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  • Protective effect of antirheumatic drugs on dementia in rheumatoid arthritis patients.

    3 July 2018

    Introduction: Rheumatoid arthritis is a systemic inflammatory disease, and classical disease-modifying antirheumatic drugs (cDMARDs) have proven efficacy. It is unknown what impact cDMARDs might have on dementia as an outcome. Methods: Incident diagnoses of rheumatoid arthritis in persons over 18 years from 1995 to 2011 were identified from the UK Clinical Practice Research Datalink. There were 3876 cDMARD users and were propensity score matched to 1938 nonusers, on a wide range of confounders. Impact on dementia was assessed using survival models. Results: cDMARD users were at reduced risk of dementia (hazard ratio: 0.60; 95% confidence interval: 0.42-0.85). The effect was strongest in methotrexate users (hazard ratio: 0.52; 95% confidence interval; 0.34-0.82). Discussion: The strong effect of cDMARD use on halving of dementia risk requires replication in a trial and may provide an important therapeutic pharmacological treatment.

  • Real-world antidiabetic drug use and fracture risk in 12,277 patients with type 2 diabetes mellitus: a nested case-control study.

    2 July 2018

    We conducted a nested case-control study to study the association between antidiabetic treatments (alone or in combination) use and fracture risk among incident type 2 Diabetes mellitus patients. We found an increased risk of bone fracture with insulin therapy compared to metformin monotherapy. INTRODUCTION: Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fragility fractures, to which antidiabetic therapies may contribute. We aimed to characterize the risk of fracture associated with different antidiabetic treatments as usually prescribed to T2DM patients in actual practice conditions. METHODS: A case-control study was nested within a cohort of incident T2DM patients registered in 2006-2012 in the Information System for Research Development in Primary Care (Catalan acronym, SIDIAP), a database which includes records for > 5.5 million patients in Catalonia (Spain). Each case (incident major osteoporotic fracture) was risk-set matched with up to five same-sex controls by calendar year of T2DM diagnosis and year of birth (± 10 years). Study exposure included previous use of all antidiabetic medications (alone or in combination), as dispensed in the 6 months before the index date, with metformin (MTF) monotherapy, the most commonly used drug, as a reference group (active comparator). RESULTS: Data on 12,277 T2DM patients (2049 cases and 10,228 controls) were analyzed. Insulin use was associated with increased fracture risk (adjusted OR 1.63 (95% CI 1.30-2.04)), as was the combination of MTF and sulfonylurea (SU) (adjusted OR 1.29 (1.07-1.56)), compared with MTF monotherapy. Sensitivity analyses suggest possible causality for insulin therapy but not for the MTF + SU combination association. No significant association was found with any other antidiabetic medications. CONCLUSIONS: Insulin monotherapy was associated with an increased fracture risk compared to MTF monotherapy in T2DM patients. Fracture risk should be taken into account when starting a glucose-lowering drug as part of T2DM treatment.

  • Use of platelet transfusions prior to lumbar punctures or epidural anaesthesia for the prevention of complications in people with thrombocytopenia.

