Total Synthesis of Pyrrolidine and Piperidine Natural Products via TMSOTf-Mediated "5/6-endo-dig" Reductive Hydroamination of Enynyl Amines.

Stereoselective syntheses of pyrrolidines and piperidines bearing hydrophobic chains have been achieved through a metal free, Lewis acid-mediated 5/6-endo-dig reductive hydroamination cascade of enynyl amines. The brevity of the developed strategy allowed for the collective stereoselective total synthesis of various alkaloids, including (±)-pyrrolidine cis-225H, (±)-epi-197B, (±)-epi-225C, the family of (+)-solenopsins and (+)-isosolenopsins, and the formal synthesis of (±)-bgugaine and (+)-azimic acid.

Transposition of an acrylate moiety in TMSOTf-mediated reaction of alkynyl vinylogous carbonates gives heterocyclic dienes.

TMSOTf-mediated reaction of alkynyl vinylogous carbonates serendipitously gave 1,4-oxazepine and dihydropyran dienes via transposition of an ethyl acrylate moiety involving intramolecular cascade Prins-type cyclization/retro-oxa-Michael reaction/cycloisomerisation. The developed atom-economical protocol selectively provides an E double bond geometry. Dihydropyran dienes could be reduced diastereoselectively using Et3SiH/TMSOTf or could be transformed into polycyclic heterocycles by Heck reaction.

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.

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.

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.

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.

What are the difficulties in conducting randomised controlled trials of thromboprophylaxis in myeloma patients and how can we address these? Lessons from apixaban versus LMWH or aspirin as thromboprophylaxis in newly diagnosed multiple myeloma (TiMM) feasibility clinical trial.

Routine thromboprophylaxis (TP) in newly-diagnosed multiple myeloma (NDMM) patients comprises either aspirin for standard risk patients or low molecular weight heparin for high risk patients. Studies using DOACs in cancer patients include few with myeloma. The aim of this feasibility clinical trial was to establish the foundations for creating a multicentre trial and identify any safety concerns with apixaban. Patient perspectives were sought. NDMM patients were stratified according to VTE risk and randomised to either standard TP or apixaban 2.5 mg BD and reviewed every 3 weeks throughout their chemotherapy. Two focus groups were carried out on 2 occasions at King's College Hospital and Guy's Hospital, London. Each lasted an hour, were recorded, transcribed and themes explored using NVivo 11. Ten patients were recruited, 2 considered high risk and received apixaban and 8 standard risk; 4 randomised to aspirin and 4 to apixaban. Five patients and 2 carers participated in the focus groups. There were no major bleeding or VTE events. Patients were not aware of the thrombotic risk associated with cancer. There is a lack of both written and verbal information on this topic. Myeloma patients were happy to be included in more than one trial simultaneously. Our study provides information on the difficulties facing physicians and patients on obtaining evidence of the safety of DOACs in the context of myeloma. Despite patients being happy to co-recruit into thromboprophylaxis trials along with chemotherapy trials this is not current practice.EudraCT Number: 2015-002668-18.

TMSOTf mediated '5/6-endo-dig' reductive hydroamination for the stereoselective synthesis of pyrrolidine and piperidine derivatives.

A TMSOTf mediated 5/6-endo-dig reductive hydroamination cascade on internal alkynylamines gave expedient, stereoselective access to pyrrolidine and piperidine derivatives. We also demonstrate that a protecting group on nitrogen has a profound effect on the reactivity as well as diastereoselectivity of the reductive hydroamination cascade.

Progress in the monitoring of direct oral anticoagulant therapy.

The availability of direct oral anticoagulants (DOACs) has led to a paradigm shift in the field of anticoagulation, with DOACs increasingly being prescribed for patients in preference to vitamin K antagonists and low molecular weight heparin. Despite good experience with the use of these agents at fixed doses, there are clinical scenarios where monitoring is recommended. Data from phase III studies of the DOACs and small real-world studies suggest a relationship between DOAC concentration and clinical events. The DOACs have differing impacts on the common tests of haemostasis and it is important that clinicians are familiar with the sensitivity of the reagents used in their laboratory to individual DOACs. The specific DOAC drug concentrations can be assayed in the laboratory, when required, to guide appropriate clinical decision-making. Studies from the real world with sufficient numbers evaluating the association of DOAC concentrations with outcomes should be a research priority in order to understand if we could do better through dose individualisation.

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.