We designed anagreement study to compare the results of bleeding assessments done in tandem by ITP patients and trained research staff. We used a modified version of the ITP Bleeding Scale, which captured the patients' worst bleeding event at any of nine anatomical sites since the time of the last assessment. Interrater agreement was determined using the 2-way kappa for the assessment of severe vs. non-severe bleeds. We analyzed 108 consecutive patients with ITP from the McMaster ITP Registry who had duplicate bleeding assessments. Two-way agreement was excellent for gynecological (k = 0.86, 95% CI 0.71-1.02), gastrointestinal (k = 1), genitourinary (k = 1), pulmonary (k = 1) and intracranial (k = 1) bleeds; good for skin (k = 0.68, 95% CI, 0.54-0.82), oral (k = 0.76, 95% CI, 0.53-0.98) and ocular (k = 0.66, 95% CI, 0.04-1-28) bleeds; and moderate for epistaxis (k = 0.58, 95% CI, 0.21-0.95). Bleeding self-assessments by ITP patients were similar to trained research staff, but disagreements in severity grades were more frequent with skin bleeds, oral bleeds and epistaxis. Bleeding self-assessments could simplify bleeding assessments in clinical trials.
Background: Patients with immune thrombocytopenia (ITP) are at risk of bleeding during surgery. Intravenous immune globulin (IVIG) is a blood product that is commonly used to increase platelet counts before surgery or invasive procedures for patients with ITP; however, eltrombopag, an oral thrombopoietin receptor agonist, may be an effective alternative. Methods: We conducted a multicenter randomised trial to determine whether eltrombopag was non-inferior to IVIG for the achievement of perioperative platelet count targets without the use of rescue treatment. We did an intention to treat and per-protocol analysis using an absolute non-inferiority margin of -10%. Secondary endpoints were thrombosis, bleeding, adverse events and treatment satisfaction. We enrolled 74 patients with ITP who had a planned major or minor surgery and with a platelet count below 100 x109/L or 50 x109/L respectively. Patients were randomised to receive oral daily eltrombopag from 21 days preoperatively, or IVIG (1 or 2g per kg) seven days preoperatively. Findings: By intention to treat, perioperative platelet targets were achieved by 30 of 38 patients (78·9%) assigned to eltrombopag and 22 of 36 patients (61·1%) assigned to IVIG (absolute difference, 17·8%; one-sided lower limit of the 95% confidence interval, 0·4%; p=0·005 for non-inferiority). Results were similar for patients who completed the protocol. One patient in the eltrombopag group developed a pulmonary embolism 14 days after minor surgery, and one patient in the IVIG group developed a distal deep vein thrombosis 30 days after major surgery. There was no difference in bleeding or adverse events. Patients reported higher treatment satisfaction with eltrombopag. Interpretation: Eltrombopag was no worse than IVIG for the achievement of platelet count targets around the time of surgery for patients with ITP. This population may be at increased risk of thrombosis. Trial Registration: www.clinicaltrials.gov number as NCT01621204.Funding Statement: This trial was funded by GlaxoSmithKline and Novartis.Declaration of Interests: N.M.H., R.J.C., M.B., J.K., A.T., M.S., M.W., P.V., J.C., N.L., S.L., and J.G.K. report no competing financial interests. D.M.A. reports grants from GlaxoSmithKline and Novartis during the conduct of the study; grants and/or personal fees from Novartis, Amgen, Bristol Myers Squibb, UCB, Principia, and Rigel outside the submitted work. C.H. reports personal fees from Novartis, Amgen, and GSK, outside the submitted work. E.J. reports personal fees from Novartis, outside the submitted work. M.S. reports personal fees from Novartis, outside the submitted work. Y.L. reports grants from Novartis during the conduct of the study, and other fees from Pfizer, outside the submitted work. L.L. reports personal fees from Novartis during the conduct of the study. S.A. reports grants from Novartis NL during the conduct of the study; grants from Amgen, outside the submitted work. W.L. reports personal fees from Novartis, outside the submitted work. Ethics Approval Statement: The trial was approved by the research ethics boards at each participating center. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.
