Systematic review of Hematuria and Acute Renal failure with tranexamic acid
Lee SG, Fralick J, Wallis CJD, Boctor M, Sholzberg M, Fralick M
European journal of haematology. 2022
OBJECTIVES To conduct a systematic review of tranexamic acid (TXA) and the risk of renal failure from urinary clots in adult patients with hematuria. METHODS A systematic review of Medline, Embase, CENTRAL, www. CLINICAL TRIALS gov and Google Scholar were searched. Randomized control trials (RCTs) and observational studies that assessed the risk of renal failure with use of TXA among adults with hematuria were included. The primary outcome was renal failure due to urinary tract clots with TXA compared to no TXA (or placebo) or comparator. RESULTS We identified three RCTs (N=466 patients) and three retrospective cohort studies (N=220 patients), and a total of 342 patients that had hematuria and received TXA. The patient population of the six studies included medical and surgical patients, with two of the three RCTs comprised of patients undergoing percutaneous nephrolithotomy, and the third RCT comprised of patients undergoing transurethral resection of the prostate. Documentation of renal function before and after TXA administration was documented in only two studies (N= 28 patients), and neither identified worsening renal function in those exposed to TXA. CONCLUSIONS There are limited studies evaluating the risk of renal failure in patients with hematuria who were exposed to TXA, and the available data does not suggest an increased risk.
Randomized trials of therapeutic heparin for COVID-19: A meta-analysis
Sholzberg M, da Costa BR, Tang GH, Rahhal H, AlHamzah M, Baumann Kreuziger L, Ní Áinle F, Almarshoodi MO, James PD, Lillicrap D, et al
Research and practice in thrombosis and haemostasis. 2021;5(8):e12638
BACKGROUND Pulmonary endothelial injury and microcirculatory thromboses likely contribute to hypoxemic respiratory failure, the most common cause of death, in patients with COVID-19. Randomized controlled trials (RCTs) suggest differences in the effect of therapeutic heparin between moderately and severely ill patients with COVID-19. We did a systematic review and meta-analysis of RCTs to determine the effects of therapeutic heparin in hospitalized patients with COVID-19. METHODS We searched PubMed, Embase, Web of Science, medRxiv, and medical conference proceedings for RCTs comparing therapeutic heparin with usual care, excluding trials that used oral anticoagulation or intermediate doses of heparin in the experimental arm. Mantel-Haenszel fixed-effect meta-analysis was used to combine odds ratios (ORs). RESULTS AND CONCLUSIONS There were 3 RCTs that compared therapeutic heparin to lower doses of heparin in 2854 moderately ill ward patients, and 3 RCTs in 1191 severely ill patients receiving critical care. In moderately ill patients, there was a nonsignificant reduction in all-cause death (OR, 0.76; 95% CI, 0.57-1.02), but significant reductions in the composite of death or invasive mechanical ventilation (OR, 0.77; 95% CI, 0.60 0.98), and death or any thrombotic event (OR, 0.58; 95% CI, 0.45-0.77). Organ support-free days alive (OR, 1.29; 95% CI, 1.07-1.57) were significantly increased with therapeutic heparin. There was a nonsignificant increase in major bleeding. In severely ill patients, there was no evidence for benefit of therapeutic heparin, with significant treatment-by-subgroup interactions with illness severity for all-cause death (P = .034). In conclusion, therapeutic heparin is beneficial in moderately ill patients but not in severely ill patients hospitalized with COVID-19.
Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial
Sholzberg M, Tang GH, Rahhal H, AlHamzah M, Kreuziger LB, Áinle FN, Alomran F, Alayed K, Alsheef M, AlSumait F, et al
BMJ (Clinical research ed.). 2021;375:n2400
OBJECTIVE To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards. DESIGN Randomised controlled, adaptive, open label clinical trial. SETTING 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US. PARTICIPANTS 465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n=228) or prophylactic dose heparin (n=237). INTERVENTIONS Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death. MAIN OUTCOME MEASURES The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated. RESULTS The mean age of participants was 60 years; 264 (56.8%) were men and the mean body mass index was 30.3 kg/m(2). At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P=0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P=0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P=0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P=0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P=0.69). CONCLUSIONS In moderately ill patients with covid-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial. TRIAL REGISTRATION ClinicalTrials.gov NCT04362085.