    29 June 2018

    BACKGROUND: People with a low platelet count (thrombocytopenia) often require lumbar punctures or an epidural anaesthetic. Lumbar punctures can be diagnostic (haematological malignancies, subarachnoid haematoma, meningitis) or therapeutic (spinal anaesthetic, administration of chemotherapy). Epidural catheters are placed for administration of epidural anaesthetic. Current practice in many countries is to correct thrombocytopenia with platelet transfusions prior to lumbar punctures and epidural anaesthesia, in order to mitigate the risk of serious procedure-related bleeding. However, the platelet count threshold recommended prior to these procedures varies significantly from country to country. This indicates significant uncertainty among clinicians regarding the correct management of these patients. The risk of bleeding appears to be low, but if bleeding occurs it can be very serious (spinal haematoma). Consequently, people may be exposed to the risks of a platelet transfusion without any obvious clinical benefit.This is an update of a Cochrane Review first published in 2016. OBJECTIVES: To assess the effects of different platelet transfusion thresholds prior to a lumbar puncture or epidural anaesthesia in people with thrombocytopenia (low platelet count). SEARCH METHODS: We searched for randomised controlled trials (RCTs), non-randomised controlled trials (nRCTs), controlled before-after studies (CBAs), interrupted time series studies (ITSs), and cohort studies in CENTRAL (the Cochrane Library 2018, Issue 1), MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 13 February 2018. SELECTION CRITERIA: We included RCTs, nRCTs, CBAs, ITSs, and cohort studies involving transfusions of platelet concentrates, prepared either from individual units of whole blood or by apheresis, and given to prevent bleeding in people of any age with thrombocytopenia requiring insertion of a lumbar puncture needle or epidural catheter.The original review only included RCTs. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane for including RCTs, nRCTs, CBAs, and ITSs. Two review authors independently assessed studies for eligibility and risk of bias and extracted data. Results were only expressed narratively. MAIN RESULTS: We identified no completed or ongoing RCTs, nRCTs, CBAs, or ITSs. No studies included people undergoing an epidural procedure. No studies compared different platelet count thresholds prior to a procedure.In this update we identified three retrospective cohort studies that contained participants who did and did not receive platelet transfusions prior to lumbar puncture procedures. All three studies were carried out in people with cancer, most of whom had a haematological malignancy. Two studies were in children, and one was in adults.The number of participants receiving platelet transfusions prior to the lumbar puncture procedures was not reported in one study. We therefore only summarised in a narrative form the relevant outcomes from two studies (150 participants; 129 children and 21 adults), in which the number of participants who received the transfusion was given.We judged the overall risk of bias for all reported outcomes for both studies as 'serious' based on the ROBINS-I tool.No procedure-related major bleeding occurred in the two studies that reported this outcome (2 studies, 150 participants, no cases, very low-quality evidence).There was no evidence of a difference in the risk of minor bleeding (traumatic tap) in participants who received platelet transfusions before a lumbar puncture and those who did not receive a platelet transfusion before the procedure (2 studies, 150 participants, very low-quality evidence). One of the 14 adults who received a platelet transfusion experienced minor bleeding (traumatic tap; defined as at least 500 x 106/L red blood cells in the cerebrospinal fluid); none of the seven adults who did not receive a platelet transfusion experienced this event. Ten children experienced minor bleeding (traumatic taps; defined as at least 100 x 106/L red blood cells in the cerebrospinal fluid), six out of the 57 children who received a platelet transfusion and four out of the 72 children who did not receive a platelet transfusion.No serious adverse events occurred in the one study that reported this outcome (1 study, 21 participants, very low-quality evidence).We found no studies that evaluated all-cause mortality within 30 days from the lumbar puncture procedure, length of hospital stay, proportion of participants who received platelet transfusions, or quality of life. AUTHORS' CONCLUSIONS: We found no evidence from RCTs or non-randomised studies on which to base an assessment of the correct platelet transfusion threshold prior to insertion of a lumbar puncture needle or epidural catheter. There are no ongoing registered RCTs assessing the effects of different platelet transfusion thresholds prior to the insertion of a lumbar puncture or epidural anaesthesia in people with thrombocytopenia. Any future study would need to be very large to detect a difference in the risk of bleeding. A study would need to be designed with at least 47,030 participants to be able to detect an increase in the number of people who had major procedure-related bleeding from 1 in 1000 to 2 in 1000. The use of a central data collection register or routinely collected electronic records (big data) is likely to be the only method to systematically gather data relevant to this population.

  • Comparison of a therapeutic-only versus prophylactic platelet transfusion policy for people with congenital or acquired bone marrow failure disorders.

