SummaryBackgroundBullous pemphigoid is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline gives acceptable short-term blister control while conferring long-term safety advantages over starting treatment with oral corticosteroids.MethodsWe did a pragmatic, multicentre, parallel-group randomised controlled trial of adults with bullous pemphigoid (three or more blisters at two or more sites and linear basement membrane IgG or C3). Participants were randomly assigned to doxycycline (200 mg per day) or prednisolone (0·5 mg/kg per day) using random permuted blocks of randomly varying size, and stratified by baseline severity (3–9, 10–30, and >30 blisters for mild, moderate, and severe disease, respectively). Localised adjuvant potent topical corticosteroids (<30 g per week) were permitted during weeks 1–3. The non-inferiority primary effectiveness outcome was the proportion of participants with three or fewer blisters at 6 weeks. We assumed that doxycycline would be 25% less effective than corticosteroids with a 37% acceptable margin of non-inferiority. The primary safety outcome was the proportion with severe, life-threatening, or fatal (grade 3–5) treatment-related adverse events by 52 weeks. Analysis (modified intention to treat [mITT] for the superiority safety analysis and mITT and per protocol for non-inferiority effectiveness analysis) used a regression model adjusting for baseline disease severity, age, and Karnofsky score, with missing data imputed. The trial is registered at ISRCTN, number ISRCTN13704604.FindingsBetween March 1, 2009, and Oct 31, 2013, 132 patients were randomly assigned to doxycycline and 121 to prednisolone from 54 UK and seven German dermatology centres. Mean age was 77·7 years (SD 9·7) and 173 (68%) of 253 patients had moderate-to-severe baseline disease. For those starting doxycycline, 83 (74%) of 112 patients had three or fewer blisters at 6 weeks compared with 92 (91%) of 101 patients on prednisolone, an adjusted difference of 18·6% (90% CI 11·1–26·1) favouring prednisolone (upper limit of 90% CI, 26·1%, within the predefined 37% margin). Related severe, life-threatening, and fatal events at 52 weeks were 18% (22 of 121) for those starting doxycycline and 36% (41 of 113) for prednisolone (mITT), an adjusted difference of 19·0% (95% CI 7·9–30·1), p=0·001.InterpretationStarting patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control in bullous pemphigoid and significantly safer in the long-term.FundingNIHR Health Technology Assessment Programme.

Multidrug-resistant (MDR) tuberculosis (TB) is a threat to global TB control, as suboptimal and poorly tolerated treatment options have resulted in largely unfavourable outcomes for these patients. The last of six cohort studies conducted in Bangladesh which assessed a new shorter regimen using currently available TB drugs showed promising results and offered the possibility of a more acceptable and more effective regimen than the one recommended by the World Health Organization (WHO). The aims of stage 1 of the STREAM (Evaluation of a Standardised Treatment Regimen of Anti-tuberculosis Drugs for Patients with Multidrug-resistant Tuberculosis) trial are to evaluate the efficacy and safety of this regimen, compared to the current WHO-recommended standard of care. Stage 2 evaluates two new bedaquiline-containing regimens: one an all-oral regimen and the second a further shortened and simplified version of the stage 1 study regimen, comparing the efficacy and safety of each to that of the stage 1 study regimen and also to the WHO-recommended standard of care. Success of the stage 1 study regimen would in all probability provide a new standard of care for MDR-TB patients, while positive results from the bedaquiline-containing regimens in stage 2 may allow for even greater progress in the management of this difficult population. @ERSpublications A review of the STREAM trial, which evaluates the safety and efficacy of new treatment regimens for MDR-TB http://ow.ly/VtVkQ

Pfizer.

BackgroundIntensification of metformin monotherapy with additional glucose-lowering drugs is often required in patients with type 2 diabetes (T2D). This study evaluated changes in HbA1c and weight, as well as treatment persistence, associated with different second-line therapies used in UK clinical practice.MethodsThe UK Clinical Practice Research Datalink was used to identify patients with T2D who initiated second-line therapy after metformin monotherapy between 1 August 2013 and 14 June 2016. Treatment persistence and changes in HbA1c and weight were assessed at 6-month intervals up to 18 months.ResultsIn total, 9097 patients (mean age 61.2 years, 57.2% men, mean [standard deviation] HbA1c 9.0% [1.8]/ 75 mmol/mol [19.7]) were included in the analysis, with a median 2.3 years between initiating metformin monotherapy and initiating second-line therapy. Patients were stratified according to second-line therapy: metformin in combination with sulfonylurea (SU; n = 4655 [51.2%]), a dipeptidyl peptidase-4 inhibitor (DPP-4 inhibitor; n = 2899 [31.9%]), or a sodium–glucose cotransporter-2 inhibitor (SGLT-2 inhibitor; n = 441 [4.9%]) or other therapies (all other second-line treatments; n = 1102 [12.1%]). At 18 months, the cumulative proportion of patients changing treatment was lowest for those who received metformin plus an SGLT-2 inhibitor (42.3%), followed by patients on metformin plus SU or metformin plus a DPP-4 inhibitor (46.8%). HbA1c reductions were seen with all second-line therapies, with an overall mean (standard error) reduction of −1.23% (0.05)/−13.4 mmol/mol (0.5). Changes were directly, but not linearly, related to baseline HbA1c and were greater in those with higher HbA1c at baseline. Weight loss from baseline was greatest in patients treated with metformin plus either an SGLT-2 inhibitor (−4.2 kg) or a DPP-4 inhibitor (−1.5 kg). The highest proportion of patients who achieved the composite outcome of HbA1c reduction ≥ 0.5%, body weight loss ≥ 2.0 kg and treatment persistence for 18 months was observed in those receiving metformin plus an SGLT-2 inhibitor (36.5%).ConclusionsIn this population-based cohort, all second-line therapies added to metformin monotherapy improved glycaemic control, but the lowest treatment change/discontinuation rate and most sustained weight loss was seen with patients receiving metformin plus an SGLT-2 inhibitor.Electronic supplementary materialThe online version of this article (10.1186/s12916-018-1085-8) contains supplementary material, which is available to authorized users.

