Long-term adherence to direct acting oral anticoagulants and the influence of health beliefs after switching from vitamin-K antagonists: Findings from the Switching Study.

AIMS: Switching non-adherent patients prescribed anticoagulant treatment to a regime with less monitoring could lead to significant non-adherence. Health beliefs are known to influence medication adherence; however, the extent of this influence is unknown in patients switched from vitamin-K antagonists (VKAs) to direct oral anticoagulants (DOACs). This study aimed to determine adherence to long-term therapy in patients switched from VKAs to DOAC due to low time in therapeutic range (TTR) and if adherence is associated with health beliefs. METHODS: The Switching Study is a longitudinal observational cohort study following patients for at least 1-year. 254 patients anticoagulated with VKAs for stroke prevention in atrial fibrillation (AF) or secondary prevention of venous thromboembolism (VTE) and TTR < 50% were recruited from anticoagulation clinics at King's College Hospital, London, UK. All participants were switched to DOAC and had health beliefs measured at baseline with VKA, 1-month and 12-months after switching. RESULTS: Of the 220 patients who completed 12-month follow-up 39% had sub-optimal adherence measured by self-report. 23% were non-adherent according to prescriptions issued. Increasing concerns about anticoagulation over time relative to beliefs about necessity was associated with lower self-reported adherence (OR = 0.902 95%C.I: 0.836, 0.974; p = 0.008). At baseline, believing that medications in general were overused in healthcare was negatively associated with adherence to DOAC (ß = -1.5, 95%C.I: -2.7, -0.3; p = 0.013). CONCLUSIONS: Although many patients who switched were adherent to therapy long-term, between 23 and 39% of patients exhibited sub-optimal adherence: these patients can be identified through their modifiable health beliefs at the time of switching.

Postdischarge venous thromboembolism following hospital admission with COVID-19.

The association of severe coronavirus disease 2019 (COVID-19) with an increased risk of venous thromboembolism (VTE) has resulted in specific guidelines for its prevention and management. The VTE risk appears highest in those with critical care admission. The need for postdischarge thromboprophylaxis remains controversial, which is reflected in conflicting expert guideline recommendations. Our local protocol provides thromboprophylaxis to COVID-19 patients during admission only. We report postdischarge VTE data from an ongoing quality improvement program incorporating root-cause analysis of hospital-associated VTE (HA-VTE). Following 1877 hospital discharges associated with COVID-19, 9 episodes of HA-VTE were diagnosed within 42 days, giving a postdischarge rate of 4.8 per 1000 discharges. Over 2019, following 18 159 discharges associated with a medical admission; there were 56 episodes of HA-VTE within 42 days (3.1 per 1000 discharges). The odds ratio for postdischarge HA-VTE associated with COVID-19 compared with 2019 was 1.6 (95% confidence interval, 0.77-3.1). COVID-19 hospitalization does not appear to increase the risk of postdischarge HA-VTE compared with hospitalization with other acute medical illness. Given that the risk-benefit ratio of postdischarge thromboprophylaxis remains uncertain, randomized controlled trials to evaluate the role of continuing thromboprophylaxis in COVID-19 patients following hospital discharge are required.

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.

Associations between illness beliefs, medication beliefs, anticoagulation-related quality of life, and INR control: Insights from the Switching Study.

BACKGROUND: Anticoagulation control with vitamin-K antagonists (VKAs) in patients with atrial fibrillation (AF) or venous thromboembolism (VTE) can be measured using time in therapeutic range (TTR), where TTR >65% is considered good and low TTR may be associated with low adherence. METHODS: This cross-sectional observational study compared illness beliefs, treatment beliefs, and treatment satisfaction of patients with TTR >75% and TTR <50% using validated tools to determine their association with TTR. Adults requiring chronic VKA therapy were recruited from 2 hospital anticoagulation clinics in London, UK. RESULTS: 311 patients with TTR >75% and 214 with TTR <50% were recruited. TTR >75% patients had been taking warfarin on average over 2 years longer than TTR <50% patients (P < .001). Statistically significant differences in beliefs were found in all subscales other than in treatment control, general harm, and general overuse. Cluster analysis determined there were 4 distinct clusters of beliefs among patients. Multivariate binary logistic regression found VTE patients were least likely to have poor TTR (OR = 0.49; 95% CI 0.29, 0.77). Patients in the "cautious of therapy and fearful of illness" cluster were most likely to have low TTR (OR = 4.75; 95% CI 2.75, 8.77). CONCLUSION: Illness perceptions, medication beliefs and treatment satisfaction were associated with INR control. VTE patients and those who were accepting of both illness and treatment were most likely to have optimal INR control.

Exploration of adherence and patient experiences with DOACs one year after switching from vitamin-K antagonists- insights from the switching study.