Fostamatinib is an effective second-line therapy in patients with immune thrombocytopenia
Boccia R, Cooper N, Ghanima W, Boxer MA, Hill QA, Sholzberg M, Tarantino MD, Todd LK, Tong S, Bussel JB
British journal of haematology. 2020;190(6):933-938
Fostamatinib demonstrated efficacy in phase 3 trials of adults with immune thrombocytopenia (ITP). Post hoc analysis compared patients who received fostamatinib as second-line therapy (after steroids ± immunoglobulins) versus third-or-later-line therapy (after ≥2 prior lines of therapy including a second-line agent). Platelet responses ≥50 000/µl were observed in 25/32 (78%) second-line and 54/113 (48%) third-or-later-line patients. Bleeding events were less frequent in second-line (28%) versus third-or-later-line (45%) patients. Responses once achieved tended to be durable in both groups. The safety profile was similar in both groups. In this post hoc analysis, fostamatinib was more effective as second-line than third-or-later-line therapy for ITP.
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
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.
The safety and efficacy of ferumoxytol in the treatment of iron deficiency: a systematic review and meta-analysis
Abdulrehman J, Tang GH, Auerbach M, Santesso N, Sholzberg M
INTRODUCTION Ferumoxytol is an intravenous (IV) iron formulation for treatment of iron deficiency (ID) that faced post-marketing reports of serious adverse events (SAEs). OBJECTIVES To determine the safety and efficacy of ferumoxytol compared to other iron formulations and placebo. METHODS We searched the Cochrane Library, Medline, and EMBASE from inception until February 2018 as well as trial registries and reference lists of relevant articles for randomized or quasi-randomized controlled trials. RESULTS The review included nine studies with 5691 participants. Studies were at low risk of bias. When comparing ferumoxytol to other IV iron formulations, there is moderate quality evidence (QE) of little to no difference in treatment emergent adverse events (TEAEs) (risk ratio [RR] 0.88, 95% confidence interval [CI] 0.80-0.97), treatment related adverse events (TRAEs) (RR 0.73, 95% CI 0.61-0.88), SAEs (RR 1.13, 95% CI 0.77-1.67), hypotension or hypersensitivity reactions (RR 0.58, 95% CI 0.31-1.09), or composite cardiovascular outcomes (RR 0.56, 95% CI 0.24-1.29), low QE of little to no difference in related SAEs (RR 0.55, 95% CI 0.05-6.16), and high QE of little to no difference in the number of patients with an increase in hemoglobin by at least 1 g/dL (RR 1.04, 95% CI 0.96-1.12). Ferumoxytol had less TEAEs compared to oral iron (RR 0.78, 95% CI 0.61-0.98), but more compared to placebo (RR 1.62, 95% CI 1.01-2.61). DISCUSSION Ferumoxytol is as efficacious and safe as alternative IV iron formulations with no clear safety concerns.
Peri-Operative Eltrombopag or Immune Globulin for Patients with Immune Thrombocytopaenia (The Bridging ITP Trial): Methods and Rationale
Arnold DM, Jamula E, Heddle NM, Cook RJ, Hsia C, Sholzberg M, Lin Y, Kassis J, Blostein M, Larratt L, et al
Thrombosis and haemostasis. 2019
BACKGROUND The Bridging ITP Trial is an open-label randomized trial designed to compare the oral thrombopoietin receptor agonist eltrombopag and intravenous immune globulin (IVIG) for patients with immune thrombocytopaenia (ITP) who require an increase in platelet count before elective surgery. Here, we report the study methods and rationale. METHODS We designed a multi-centre, non-inferiority randomized trial comparing daily oral eltrombopag starting 3 weeks pre-operatively, and IVIG administered 1 week pre-operatively for patients with ITP requiring a platelet count increase prior to surgery. Starting dose of eltrombopag is 50 mg daily with a weekly pre-operative dose titration schedule, and treatment is continued for 1 week after surgical haemostasis is achieved. IVIG is administered at a dose of 1 to 2 g/kg 1 week pre-operatively with the allowance for a second dose within 1 week after surgical haemostasis. The objective of the study is to demonstrate non-inferiority of eltrombopag for the primary endpoint of achieving the pre-operative platelet count threshold (50 x 10(9)/L for minor surgery; or 100 x 10(9)/L for major surgery) and sustaining platelet count levels above the threshold for 1 week after surgical haemostasis is achieved, without the use of rescue treatment. Secondary endpoints include thrombosis, bleeding and patient satisfaction. CONCLUSION The Bridging ITP Trial will evaluate the efficacy and safety of eltrombopag as an alternative to IVIG in the peri-operative setting for patients with ITP. The protocol was designed to provide a management strategy that can be applied in clinical practice. CLINICALTRIALS. GOV IDENTIFIER NCT01621204.