AimTo investigate determinants of change in glycated haemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM) at 6 months after initiating uninterrupted second‐line glucose‐lowering therapies.Materials and MethodsThis cohort study utilized retrospective data from 10 256 patients with T2DM who initiated second‐line glucose‐lowering therapy (switch from or add‐on to metformin) between 2011 and 2014 in Germany and the UK. Effects of pre‐specified patient characteristics on 6‐month HbA1c changes were assessed using analysis of covariance.ResultsPatients had a mean (standard error [SE]) baseline HbA1c of 8.68% (0.02); 28.5% of patients discontinued metformin and switched to an alternative therapy and the remainder initiated add‐on therapy. Mean (SE) unadjusted 6‐month HbA1c change was −1.27% (0.02). When adjusted for baseline HbA1c, 6‐month changes depended markedly on the magnitude of the baseline HbA1c (HbA1c <9%, −0.45% per unit increase in HbA1c; HbA1c ≥9%, −0.87% per unit increase in HbA1c). Adjusted mean 6‐month HbA1c reductions showed slight treatment differences (range, 0.92–1.09%; P < .001). Greater reductions in HbA1c were associated with second‐line treatment initiation within 6 months of T2DM diagnosis (1.36% vs 1.03% [P < .001]) and advanced age (≥70 years, 1.13%; <70 years, 1.02% [P < .001]).ConclusionsMany patients with T2DM have very high HbA1c levels when initiating second‐line therapy, indicating the need for earlier treatment intensification. Patient‐specific factors merit consideration when making treatment decisions.

BackgroundBullous pemphigoid (BP) is an autoimmune blistering skin disorder with increased morbidity and mortality in the elderly.ObjectivesTo evaluate the effectiveness, safety and cost-effectiveness of a strategy of initiating BP treatment with oral doxycycline or oral prednisolone. We hypothesised that starting treatment with doxycycline gives acceptable short-term blister control while conferring long-term safety advantages over starting treatment with oral prednisolone.DesignPragmatic multicentre two-armed parallel-group randomised controlled trial with an economic evaluation.SettingA total of 54 dermatology secondary care centres in the UK and seven in Germany.ParticipantsAdults with BP [three or more blisters at two sites and positive direct and/or indirect immunofluorescence (immunoglobulin G and/or complement component 3 immunofluorescence at the dermal-epidermal junction)] and able to give informed consent.InterventionsParticipants were allocated using online randomisation to initial doxycycline treatment (200 mg/day) or prednisolone (0.5 mg/kg/day). Up to 30 g/week of potent topical corticosteroids was permitted for weeks 1–3. After 6 weeks, clinicians could switch treatments or alter the prednisolone dose as per normal practice.Main outcome measuresPrimary outcomes: (1) the proportion of participants with three or fewer blisters at 6 weeks (investigator blinded) and (2) the proportion with severe, life-threatening and fatal treatment-related events at 52 weeks. A regression model was used in the analysis adjusting for baseline disease severity, age and Karnofsky score, with missing data imputed. Secondary outcomes included the effectiveness of blister control after 6 weeks, relapses, related adverse events and quality of life. The economic evaluation involved bivariate regression of costs and quality-adjusted life-years (QALYs) from a NHS perspective.ResultsIn total, 132 patients were randomised to doxycycline and 121 to prednisolone. The mean patient age was 77.7 years and baseline severity was as follows: mild 31.6% (three to nine blisters), moderate 39.1% (10–30 blisters) and severe 29.3% (> 30 blisters). For those starting on doxycycline, 83 out of 112 (74.1%) had three or fewer blisters at 6 weeks, whereas for those starting on prednisolone 92 out of 101 (91.1%) had three or fewer blisters at 6 weeks, an adjusted difference of 18.6% in favour of prednisolone [90% confidence interval (CI) 11.1% to 26.1%], using a modified intention-to-treat (mITT) analysis. Per-protocol analysis showed similar results: 74.4% compared with 92.3%, an adjusted difference of 18.7% (90% CI 9.8% to 27.6%). The rate of related severe, life-threatening and fatal events at 52 weeks was 18.2% for those started on doxycycline and 36.6% for those started on prednisolone (mITT analysis), an adjusted difference of 19.0% (95% CI 7.9% to 30.1%;p = 0.001) in favour of doxycycline. Secondary outcomes showed consistent findings. There was no significant difference in costs or QALYs per patient at 1 year between doxycycline-initiated therapy and prednisolone-initiated therapy (incremental cost of doxycycline-initiated therapy £959, 95% CI –£24 to £1941; incremental QALYs of doxycycline-initiated therapy –0.024, 95% CI –0.088 to 0.041). Using a willingness-to-pay criterion of < £20,000 per QALY gained, the net monetary benefit associated with doxycycline-initiated therapy was negative but imprecise (–£1432, 95% CI –£3094 to £230).ConclusionsA strategy of starting BP patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control and considerably safer in the long term. The limitations of the trial were the wide non-inferiority margin, the moderate dropout rate and that serious adverse event collection was unblinded. Future work might include inducing remission with topical or oral corticosteroids and then randomising to doxycycline or prednisolone for maintenance.Trial registrationCurrent Controlled Trials ISRCTN13704604.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 21, No. 10. See the NIHR Journals Library website for further project information.

