Mortality outcomes in patients transfused with fresher versus older red blood cells: a meta-analysis.

BACKGROUND: Among transfused patients, the effect of the duration of red blood cell storage on mortality remains unclear. This study aims to compare the mortality of patients who were transfused with fresher versus older red blood cells. METHODS: We performed an updated systematic search in the CENTRAL, MEDLINE, EMBASE and CINAHL databases, from January 2015 to October 2016. RCTs of hospitalized patients of any age comparing transfusion of fresher versus older red blood cells were eligible. We used a random-effects model to calculate pooled risk ratios (RRs) with corresponding 95% confidence interval (CI). RESULTS: We identified 14 randomized trials that enrolled 26 374 participants. All-cause mortality occurred in 1219 of 9531 (12·8%) patients who received a transfusion of fresher red blood cells and 1810 of 16 843 (10·7%) in those who received older red blood cells (RR: 1·04, 95% CI: 0·98-1·12, P = 0·90, I2 = 0%, high certainty for ruling out benefit of fresh blood, moderate certainty for ruling out harm of fresh blood). In six studies, in-hospital death occurred in 691 of 7479 (9·2%) patients receiving fresher red cells and 1291 of 14 757 (8·8%) receiving older red cells (RR: 1·06, 95% CI: 0·97-1·15, P = 0·81, I2 = 0%, high certainty for ruling out benefit of fresh blood, moderate certainty for ruling out harm of fresh blood). CONCLUSION: Transfusion of fresher red blood cells does not reduce overall or in-hospital mortality when compared with older red blood cells. Our results support the practice of transfusing patients with the oldest red blood cells available in the blood bank.

A systematic review of definitions and reporting of bleeding outcome measures in haemophilia.

INTRODUCTION: Bleeding frequency is an important outcome commonly used in haemophilia studies. There is a variation in practice in how bleeding is measured and defined. AIM: The primary objective of this study was to determine how investigators define and report bleeding outcome measures. METHODS: MEDLINE, EMBASE and the CENTRAL were searched from January 1990 to January 2014. We retrieved all published studies that included patients with haemophilia A or B and reported some measures of bleeding. Two reviewers independently performed title and abstract screening, full-text review and data abstraction of the identified studies. RESULTS: A total of 118 studies fulfilled the inclusion criteria. Study designs were randomized controlled trials (RCT; 14%), cohort (68%), cross-sectional (5%) and others design (11%). The median duration of follow-up (Q1, Q3) was 20 (7.9, 50) months. We found 10 different bleeding outcomes reported [absolute number of bleeding 60 (50.8%) studies, annualized bleeding rate 60 (50.8%) studies, bleed per month 10 (8.5%) studies and others 11 (9.3%) studies]. Of these, 32 (27%) studies reported only mean or median without dispersion and 33 (28%) studies did not report any measures of central tendency (dispersion). CONCLUSIONS: There is substantial variation in definitions and measures of bleeding outcomes in the haemophilia literature. This creates difficulty and limitations in comparing the outcomes between studies and in performing meta-analysis. The haemophilia research community needs to develop a consensus on a clear definition of bleeding and how to address the limitations associated with variations in measures of bleeding between centres and studies.

Younger age at presentation of acquired haemophilia A in Asian countries: a single-centre study and systematic review.

Acquired haemophilia A is a rare bleeding disorder caused by autoantibodies against factor VIII (FVIII). There is a scarcity of acquired haemophilia A studies from Asian countries. The aim of this study was to evaluate clinical characteristics and outcomes of acquired haemophilia A among Asian populations. Data were collected from a retrospective case series and combined with a systematic review. The case series included all patients with acquired haemophilia A from 1999 to 2012 at Chiang Mai University Hospital. The systematic review searched MEDLINE and EMBASE databases for relevant keywords. A total of 111 patients were reviewed in this study (including 26 patients from the present series). There were 56 male (50.5%) and 55 female (49.5%) patients. We compared the demographic data with ECAH2 and UKHCDO studies. The weighted mean (SD) age at diagnosis was 58.10 (16.96) years compared with 75.70 (14.47) years in the European series (absolute difference 17.6 years, 95% confidence interval [CI] 14.20­20.99, P = 0.025). The mean (SD) FVIII activity was 2.97 (3.81) IU dL(−1) and the mean (SD) FVIII inhibitor titre was 26.35 (399.16) BU mL(−1). Fifty-six per cent of the patients underwent immunosuppression with steroids alone. The pool complete remission rate was comparable to the European studies, at 67.2% vs. 66.6% respectively (absolute difference 0.7, 95% CI 0.18 to 1.22, P = 0.99). This study reveals a novel finding of younger age at diagnosis of acquired haemophilia A among Asian patients.

