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Thalidomide for Recurrent Bleeding Due to Small-Intestinal Angiodysplasia
Chen, H., Wu, S., Tang, M., Zhao, R., Zhang, Q., Dai, Z., Gao, Y., Yang, S., Li, Z., Du, Y., et al
The New England journal of medicine. 2023;389(18):1649-1659
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Editor's Choice
Abstract
BACKGROUND Recurrent bleeding from the small intestine accounts for 5 to 10% of cases of gastrointestinal bleeding and remains a therapeutic challenge. Thalidomide has been evaluated for the treatment of recurrent bleeding due to small-intestinal angiodysplasia (SIA), but confirmatory trials are lacking. METHODS We conducted a multicenter, double-blind, randomized, placebo-controlled trial to investigate the efficacy and safety of thalidomide for the treatment of recurrent bleeding due to SIA. Eligible patients with recurrent bleeding (at least four episodes of bleeding during the previous year) due to SIA were randomly assigned to receive thalidomide at an oral daily dose of 100 mg or 50 mg or placebo for 4 months. Patients were followed for at least 1 year after the end of the 4-month treatment period. The primary end point was effective response, which was defined as a reduction of at least 50% in the number of bleeding episodes that occurred during the year after the end of thalidomide treatment as compared with the number that occurred during the year before treatment. Key secondary end points were cessation of bleeding without rebleeding, blood transfusion, hospitalization because of bleeding, duration of bleeding, and hemoglobin levels. RESULTS Overall, 150 patients underwent randomization: 51 to the 100-mg thalidomide group, 49 to the 50-mg thalidomide group, and 50 to the placebo group. The percentages of patients with an effective response in the 100-mg thalidomide group, 50-mg thalidomide group, and placebo group were 68.6%, 51.0%, and 16.0%, respectively (P<0.001 for simultaneous comparison across the three groups). The results of the analyses of the secondary end points supported those of the primary end point. Adverse events were more common in the thalidomide groups than in the placebo group overall; specific events included constipation, somnolence, limb numbness, peripheral edema, dizziness, and elevated liver-enzyme levels. CONCLUSIONS In this placebo-controlled trial, treatment with thalidomide resulted in a reduction in bleeding in patients with recurrent bleeding due to SIA. (Funded by the National Natural Science Foundation of China and the Shanghai Municipal Education Commission, Gaofeng Clinical Medicine; ClinicalTrials.gov number, NCT02707484.).
PICO Summary
Population
Adult patients with recurrent bleeding due to small-intestinal angiodysplasia (n= 150).
Intervention
Thalidomide at an oral daily dose of 100 mg (n= 51).
Comparison
Thalidomide at an oral daily dose of 50 mg (n= 49). Placebo (n= 50).
Outcome
Patients were followed for at least 1 year after the end of the 4-month treatment period. The primary end point was effective response, which was defined as a reduction of at least 50% in the number of bleeding episodes that occurred during the year after the end of thalidomide treatment as compared with the number that occurred during the year before treatment. The percentages of patients with an effective response in the 100-mg thalidomide group, 50-mg thalidomide group, and placebo group were 68.6%, 51.0%, and 16.0%, respectively. The results of the analyses of the secondary end points supported those of the primary end point. Adverse events were more common in the thalidomide groups than in the placebo group overall; specific events included constipation, somnolence, limb numbness, peripheral edema, dizziness, and elevated liver-enzyme levels.
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Role of Oral Iron Supplementation for Anemia Secondary to Acute Nonvariceal Upper Gastrointestinal Bleeding: A Randomized Controlled Trial
Chang A, Rugivarodum M, Pungpipattrakul N, Akarapatima K, Suwanno K, Rattanasupar A, Ovartlarnporn B, Prachayakul V
Journal of gastroenterology and hepatology. 2023
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Editor's Choice
Abstract
BACKGROUND AND AIM Although acute upper gastrointestinal bleeding (UGIB) can lead to anemia, evidence regarding the effects of oral iron supplementation on UGIB-induced anemia following discharge remains lacking. The present study aimed to investigate the effects of oral iron supplementation on hemoglobin response and iron storage in patients with anemia secondary to nonvariceal UGIB. METHODS This randomized controlled trial included 151 patients with nonvariceal UGIB who had anemia at discharge. Patients were assigned to a 1:1 block in which they were either administered 6 weeks of 600 mg/d oral ferrous fumarate (treatment group, n=77) or treated without iron supplementation (control group, n=74). The primary outcome was composite hemoglobin response (hemoglobin elevation greater than 2 g/dL or no anemia at the end of treatment [EOT]). RESULTS The proportion of patients achieving composite hemoglobin response was greater in the treatment group than in the control group (72.7% vs. 45.9%; adjusted risk ratio [RR], 2.980; p=0.004). At EOT, the percentage change in the hemoglobin level (34.2 ± 24.8 % vs. 19.4 ± 19.9 %; adjusted coefficient, 11.543; p<0.001) was significantly higher in the treatment group than in the control group; however, the proportions of patients with a serum ferritin level <30 μg/L and a transferrin saturation <16% were lower in the treatment group (all p<0.05). No significant differences in treatment-associated adverse effects and adherence rates were observed between the groups. CONCLUSIONS Oral iron supplementation exerts beneficial effects on anemia and iron storage following nonvariceal UGIB without significantly impacting rates of adverse effects or adherence. CLINICAL TRIAL REGISTRATION TCTR20190225002.
