OpenSAFELY: The impact of COVID-19 on azathioprine, leflunomide and methotrexate monitoring, and factors associated with change in monitoring rate.

AIMS: The COVID-19 pandemic created unprecedented pressure on healthcare services. This study investigates whether disease-modifying antirheumatic drug (DMARD) safety monitoring was affected during the COVID-19 pandemic. METHODS: A population-based cohort study was conducted using the OpenSAFELY platform to access electronic health record data from 24.2 million patients registered at general practices using TPP's SystmOne software. Patients were included for further analysis if prescribed azathioprine, leflunomide or methotrexate between November 2019 and July 2022. Outcomes were assessed as monthly trends and variation between various sociodemographic and clinical groups for adherence with standard safety monitoring recommendations. RESULTS: An acute increase in the rate of missed monitoring occurred across the study population (+12.4 percentage points) when lockdown measures were implemented in March 2020. This increase was more pronounced for some patient groups (70-79 year-olds: +13.7 percentage points; females: +12.8 percentage points), regions (North West: +17.0 percentage points), medications (leflunomide: +20.7 percentage points) and monitoring tests (blood pressure: +24.5 percentage points). Missed monitoring rates decreased substantially for all groups by July 2022. Consistent differences were observed in overall missed monitoring rates between several groups throughout the study. CONCLUSION: DMARD monitoring rates temporarily deteriorated during the COVID-19 pandemic. Deterioration coincided with the onset of lockdown measures, with monitoring rates recovering rapidly as lockdown measures were eased. Differences observed in monitoring rates between medications, tests, regions and patient groups highlight opportunities to tackle potential inequalities in the provision or uptake of monitoring services. Further research should evaluate the causes of the differences identified between groups.

The impact of COVID-19 on medication reviews in English primary care. An OpenSAFELY-TPP analysis of 20 million adult electronic health records.

AIMS: The COVID-19 pandemic caused significant disruption to routine activity in primary care. Medication reviews are an important primary care activity ensuring safety and appropriateness of prescribing. A disruption could have significant negative implications for patient care. Using routinely collected data, our aim was first to describe codes used to record medication review activity and then to report the impact of COVID-19 on the rates of medication reviews. METHODS: With the approval of NHS England, we conducted a cohort study of 20 million adult patient records in general practice, in-situ using the OpenSAFELY platform. For each month, between April 2019 and March 2022, we report the percentage of patients with a medication review coded monthly and in the previous 12 months with breakdowns by regional, clinical and demographic subgroups and those prescribed high-risk medications. RESULTS: In April 2019, 32.3% of patients had a medication review coded in the previous 12 months. During the first COVID-19 lockdown, monthly activity decreased (-21.1% April 2020), but the 12-month rate was not substantially impacted (-10.5% March 2021). The rate of structured medication review in the last 12 months reached 2.9% by March 2022, with higher percentages in high-risk groups (care home residents 34.1%, age 90+ years 13.1%, high-risk medications 10.2%). The most used medication review code was Medication review done 314530002 (59.5%). CONCLUSIONS: There was a substantial reduction in the monthly rate of medication reviews during the pandemic but rates recovered by the end of the study period. Structured medication reviews were prioritized for high-risk patients.

Keeping warfarin patients safe during the COVID-19 pandemic: review of an INR self-testing programme.

BACKGROUND: Anticoagulation clinics faced an unprecedented challenge during the COVID-19 pandemic to safely manage patients on warfarin therapy. METHODS: A London teaching hospital trust received INR point-of-care (POC) testing devices from its clinical commissioning group. The Trust distributed the devices to patients who were cognitively and physically able to self-test and evaluated clinical outcomes and patient experience. FINDINGS: A significant improvement in warfarin control (mean time in therapeutic range (TTR) before POC 52%, standard deviation (SD) 24.8, vs mean after 60.7%, SD 19.7; P>0.009) and a 39% reduction in missed appointments were seen in self-testing patients. Positive patient satisfaction and lifestyle outcomes were identified through a telephone survey. A minority of patients struggled with the technique, leading to frustration. Some patients used many test strips through unsuccessful and additional tests. CONCLUSION: POC testing in a carefully selected group of patients on warfarin therapy resulted in positive clinical and patient satisfaction outcomes. Appropriate governance processes are needed, and clinical expertise is required to support patients. Cost-effectiveness of POC testing needs careful monitoring.

