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Perioperative oral eltrombopag versus intravenous immunoglobulin in patients with immune thrombocytopenia: a non-inferiority, multicentre, randomised trial
Arnold DM, Heddle NM, Cook RJ, Hsia C, Blostein M, Jamula E, Sholzberg M, Lin Y, Kassis J, Larratt L, et al
The Lancet. Haematology. 2020;7(9):e640-e648
Abstract
BACKGROUND Patients with immune thrombocytopenia are at risk of bleeding during surgery, and intravenous immunoglobulin is commonly used to increase the platelet count. We aimed to establish whether perioperative eltrombopag was non-inferior to intravenous immunoglobulin. METHODS We did a randomised, open-label trial in eight academic hospitals in Canada. Patients were aged at least 18 years, with primary or secondary immune thrombocytopenia and platelet counts less than 100 × 10(9) cells per L before major surgery or less than 50 × 10(9) cells per L before minor surgery. Previous intravenous immunoglobulin within 2 weeks or thrombopoietin receptor agonists within 4 weeks before randomisation were not permitted. Patients were randomly assigned to receive oral daily eltrombopag 50 mg from 21 days preoperatively to postoperative day 7 or intravenous immunoglobulin 1 g/kg or 2 g/kg 7 days before surgery. Eltrombopag dose adjustments were allowed weekly based on platelet counts. The randomisation sequence was generated by a computerised random number generator, concealed and stratified by centre and surgery type (major or minor). The central study statistician was masked to treatment allocation. The primary outcome was achievement of perioperative platelet count targets (90 × 10(9) cells per L before major surgery or 45 × 10(9) cells per L before minor surgery) without rescue treatment. We did intention-to-treat and per-protocol analyses using an absolute non-inferiority margin of -10%. This trial is registered with ClinicalTrials.gov, NCT01621204. FINDINGS Between June 5, 2013, and March 7, 2019, 92 patients with immune thrombocytopenia were screened, of whom 74 (80%) were randomly assigned: 38 to eltrombopag and 36 to intravenous immunoglobulin. Median follow-up was 50 days (IQR 49-55). By intention-to-treat analysis, perioperative platelet targets were achieved for 30 (79%) of 38 patients assigned to eltrombopag and 22 (61%) of 36 patients assigned to intravenous immunoglobulin (absolute risk difference 17·8%, one-sided lower limit of the 95% CI 0·4%; p(non-inferiority)=0·005). In the per-protocol analysis, perioperative platelet targets were achieved for 29 (78%) of 37 patients in the eltrombopag group and 20 (63%) of 32 in the intravenous immunoglobulin group (absolute risk difference 15·9%, one-sided lower limit of the 95% CI -2·1%; p(non-inferiority)=0·009). Two serious adverse events occurred in the eltrombopag group: one treatment-related pulmonary embolism and one vertigo. Five serious adverse events occurred in the intravenous immunoglobulin group (atrial fibrillation, pancreatitis, vulvar pain, chest tube malfunction and conversion to open splenectomy); all were related to complications of surgery. No treatment-related deaths occurred. INTERPRETATION Eltrombopag is an effective alternative to intravenous immunoglobulin for perioperative treatment of immune thrombocytopenia. However, treatment with eltrombopag might increase risk of thrombosis. The decision to choose one treatment over the other will depend on patient preference, resource limitations, cost, and individual risk profiles. FUNDING GlaxoSmithKline and Novartis.