    9 August 2018

    BACKGROUND: Bone marrow disorders encompass a group of diseases characterised by reduced production of red cells, white cells, and platelets, or defects in their function, or both. The most common bone marrow disorder is myelodysplastic syndrome. Thrombocytopenia, a low platelet count, commonly occurs in people with bone marrow failure. Platetet transfusions are routinely used in people with thrombocytopenia secondary to bone marrow failure disorders to treat or prevent bleeding. Myelodysplastic syndrome is currently the most common reason for receiving a platelet transfusion in some Western countries. OBJECTIVES: To determine whether a therapeutic-only platelet transfusion policy (transfusion given when patient is bleeding) is as effective and safe as a prophylactic platelet transfusion policy (transfusion given to prevent bleeding according to a prespecified platelet threshold) in people with congenital or acquired bone marrow failure disorders. SEARCH METHODS: We searched for randomised controlled trials (RCTs), non-RCTs, and controlled before-after studies (CBAs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2017, Issue 9), Ovid MEDLINE (from 1946), Ovid Embase (from 1974), PubMed (e-publications only), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 12 October 2017. SELECTION CRITERIA: We included RCTs, non-RCTs, and CBAs that involved the transfusion of platelet concentrates (prepared either from individual units of whole blood or by apheresis any dose, frequency, or transfusion trigger) and given to treat or prevent bleeding among people with congenital or acquired bone marrow failure disorders.We excluded uncontrolled studies, cross-sectional studies, and case-control studies. We excluded cluster-RCTs, non-randomised cluster trials, and CBAs with fewer than two intervention sites and two control sites due to the risk of confounding. We included all people with long-term bone marrow failure disorders that require platelet transfusions, including neonates. We excluded studies of alternatives to platelet transfusion, or studies of people receiving intensive chemotherapy or a stem cell transplant. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures outlined by Cochrane. Due to the absence of evidence we were unable to report on any of the review outcomes. MAIN RESULTS: We identified one RCT that met the inclusion criteria for this review. The study enrolled only nine adults with MDS over a three-year study duration period. The trial was terminated due to poor recruitment rate (planned recruitment 60 participants over two years). Assessment of the risk of bias was not possible for all domains. The trial was a single-centre, single-blind trial. The clinical and demographic characteristics of the participants were never disclosed. The trial outcomes relevant to this review were bleeding assessments, mortality, quality of life, and length of hospital stay, but no data were available to report on any of these outcomes.We identified no completed non-RCTs or CBAs.We identified no ongoing RCTs, non-RCTs, or CBAs. AUTHORS' CONCLUSIONS: We found no evidence to determine the safety and efficacy of therapeutic platelet transfusion compared with prophylactic platelet transfusion for people with long-term bone marrow failure disorders. This review underscores the urgency of prioritising research in this area. People with bone marrow failure depend on long-term platelet transfusion support, but the only trial that assessed a therapeutic strategy was halted. There is a need for good-quality studies comparing a therapeutic platelet transfusion strategy with a prophylactic platelet transfusion strategy; such trials should include outcomes that are important to patients, such as quality of life, length of hospital admission, and risk of bleeding.

  • Interventions for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia.