Venous thromboembolism and women's health.

The prevention and treatment of venous thromboembolism (VTE) poses distinct gender-specific challenges. Women of childbearing age are at an increased risk of VTE secondary to the transient risk factors of combined hormonal contraception (CHC) and pregnancy. Cancers specific to women are associated with a significant burden of VTE; whilst the incidence of VTE in localised breast cancer is 5 per 1000 person-years, more cases are seen due to the prevalence of breast cancer. Treatment of VTE in women can be complicated by abnormal uterine bleeding, now increasingly reported with direct oral anticoagulants (DOACs) as well as vitamin K antagonists. Divergence between international guidelines regarding the use of CHC following an oestrogen-associated VTE and appropriate withdrawal of such contraception requires clarification for clinicians. Additionally, there is uncertainty as to whether to consider such events provoked or unprovoked and, consequently, the optimal duration of treatment in these women remains unclear. During pregnancy and the puerperium, the traditional anticoagulants remain the agents of choice with no further advances in DOAC safety data, and similarly in lactation. Further studies evaluating the safety and optimal treatment strategies in these women are awaited.

Safety of direct-acting oral anticoagulant (DOAC) prescribing: OpenSAFELY-TPP analysis of 20.5 million adults' electronic health records.

BACKGROUND: During the COVID-19 pandemic many patients were switched from warfarin to direct-acting oral anticoagulants (DOACs), which require the creatinine clearance (CrCl) calculated to ensure the correct dose is prescribed to avoid bleeding or reduced efficacy. AIM: To identify the study population proportion prescribed a DOAC. Of these, the proportion with recorded: weight, estimated glomerular filtration rate (eGFR), creatinine, CrCl and atrial fibrillation (AF). To analyse the proportion of patients with recorded AF and CrCl prescribed a recommended DOAC dose. DESIGN & SETTING: A retrospective cohort study of 20.5 million adult NHS patients' electronic health records (EHRs) in England in the OpenSAFELY-TPP platform (January 2018-February 2023). METHOD: Patients on DOACs were analysed for age, sex, recorded weight, eGFR, creatinine, CrCl and AF. Prescribed DOAC doses in patients with recorded AF were compared with recommended doses for recorded CrCl and determined as either recommended, higher than recommended (overdose), or lower than recommended (underdose). RESULTS: In February 2023, weight, eGFR, creatinine, CrCl, and AF were recorded in 72.8%, 92.4%, 94.3%, 73.5%, and 73.9% of study population, respectively. Both AF and CrCl were recorded for 56.7% of patients. Of these, 86.2% received the recommended, and 13.8% non-recommended, DOAC doses. CONCLUSION: CrCl is not recorded for a substantial number of patients on DOACs. We recommend that national organisations tasked with safety, collectively update guidance on the appropriate weight to use in the Cockcroft-Gault equation, clarify that CrCl is not equivalent to eGFR, and work with GP clinical system suppliers to standardise the calculation of CrCl in the EHR.

Changes in opioid prescribing during the COVID-19 pandemic in England: an interrupted time-series analysis in the OpenSAFELY-TTP cohort.

BACKGROUND: The COVID-19 pandemic disrupted health-care delivery, including difficulty accessing in-person care, which could have increased the need for strong pharmacological pain relief. Due to the risks associated with overprescribing of opioids, especially to vulnerable populations, we aimed to quantify changes to measures during the COVID-19 pandemic, overall, and by key subgroups. METHODS: For this interrupted time-series analysis study conducted in England, with National Health Service England approval, we used routine clinical data from more than 20 million general practice adult patients in OpenSAFELY-TPP, which is a a secure software platform for analysis of electronic health records. We included all adults registered with a primary care practice using TPP-SystmOne software. Using interrupted time-series analysis, we quantified prevalent and new opioid prescribing before the COVID-19 pandemic (January, 2018-February, 2020), during the lockdown (March, 2020-March, 2021), and recovery periods (April, 2021-June, 2022), overall and stratified by demographics (age, sex, deprivation, ethnicity, and geographical region) and in people in care homes identified via an address-matching algorithm. FINDINGS: There was little change in prevalent prescribing during the pandemic, except for a temporary increase in March, 2020. We observed a 9·8% (95% CI -14·5 to -6·5) reduction in new opioid prescribing from March, 2020, with a levelling of the downward trend, and rebounding slightly after April, 2021 (4·1%, 95% CI -0·9 to 9·4). Opioid prescribing rates varied by demographics, but we found a reduction in new prescribing for all subgroups except people aged 80 years or older. Among care home residents, in April, 2020, parenteral opioid prescribing increased by 186·3% (153·1 to 223·9). INTERPRETATION: Opioid prescribing increased temporarily among older people and care home residents, likely reflecting use to treat end-of-life COVID-19 symptoms. Despite vulnerable populations being more affected by health-care disruptions, disparities in opioid prescribing by most demographic subgroups did not widen during the pandemic. Further research is needed to understand what is driving the changes in new opioid prescribing and its relation to changes to health-care provision during the pandemic. FUNDING: The Wellcome Trust, Medical Research Council, The National Institute for Health and Care Research, UK Research and Innovation, and Health Data Research UK.