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Exploring the components of bleeding outcomes in transfusion trials for patients with hematologic malignancy
Balitsky AK, Liu Y, Van der Meer PF, Heddle NM, Arnold DM
Transfusion. 2020
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Editor's Choice
Abstract
Clinically significant bleeding in patients with hematologic malignancies is a heterogeneous composite outcome currently defined as World Health Organization (WHO) bleeding Grades 2, 3, and 4. However, the clinical significance of some minor bleeds categorized as WHO Grades 1 and 2 remains controversial. We analyzed the number and frequency of individual signs and symptoms of WHO Grades 1 and 2 bleeds and explored their association with more severe incident bleeds graded as WHO Grades 3 and 4. STUDY DESIGN AND METHODS We aggregated daily bleeding assessment data from three randomized controlled trials conducted in patients with hematologic malignancies that used bleeding as an outcome. Cox proportional hazard regression analysis was used to identify signs and symptoms categorized as WHO Grades 1 and 2 bleeds that were associated with more severe bleeds (Grades 3 and 4). RESULTS We collected data from 315 patients (n = 5476 daily bleeding assessments; 3383 [61.8%] with a bleed documented). A total of 98.3% (3326/3383) were Grade 1 and 2 bleeds and 1.7% (57/3383) were Grades 3 and 4. Grade 1 and 2 bleeds were composed of 20 different bleeding signs and symptoms. Hematuria (hazard ratio, 16.1; 95% confidence interval, 4.4-59.2; P < .0001) was associated with incident Grade 3 or 4 bleeds. CONCLUSION In patients with hematologic malignancy, only hematuria (microscopic and/or macroscopic) was associated with more severe incident bleeds. This findings require validation in independent data sets.
PICO Summary
Population
Patients with haematologic malignancies and chemotherapy-induced thrombocytopenia (3 randomised controlled trials (RCTs), n= 315).
Intervention
Less severe bleeds (WHO Grades 1 and 2).
Comparison
More severe bleeds (WHO Grades 3 and 4).
Outcome
The total data aggregated from the 3 RCTs was 5,476 daily bleeding assessments, 61.8% with a bleed documented. A total of 98.3% were Grade 1 and 2 bleeds and 1.7% were Grades 3 and 4. Grade 1 and 2 bleeds were composed of 20 different bleeding signs and symptoms. Haematuria was associated with incident Grade 3 or 4 bleeds. In patients with haematologic malignancy, only haematuria was associated with more severe bleeds.
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A randomized controlled trial comparing standard- and low-dose strategies for transfusion of platelets (SToP) to patients with thrombocytopenia
Heddle NM, Cook RJ, Tinmouth A, Kouroukis CT, Hervig T, Klapper E, Brandwein JM, Szczepiorkowski ZM, AuBuchon JP, Barty RL, et al
Blood. 2009;113((7):):1564-73.
Abstract
A noninferiority study was performed comparing low-dose and standard-dose prophylactic platelet transfusions. A double-blind randomized controlled trial (RCT) was performed in 6 sites in 3 countries. Thrombocytopenic adults requiring prophylactic platelet transfusion were randomly allocated to standard-dose (300-600 x 10(9) platelets/product) or low-dose (150- < 300 x 10(9) platelets/product) platelets. The primary outcome (World Health Organization [WHO] bleeding > or = grade 2) was assessed daily through clinical examination, patient interview, and chart review. A WHO grade was assigned through adjudication. The Data Safety Monitoring Board stopped the study because the difference in the grade 4 bleeding reached the prespecified threshold of 5%. At this time, 129 patients had been randomized and 119 patients were included in the analysis (58 low dose; 61 standard dose). Three patients in the low-dose arm (5. 2%) had grade 4 bleeds compared with none in the standard-dose arm. WHO bleeding grade 2 or higher was 49. 2% (30/61) in the standard-dose arm and 51. 7% (30/58) in the low-dose group (relative risk [RR], 1. 052; 95% confidence interval [CI], 0. 737-1. 502). A higher rate of grade 4 bleeding in patients receiving low-dose prophylactic platelet transfusions resulted in this RCT being stopped. Whether this finding was due to chance or represents a real difference requires further investigation. These clinical studies are registered on (http://www. clinicaltrials. gov) as NCT00420914.
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A multicenter pilot-randomized controlled trial of the feasibility of an augmented red blood cell transfusion strategy for patients treated with induction chemotherapy for acute leukemia or stem cell transplantation
Webert KE, Cook RJ, Couban S, Carruthers J, Lee KA, Blajchman MA, Lipton JH, Brandwein JM, Heddle NM
Transfusion. 2008;48((1):):81-91.