Resumption of anticoagulant therapy after anticoagulant-related gastrointestinal bleeding: A systematic review and meta-analysis.

INTRODUCTION: Oral anticoagulation (OAC) is permanently discontinued in up to 50% of patients following a gastrointestinal (GI) bleed. A previous meta-analysis showed a reduced risk of thromboembolism and death, and a non-statistically significant increased risk of re-bleeding associated with resumption. We conducted an updated meta-analysis to determine the risks of recurrent GI bleeding, thromboembolism, and death in patients who resumed OAC compared to those who did not. MATERIALS AND METHODS: We searched EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials for new references from January 2014 to September 2017. Randomized controlled trials and observational studies involving adults with OAC-related GI bleeding were included. Risk of bias was assessed using the Cochrane Collaboration's ROBINS-I tool. Pooled relative risk (RR) ratios were calculated using a random-effects model. RESULTS: We identified 12 observational studies involving 3098 patients. There was an increased risk of recurrent GI bleeding (RR 1.91, 95% CI 1.47-2.48, I2 = 0%, 11 studies), and a reduced risk of thromboembolism (RR 0.30, 95% CI 0.13-0.68, I2 = 59.8%, 9 studies) and death (RR 0.51, 95% CI 0.38-0.70, I2 = 71.8%, 8 studies) in patients who resumed OAC compared to those who did not. Eleven studies were judged to be at serious risk of bias due to confounding. CONCLUSIONS: Resuming OAC after OAC-related GI bleeding appears to be associated with an increase in recurrent GI bleeding, but a reduction in thromboembolism and death. Further prospective data are needed to identify patients for whom the net clinical benefit favours OAC resumption and the optimal timing of resumption.

Reduced-dose direct oral anticoagulants in the extended treatment of venous thromboembolism: a systematic review and meta-analysis.

Essentials In venous thromboembolism (VTE), benefits of extended treatment are balanced by bleeding risks. This is a meta-analysis of reduced-dose direct oral anticoagulants (DOACs) in extended treatment. Reduced-dose DOACs are as effective as full anticoagulation with bleeding risks similar to placebo. Reduced-dose DOACs are an attractive option for patients in the extended phase of VTE treatment. SUMMARY: Background Extended-duration anticoagulation is beneficial for preventing recurrent venous thromboembolism (VTE). Reduced-dose direct oral anticoagulants (DOACs) may be preferable if they preserve efficacy and cause less bleeding. We conducted a systematic review and meta-analysis of trials comparing reduced-dose DOACs with full-dose DOACs and aspirin or placebo in the extended phase of VTE treatment. Methods A literature search was conducted by use of the MEDLINE, EMBASE and CINAHL databases, supplemented by hand-searching. One thousand three hundred and ninety-nine titles were screened, with data from accepted studies being extracted by two independent reviewers. Major outcomes analyzed included recurrent VTE and major and clinically relevant non-major bleeding events, presented as risk ratios (RRs) and 95% confidence intervals (CI). Results Two trials met the prespecified inclusion criteria. Data from 5847 patients were analyzed for efficacy outcomes, and from 5842 patients for safety outcomes. Reduced-dose DOACs were as effective as full-dose treatment in preventing recurrent VTE at 1 year (RR 1.12 [95% CI 0.67-1.87]), and more effective than aspirin or placebo (RR 0.26 [95% CI 0.14-0.46]). Rates of major or clinically relevant non-major bleeding events were similar between patients receiving reduced-dose DOACs and and those receiving aspirin or placebo (RR 1.19 [95% CI 0.81-1.77]). There was a trend towards less bleeding when reduced-dose and full-dose DOACs were compared (RR 0.74 [95% CI 0.52-1.05]). Conclusions Extended-duration treatment of VTE with reduced-dose DOACs may be as efficacious as full-dose treatment, with rates of major bleeding being similar to those in patients receiving treatment with aspirin or placebo, but further long-term studies are needed.