Incidence and treatment of group A streptococcal infections during covid-19 pandemic and 2022 outbreak: retrospective cohort study in England using OpenSAFELY-TPP.

Objective: To investigate the effect of the covid-19 pandemic on the number of patients with group A streptococcal infections and related antibiotic prescriptions. Design: Retrospective cohort study in England using OpenSAFELY-TPP. Setting: Primary care practices in England that used TPP SystmOne software, 1 January 2018 to 31 March 2023, with the approval of NHS England. Participants: Patients registered at a TPP practice at the start of each month of the study period. Patients with missing data for sex or age were excluded, resulting in a population of 23 816 470 in January 2018, increasing to 25 541 940 by March 2023. Main outcome measures: Monthly counts and crude rates of patients with group A streptococcal infections (sore throat or tonsillitis, scarlet fever, and invasive group A streptococcal infections), and recommended firstline, alternative, and reserved antibiotic prescriptions linked with a group A streptococcal infection before (pre-April 2020), during, and after (post-April 2021) covid-19 restrictions. Maximum and minimum count and rate for each infectious season (time from September to August), as well as the rate ratio of the 2022-23 season compared with the last comparably high season (2017-18). Results: The number of patients with group A streptococcal infections, and antibiotic prescriptions linked to an indication of group A streptococcal infection, peaked in December 2022, higher than the peak in 2017-18. The rate ratios for monthly sore throat or tonsillitis (possible group A streptococcal throat infection), scarlet fever, and invasive group A streptococcal infection in 2022-23 relative to 2017-18 were 1.39 (95% confidence interval (CI) 1.38 to 1.40), 2.68 (2.59 to 2.77), and 4.37 (2.94 to 6.48), respectively. The rate ratio for prescriptions of first line, alternative, and reserved antibiotics to patients with group A streptococcal infections in 2022-23 relative to 2017-18 were 1.37 (95% CI 1.35 to 1.38), 2.30 (2.26 to 2.34), and 2.42 (2.24 to 2.61), respectively. For individual antibiotic prescriptions in 2022-23, azithromycin showed the greatest relative increase versus 2017-18, with a rate ratio of 7.37 (6.22 to 8.74). This finding followed a marked decrease in the recording of patients with group A streptococcal infections and associated prescriptions during the period of covid-19 restrictions where the maximum count and rates were lower than any minimum rates before the covid-19 pandemic. Conclusions: Recording of rates of scarlet fever, sore throat or tonsillitis, and invasive group A streptococcal infections, and associated antibiotic prescribing, peaked in December 2022. Primary care data can supplement existing infectious disease surveillance through linkages with relevant prescribing data and detailed analysis of clinical and demographic subgroups.

Use of direct oral anticoagulants for venous thromboembolism treatment at extremes of body weight, renal and liver function: an illustrated review.