Background and Objectives Selection of a compatible red blood cell ( RBC ) unit does not include matching for donor sex. This systematic review and meta‐analysis aims to summarize the evidence examining the impact of sex‐mismatched RBC transfusion on recipient mortality. Materials and Methods Ovid MEDLINE , Ovid EMBASE , CINAHL , PubMed, Web of Science and the Cochrane Database of Systematic Reviews were searched from inception up to 23 November 2018. Randomized controlled trials and observational studies were included in the search. Eligible studies reported on the impact of sex‐matched compared to sex‐mismatched RBC transfusion on recipient mortality. Two investigators independently extracted data and assessed study quality. A three‐level meta‐analytic model was applied to emphasize the unknown dependence among the effect sizes. Results Five retrospective observational studies ( n = 86 737) were included; no RCT s were found. Sex‐mismatched RBC transfusions were associated with a higher risk of death compared with sex‐matched transfusions (pooled hazard ratio [ HR ]: 1·13; 95% confidence interval [ CI ]: 1·02–1·24). In the subgroup of cardiovascular surgery ( n = 57 712), there was no significant increase in mortality with sex‐mismatched transfusions (pooled HR : 1·08; 95% CI : 0·95–1·22). The data were prone to confounding, selection bias and reporting bias. Certainty of the evidence was very low. Conclusion Sex‐mismatched RBC transfusions were associated with an increased risk of death in this pooled analysis. However, the certainty of the evidence was very low from observational studies. The need to match donor and recipient sex for transfusions requires further investigation because of the potential widespread impact.
SUMMARY Objective Retrospective audit of IVIG Request Forms in four Ontario tertiary care centres: to determine the case mix of new IVIG requests, to authenticate information provided, and to determine documentation of clinical efficacy. Aims To understand contributors to increases in IVIG utilisation and to determine whether IVIG is being used and monitored appropriately. Introduction Intravenous immunoglobulin ( IVIG ) use in Canada is high compared with other developed countries. We performed a retrospective audit of new IVIG Request Forms across four tertiary care centres in Ontario, one with an active surveillance programme, to determine the case mix, authenticate information provided and assess documentation of efficacy. Methods Consecutive adult patients with a first‐time IVIG request in 2014 were included. The ordering physician specialty, form completeness, documentation of diagnostic criteria for the medical condition and indication for IVIG use and documentation of efficacy were assessed by form and chart review. Results Of 178 patients, the most common indications for IVIG were immune thrombocytopenia (24.2%) and secondary immune deficiency (20.2%). The most frequent prescribers were haematologists (37.6%) and neurologists (10.7%). Other conditions not listed on the form represented 24.2% of cases, with most not indicated in current guidelines. A total of 32.6% of cases overall lacked verification of diagnostic criteria and 51.7% lacked verification for IVIG utilisation criteria, with the number of cases meeting criteria based on documentation being higher at the active surveillance site ( P = 0.005). A total of 19.1% of cases had a discrepancy between the indication written on the form and the documented clinical diagnosis. A total of 18.7% of clinic notes following IVIG had no mention of efficacy. Conclusion Our audit demonstrates a lack of compliance with IVIG Request Form requirements, a lack of documentation of diagnostic criteria and efficacy, and suggests inappropriate use of IVIG . Current implementation of the form may not be sufficient as a strategy for improving appropriate IVIG use.
The associations between RBC transfusion dependence (TD) in patients with myelodysplastic syndromes (MDS) and lower survival, quality of life (QOL), iron overload and cardiac morbidity were recently summarized in a systematic review.1 However, red blood cell (RBC) TD remains the reality for many patients with MDS with a paucity of data to inform optimal transfusion policy for these patients. With only inpatient data2 or expert opinion to guide decisions,3 transfusion thresholds are heterogeneous4, 5 ranging from hemoglobin (Hb) 70 to 90 g/L and 26% of patients wishing they were transfused at higher thresholds.5 Two parallel blinded randomized feasibility trials of similar design comparing liberal with restrictive transfusion thresholds were conducted in the United Kingdom/Australia/New Zealand (REDDS)6 and Canada (RBC-Enhance) (in press, Transfusion). We combined our data sets in a secondary analysis to better evaluate feasibility, explore the impact of higher Hb transfusion thresholds on QOL, and obtain insights in improving the design of future trials. Methods have been previously published.6 Patients with MDS and MDS/MPN including chronic myelomonocytic leukemia (CMML) with a life expectancy of more than 6 months who were stably transfusion dependent (minimum of 1 unit in 8 weeks) were randomized 1:1 using computerized block randomization to a liberal (maintain Hb 110–125 g/L) or restrictive (maintain Hb 85–100 g/L) transfusion strategy with minor differences summarized in Table S1. The transfusion strategy was applied for 12 weeks. The schedule and number of transfusions were dictated by the transfusion algorithms created for the trials (Table S1). Upon