Real-world use of thrombopoietin receptor agonists for the management of immune thrombocytopenia in adult patients in the United Kingdom: Results from the TRAIT study.

Few studies have reported the real-world use of both romiplostim and eltrombopag in immune thrombocytopenia (ITP). TRAIT was a retrospective observational study aimed to evaluate the platelet responses and adverse effects associated with the use of these thrombopoietin receptor agonists (TPO-RAs) in adult patients with ITP in the United Kingdom. Of 267 patients (median age at diagnosis, 48 years) with ITP (primary ITP [n = 218], secondary ITP [n = 49]) included in the study, 112 (42%) received eltrombopag and 155 (58%) received romiplostim as the first prescribed TPO-RA. A platelet count ≥30 × 109 /L was achieved in 89% of patients with the first TPO-RA treatments, while 68% achieved a platelet count ≥100 × 109 /L. Treatment-free response (TFR; platelet count ≥30 × 109 /L, 3 months after discontinuing treatment) was achieved by 18% of the total patients. Overall, 61 patients (23%) switched TPO-RAs, most of whom achieved platelet counts ≥30 × 109 /L with the second TPO-RA (23/25 who switched from eltrombopag to romiplostim [92%]; 28/36 who switched from romiplostim to eltrombopag [78%]). TFR was associated with secondary ITP, early TPO-RA initiation after diagnosis, the presence of comorbidity and no prior splenectomy or treatment with steroids or mycophenolate mofetil. Both TPO-RAs had similar efficacy and safety profiles to those reported in clinical studies.

Pharmacological thromboprophylaxis to prevent venous thromboembolism in patients with temporary lower limb immobilization after injury: systematic review and network meta-analysis.

BACKGROUND: Thromboprophylaxis has the potential to reduce venous thromboembolism (VTE) following lower limb immobilization resulting from injury. OBJECTIVES: We aimed to estimate the effectiveness of thromboprophylaxis, compare different agents, and identify any factors associated with effectiveness. METHODS: We undertook a systematic review and network meta-analysis (NMA) of randomized trials reporting VTE or bleeding outcomes that compared thromboprophylactic agents with each other or to no pharmacological prophylaxis, for this indication. An NMA was undertaken for each outcome or agent used, and a series of study-level network meta-regressions examined whether population characteristics, type of injury, treatment of injury, or duration of thromboprophylaxis were associated with treatment effect. RESULTS: Data from 6857 participants across 13 randomized trials showed that, compared with no treatment, low molecular weight heparin (LMWH) reduced the risk of any VTE (odds ratio [OR]: 0.52; 95% credible interval [CrI]: 0.37-0.71), clinically detected deep vein thrombosis (DVT) (OR: 0.39; 95% CrI: 0.12-0.94) and pulmonary embolism (PE) (OR: 0.16; 95% CrI: 0.01-0.74), whereas fondaparinux reduced the risk of any VTE (OR: 0.13; 95% CrI: 0.05-0.30) and clinically detected DVT (OR: 0.10; 95% CrI: 0.01-0.86), with inconclusive results for PE (OR: 0.40; 95% CrI: 0.01-7.53). CONCLUSIONS: Thromboprophylaxis with either fondaparinux or LMWH appears to reduce the odds of both asymptomatic and clinically detected VTE in people with temporary lower limb immobilization following an injury. Treatment effects vary by outcome and are not always conclusive. We were unable to identify any treatment effect modifiers other than thromboprophylactic agent used.

Different strategies for pharmacological thromboprophylaxis for lower-limb immobilisation after injury: systematic review and economic evaluation.

