A core-genome multilocus sequence typing scheme for the detection of genetically related Streptococcus pyogenes clusters.

The recently observed increase in invasive Streptococcus pyogenes infections causes concern in Europe. However, conventional molecular typing methods lack discriminatory power to aid investigations of outbreaks caused by S. pyogenes. Therefore, there is an urgent need for high-resolution molecular typing methods to assess genetic relatedness between S. pyogenes isolates. In the current study, we aimed to develop a novel high-resolution core-genome multilocus sequence typing (cgMLST) scheme for S. pyogenes and compared its discriminatory power to conventional molecular typing methods. The cgMLST scheme was designed with the commercial Ridom SeqSphere+ software package. To define a cluster threshold, the scheme was evaluated using publicly available data from nine defined S. pyogenes outbreaks in the United Kingdom. The cgMLST scheme was then applied to 23 isolates from a suspected S. pyogenes outbreak and 117 S. pyogenes surveillance isolates both from the Netherlands. MLST and emm-typing results were used for comparison to cgMLST results. The allelic differences between isolates from defined outbreaks ranged between 6 and 31 for isolates with the same emm-type, resulting in a proposed cluster threshold of <5 allelic differences out of 1,095 target loci. Seven out of twenty-three (30%) isolates from the suspected outbreak had an allelic difference of <2, thereby identifying a potential cluster that could not be linked to other isolates. The proposed cgMLST scheme shows a higher discriminatory ability when compared to conventional typing methods. The rapid and simple analysis workflow allows for extended detection of clusters of potential outbreak isolates and surveillance and may facilitate the sharing of sequencing results between (inter)national laboratories.

Time Trends in Patient Characteristics, Anticoagulation Treatment, and Prognosis of Incident Nonvalvular Atrial Fibrillation in the Netherlands.

Importance: The temporal trend in adverse events regarding stroke prevention for nonvalvular atrial fibrillation (NVAF) in the direct oral anticoagulant (DOAC) era was rarely investigated comprehensively, especially taking into account potential changes in patient characteristics and anticoagulation treatment. Objective: To investigate time trends in patient characteristics, anticoagulation treatment, and prognosis of patients with incident NVAF in the Netherlands. Design, Setting, and Participants: This retrospective cohort study assessed patients with incident NVAF initially recognized within a hospitalization between 2014 and 2018, using data from Statistics Netherlands. Participants were followed-up for 1 year from the hospital admission at which the incident NVAF diagnosis was made or until death, whichever occurred first. Data were analyzed from January 15, 2021, to March 8, 2023. Exposure: Calendar year of the incident NVAF diagnosis, according to which the participants were categorized into 5 cohorts. Main Outcomes and Measures: Outcomes of interest were baseline patient characteristics, anticoagulation treatment, and occurrence of ischemic stroke or major bleeding within the 1-year follow-up after incident NVAF. Results: Between 2014 and 2018, 301 301 patients (mean [SD] age, 74.2 [11.9] years; 169 748 [56.3%] male patients) experienced incident NVAF in the Netherlands, each of whom was categorized into 1 of 5 cohorts by calendar year. Baseline patient characteristics were broadly the same between cohorts with a mean (SD) CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years [doubled], diabetes, stroke [doubled], vascular disease, age 65 to 74 years, and sex category [female]) score of 2.9 (1.7). The median (IQR) proportion of days covered by OACs (ie, vitamin K antagonists or DOACs) within the 1-year follow-up increased from 56.99% (0%-86.30%) to 75.62% (0%-94.52%), and DOACs increased from 5102 patients (13.5%) to 32 314 patients (72.0%) among those who received OACs, gradually replacing VKAs as the first choice of OACs. Over the course of the study, there were statistically significant decreases in the 1-year cumulative incidence of ischemic stroke (from 1.63% [95% CI, 1.52%-1.73%] to 1.39% [95% CI, 1.30%-1.48%) and major bleeding (from 2.50% [95% CI, 2.37%-2.63%] to 2.07% [95% CI, 1.96%-2.19%]), and the association was consistent after adjusting for baseline patient characteristics and excluding those with preexisting chronic anticoagulation. Conclusions and Relevance: This cohort study of patients with incident NVAF diagnosed between 2014 and 2018 in the Netherlands found similar baseline characteristics, increased OAC use with DOACs being favored over time, and improved 1-year prognosis. Comorbidity burden, potential underuse of anticoagulation medications, and specific subgroups of patients with NVAF remain directions for future investigations and further improvement.

Inter- and intra-individual concentrations of direct oral anticoagulants: The KIDOAC study.