Abstract
BACKGROUND Anemia may be an important factor contributing to an increased risk of bleeding, particularly in patients with thrombocytopenia. STUDY DESIGN AND METHODS A multicenter, single-blinded pilot randomized controlled trial (RCT) was performed to evaluate the feasibility of conducting a larger RCT to determine the effect of the hemoglobin (Hb) concentration on bleeding risk. Patients with acute leukemia receiving induction chemotherapy or those undergoing stem cell transplantation were assigned to one of two treatment groups: standard transfusion strategy (transfusion of 2 units of red blood cells [RBCs] when their Hb level was less than 80 g/L) or an augmented transfusion strategy (transfusion of 2 units of RBCs when their Hb level was less than 120 g/L). RESULTS Sixty patients were enrolled: 29 in the control group and 31 in the experimental group. The proportions of patients experiencing clinically significant bleeding and the time to first bleed were not significantly different between the control and experimental groups. The experimental group received more RBC transfusions (transfusions/patient-day) than the control group (0. 233 vs. 0. 151; relative risk, 1. 56; 95% confidence interval, 1. 16-2. 10; p = 0. 003). The proportion of patient-days with platelet (PLT) transfusions was not different between the experimental and control groups. The mean number of donor exposures (PLT and RBC transfusions) was not different between experimental and control groups. Bleeding symptoms were systematically documented. CONCLUSION This pilot study thus indicated that it would be feasible to enroll the required number of patients to enable the performance of a large RCT to investigate the effect of Hb on bleeding risk in thrombocytopenic patients.
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Methodologic issues in the use of bleeding as an outcome in transfusion medicine studies
Heddle NM, Cook RJ, Webert KE, Sigouin C, Rebulla P
Transfusion. 2003;43((6):):742-752.
Abstract
BACKGROUND Prophylactic platelet transfusions are given to thrombocytopenic patients to prevent bleeding. The benefit of platelet transfusions has frequently been assessed by measuring the count increment; however, more recently, an assessment of bleeding has been used because it is a more clinically relevant outcome measure. The purpose of this study was to identify platelet transfusion trigger studies that used bleeding as an outcome measure, compare and contrast methods used to document bleeding and analyze bleeding outcomes, and identify and discuss methodologic issues to consider when bleeding is used as a study outcome. STUDY DESIGN AND METHODS A systematic search to identify platelet transfusion trigger studies was performed. Relevant articles were reviewed to identify how bleeding data was captured and analyzed, and methodologic considerations were identified. RESULTS Seven articles meeting the predefined entry criteria were identified. Methods used to document bleeding included chart review and clinical assessment. The frequency of assessment and the type of personnel performing the assessment were variable. Four approaches to analysis were identified: descriptive; comparison of the proportions of patients having at least one bleed; comparison of patient days with bleeding expressed as a proportion of the total days at risk of bleeding; and time-to-event (first bleed) analysis. CONCLUSION Methodologic issues for consideration when designing a clinical study with bleeding as the outcome measure included approaches to minimize bias in the documentation and classification of bleeding and selection of an analysis approach that is appropriate to the question being asked. The need for development of a valid and reliable bleeding scale was also identified.
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Platelet transfusions in children: results of a randomized, prospective, crossover trial of plasma removal and a prospective audit of WBC reduction
Couban S, Carruthers J, Andreou P, Klama LN, Barr R, Kelton JG, Heddle NM
Transfusion. 2002;42((6):):753-8.
Abstract
BACKGROUND Febrile nonhemolytic transfusion reactions (FNHTRs) complicate 2 to 37 percent of platelet transfusions in adults, but the incidence of such reactions in children is not known. The effectiveness of plasma reduction after storage and WBC reduction of platelet concentrates before storage was studied in pediatric recipients of platelet transfusions. STUDY DESIGN AND METHODS In the first study, a prospective randomized crossover design was used in which patients received either unmodified whole-blood-derived or apheresis platelets or platelets from which most of the plasma supernatant had been removed just before transfusion. The second study was a prospective audit of recipients of prestorage WBC-reduced platelets. Children between 3 months and 17 years of age were eligible for both studies. Patients were assessed for signs and symptoms that are characteristic of a reaction during, immediately after, and 2 hours following transfusion. RESULTS There were 226 platelet transfusions administered to 66 children. One hundred and sixty transfusions were given to 35 children enrolled in the randomized study, and 66 transfusions were given to 33 children during the audit. In the randomized study, nine of the 75 transfusions of unmodified platelets (12%) and six of 85 transfusions of poststorage plasma-removed platelets (7%) were associated with an FNHTR (p=0.42). In the audit, three of 66 transfusions of prestorage WBC-reduced platelets (5%) were associated with an FNHTR. Allergic reactions occurred with 5 percent (4 of 75), 6 percent (5 of 85), and 6 percent (4 of 66) of platelet transfusions, respectively. CONCLUSION FNHTRs appear to be less common among pediatric recipients of platelet transfusions than in adults. In our two studies, there was a trend toward a lower frequency of FNHTRs with poststorage plasma removal and prestorage WBC reduction than with standard platelets, but this was not significant.