    9 August 2018

    BACKGROUND: Regularly transfused people with sickle cell disease (SCD) and people with thalassaemia (who are transfusion-dependent or non-transfusion-dependent) are at risk of iron overload. Iron overload can lead to iron toxicity in vulnerable organs such as the heart, liver and endocrine glands; which can be prevented and treated with iron chelating agents. The intensive demands and uncomfortable side effects of therapy can have a negative impact on daily activities and well-being, which may affect adherence. OBJECTIVES: To identify and assess the effectiveness of interventions (psychological and psychosocial, educational, medication interventions, or multi-component interventions) to improve adherence to iron chelation therapy in people with SCD or thalassaemia. SEARCH METHODS: We searched CENTRAL (the Cochrane Library), MEDLINE, Embase, CINAHL, PsycINFO, Psychology and Behavioral Sciences Collection, Web of Science Science & Social Sciences Conference Proceedings Indexes and ongoing trial databases (01 February 2017). We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register (12 December 2017). SELECTION CRITERIA: For trials comparing medications or medication changes, only randomised controlled trials (RCTs) were eligible for inclusion.For studies including psychological and psychosocial interventions, educational Interventions, or multi-component interventions, non-RCTs, controlled before-after studies, and interrupted time series studies with adherence as a primary outcome were also eligible for inclusion. DATA COLLECTION AND ANALYSIS: Three authors independently assessed trial eligibility, risk of bias and extracted data. The quality of the evidence was assessed using GRADE. MAIN RESULTS: We included 16 RCTs (1525 participants) published between 1997 and 2017. Most participants had β-thalassaemia major; 195 had SCD and 88 had β-thalassaemia intermedia. Mean age ranged from 11 to 41 years. One trial was of medication management and 15 RCTs were of medication interventions. Medications assessed were subcutaneous deferoxamine, and two oral-chelating agents, deferiprone and deferasirox.We rated the quality of evidence as low to very low across all outcomes identified in this review.Three trials measured quality of life (QoL) with validated instruments, but provided no analysable data and reported no difference in QoL.Deferiprone versus deferoxamineWe are uncertain whether deferiprone increases adherence to iron chelation therapy (four trials, very low-quality evidence). Results could not be combined due to considerable heterogeneity (participants' age and different medication regimens). Medication adherence was high (deferiprone (85% to 94.9%); deferoxamine (71.6% to 93%)).We are uncertain whether deferiprone increases the risk of agranulocytosis, risk ratio (RR) 7.88 (99% confidence interval (CI) 0.18 to 352.39); or has any effect on all-cause mortality, RR 0.44 (95% CI 0.12 to 1.63) (one trial; 88 participants; very low-quality evidence).Deferasirox versus deferoxamineWe are uncertain whether deferasirox increases adherence to iron chelation therapy, mean difference (MD) -1.40 (95% CI -3.66 to 0.86) (one trial; 197 participants; very-low quality evidence). Medication adherence was high (deferasirox (99%); deferoxamine (100%)). We are uncertain whether deferasirox decreases the risk of thalassaemia-related serious adverse events (SAEs), RR 0.95 (95% CI 0.41 to 2.17); or all-cause mortality, RR 0.96 (95% CI 0.06 to 15.06) (two trials; 240 participants; very low-quality evidence).We are uncertain whether deferasirox decreases the risk of SCD-related pain crises, RR 1.05 (95% CI 0.68 to 1.62); or other SCD-related SAEs, RR 1.08 (95% CI 0.77 to 1.51) (one trial; 195 participants; very low-quality evidence).Deferasirox film-coated tablet (FCT) versus deferasirox dispersible tablet (DT)Deferasirox FCT may make little or no difference to adherence, RR 1.10 (95% CI 0.99 to 1.22) (one trial; 173 participants; low-quality evidence). Medication adherence was high (FCT (92.9%); DT (85.3%)).We are uncertain if deferasirox FCT increases the incidence of SAEs, RR 1.22 (95% CI 0.62 to 2.37); or all-cause mortality, RR 2.97 (95% CI 0.12 to 71.81) (one trial; 173 participants; very low-quality evidence).Deferiprone and deferoxamine combined versus deferiprone alone We are uncertain if deferiprone and deferoxamine combined increases adherence to iron chelation therapy (very low-quality evidence). Medication adherence was high (deferiprone 92.7% (range 37% to 100%) to 93.6% (range 56% to 100%); deferoxamine 70.6% (range 25% to 100%).Combination therapy may make little or no difference to the risk of SAEs, RR 0.15 (95% CI 0.01 to 2.81) (one trial; 213 participants; low-quality evidence).We are uncertain if combination therapy decreases all-cause mortality, RR 0.77 (95% CI 0.18 to 3.35) (two trials; 237 participants; very low-quality evidence).Deferiprone and deferoxamine combined versus deferoxamine aloneDeferiprone and deferoxamine combined may have little or no effect on adherence to iron chelation therapy (four trials; 216 participants; low-quality evidence). Medication adherence was high (deferoxamine 91.4% to 96.1%; deferiprone: 82.4%)Deferiprone and deferoxamine combined, may have little or no difference in SAEs or mortality (low-quality evidence). No SAEs occurred in three trials and were not reported in one trial. No deaths occurred in two trials and were not reported in two trials.Deferiprone and deferoxamine combined versus deferiprone and deferasirox combinedDeferiprone and deferasirox combined may improve adherence to iron chelation therapy, RR 0.84 (95% CI 0.72 to 0.99) (one trial; 96 participants; low-quality evidence). Medication adherence was high (deferiprone and deferoxamine: 80%; deferiprone and deferasirox: 95%).We are uncertain if deferiprone and deferasirox decreases the incidence of SAEs, RR 1.00 (95% CI 0.06 to 15.53) (one trial; 96 participants; very low-quality evidence).There were no deaths in the trial (low-quality evidence).Medication management versus standard careWe are uncertain if medication management improves health-related QoL (one trial; 48 participants; very low-quality evidence). Adherence was only measured in one arm of the trial. AUTHORS' CONCLUSIONS: The medication comparisons included in this review had higher than average adherence rates not accounted for by differences in medication administration or side effects.Participants may have been selected based on higher adherence to trial medications at baseline. Also, within the clinical trial context, there is increased attention and involvement of clinicians, thus high adherence rates may be an artefact of trial participation.Real-world, pragmatic trials in community and clinic settings are needed that examine both confirmed or unconfirmed adherence strategies that may increase adherence to iron chelation therapy.Due to lack of evidence this review cannot comment on intervention strategies for different age groups.

  • Ten simple rules for measuring the impact of workshops.

    3 September 2018

    Workshops are used to explore a specific topic, to transfer knowledge, to solve identified problems, or to create something new. In funded research projects and other research endeavours, workshops are the mechanism used to gather the wider project, community, or interested people together around a particular topic. However, natural questions arise: how do we measure the impact of these workshops? Do we know whether they are meeting the goals and objectives we set for them? What indicators should we use? In response to these questions, this paper will outline rules that will improve the measurement of the impact of workshops.