enrollment, patient and disease characteristics were captured including WHO classification, risk scores, iron status, transfusions, and treatment. REDDS and RBC-ENHANCE recorded QOL using EQ-5D-3L7 and EORTC-QLQ-C308 at baseline, pre-transfusion, 5–7 days later, and monthly. The primary outcome for both studies was feasibility. For the combined analysis, feasibility outcomes were defined as (1) more than 70% compliance of the pre-transfusion Hb being below the target range of the assigned transfusion threshold; and (2) achievement of at least a 20 g/L (REDDS) or 15 g/L (RBC-ENHANCE) difference between the mean pre-transfusion Hb in the liberal and restrictive strategy groups. Secondary outcomes included enrollment rates, transfusion utilization and visits, adverse events (transfusion reactions and iron assessment), completion of QOL questionnaires, and magnitude of changes in QOL. The statistical considerations, CONSORT diagrams, definitions of clinically significant differences in QOL scores are summarized in the Supplement. Both trials received ethics committee approval at participating institutions. All patients provided informed consent and studies were registered in clinical trial registries (ISRCTN26088319 and NCT02099669). After screening 252 patients in both studies, 66 patients (n = 33 restrictive and n = 33 liberal) were randomized between January 2015 and February 2020. The enrollment rate was 0.46–1 patients/month. There were no significant differences in baseline characteristics between the two transfusion arms (Table S2). Of the 66 randomized patients, 61 received transfusions while on study. The mean (SD) pre-transfusion Hb for the restrictive and liberal arms were significantly different at 85.9 ± 9 and 98.8 ± 9 g/L, respectively, with a mean difference of 12.9 g/L (95% confidence interval [CI] 11.2–14.6; p < .0001) as was the mean Hb of all measured Hb values according to transfusion strategy (liberal 100.4 ± 4.6 vs. restrictive 89.9 ± 6.8 g/L; Figure S1a). There was a significant difference in Hb over time (p = .0025) with a net positive slope in the liberal (slope = 0.49) and a net negative slope for the restrictive arm (slope = −0.32). In the restrictive arm, the percentage of pre-transfusion Hb falling below the allocated transfusion target range (85–100 g/L) was 58%. In the liberal arm, the percentage of pre-transfusion Hb falling below the allocated transfusion target range was 81%. In a post-hoc sum of squares analysis, we found that the mean individual amplitude of variation in Hb was 42% higher in the restrictive versus the liberal arm at 74 ± 59 and 43 ± 31, respectively. In total, 232 and 471 units of RBC were transfused in the restrictive and liberal arms, respectively. Patients in the liberal arm had more CBCs (13.8 vs. 10.3, p = .001), a mean of 3.1 ± 2.9 more transfusion visits, and a mean of 6.3 ± 5.9 extra units of blood during the 12-week study. The mean number of days between transfusions was 18.9 ± 9.9 in restrictive and 13.0 ± 7.5 in liberal arms, respectively (Table 1). There was one episode of allo-immunization and one febrile non-hemolytic transfusion reaction in the liberal arm. Mean ferritin was similarly elevated at baseline but increased by 926 μg/L (95% CI 1446–2095) and 28 μg/L (95% CI −864 to 922) above baseline in the liberal and restrictive arms, respectively (Figure S2). Rates of QOL completion were high: pre- (91%) and post-transfusion (89%). There appeared to be greater stability in the EQ-5D health utility scores for patients in the liberal arm (Figure S1b). The QOL scores measured immediately pre- and 5–7 days post-transfusion were compared between both arms. The pre-transfusion EQ5D health utility scores (0.77 vs. 0.7, p = .003), visual analog scores (71.4 vs. 62.7, p = .001), EORTC QLQ-C30 emotional functioning (84.3 vs. 75.1, p = .002), fatigue (35.7 vs. 43.1, p = .01), nausea/vomiting (3.3 vs. 6.8, p = .01), and appetite loss (12.3 vs. 20.0, p = .02) scores were superior for patients in the liberal arm. Post-transfusion, EQ-5D health utility (0.77 vs. 0.71, p = .01), visual analog scores (72.2 vs. 66.6, p = .03), emotional functioning (84.7 vs. 77.8, p = .01), and constipation scores (17.2 vs. 22.4, p = .03) remained superior in the liberal arm. Pre-transfusion, a higher percentage of patients treated in the liberal arm experienced improvement in physical and social functioning, fatigue, dyspnea, and insomnia while a higher percentage of patients in the restrictive arm experienced improvement in emotional functioning, and financial problems compared with baseline (Figure S3a). Post-transfusion, some but not all of these differences were maintained (Figure S3b). Individual changes in patient mean pre-transfusion QOL scores compared with baseline are presented in waterfall plots for EQ5D health utility, EQ-5D visual analog, physical functioning, social functioning, global QOL, fatigue, and dyspnea (Figure S4a–g). While there were more patients in the liberal arms experiencing benefit (above the x-axis), there were patients who had stability or decrements in selected symptoms and function domains in both treatment arms. We present a combined analysis of two feasibility trials of similar design, providing data on 66 RBC TD patients with MDS randomized to restrictive versus liberal transfusion thresholds. We found a mean pre-transfusion Hb difference of 12.9 g/L between liberal and restrictive arms. Maintaining this mean Hgb difference for 12 weeks required the transfusion of 6.3 extra units of blood over 3.1 extra