Direct oral anticoagulants (DOACs) have been a welcome addition to clinical practice due to the practical advantages they confer over traditional anticoagulants. In many countries, DOACs are now used as first-line treatment for the management of venous thromboembolism (VTE). Traditional anticoagulants allow for a degree of individualization, either through monitoring the international normalized ratio in the case of vitamin-K antagonists or through dose titration according to bodyweight in the case of low-molecular-weight heparin. However, the use of fixed doses and removal of the need for routine monitoring has created uncertainty in prescribing DOACs for patients at the extremes of bodyweight, renal function, and patients with liver impairment, who were not well represented in the DOAC licensing clinical trials. The discipline of pharmacokinetics is concerned with the movement of drugs through the body. Although the extremes of bodyweight and renal and liver function will influence the pharmacokinetics of DOACs, are these changes significant enough to affect clinical outcomes of bleeding and thrombosis? In other words, can the fixed-dosing strategy of DOACs accommodate these differences in physiology? In this review, we recap key pharmacokinetic principles for drug dosing; review venous thromboembolism trial and real-world data on patients prescribed DOACs at the extremes of bodyweight, renal function, and liver function; relate this to the pharmacokinetic properties of DOACs; and summarize the state of the field and current unknowns.

Comparative effectiveness of nirmatrelvir/ritonavir versus sotrovimab and molnupiravir for preventing severe COVID-19 outcomes in non-hospitalised high-risk patients during Omicron waves: observational cohort study using the OpenSAFELY platform.

Background: Timely evidence of the comparative effectiveness between COVID-19 therapies in real-world settings is needed to inform clinical care. This study aimed to compare the effectiveness of nirmatrelvir/ritonavir versus sotrovimab and molnupiravir in preventing severe COVID-19 outcomes in non-hospitalised high-risk COVID-19 adult patients during Omicron waves. Methods: With the approval of NHS England, we conducted a real-world cohort study using the OpenSAFELY-TPP platform. Patient-level primary care data were obtained from 24 million people in England and were securely linked with data on COVID-19 infection and therapeutics, hospital admission, and death, covering a period where both nirmatrelvir/ritonavir and sotrovimab were first-line treatment options in community settings (February 10, 2022-November 27, 2022). Molnupiravir (third-line option) was used as an exploratory comparator to nirmatrelvir/ritonavir, both of which were antivirals. Cox proportional hazards model stratified by area was used to compare the risk of 28-day COVID-19 related hospitalisation/death across treatment groups. Findings: A total of 9026 eligible patients treated with nirmatrelvir/ritonavir (n = 5704) and sotrovimab (n = 3322) were included in the main analysis. The mean age was 52.7 (SD = 14.9) years and 93% (8436/9026) had three or more COVID-19 vaccinations. Within 28 days after treatment initiation, 55/9026 (0.61%) COVID-19 related hospitalisations/deaths were observed (34/5704 [0.60%] treated with nirmatrelvir/ritonavir and 21/3322 [0.63%] with sotrovimab). After adjusting for demographics, high-risk cohort categories, vaccination status, calendar time, body mass index and other comorbidities, we observed no significant difference in outcome risk between nirmatrelvir/ritonavir and sotrovimab users (HR = 0.89, 95% CI: 0.48-1.63; P = 0.698). Results from propensity score weighted model also showed non-significant difference between treatment groups (HR = 0.82, 95% CI: 0.45-1.52; P = 0.535). The exploratory analysis comparing nirmatrelvir/ritonavir users with 1041 molnupiravir users (13/1041 [1.25%] COVID-19 related hospitalisations/deaths) showed an association in favour of nirmatrelvir/ritonavir (HR = 0.45, 95% CI: 0.22-0.94; P = 0.033). Interpretation: In routine care of non-hospitalised high-risk adult patients with COVID-19 in England, no substantial difference in the risk of severe COVID-19 outcomes was observed between those who received nirmatrelvir/ritonavir and sotrovimab between February and November 2022, when Omicron subvariants BA.2, BA.5, or BQ.1 were dominant. Funding: UK Research and Innovation, Wellcome Trust, UK Medical Research Council, National Institute for Health and Care Research, and Health Data Research UK.

Eleven key measures for monitoring general practice clinical activity during COVID-19: A retrospective cohort study using 48 million adults' primary care records in England through OpenSAFELY.

