-treat (ITT) analyses. Cohorts were well balanced at baseline (median age 61 years, 59% men, diabetes mellitus duration 6.6 years, 30% with preexisting cardiovascular disease). During mean follow-up of 1.1 years in OT and 1.5 years in ITT analyses, empagliflozin versus liraglutide was associated with a similar rate of expanded major adverse cardiac events (OT aHR, 1.02; 95% CI, 0.91-1.14; ITT aHR, 1.06; 95% CI, 0.96-1.17), and HHF or all-cause death (OT aHR, 0.97; 95% CI, 0.85-1.11; ITT aHR, 1.02; 95% CI, 0.91-1.14); and a decreased rate of a first incident HHF or loop-diuretic initiation (OT aHR, 0.80; 95% CI, 0.68-0.94; ITT aHR, 0.87; 95% CI, 0.76-1.00), and of all-cause hospitalization or death (OT aHR, 0.93; 95% CI, 0.89-0.98; ITT aHR, 0.93; 95% CI, 0.90-0.97). Conclusions Empagliflozin and liraglutide initiators had comparable rates of expanded major adverse cardiac events, and HHF or all-cause death, whereas empagliflozin initiators had a lower rate of a first HHF or loop-diuretic initiation.