BACKGROUND: Direct oral anticoagulants (DOACs) do not require concentration monitoring. However, whether DOAC concentrations are stable and their variation between and within patients is not well studied. METHODS: Patients on vitamin K antagonists (VKA) who switched to rivaroxaban, apixaban, or dabigatran were included between 2018 and 2020. Blood was drawn at DOAC trough and peak concentrations at week 0, 2, and 8. Plasma drug concentrations were determined by anti-factor Xa concentrations (rivaroxaban, apixaban) or diluted thrombin time (dabigatran). Inter- and intra-individual variability was assessed by calculating the coefficient of variation (CV). Linear regression models were employed to evaluate associations between DOAC trough concentrations and previous VKA dosage, creatinine clearance, and body mass index (BMI). RESULTS: One hundred fifty-two patients were included, of whom 96 (63%) were male and with a mean age of 73.9 ± 8.4 years. For the inter-individual variability, the CV ranged between 48% and 81% for trough values and between 25% and 69% for peak values among patients using the recommended DOAC dose. Intra-individual variability was substantially lower, as here the CV ranged between 18% and 33% for trough values and between 15% and 29% for peak values among patients using the recommended DOAC dose. Previous VKA dosage and creatinine clearance were inversely associated with DOAC trough concentrations. No association was found between BMI and DOAC trough concentrations. CONCLUSION: Inter-individual variability of DOAC concentrations was higher than intra-individual variability. Lower previous VKA dosage and creatinine clearance were associated with higher DOAC trough concentrations. These findings support further study into an optimal target range, in which the risks of both bleeding and thrombosis are minimal.

Switching from vitamin K antagonists to direct oral anticoagulants in non-valvular atrial fibrillation patients: Does low time in therapeutic range affect persistence?

BACKGROUND: Non-valvular atrial fibrillation (NVAF) patients are advised to switch from a vitamin K antagonist (VKA) to direct oral anticoagulant (DOAC) when time in therapeutic range (TTR) is low. OBJECTIVE: To examine if pre-switch TTR determines persistence patterns in NVAF patients who are switched from a VKA to DOAC. PATIENTS/METHODS: Adult NVAF patients from three Dutch anticoagulation clinics who were newly switched from a VKA to DOAC between July 1, 2013 and September 30, 2018 were stratified by pre-switch TTR levels. DOAC prescription records were examined to determine persistence patterns according to a 100-day prescription gap. Cumulative incidences of non-persistence to DOAC were estimated using the cumulative incidence competing risk method. The association of pre-switch TTR levels with DOAC non-persistence was evaluated by Cox regression models. RESULTS: A total of 3696 NVAF patients were included, of whom 690 (18.7%) had a pre-switch TTR ≤ 45%. After switching from VKA to DOAC, 14.0% (95% confidence interval [CI] 11.3-17.0%) of the patients with a pre-switch TTR ≤ 45% became non-persistent to DOAC within 1 year, while 9.8% (95% CI 8.7-11.0%) did in those with a pre-switch TTR > 45%. In a multivariable model, a pre-switch TTR ≤ 45% was associated with a higher risk of non-persistence to DOAC (adjusted hazard ratio 1.55, 95% CI 1.22-1.97). Results were similar when using other cut-off points (60% or 70%) to define a low TTR. CONCLUSION: NVAF patients switching from VKA to DOAC due to a low pre-switch TTR saw a worse persistence pattern to DOAC after the switch compared to patients with a high pre-switch TTR.

Predictors, time course, and outcomes of persistence patterns in oral anticoagulation for non-valvular atrial fibrillation: a Dutch Nationwide Cohort Study.

AIMS: Persistence with direct oral anticoagulants (DOACs) has become a concern in non-valvular atrial fibrillation (NVAF) patients, but whether this affects prognosis is rarely studied. We investigated the persistence with oral anticoagulants (OACs) and its association with prognosis among a nationwide cohort of NVAF patients. METHODS AND RESULTS: DOAC-naive NVAF patients who started to use DOACs for ischaemic stroke prevention between 2013 and 2018 were included using Dutch national statistics. Persistence with OACs was determined based on the presence of a 100-day gap between the last prescription and the end of study period. In 93 048 patients, 75.7% had a baseline CHA2DS2-VASc score of ≥2. The cumulative incidence of persistence with OACs was 88.1% [95% confidence interval (CI) 87.9-88.3%], 82.6% (95% CI 82.3-82.9%), 77.7% (95% CI 77.3-78.1%), and 72.0% (95% CI 71.5-72.5%) at 1, 2, 3, and 4 years after receiving DOACs, respectively. Baseline characteristics associated with better persistence with OACs included female sex, age range 65-74 years, permanent atrial fibrillation, previous exposure to vitamin K antagonists, stroke history (including transient ischaemic attack), and a CHA2DS2-VASc score ≥2. Non-persistence with OACs was associated with an increased risk of the composite outcome of ischaemic stroke and ischaemic stroke-related death [adjusted hazard ratio (aHR) 1.79, 95% CI 1.49-2.15] and ischaemic stroke (aHR 1.58, 95% CI 1.29-1.93) compared with being persistent with OACs. CONCLUSION: At least a quarter of NVAF patients were non-persistent with OACs within 4 years, which was associated with poor efficacy of ischaemic stroke prevention. The identified baseline characteristics may help identify patients at risk of non-persistence.