BACKGROUND: Thromboprophylaxis can reduce the risk of venous thromboembolism (VTE) during lower-limb immobilisation, but it is unclear whether or not this translates into meaningful health benefit, justifies the risk of bleeding or is cost-effective. Risk assessment models (RAMs) could select higher-risk individuals for thromboprophylaxis. OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of different strategies for providing thromboprophylaxis to people with lower-limb immobilisation caused by injury and to identify priorities for future research. DATA SOURCES: Ten electronic databases and research registers (MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Review of Effects, the Cochrane Central Register of Controlled Trials, Health Technology Assessment database, NHS Economic Evaluation Database, Science Citation Index Expanded, ClinicalTrials.gov and the International Clinical Trials Registry Platform) were searched from inception to May 2017, and this was supplemented by hand-searching reference lists and contacting experts in the field. REVIEW METHODS: Systematic reviews were undertaken to determine the effectiveness of pharmacological thromboprophylaxis in lower-limb immobilisation and to identify any study of risk factors or RAMs for VTE in lower-limb immobilisation. Study quality was assessed using appropriate tools. A network meta-analysis was undertaken for each outcome in the effectiveness review and the results of risk-prediction studies were presented descriptively. A modified Delphi survey was undertaken to identify risk predictors supported by expert consensus. Decision-analytic modelling was used to estimate the incremental cost per quality-adjusted life-year (QALY) gained of different thromboprophylaxis strategies from the perspectives of the NHS and Personal Social Services. RESULTS: Data from 6857 participants across 13 trials were included in the meta-analysis. Thromboprophylaxis with low-molecular-weight heparin reduced the risk of any VTE [odds ratio (OR) 0.52, 95% credible interval (CrI) 0.37 to 0.71], clinically detected deep-vein thrombosis (DVT) (OR 0.40, 95% CrI 0.12 to 0.99) and pulmonary embolism (PE) (OR 0.17, 95% CrI 0.01 to 0.88). Thromboprophylaxis with fondaparinux (Arixtra®, Aspen Pharma Trading Ltd, Dublin, Ireland) reduced the risk of any VTE (OR 0.13, 95% CrI 0.05 to 0.30) and clinically detected DVT (OR 0.10, 95% CrI 0.01 to 0.94), but the effect on PE was inconclusive (OR 0.47, 95% CrI 0.01 to 9.54). Estimates of the risk of major bleeding with thromboprophylaxis were inconclusive owing to the small numbers of events. Fifteen studies of risk factors were identified, but only age (ORs 1.05 to 3.48), and injury type were consistently associated with VTE. Six studies of RAMs were identified, but only two reported prognostic accuracy data for VTE, based on small numbers of patients. Expert consensus was achieved for 13 risk predictors in lower-limb immobilisation due to injury. Modelling showed that thromboprophylaxis for all is effective (0.015 QALY gain, 95% CrI 0.004 to 0.029 QALYs) with a cost-effectiveness of £13,524 per QALY, compared with thromboprophylaxis for none. If risk-based strategies are included, it is potentially more cost-effective to limit thromboprophylaxis to patients with a Leiden thrombosis risk in plaster (cast) [L-TRiP(cast)] score of ≥ 9 (£20,000 per QALY threshold) or ≥ 8 (£30,000 per QALY threshold). An optimal threshold on the L-TRiP(cast) receiver operating characteristic curve would have sensitivity of 84-89% and specificity of 46-55%. LIMITATIONS: Estimates of RAM prognostic accuracy are based on weak evidence. People at risk of bleeding were excluded from trials and, by implication, from modelling. CONCLUSIONS: Thromboprophylaxis for lower-limb immobilisation due to injury is clinically effective and cost-effective compared with no thromboprophylaxis. Risk-based thromboprophylaxis is potentially optimal but the prognostic accuracy of existing RAMs is uncertain. FUTURE WORK: Research is required to determine whether or not an appropriate RAM can accurately select higher-risk patients for thromboprophylaxis. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017058688. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

People who have their leg immobilised in a plaster cast or brace following an injury are at risk of developing a blood clot. Sometimes the clot can break up and lodge in the lungs, which can make the person seriously ill. Drugs that thin the blood (anticoagulants) can reduce the risk of blood clots, but they carry a small risk of serious bleeding. This study analysed all published trials of anticoagulants for people with leg immobilisation and found that, without treatment, there was a 1­2% risk of a serious blood clot. This risk was roughly halved by using anticoagulant treatment. These estimates were used in a simulation model of patient treatment and it was found that the benefit of anticoagulants in reducing blood clots (in terms of length and quality of life) outweighed the risks of bleeding. Next, all published studies of risk assessment tools were analysed. Risk assessment tools can be used to predict who is most likely to get a blood clot. There were only a few studies and they had significant weaknesses. The risk assessment tools in the simulation model were evaluated and it was found that the most cost-effective approach was to use a risk assessment tool to select approximately half of the patients for treatment (those at higher risk), while not treating those at lower risk. Treating only the higher-risk patients would be a cost-effective use of NHS resources, compared with treating nobody. Treating everybody, compared with just treating higher-risk patients, would improve outcomes for some patients but would not be a cost-effective use of NHS resources. This study suggests that anticoagulant drugs are an effective and potentially cost-effective way of preventing blood clots in people with leg immobilisation due to injury. Research is needed to determine whether or not risk assessment tools can accurately predict who needs anticoagulant drugs and who does not.

Retrospective Review of a Prothrombin Complex Concentrate (Beriplex P/N) for the Management of Perioperative Bleeding Unrelated to Oral Anticoagulation.