Intravenous iron versus oral iron or observation for gastrointestinal malignancies: a systematic review
Tang GH, Dhir V, Scheer AS, Tricco AC, Sholzberg M, Brezden-Masley C
European journal of gastroenterology & hepatology. 2019
BACKGROUND Anemia is a common condition in patients with gastrointestinal cancer. Current evidence for the use of intravenous compared with oral iron in this clinical setting is inconclusive. A systematic review was performed to assess evidence on the efficacy of intravenous iron versus oral/observation in gastrointestinal cancer patients in the preoperative and postoperative setting. MATERIALS AND METHODS We searched Medline and Embase from inception until December 2017 with no language restrictions. Outcomes included hemoglobin response, red blood cell transfusion, and adverse events. Screening, data abstraction, and risk of bias appraisal were performed by two independent reviewers. The risk of bias was assessed using the Cochrane tools for randomized and nonrandomized studies. RESULTS A total of 10 studies (three randomized-controlled trials and seven nonrandomized studies) were included. Of the six preoperative studies, five reported that hemoglobin was significantly higher in the intravenous group compared with oral iron/observation. Among the four postoperative studies, three studies suggested that hemoglobin was significantly higher in the intravenous group compared with oral iron/observation. The overall risk of bias for all randomized-controlled trials was low. Quality assessments for nonrandomized studies found the risk of bias to be moderate for four studies and critical for three studies. CONCLUSION Despite the limitations of the current body of evidence, there is a likely benefit to the use of intravenous iron in this patient population. Further confirmatory research is needed to draw empirical conclusions.
Safety and efficacy of thrombopoietin-receptor agonists in myelodysplastic syndromes: a systematic review and meta-analysis of randomized controlled trials
Prica A, Sholzberg M, Buckstein R
British Journal of Haematology. 2014;167((5):):626-638.
Thrombocytopenia is common (40-65%) and potentially serious in myelodysplastic syndromes (MDS). A systematic review was conducted to determine the safety and efficacy of adding a thrombopoietin-receptor (THPO-R) agonist to standard MDS treatment. MEDLINE, EMBASE and CENTRAL databases were searched. We included randomized controlled trials comparing a THPO-R agonist to placebo. A meta-analysis of the effects was performed. Endpoints included bleeding and platelet transfusion rates, risk of progression to acute myeloid leukaemia (AML) and mortality. Three hundred and eighty four patients from five trials were included, four using romiplostim and one using eltrombopag. Overall, the relative risk (RR) of bleeding with romiplostim versus placebo was 084 [95% confidence interval (CI): 057-124]. However, compared to placebo, romiplostim significantly decreased the exposure-adjusted bleeding rate (RR 092; 95% CI: 086-099), as well as the exposure-adjusted platelet transfusion rate (RR 069; 95% CI: 053-088). The RR of AML progression with romiplostim was 136 (95% CI: 054-340), however the outcome data were judged as higher risk of bias. Romiplostim is promising in its ability to decrease patient-important outcomes: bleeding and platelet transfusion need. Although the risk of AML progression was not increased, due to unclear risk of bias in the data, this safety concern is difficult to assess. Therefore, romiplostim cannot yet be routinely recommended. Early eltrombopag data is promising. 2014 John Wiley & Sons Ltd.
Thrombopoietin (TPO)-receptor agonists in myelodysplastic syndromes (MDS): a systematic review and meta-analysis
Prica A, Sholzberg M, Buckstein R
Blood. 2013;122((21):): Abstract No. 2806.