BACKGROUND: Current UK and European guidelines recommend anticoagulated patients prescribed warfarin with time in therapeutic range (TTR) <65% be considered for DOAC therapy. There has been considerable concern that adherence with DOACs may be poor compared with warfarin. Little is known about the patient experience of switching from warfarin to DOAC and how patients manage their DOAC long term. Our aim was to conduct focus groups exploring patient's previous experiences with warfarin, their current experience with DOACs, their adherence to DOACs and the long-term service provision they envisage. METHODS: Patients enrolled on the Switching Study who had been switched from warfarin to a DOAC >1year previously were invited to participate in focus groups. Two focus groups for atrial fibrillation (AF) and two for secondary prevention of venous thromboembolism (VTE) patients were held at anticoagulation clinics in South London, UK. Data was analysed using framework analysis to extract dominant themes. RESULTS: Five VTE patients and 15 AF patients attended the focus groups. Dominant themes that emerged were: indication specific anticoagulation prioritisation, warfarin as a necessary inconvenience, DOACs as the anticoagulant of choice, concerns regarding DOAC monitoring, high adherence to DOACs and desire for long-term access to specialist anticoagulation services. DISCUSSION: VTE patients prioritised anticoagulation over other therapies whereas AF patients did not. All participants reported high levels of adherence to DOACs. Patients derived confidence from long-term management in specialist anticoagulation clinics stating a preference to be managed in such a service.

Anticoagulated patient's perception of their illness, their beliefs about the anticoagulant therapy prescribed and the relationship with adherence: impact of novel oral anticoagulant therapy - study protocol for The Switching Study: a prospective cohort study.

BACKGROUND: Anticoagulant therapy is prescribed for millions of patients worldwide for the prevention and treatment of both arterial and venous thrombosis. Historically, only vitamin K antagonists have been available for clinicians to prescribe. The anticoagulation landscape is changing. The recent availability of the novel oral anticoagulants overcome many of the disadvantages associated with vitamin K antagonists. However the lack of formal monitoring and clinic follow-up is a concern for clinicians, as medication adherence is being assumed, which is known to decline in patients prescribed medications for chronic conditions. The switching study is a programme of work investigating the association between medication adherence and patient's beliefs about anticoagulation therapy (warfarin and subsequently novel oral anticoagulants), together with beliefs about their illness and anticoagulation related quality of life. METHODS/DESIGN: The anticoagulation database at King's College Hospital will be interrogated and two groups of patients will be identified; those with a time in therapeutic range on warfarin of ≥75 % and those <50 %. These groups of patients will have their illness perceptions, anticoagulation specific quality of life and beliefs about medications compared. Those patients in the time in therapeutic range <50 % group, will be then be invited to switch to a novel oral anticoagulant, as per local guidance. Those patients, who do switch, will then be followed longitudinally and have their adherence, illness perceptions, anticoagulation specific quality of life and beliefs about medications, re-evaluated on the novel agent. The results from these sub-studies, will inform a clinical pathway to support patients on these novel agents, which will be evaluated in an independent group of patients. DISCUSSION: The results from the switching study will be used to develop a clinical pathway to support patient's prescribed novel oral anticoagulant therapy long-term.

Two novel mutations in the L ferritin coding sequence associated with benign hyperferritinaemia unmasked by glycosylated ferritin assay.

Investigating persistent hyperferritinaemia without apparent iron overload is challenging. Even when inflammation, cirrhosis, Still's disease, fatty liver and malignancy are excluded, there remains a group of patients with unexplained hyperferritinaemia for whom rare forms of haemochromatosis (ferroportin disease) are a consideration. Preliminary results suggest that abnormal percentage glycosylation of serum ferritin is seen in some cases of genetically determined hyperferritinaemia. Serum ferritin is normally 50-81% glycosylated, but low glycosylation (20-42%) prevails in hereditary hyperferritinaemia cataract syndrome. This contrasts with hyperglycosylation (>90%) associated with the benign hyperferritinaemia related to missense L ferritin (p.Thr30Ile) mutation. Here, we describe two novel missense L ferritin variants also associated with hyperglycosylation, p.Gln26Ile and p.Ala27Val. Ferritin glycosylation, a comparatively simple measurement, can identify patients for DNA sequencing as hyperglycosylation (>90%) is associated with benign hyperferritinaemia and mutant L ferritin chain.

Evidence for reduced B-cell progenitors in early (low-risk) myelodysplastic syndrome.

Early, low-risk International Prognostic Scoring System (IPSS) myelodysplastic syndrome (MDS) is a heterogeneous disorder where the molecular and cellular hematopoietic defects are poorly understood. To gain insight into this condition, we analyzed gene expression profiles of marrow CD34+ progenitor cells from normal-karyotype, low-blast-count MDS patients, age-matched controls, and patients with non-MDS anemia. Given the heterogeneity of early MDS, a surprisingly consistent finding was decreased expression of B-cell lineage-affiliated genes in MDS patients compared with healthy controls and 3 of 5 samples with non-MDS anemia. Both patients with non-MDS anemia with reduced B-cell gene expression were on chemotherapy. In 25 of 27 of the original samples and 9 further MDS samples, Taqman real-time polymerase chain reaction (PCR) confirmed these data. Flow cytometry on unfractionated marrow from independent samples also demonstrated reduced B-cell progenitors in MDS patients compared with healthy controls. These novel findings suggest a common perturbation in early MDS hematopoiesis. They also provide the rationale for a larger study to evaluate the diagnostic utility of reduced B-cell progenitor number as a diagnostic biomarker of early low-risk MDS, which can pose a diagnostic challenge.