A multicenter, retrospective, observational study of 4-factor prothrombin complex concentrate (PCC) and/or fresh frozen plasma (FFP) use within routine clinical care unrelated to vitamin K antagonists was conducted. The PCC was administered preprocedure for correction of coagulopathy (prophylactic cohort) and treatment of bleeding postsurgery (treatment cohort). Of the 445 patients included, 40 were in the prophylactic cohort (PCC alone [n = 16], PCC and FFP [n = 5], FFP alone [n = 19]) and 405 were in the treatment cohort (PCC alone [n = 228], PCC and FFP [n = 123], FFP alone [n = 54]). Cardiovascular surgery was the most common setting. PCC doses ranged between 500 and 5000 IU. Effectiveness (assessed retrospectively) was reported as effective in 93.0% in the PCC-only group (95% confidence interval, 89.1% to 95.9%), 78.9% (70.8% to 85.6%) with PCC and FFP, and 86.3% (76.2% to 93.2%) with FFP alone. In the treatment cohort, international normalized ratio was significantly reduced in all 3 groups. In patients who received PCC, the rate of thromboembolic events (1.9%) was below rates in the literature for similar procedures. PCCs offer a potential alternative to FFP in the management of perioperative bleeding unrelated to oral anticoagulant therapy.

Ensuring timely thromboprophylaxis on a Medical Assessment Unit.

The Department of Health has defined hospital acquired venous thromboembolism (VTE) as any VTE event occurring within 90 days of hospital admission or surgery. 1 Hospital acquired thrombosis (HAT) is common during and after hospital admission and is considered a major patient safety issue. Current NICE guideline (CG 92) 2010, recommends that medical patients assessed at risk of VTE should have pharmacological prophylaxis commenced as soon as possible after risk assessment has been completed and continued until the patient is no longer at increased risk of VTE. 2 This quality improvement project was carried out in the medical assessment unit in Derriford Hospital, Plymouth. We aimed to increase appropriate VTE pharmacological prophylaxis to 100% prescribed in 6 hours by the end of May 2016 using the Plan-Do-Study-Act (PDSA) methodology. The primary outcome measure was whether or not enoxaparin was given within 6 hours of admission. Analysis showed that a major contributing factor to the prolonged time interval was lack of awareness of the Trust VTE guidelines which had recently been updated in accordance with NICE recommendations. Baseline measurement demonstrated that 29% of patients had first dose of enoxaparin within the 6-hour target, with a mean delay of 12 hours 22 minutes. With implementation of an education programme and development of a local VTE prevention care pathway to raise awareness of the new guidelines, a significant improvement was achieved with 71% of patients meeting the 6-hour target in PDSA cycle 1 and 83% of patients in PDSA cycle 2. The average time interval also reduced to 5 hours 52 minutes in PDSA cycle 1 and 5 hours 7 minutes in PDSA cycle 2. In conclusion, through utilization of simple change methodology, enoxaparin prescribing practice significantly improved. Potentially this may reduce morbidity (and mortality) associated with HAT together with cost implications of its management.

Three-year clinical experience with VQ SPECT for diagnosing pulmonary embolism: diagnostic performance.

Ventilation-perfusion (VQ) single-photon emission computed tomography (SPECT) comprised the administration of SmartVent (n=386) or Technegas (n=1564) and 200 MBq (99m)Tc-MAA. 1406 scans were normal, 462 showed PE, 61 showed a singular subsegmental mismatched defect, 21 scans were non-diagnostic. 26% of scans performed with Technegas showed PE, compared to 15% with SmartVent. VQ SPECT had a sensitivity of 95.7%, specificity 98.6%, positive predictive value 95.7%, negative predictive value 98.6%. A normal VQ SPECT scan implied a more than ten-fold lower cause-specific mortality (1 in 1406) than a scan showing PE (1 in 116). NPV of a negative D-dimer was 94.3%.

The implementation of NICE guidance on venous thromboembolism risk assessment and prophylaxis: a before-after observational study to assess the impact on patient safety across four hospitals in England.

BACKGROUND: Venous thromboembolism (VTE) is a major cause of morbidity and mortality in hospitalised patients. VTE prevention has been identified as a major health need internationally to improve patient safety. A National Institute for Health and Clinical Excellence (NICE) guideline was issued in February 2010. Its key priorities were to assess patients for risk of VTE on admission to hospital, assess patients for bleeding risk and evaluate the risks and benefits of prescribing VTE prophylaxis. The aim of this study was to evaluate the implementation of NICE guidance and its impact on patient safety. METHODS: A before-after observational design was used to investigate changes in VTE risk assessment documentation and inappropriate prescribing of prophylaxis between the year prior to (2009) and the year following (2010) the implementation of NICE guidance, using data from a 3-week period during each year. A total of 408 patients were sampled in each year across four hospitals in the NHS South region. RESULTS: Implementation strategies such as audit, education and training were used. The percentage of patients for whom a VTE risk assessment was documented increased from 51.5% (210/408) in 2009 to 79.2% (323/408) in 2010; difference 27.7% (95% CI: 21.4% to 33.9%; p < 0.001). There was little evidence of change in the percentage who were prescribed prophylaxis amongst patients without a risk assessment (71.7% (142/198) in 2009 and 68.2% (58/85) in 2010; difference -3.5% (95% CI: -15.2% to 8.2%; p =0.56) nor the percentage who were prescribed low molecular weight heparin amongst patients with a contraindication (14% (4/28) in 2009 and 15% (6/41) in 2010; RD = 0.3% (95% CI: -16.5% to 17.2%; p =0.97). CONCLUSIONS: The documentation of risk assessment improved following the implementation of NICE guidance; it is questionable, however, whether this led to improved patient safety with respect to prescribing appropriate prophylaxis.