Risk of thrombotic complications in influenza versus COVID-19 hospitalized patients.

Background: Whereas accumulating studies on patients with coronavirus disease 2019 (COVID-19) report high incidences of thrombotic complications, large studies on clinically relevant thrombosis in patients with other respiratory tract infections are lacking. How this high risk in COVID-19 patients compares to those observed in hospitalized patients with other viral pneumonias such as influenza is unknown. Objectives: To assess the incidence of venous and arterial thrombotic complications in hospitalized patients with influenza as opposed to that observed in hospitalized patients with COVID-19. Methods: This was a retrospective cohort study; we used data from Statistics Netherlands (study period: 2018) on thrombotic complications in hospitalized patients with influenza. In parallel, we assessed the cumulative incidence of thrombotic complications-adjusted for competing risk of death-in patients with COVID-19 in three Dutch hospitals (February 24 to April 26, 2020). Results: Of the 13 217 hospitalized patients with influenza, 437 (3.3%) were diagnosed with thrombotic complications, versus 66 (11%) of the 579 hospitalized patients with COVID-19. The 30-day cumulative incidence of any thrombotic complication in influenza was 11% (95% confidence interval [CI], 9.4-12) versus 25% (95% CI, 18-32) in COVID-19. For venous thrombotic (VTC) complications and arterial thrombotic complications alone, these numbers were, respectively, 3.6% (95% CI, 2.7-4.6) and 7.5% (95% CI, 6.3-8.8) in influenza versus 23% (95% CI, 16-29) and 4.4% (95% CI, 1.9-8.8) in COVID-19. Conclusions: The incidence of thrombotic complications in hospitalized patients with influenza was lower than in hospitalized patients with COVID-19. This difference was mainly driven by a high risk of VTC complications in the patients with COVID-19 admitted to the Intensive Care Unit. Remarkably, patients with influenza were more often diagnosed with arterial thrombotic complications.

High Soluble Thrombomodulin Is Associated with an Increased Risk of Major Bleeding during Treatment with Oral Anticoagulants: A Case-Cohort Study.

BACKGROUND: Major bleeding occurs in 1 to 3% of patients treated with oral anticoagulants per year. Biomarkers may help to identify high-risk patients. A proposed marker for major bleeding while using anticoagulants is soluble thrombomodulin (sTM). METHODS: Plasma was available from 16,570 patients of the BLEEDS cohort that consisted of patients who started treatment with vitamin K antagonists between 2012 and 2014. A case-cohort study was performed including all patients with a major bleed (n = 326) during follow-up and a random sample of individuals selected at baseline (n = 652). Plasma sTM levels were measured and stratified by percentiles. Patients were also categorized by international normalized ratio (INR). Adjusted hazard ratios (for age, sex, hypertension, and diabetes) with 95% confidence intervals (CIs) were estimated by means of Cox regression. RESULTS: Plasma sTM levels were available for 263 patients with a major bleed and 538 control subjects. sTM levels were dose-dependently associated with risk of major bleeding, with a 1.9-fold increased risk (95% CI: 1.1-3.1) for levels above the 85th percentile versus the <25th percentile. A high INR (≥4) in the presence of high (≥70th percentile) sTM levels was associated with a 7.1-fold (95% CI: 4.1-12.3) increased risk of major bleeding, corresponding with a bleeding rate of 14.1 per 100 patient-years. CONCLUSION: High sTM levels at the start of treatment are associated with major bleeding during vitamin K antagonist treatment, particularly in the presence of a high INR.

Why crowding matters in the time of COVID-19 pandemic? - a lesson from the carnival effect on the 2017/2018 influenza epidemic in the Netherlands.

BACKGROUND: To evaluate the association between crowding and transmission of viral respiratory infectious diseases, we investigated the change in transmission patterns of influenza and COVID-19 before and after a mass gathering event (i.e., carnival) in the Netherlands. METHODS: Information on individual hospitalizations related to the 2017/2018 influenza epidemic were accessed from Statistics Netherlands. The influenza cases were stratified between non-carnival and carnival regions. Distributions of influenza cases were plotted with time and compared between regions. A similar investigation in the early outbreak of COVID-19 was also conducted using open data from the Dutch National Institute for Public Health and the Environment. RESULTS: Baseline characteristics between non-carnival and carnival regions were broadly similar. There were 13,836 influenza-related hospitalizations in the 2017/2018 influenza epidemic, and carnival fell about 1 week before the peak of these hospitalizations. The distributions of new influenza-related hospitalizations per 100,000 inhabitants with time between regions followed the same pattern with a surge of new cases in the carnival region about 1 week after carnival, which did not occur in the non-carnival region. The increase of new cases for COVID-19 in the carnival region exceeded that in the non-carnival region about 1 week after the first case was reported, but these results warrant caution as for COVID-19 there were no cases reported before the carnival and social measures were introduced shortly after carnival. CONCLUSION: In this study, a mass gathering event (carnival) was associated with aggravating the spread of viral respiratory infectious diseases.