transfusion visits. This differs from the findings of a small Nordic group study in which the achievement and maintenance of a Hb >120 g/L did not confer a higher transfusion rate once the hemoglobin target was reached.9 Overall, we observed less variability in Hgb levels in the liberal arm with patients reporting clinically important improvements pre- and post-transfusion (compared with baseline) in selected symptom and functional domains. However, many patients in both transfusion arms experienced stability or declines in their scores. This underscores the complex interplay of factors that contribute to QOL in MDS patients such as frailty, comorbidity, disability, and disease-related inflammation. Further research into the impact of transfusions on functional outcomes in sufficiently large cohorts of patients is needed. We thank all participating sites and investigators in RBC-ENHANCE, REDDS, and the NHSBT CTU. We also acknowledge the agreement of the sponsor (NHSBT) to share REDDS trial data. REDDS was funded by NHSBT R&D, the Australian and New Zealand Society of Blood Transfusions (ANZSBT), and the Wellington Division of New Zealand Cancer Society. RBC-ENHANCE was funded by Canadian Cancer Society Research Institute Grant QOLL-14 and MOSPI Fund 2014. All of this research is original and has not been published elsewhere. No medical writers were used to compose this manuscript. The authors declare no conflicts of interest. The data that supports the findings of this study are available from the corresponding author upon reasonable request. Data S1: Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
In the version of this Article initially published, a versioning error led to a mistake in the third paragraph of the Discussion.In the text now reading "In our dataset, the most extreme and sustained increase in SARS-CoV-2 cases associated with school opening was in the South, where school opening was associated with a weekly increase in cases ranging from 9.8 to 21.3 per 100,000 people, " the range initially reported was "7.8 to 18.9 per 100,000." The results presented in the text and figures are unaffected.
Introduction Immune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet counts and increased risk of bleeding. After corticosteroids with or without intravenous immune globulin (first-line treatment), second-line treatment options include rituximab, splenectomy, thrombopoietin receptor agonists (TPO-RAs), and fostamatinib. In Canada, the choice of second-line therapy is influenced by access to medications. The goals of this narrative review are to 1) summarize the evidence for the use of TPO-RAs and other second-line therapies in ITP and 2) highlight differences in public funding criteria for TPO-RAs across provinces and territories in Canada. Methods We conducted a literature review of second-line therapies for ITP. We solicited information on public funding programs for TPO-RAs in Canada from health care providers, pharmacists, and provincial ministries of health. Results Head-to-head trials involving TPO-RAs, rituximab, splenectomy, and fostamatinib are lacking. There is substantial evidence of effect for TPO-RAs in improving platelet count levels, health-related quality of life, bleeding, and fatigue from placebo-controlled trials and observational studies; however, access to TPO-RAs through provincial funding programs in Canada is variable. Splenectomy failure is a prerequisite for the funding of TPO-RAs in Ontario, Manitoba, and Saskatchewan, but not in Alberta or Quebec. Other provinces either do not have access to public funding or funding is provided on a case-by-case basis. Discussion TPO-RAs are effective second-line therapies for the treatment of ITP; however, access is variable across Canada, which results in health disparities and poor uptake of international treatment guidelines.
Eltrombopag has been shown to be noninferior to intravenous immunoglobulin (IVIG) for improving perioperative platelet counts in patients with immune thrombocytopenia (ITP) in a randomized trial; thus, cost is an important factor for treatment and policy decisions. We used patient-level data from the trial to conduct a cost-effectiveness analysis comparing perioperative eltrombopag 50 mg daily starting dose, with IVIG 1 or 2 g/kg (according to local practice) from a Canadian public health care payer's perspective over the observation period, from preoperative day 21 to postoperative day 28. Resource utilization data were obtained from the trial data (eltrombopag, n = 38; IVIG, n = 36), and unit costs were collected from the Ontario Schedule of Benefits, Ontario Drug Formulary, and secondary sources. All costs were adjusted to 2020 Canadian dollars. We calculated the incremental cost per patient for all patients randomized. Uncertainty was addressed using nonparametric bootstrapping. The use of perioperative eltrombopag for patients with ITP resulted in a cost-saving of $413 Canadian per patient. Compared with IVIG, the probability of eltrombopag being cost effective was 70% even with no willingness to pay. In a sensitivity analysis based on IVIG dose, we found that with the higher dose of IVIG (2 g/kg), eltrombopag saved $2,714 per patient, whereas with the lower dose of IVIG (1 g/kg), eltrombopag had a higher mean cost of $562 per patient. In summary, based on data from the randomized trial that demonstrated noninferiority, the use of eltrombopag for the management of ITP in the perioperative setting was less costly than IVIG.
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