Can plasma D-dimer predict the result of a ventilation-perfusion scan?

The use of plasma D-dimer assay has been advocated for the exclusion of pulmonary embolism. We retrospectively looked at 840 patients in whom both ventilation-perfusion scan and D-dimer assay were performed within 48 h. The negative predictive value of a negative D-dimer assay was 96% for emergency admissions and 98% for inpatients. We present the cases of two patients with negative D-dimer assay results who had a high-probability lung scan, and we have found a further three patients with negative D-dimer assay results who had an intermediate-probability lung scan.

Prothrombin complex concentrate (Beriplex P/N) in severe bleeding: experience in a large tertiary hospital.

INTRODUCTION: Major blood loss can often be life-threatening and is most commonly encountered in the settings of surgery and trauma. Patients receiving anticoagulant therapy are also at increased risk of bleeding. We investigated the use of a prothrombin complex concentrate (PCC; Beriplex P/N, CSL Behring, Marburg, Germany) to treat severe bleeding in a variety of settings: cardiac surgery, warfarin therapy and other surgery. METHODS: Thirty consecutive patients who had received PCC were identified from blood transfusion records. For cardiac surgery and warfarin reversal, PCC was administered in accordance with hospital protocols. PCC was administered to cardiac and other surgical patients responding poorly to recognized blood products, whereas it was administered first-line to patients with life-threatening bleeds and requiring warfarin reversal, in accordance with British Committee for Standards in Haematology guidelines. We conducted a retrospective analysis of patient records in order to ascertain PCC dose, use of other blood products and response to PCC (clotting screen results before and after PCC administration, haemostasis achievement, and survival). RESULTS: Six patients (20%) were excluded because of inadequate documentation (n = 5) or acquired haemophilia (n = 1). Therefore, 24 patients were included in the analysis: coronary artery bypass graft (n = 5), mitral/aortic valve replacement (n = 2), other surgery (n = 9) and warfarin reversal (n = 8). Most patients (83.3%) received no more than 1500 IU of Beriplex P/N 500. Considerable reduction in administration of other blood products was seen during the 24 hours after PCC administration. Partial or complete haemostasis was achieved in 14 out of 18 cases (77.8%). In total, 12 out of 24 patients (50%) died during the study; two-thirds of the deaths were considered unrelated to bleeding. No thrombotic complications or adverse drug reactions were observed. CONCLUSION: This study emphasizes the value of PCC in reversing the effects of oral anticoagulant therapy in bleeding patients. It also demonstrates the potential value of PCC in controlling bleeding in patients undergoing cardiac and other surgical procedures. The use of PCC in bleeding patients without hereditary or anticoagulation-related coagulopathy is novel, and further investigation is warranted. In the future, it may be possible to use PCC as a substitute for fresh frozen plasma in this setting; adequate documentation is crucial for all blood products.

The training/service continuum: exploring the training/service balance of senior house officer activities.

BACKGROUND: The continued reduction in junior doctors' hours in the UK has made it necessary to re-examine traditional assumptions about the synonymous natures of training and service. This paper researches senior house officers' (SHOs) perceptions of 'service' and 'training', with reference to where they place activities along the training/service continuum, and the factors that lead them to classify these activities in the way they do. METHODS: Questionnaires were sent to all identified SHOs at Plymouth Hospitals NHS Trust (40% response rate). Three focus groups were held with 5 SHOs, 3 consultants and 2 clinical tutors. Quantitative data derived from the questionnaires were analysed using spss. Qualitative data collected in the focus groups was coded with the aid of n6, which facilitated the thematic analysis of transcripts. RESULTS: Analysis of the quantitative data allowed the construction of the training/service continuum diagram. Identified factors affecting the perceived training/service balance of SHO activities included: frequency, time, type and nature of work, number of patients, supervision, interaction, other commitments, purpose and focus of the activity, the individual trainee and trainer, and experience and competence. DISCUSSION: It is no longer appropriate to assume that all junior doctor activities represent either training or service individually: activities are perceived differently along the training/service continuum depending on their execution and their relation to the SHOs' learning curves. Within the reduced hours framework, it is necessary to match this balance to experience, in order for both training and service requirements to be satisfied.