PICO Summary
Population
Patients with anaemia secondary to nonvariceal upper gastrointestinal bleeding (n= 151).
Intervention
Six weeks of 600 mg/d oral ferrous fumarate (treatment group, n= 77).
Comparison
No iron supplementation (control group, n= 74).
Outcome
The proportion of patients achieving composite haemoglobin response was greater in the treatment group than in the control group (72.7% vs. 45.9%; adjusted risk ratio [RR], 2.980). At end of treatment, the percentage change in the haemoglobin level (34.2 ± 24.8 % vs. 19.4 ± 19.9 %; adjusted coefficient, 11.543) was significantly higher in the treatment group than in the control group; however, the proportions of patients with a serum ferritin level <30 μg/L and a transferrin saturation <16% were lower in the treatment group. No significant differences in treatment-associated adverse effects and adherence rates were observed between the groups.
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Ferric carboxymaltose versus ferrous fumarate in anemic children with inflammatory bowel disease: the POPEYE randomized controlled clinical trial
Bevers N, Van de Vijver E, Aliu A, Ardabili AR, Rosias P, Stapelbroek J, Maartens IAB, van de Feen C, Escher JC, Oudshoorn A, et al
The Journal of pediatrics. 2022
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Editor's Choice
Abstract
OBJECTIVE To determine whether intravenous (IV) or oral iron suppletion is superior in improving physical fitness in anemic children with inflammatory bowel disease (IBD). STUDY DESIGN We conducted a clinical trial at 11 centers. Children aged 8 to 18 with IBD and anemia (defined as hemoglobin (Hb) z-score < -2) were randomly assigned to a single IV dose of ferric carboxymaltose or 12 weeks of oral ferrous fumarate. Primary endpoint was the change in 6-minute walking distance (6MWD) from baseline, expressed as z-score. Secondary outcome was a change in Hb z-score from baseline. RESULTS We randomized 64 patients (33 IV iron; 31 oral iron) and followed them for 6 months. One month after the start of iron therapy, the 6MWD z-score of patients in the IV group had increased by 0.71 compared with -0.11 in the oral group (P=0.01). At 3- and 6-months follow-up, no significant differences in 6MWD z-scores were observed. Hb z-scores gradually increased in both groups and the rate of increase was not different between groups at 1, 3 and 6 months after initiation of iron therapy (overall P=0.97). CONCLUSION In this trial involving anemic children with IBD, a single dose of IV ferric carboxymaltose was superior to oral ferrous fumarate with respect to quick improvement of physical fitness. At 3 and 6 months after initiation of therapy, no differences were discovered between oral or IV therapy. The increase of Hb over time was comparable in both treatment groups. TRIAL REGISTRATION NTR4487 [Netherlands Trial Registry].
PICO Summary
Population
Children with anaemia and inflammatory bowel disease, enrolled in the POPEYE trial, in 9 Dutch and 2 Belgian hospitals (n= 64).
Intervention
Single intravenous dose of ferric carboxymaltose (IV group), (n= 33).
Comparison
12 weeks of oral ferrous fumarate (oral group), (n= 31).
Outcome
The primary endpoint was the change in 6-minute walking distance (6MWD) from baseline, expressed as z-score. The secondary outcome was a change in Hb z-score from baseline. One month after the start of iron therapy, the 6MWD z-score of patients in the IV group had increased by 0.71 compared with -0.11 in the oral group. At 3- and 6- months follow-up, no significant differences in 6MWD z-scores were observed. Hb z-scores gradually increased in both groups and the rate of increase was not different between groups at 1, 3 and 6 months after initiation of iron therapy.