The Patient Reported Outcomes, Burdens and Experiences (PROBE) Project: development and evaluation of a questionnaire assessing patient reported outcomes in people with haemophilia.

BACKGROUND: The interest of health care agencies, private payers and policy makers for patient-reported outcomes (PRO) is continuously increasing. There is a substantial need to improve capacity to collect and interpret relevant PRO data to support implementation of patient-centered research and optimal care in haemophilia. The Patient Reported Outcomes, Burdens and Experiences (PROBE) Project aims to develop a patient-led research network, to develop a standardized questionnaire to gather patient-reported outcomes and to perform a feasibility study of implementing the PROBE questionnaire. METHODS: A pilot questionnaire was developed using focus group methodology. Content and face validity were assessed by a pool of persons living with haemophilia (PWH) and content experts through interactive workshops. The PROBE questionnaire was translated with the forward-backward approach. PROBE recruited national haemophilia patient non-governmental organizations (NGOs) to administer the questionnaire to people with and without haemophilia. PROBE measured the time to complete the questionnaire and gathered feedback on its content and clarity; staff time and cost required to implement the questionnaire were also collected. RESULTS: The PROBE questionnaire is comprised of four major sections (demographic data, general health problems, haemophilia-related health problems and health-related quality of life using EQ-5D-5L and EQ-VAS). Seventeen NGOs participated in the pilot study of the PROBE Project, recruiting 656 participants. Of these, 71% completed the questionnaire within 15 min, and all participants completed within 30 min. The median total staff and volunteer time required for the NGOs to carry out the study within their country was 9 h (range 2 to 40 h). NGO costs ranged from $22.00 to $543.00 USD per country, with printing and postage being the most commonly reported expenditures. CONCLUSIONS: The PROBE questionnaire assesses patient-important reported outcomes in PWH and control participants, with a demonstrated short completion time. PROBE proved the feasibility to engage diverse patient communities in the structured generation of real-world outcome research at all stages. TRIAL REGISTRATION: Trial registration: NCT02439710.

Association of body weight with efficacy and safety outcomes in phase III randomized controlled trials of direct oral anticoagulants: a systematic review and meta-analysis.

Essentials The association of body weight and patient-important outcomes remains unknown. Phase III randomized controlled trials of direct oral anticoagulants (DOACs) were searched. Risk of outcomes varying among body weight subgroups is not attributable to anticoagulant type. Dose adjustment of DOACs, outside that recommended, is unlikely to improve the outcomes. Click to hear Dr Braunwald's perspective on antithrombotic therapy in cardiovascular disease SUMMARY: Background Concerns have arisen in direct oral anticoagulant (DOAC)-treated patients about safety and efficacy in extremes of body weight. The aims of this systematic review were to investigate the association of body weight and patient-important outcomes in patients treated with DOACs or warfarin, and to demonstrate the fixed-dose effect of DOACs. Methods MEDLINE and EMBASE were searched until November 2016. Phase III randomized controlled trials (RCTs) using DOACs in atrial fibrillation (AF) and acute venous thromboembolism (VTE) were included. Relative risk and 95% confidence interval were calculated. The pooled estimates were performed using a Mantel-Haenszel random effects model. Results A total of 11 phase III RCTs were included. Low body weight was associated with increased risk of thromboembolism compared with non-low body weight (relative risk [RR], 1.57; 95% confidence interval [CI], 1.34-1.85). High body weight was not associated with risk of thromboembolism compared with non-high body weight (RR, 0.88; 95% CI, 0.63-1.23). The subgroup of AF patients with high body weight had a lower risk of thromboembolism compared with non-high body weight (RR, 0.43; 95% CI, 0.28-0.67). Bleeding outcomes were comparable for all body weight comparisons. There were no clear interactions between types of anticoagulant in all outcomes. Conclusion The pooled effect of both the DOAC and comparison arms was likely to be attributable to differences in baseline thrombotic risk in each body weight category, rather than an effect of the type or dose of DOAC used for each indication. Dose adjustment of DOACs, outside that recommended in the package insert, is unlikely to improve safety or efficacy.