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A randomized controlled trial comparing plasma removal with white cell reduction to prevent reactions to platelets
Heddle NM, Klama L, Meyer R, Walker I, Boshkov L, Roberts R, Chambers S, Podlosky L, O'Hoski P, Levine M
Transfusion. 1999;39((3):):231-8.
Abstract
BACKGROUND Recent data suggest that most reactions to platelets are caused by white cell (WBC)-derived cytokines that accumulate in the plasma portion of the component during storage. On the basis of this theory, the effectiveness of two interventions to prevent reactions, poststorage WBC reduction and plasma depletion, were compared. STUDY DESIGN A multiple crossover design was used, in which platelet components for transfusion to a patient randomly were WBC reduced after storage, or the plasma supernatant was removed. Adults >17 years of age, with a hematologic disease requiring platelet transfusion support, were eligible for the study. Patients were assessed for signs and symptoms characteristic of a reaction during, immediately after, and 1 hour after transfusion. Reactions were graded as mild, moderate, or severe. Interleukin 6 levels were also measured in the transfused platelet components. RESULTS There were 380 analyzable platelet transfusions to 30 patients. The frequency of reactions was 25.8 percent (48/186) in the transfusions of poststorage WBC-reduced platelets and 17.0 percent (33/194) in the transfusions of plasma-depleted platelets (p<0.008). The severity of the reaction was graded by the patient. Severe reactions occurred more frequently in connection with poststorage WBC-reduced platelets than with plasma-depleted platelets: 33.4 percent (16/48) versus 18.2 percent (6/33), respectively (p = 0.048). Regression analysis identified interleukin 6 as the most significant of the evaluated factors in its correlation with the risk of reaction. CONCLUSION Plasma removal is more effective than poststorage WBC reduction in preventing reactions, especially severe reactions to platelets.
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The use of anti-D to improve post-transfusion platelet response: a randomized trial
Heddle NM, Klama L, Kelton JG, Meyer R, Walker I, Dickson L, Chambers S, Levine MN
British Journal of Haematology. 1995;89((1):):163-8.
Abstract
Patients undergoing induction chemotherapy for acute leukaemia often become refractory to platelet transfusions. Increased clearance of transfused platelets due to alloimmune destruction has been identified as one of the primary mechanisms contributing to this refractory state. We performed a double-blind randomized trial to determine whether the administration of anti-D to Rh-positive individuals could prevent the refractory state and improve post-transfusion platelet response. Rh-positive patients with acute leukaemia undergoing induction chemotherapy and requiring platelet transfusions were allocated to weekly intravenous anti-D (20 micrograms/kg) or placebo. Platelets and red cell concentrates were administered according to standardized transfusion guidelines. Outcome measures included platelet transfusion utilization, red cell utilization, platelet recovery 18-24 h post-infusion, and the percentage of patients refractory to platelet transfusion. There were 43 patients studied: 21 received anti-D and 22 saline placebo. The mean number of platelet concentrates required per day of observation was 0.59 (SD 0.22) in the anti-D group and 0.61 (SD 0.22) in the placebo group, P = 0.86. No difference was detected between groups in terms of platelet recovery post-infusion, refractoriness to platelet transfusion or frequency of infection (P = 0.97). Red cell concentrate utilization was significantly increased in the anti-D group compared to the placebo group, 0.58 units per day versus 0.37 units per day respectively, P = 0.005. We conclude that the use of anti-D did not improve post-transfusion platelet response in Rh positive patients with acute leukaemia, but did result in an increased need for red cell transfusion.
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The role of the plasma from platelet concentrates in transfusion reactions
Heddle NM, Klama L, Singer J, Richards C, Fedak P, Walker I, KeltonJ-G
New England Journal of Medicine. 1994;331((10):):625-628.