BackgroundThere is little published data investigating non-invasive cardiac output monitoring in the emergency department (ED). We assessed six non-invasive fluid responsiveness monitoring methods which measure cardiac output directly or indirectly for their feasibility and repeatability of measurements in the ED: (1) left ventricular outflow tract echocardiography derived velocity time integral, (2) common carotid artery blood flow, (3) suprasternal aortic Doppler, (4) bioreactance, (5) plethysmography with digital vascular unloading method, and (6) inferior vena cava collapsibility index.MethodsThis is a prospective observational study of non-invasive methods of assessing fluid responsiveness in the ED. Participants were non-ventilated ED adult patients requiring intravenous fluid resuscitation. Feasibility of each method was determined by the proportion of clinically interpretable measurements from the number of measurement attempts. Repeatability was determined by comparing the mean difference of two paired measurements in a fluid steady state (after participants received an intravenous fluid bolus).Results76 patients were recruited in the study. A total of 207 fluid responsiveness measurement sets were analysed. Feasibility rates were 97.6% for bioreactance, 91.3% for vascular unloading method with plethysmography, 87.4% for common carotid artery blood flow, 84.1% for inferior vena cava collapsibility index, 78.7% for LVOT VTI, and 76.8% for suprasternal aortic Doppler. The feasibility rates difference between bioreactance and all other methods was statistically significant.ConclusionOur study shows that non-invasive fluid responsiveness monitoring in the emergency department may be feasible with selected methods. Higher repeatability of measurements were observed in non-ultrasound methods. These findings have implications for further studies specifically assessing the accuracy of such non-invasive cardiac output methods and their effect on patient outcome in the ED in fluid depleted states such as sepsis.Electronic supplementary materialThe online version of this article (10.1186/s13049-019-0586-6) contains supplementary material, which is available to authorized users.

The effect of variation in platelet function in platelet donors on patient outcome following platelet transfusion is unknown. This trial assessed the hypothesis that platelets collected from donors with highly responsive platelets to agonists in vitro assessed by flow cytometry (high-responder donors) are cleared more quickly from the circulation than those from low-responder donors, resulting in lower platelet count increments following transfusion. This parallel group, semirandomized double-blinded trial was conducted in a single center in the United Kingdom. Eligible patients were those 16 or older with thrombocytopenia secondary to bone marrow failure, requiring prophylactic platelet transfusion. Patients were randomly assigned to receive a platelet donation from a high- or low-responder donor when both were available, or when only 1 type of platelet was available, patients received that. Participants, investigators, and those assessing outcomes were masked to group assignment. The primary end point was the platelet count increment 10 to 90 minutes following transfusion. Analysis was by intention to treat. Fifty-one patients were assigned to receive platelets from low-responder donors, and 49 from high-responder donors (47 of which were randomized and 53 nonrandomized). There was no significant difference in platelet count increment 10 to 90 minutes following transfusion in patients receiving platelets from high-responder (mean, 21.0 × 10/L; 95% confidence interval [CI], 4.9-37.2) or low-responder (mean, 23.3 × 10/L; 95% CI, 7.8-38.9) donors (mean difference, 2.3; 95% CI, -1.1 to 5.7; = .18). These results support the current policy of not selecting platelet donors on the basis of platelet function for prophylactic platelet transfusion.