Hemodialysis for the treatment of dabigatran-associated bleeding: a case report and systematic review.

BACKGROUND: Dabigatran, a direct thrombin inhibitor, is effective for the treatment of venous thromboembolism and the prevention of stroke and systemic embolism resulting from atrial fibrillation. The most effective way of reversing the anticoagulant effect of dabigatran in patients who have bleeding complications is unknown. OBJECTIVES: To document the clinical outcomes of patients undergoing renal replacement therapy (RRT) for dabigatran-associated bleeding. METHODS: We searched MEDLINE and EMBASE up to May 2015. Articles were selected if the patients presented with dabigatran-associated bleeding, underwent RRT for dabigatran removal, and reported an effect on bleeding. RESULTS: The search yielded 22 studies representing 35 unique patient cases. The median patient age was 74.1 years (range, 56-94 years). Thirteen patients (37.1%) were female, and 32 (91.4%) patients received dabigatran for atrial fibrillation. Twenty-three patients (65.7%) underwent intermittent hemodialysis, 10 patients (28.6%) underwent continuous RRT (CRRT), and two patients underwent both intermittent hemodialysis and CRRT. Following RRT, there were significant reductions in dabigatran concentrations (P = 0.001). Rebound of the dabigatran concentration was reported in 12 (57.1%) patients following cessation of RRT. Hemostasis was reportedly achieved in 24 patients (70.6%), and 10 patients (29.4%) died because of bleeding. CONCLUSIONS: In patients with dabigatran-associated bleeding, RRT appears to be effective in reducing dabigatran concentrations, and in case reports this has been associated with a reduction in the duration and/or severity of bleeding. However, a rebound in concentrations may be seen following withdrawal of RRT, suggesting that a prolonged course of RRT may be more effective.

Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Direct oral anticoagulants (DOACs) are widely used as an alternative for warfarin. However, the impact of DOACs on mortality outcomes compared with warfarin remains unclear. OBJECTIVE: To estimate the mortality outcomes in patients treated with DOACs vs. warfarin (or another vitamin K antagonist). METHODS: MEDLINE, EMBASE and CENTRAL databases (inception to September 2014), conference abstracts and www.clinicaltrials.gov, were searched, without language restriction. Studies were selected if there were phase III, randomized trials comparing DOACs with warfarin in patients with non-valvular atrial fibrillation or venous thromboembolism. RESULTS: Thirteen randomized controlled trials involving 102 707 adult patients were included in the analysis. The case-fatality rate of major bleeding was 7.57% (95% CI, 6.53-8.68; I(2) = 0%) in patients taking DOACs and 11.04% (95% CI, 9.16-13.07; I(2) = 33.3%) in patients taking warfarin. The rate of fatal bleeding in adult patients receiving DOACs was 0.16 per 100 patient-years (95% CI, 0.12-0.20; I(2) = 36.5%). When compared with warfarin, DOACs were associated with significant reductions in fatal bleeding (RR, 0.53; 95% CI, 0.43-0.64; I(2) = 0%), cardiovascular mortality (RR, 0.88; 95% CI, 0.82-0.94; I(2) = 0%) and all-cause mortality (RR, 0.91; 95% CI, 0.87-0.96; I(2) = 0%). CONCLUSIONS: The use of DOACs compared with warfarin is associated with a lower rate of fatal bleeding, case-fatality rate of major bleeding, cardiovascular mortality and all-cause mortality.