The relationship between DOAC levels and clinical outcomes: The measures tell the tale.

Direct oral anticoagulants (DOACs) are increasingly used for treatment and prevention of thromboembolic diseases, used in fixed dose regimens. Although their safety and efficacy profiles are considered optimal, clinical events still occur. Given that anticoagulation treatment is a delicate balance between clotting and bleeding, it is possible that an optimal target spot exists where the effect of anticoagulation achieves both the lowest possible risk of bleeding and thrombosis. Other currently available anticoagulants (ie, vitamin K antagonists and heparins) provide important clues for this. If such a target spot exists, tailored DOAC therapy may further benefit patients. This opinion article summarizes the current available evidence that suggests that such a tailored strategy could work. It also describes research suggestions for conducting studies in patient populations such as patients with extremes of body weight or impaired kidney function to evaluate whether tailored treatment with DOACs could lead to better patient outcomes.

Self-reported therapy adherence and predictors for nonadherence in patients who switched from vitamin K antagonists to direct oral anticoagulants.

BACKGROUND: Many patients who used vitamin K antagonists (VKAs) for long-term prevention of thromboembolism are now actively switched to a direct oral anticoagulant (DOAC). Strict adherence to a DOAC is crucial for its success. However, therapy adherence and clinical factors that predict nonadherence are currently not well studied among patients who switched from a VKA to a DOAC. METHODS: A questionnaire was developed and sent to 2920 former patients of 3 anticoagulation clinics in the Netherlands, who switched from a VKA to a DOAC between January 2016 and December 2017. Questions concerned demographics, treatment persistence, adherence, and the occurrence of bleeding or thromboembolic events on DOACs. To identify predictors for nonadherence, logistic regression models were used to estimate crude and age/sex-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: A total of 1399 questionnaires (response rate 48%) were used for analysis. DOAC treatment persistence (94%) and adherence (86%) rates were high. Several predictors of nonadherence were identified, including young age (OR, 5.9; 95% CI, 3.6-9.8 for <60 years compared to >75 years), low consultation frequency with a specialist (OR, 1.6; 95% CI, 1.1-2.2), a history of minor bleeding on DOACs (OR, 1.9; 95% CI, 1.3-2.8), and a twice-daily dosing regimen (OR, 1.9; 95% CI, 1.3-2.6). CONCLUSIONS: Self-reported treatment persistence and adherence were high in our study population, and several predictors of nonadherence were identified. Factors that can be influenced (low consult frequency with medical specialist, daily dosing regimen) may be used to improve therapy adherence.

Switching from vitamin K antagonists to direct oral anticoagulants: Treatment satisfaction and patient concerns.

BACKGROUND: Since direct oral anticoagulants (DOACs) have been introduced for treatment and prevention of thromboembolic diseases, patients on vitamin K antagonists (VKA) have to decide whether to remain on VKA or switch to DOAC. The goal of this study was to evaluate treatment satisfaction, preferences, and concerns among those who already have switched from VKA to DOAC. METHODS: A questionnaire was sent to 2920 former patients of three anticoagulation clinics in the Netherlands, who switched from VKA to DOAC (2016-2017). Questions concerned demographics, treatment satisfaction, concerns, perspectives on antidotes, and monitoring. To identify predictors for being concerned about adverse events, logistic regression was used to estimate crude- and adjusted (age and sex) odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: One thousand, three hundred ninety-nine questionnaires (response rate 48%) were used for analysis. DOAC treatment satisfaction was high (mean 8.8 of a maximum 10-point score). A quarter of patients expressed concerns about adverse events. Predictors for being concerned were age < 60 years (vs age > 75 years, OR 4.1, 95% CI 2.6-6.4), female sex (OR 1.3, 95% CI 1.0-1.6), and high education (OR 1.6, 95% CI 1.2-2.2). Fifty-nine percent of all patients indicated antidote availability as important, 73% would be willing to participate in DOAC monitoring. CONCLUSIONS: DOAC treatment satisfaction was high. A substantial number of patients expressed concerns about adverse events, especially women, patients aged < 60 years, or highly educated patients. Our findings among patients who already had switched to DOAC may assist in the process of shared decision-making when switching a patient from VKA to DOAC is considered.