Background: The COVID-19 pandemic has had a significant impact on delivery of NHS care. We have developed the OpenSAFELY Service Restoration Observatory (SRO) to develop key measures of primary care activity and describe the trends in these measures throughout the COVID-19 pandemic. Methods: With the approval of NHS England, we developed an open source software framework for data management and analysis to describe trends and variation in clinical activity across primary care electronic health record (EHR) data on 48 million adults.We developed SNOMED-CT codelists for key measures of primary care clinical activity such as blood pressure monitoring and asthma reviews, selected by an expert clinical advisory group and conducted a population cohort-based study to describe trends and variation in these measures January 2019-December 2021, and pragmatically classified their level of recovery one year into the pandemic using the percentage change in the median practice level rate. Results: We produced 11 measures reflective of clinical activity in general practice. A substantial drop in activity was observed in all measures at the outset of the COVID-19 pandemic. By April 2021, the median rate had recovered to within 15% of the median rate in April 2019 in six measures. The remaining measures showed a sustained drop, ranging from a 18.5% reduction in medication reviews to a 42.0% reduction in blood pressure monitoring. Three measures continued to show a sustained drop by December 2021. Conclusions: The COVID-19 pandemic was associated with a substantial change in primary care activity across the measures we developed, with recovery in most measures. We delivered an open source software framework to describe trends and variation in clinical activity across an unprecedented scale of primary care data. We will continue to expand the set of key measures to be routinely monitored using our publicly available NHS OpenSAFELY SRO dashboards with near real-time data. Funding: This research used data assets made available as part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref MC_PC_20058).The OpenSAFELY Platform is supported by grants from the Wellcome Trust (222097/Z/20/Z); MRC (MR/V015757/1, MC_PC-20059, MR/W016729/1); NIHR (NIHR135559, COV-LT2-0073), and Health Data Research UK (HDRUK2021.000, 2021.0157).

Pooled Analysis of Rivaroxaban therapy for acute venous thromboembolism in FIRST registry, SWIVTER and DRESDEN NOAC registry.

Background: The direct factor Xa inhibitor rivaroxaban is approved for the treatment of venous thromboembolism (VTE), based on the results of large phase III trials. Objectives: To confirm rivaroxaban's effectiveness and safety in routine clinical care of patients with VTE. Methods: Data were obtained from prospective, noninterventional registries: the FIRST registry (United Kingdom), DRESDEN NOAC registry (Germany), and SWIVTER (Switzerland). Baseline characteristics of these registries and effectiveness and safety outcome rates for the FIRST and DRESDEN NOAC registries were compared. Results: A total of 1841 rivaroxaban-treated patients with acute VTE (57.9% male, 76.6% deep vein thrombosis [DVT]; 23.4% pulmonary embolism ± DVT; median age, 61 years) were included: 1217 from the FIRST registry, 418 from the DRESDEN NOAC registry, and 206 from SWIVTER. Median time between VTE diagnosis and initiation of rivaroxaban was 1.4 ± 1.81 days (25th-75th percentile 1-1; range, 0-15 days). On-treatment outcome rates for the FIRST and DRESDEN NOAC registries were 0.74 per 100 patient-years (95% confidence interval [CI], 0.35-1.54) versus 0.96 per 100 patient-years (95% CI, 0.46-2.01) for VTE recurrence; 1.16 per 100 patient years (95% CI, 0.64-2.09) versus 2.51 per 100 patient-years (95% CI, 1.58-3.98) for ISTH major bleeding and 1.69 per 100 patient-years (95% CI, 1.21-2.35) versus 1.73 per 100 patient-years (95% CI, 1.27-2.36) for all-cause mortality (intention-to-treat analysis), respectively. Conclusion: Overall treatment outcomes were consistent with the results of the phase III rivaroxaban trials in VTE treatment, indicating that the use of rivaroxaban offers acceptable treatment results also in routine care. However, we observed significant differences in patient characteristics and management patterns across Switzerland, the United Kingdom, and Germany, limiting direct comparisons of unadjusted outcome event rates between registries.

Adherence to rivaroxaban for the treatment of venous thromboembolism-Results from the FIRST registry.