  • Intramedullary nail fixation versus locking plate fixation for adults with a fracture of the distal tibia: the UK FixDT RCT.

    3 July 2018

    BACKGROUND: The best treatment for fractures of the distal tibia remains controversial. Most of these fractures require surgical fixation, but the outcomes are unpredictable and complications are common. OBJECTIVES: To assess disability, quality of life, complications and resource use in patients treated with intramedullary (IM) nail fixation versus locking plate fixation in the 12 months following a fracture of the distal tibia. DESIGN: This was a multicentre randomised trial. SETTING: The trial was conducted in 28 UK acute trauma centres from April 2013 to final follow-up in February 2017. PARTICIPANTS: In total, 321 adult patients were recruited. Participants were excluded if they had open fractures, fractures involving the ankle joint, contraindication to nailing or inability to complete questionnaires. INTERVENTIONS: IM nail fixation (n = 161), in which a metal rod is inserted into the hollow centre of the tibia, versus locking plate fixation (n = 160), in which a plate is attached to the surface of the tibia with fixed-angle screws. MAIN OUTCOME MEASURES: The primary outcome measure was the Disability Rating Index (DRI) score, which ranges from 0 points (no disability) to 100 points (complete disability), at 6 months with a minimum clinically important difference of 8 points. The DRI score was also collected at 3 and 12 months. The secondary outcomes were the Olerud-Molander Ankle Score (OMAS), quality of life as measured using EuroQol-5 Dimensions (EQ-5D), complications such as infection, and further surgery. Resource use was collected to inform the health economic evaluation. RESULTS: Participants had a mean age of 45 years (standard deviation 16.2 years), were predominantly male (61%, 197/321) and had experienced traumatic injury after a fall (69%, 223/321). There was no statistically significant difference in DRI score at 6 months [IM nail fixation group, mean 29.8 points, 95% confidence interval (CI) 26.1 to 33.7 points; locking plate group, mean 33.8 points, 95% CI 29.7 to 37.9 points; adjusted difference, 4.0 points, 95% CI -1.0 to 9.0 points; p = 0.11]. There was a statistically significant difference in DRI score at 3 months in favour of IM nail fixation (IM nail fixation group, mean 44.2 points, 95% CI 40.8 to 47.6 points; locking plate group, mean 52.6 points, 95% CI 49.3 to 55.9 points; adjusted difference 8.8 points, 95% CI 4.3 to 13.2 points; p < 0.001), but not at 12 months (IM nail fixation group, mean 23.1 points, 95% CI 18.9 to 27.2 points; locking plate group, 24.0 points, 95% CI 19.7 to 28.3 points; adjusted difference 1.9 points, 95% CI -3.2 to 6.9 points; p = 0.47). Secondary outcomes showed the same pattern, including a statistically significant difference in mean OMAS and EQ-5D scores at 3 and 6 months in favour of IM nail fixation. There were no statistically significant differences in complications, including the number of postoperative infections (13% in the locking plate group and 9% in the IM nail fixation group). Further surgery was more common in the locking plate group (12% in locking plate group and 8% in IM nail fixation group at 12 months). The economic evaluation showed that IM nail fixation provided a slightly higher quality of life in the 12 months after injury and at lower cost and, therefore, it was cost-effective compared with locking plate fixation. The probability of cost-effectiveness for IM nail fixation exceeded 90%, regardless of the value of the cost-effectiveness threshold. LIMITATIONS: As wound dressings after surgery are clearly visible, it was not possible to blind the patients to their treatment allocation. This evidence does not apply to intra-articular (pilon) fractures of the distal tibia. CONCLUSIONS: Among adults with an acute fracture of the distal tibia who were randomised to IM nail fixation or locking plate fixation, there were similar disability ratings at 6 months. However, recovery across all outcomes was faster in the IM nail fixation group and costs were lower. FUTURE WORK: The potential benefit of IM nail fixation in several other fractures requires investigation. Research is also required into the role of adjuvant treatment and different rehabilitation strategies to accelerate recovery following a fracture of the tibia and other long-bone fractures in the lower limb. The patients in this trial will remain in longer-term follow-up. TRIAL REGISTRATION: Current Controlled Trials ISRCTN99771224 and UKCRN 13761. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 25. See the NIHR Journals Library website for further project information.