BACKGROUND: Medication nonadherence can result in poor clinical outcomes and significant costs to health care providers. When treating venous thromboembolism (VTE), subtherapeutic anticoagulation may contribute to complications such as recurrent VTE or postthrombotic syndrome. OBJECTIVES: To describe the extent, reasons for, and predictors of nonadherence to rivaroxaban for the treatment of VTE in clinical practice in the United Kingdom reported by participants of the FIRST registry. PATIENTS/METHODS: The FIRST registry was an observational, multicenter registry reporting on the use of rivaroxaban in routine clinical practice. FIRST registry participants completed an adherence screening questionnaire during their treatment and follow-up. RESULTS: In total, 1028 participants completed 1660 questionnaires over 2 years. One hundred thirteen of 1028 (11%) reported nonadherence at 28 days (interquartile range, 21-45). Reasons given for nonadherence at 1 month were forgetfulness (8.6% vs 74.7%; P < .001), carelessness (2.7% vs 27.3%; P < .001) or a change in routine (7.4% vs 25.5%; P < .001) reported by adherent and nonadherent participants, respectively. Older age (10-year increments) was the strongest predictor of good adherence (adjusted odds ratio, 1.21; 95% confidence interval, 1.06-1.39; 1 = adherent). CONCLUSIONS: Overall adherence to rivaroxaban was high, and most nonadherence was unintentional. Identification of those at risk of nonadherence may reduce the risk of VTE recurrence and long-term complications.

Rivaroxaban in acute venous thromboembolism: UK prescribing experience.

BACKGROUND: Rivaroxaban was reported as effective as traditional therapies for the acute treatment of venous thromboembolism (VTE) with fewer major bleeding complications in the seminal Einstein program and is now a recommended option for the treatment of VTE around the world. OBJECTIVE: To report the safety and efficacy of rivaroxaban in daily care for the management of acute VTE in the United Kingdom. PATIENTS/METHOD: The FIRST registry is a UK-only, multicenter, noninterventional, observational VTE study (NCT02248610). Consecutive patients diagnosed with acute VTE, managed with rivaroxaban, were recruited and followed for up to 5 years. The primary outcomes were treatment-emergent symptomatic objectively diagnosed recurrent VTE, major and clinically relevant nonmajor bleeding (CRNMB), and all-cause mortality. RESULTS: A total of 1262 participants were recruited between 2014 and 2018. Participants were heterogeneous, with age range 18 to 95 years, weight 35 to 234 kg, and maximum body mass index 64.4 kg/m2. The median duration of treatment exposure was 135 days (interquartile range [IQR], 84-307) and overall follow-up 497 days (IQR, 175-991). There were seven episodes of symptomatic VTE recurrence, 0.6%, (0.74/100 patient-years; 95% confidence interval [CI], 0.19-1.28). There were 79 of 1239 (6.4%), 8.66 of 100 patient-years (95% CI, 6.90-10.73) first episodes of major or CRNMB, which were most frequently reported by women aged <50 years as abnormal vaginal bleeding. CONCLUSIONS: Rivaroxaban is an effective and safe single drug modality for the treatment of VTE in daily practice in the United Kingdom. Data to determine the optimal anticoagulation therapy for women of childbearing age are needed.

Fixed dose rivaroxaban can be used in extremes of bodyweight: A population pharmacokinetic analysis.

BACKGROUND: Emerging safety and efficacy data for rivaroxaban suggest traditional therapy and rivaroxaban are comparable in the morbidly obese. However, real-world data that indicate pharmacokinetic (PK) parameters are comparable at the extremes of body size are lacking. The International Society of Thrombosis and Haemostasis Scientific and Standardisation Committee (ISTH SSC) suggests avoiding the use of direct oral anticoagulants (DOACs) in patients weighing >120 kg or with a body mass index >40 kg/m2 and gives no recommendation on the use of DOACs in those <50 kg. OBJECTIVES: To generate a population PK model to understand the influence of bodyweight on rivaroxaban exposure from clinical practice data. METHOD: Rivaroxaban plasma concentrations and patient characteristics were collated between 2013 and 2018 at King's College Hospital anticoagulation clinic. A population PK model was developed using a nonlinear mixed effects approach and then used to simulate rivaroxaban concentrations at the extremes of bodyweight. RESULTS: A robust population PK model derived from 913 patients weighing between 39 kg and 172 kg was developed. The model included data from n = 86 >120 kg, n = 74 BMI >40 kg/m2 , and n = 30 <50 kg. A one-compartment model with between-subject variability on clearance and a proportional error model best described the data. Creatinine clearance calculated by Cockcroft-Gault, with lean bodyweight as the weight descriptor in this equation, was the most significant covariate influencing rivaroxaban exposure. CONCLUSIONS: Our work demonstrates rivaroxaban can be used at extremes of bodyweight provided renal function is satisfactory. We recommend that the ISTH SSC revises the current guidance with respect to rivaroxaban at extremes of body size.