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Hypophosphataemia following ferric derisomaltose and ferric carboxymaltose in patients with iron deficiency anaemia due to inflammatory bowel disease (PHOSPHARE-IBD): a randomised clinical trial
Zoller H, Wolf M, Blumenstein I, Primas C, Lindgren S, Thomsen LL, Reinisch W, Iqbal T
Gut. 2022
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Editor's Choice
Abstract
OBJECTIVE Intravenous iron-a common treatment for anaemia and iron deficiency due to inflammatory bowel disease (IBD)-can cause hypophosphataemia. This trial compared the incidence of hypophosphataemia after treatment with ferric carboxymaltose (FCM) or ferric derisomaltose (FDI). DESIGN This randomised, double-blind, clinical trial was conducted at 20 outpatient hospital clinics in Europe (Austria, Denmark, Germany, Sweden, UK). Adults with IBD and iron deficiency anaemia (IDA) were randomised 1:1 to receive FCM or FDI at baseline and at Day 35 using identical haemoglobin- and weight-based dosing regimens. The primary outcome was the incidence of hypophosphataemia (serum phosphate <2.0 mg/dL) at any time from baseline to Day 35 in the safety analysis set (all patients who received ≥1 dose of study drug). Markers of mineral and bone homeostasis, and patient-reported fatigue scores, were measured. RESULTS A total of 156 patients were screened; 97 (49 FDI, 48 FCM) were included and treated. Incident hypophosphataemia occurred in 8.3% (4/48) FDI-treated patients and in 51.0% (25/49) FCM-treated patients (adjusted risk difference: -42.8% (95% CI -57.1% to -24.6%) p<0.0001). Both iron formulations corrected IDA. Patient-reported fatigue scores improved in both groups, but more slowly and to a lesser extent with FCM than FDI; slower improvement in fatigue was associated with greater decrease in phosphate concentration. CONCLUSION Despite comparably effective treatment of IDA, FCM caused a significantly higher rate of hypophosphataemia than FDI. Further studies are needed to address the longer-term clinical consequences of hypophosphataemia and to investigate mechanisms underpinning the differential effects of FCM and FDI on patient-reported fatigue.
PICO Summary
Population
Adults with inflammatory bowel disease and iron deficiency anaemia enrolled in the PHOSPHARE-IBD trial in five European countries (n= 97).
Intervention
Ferric carboxymaltose (FCM), (n= 48).
Comparison
Ferric derisomaltose (FDI), (n= 49).
Outcome
Incident hypophosphataemia occurred in 8.3% FDI-treated patients and in 51% FCM-treated patients (adjusted risk difference: -42.8% (95% CI -57.1% to -24.6%)). Both iron formulations corrected iron deficiency anaemia. Patient-reported fatigue scores improved in both groups, but more slowly and to a lesser extent with FCM than FDI; slower improvement in fatigue was associated with greater decrease in phosphate concentration.
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Is There a Role for Tranexamic Acid in Upper GI Bleeding? A Systematic Review and Meta-Analysis
Burke E, Harkins P, Ahmed I
Surgery research and practice. 2021;2021:8876991
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Editor's Choice
Abstract
INTRODUCTION Upper gastrointestinal (GI) bleeding is associated with increased morbidity and mortality. Tranexamic acid (TXA) is an antifibrinolytic agent which is licensed in the management of haemorrhage associated with trauma. It has been suggested that tranexamic acid may be able to play a role in upper GI bleeding. However, there is currently no recommendation to support this. AIM: The aim of this study was to synthesise available evidence of the effect of TXA on upper GI bleeding. METHODS AND MATERIALS A systematic review was conducted. PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for relevant studies. A random effects meta-analysis was performed to determine the risk ratio of primary and secondary outcomes pertaining to the use of TXA in upper GI bleeding. RESULTS A total of 8 studies were included in this systematic review. The total number of patients in all studies was 12994 including 4550 females (35%) and 8444 males (65%). The mean age of participants in 6 of the studies was 59.3; however the mean age for either intervention or placebo group was not reported in two of the studies. All studies reported on the effect of TXA on mortality, and the risk ratio was 0.95; however, with the 95% CI ranging from 0.80 to 1.13, this was not statistically significant. 6 of the studies reported on rebleeding rate, the risk ratio was 0.64, and with a 95% CI ranging from 0.47 to 0.86, this was statistically significant. 3 of the studies reported on the risk of adverse thromboembolic events, and the risk ratio was 0.93; however, the 95% CI extended from 0.62 to 1.39 and so was not statistically significant. 7 of the studies reported on the need for surgery, and the risk ratio was 0.59 and was statistically significant with a 95% CI ranging from 0.38 to 0.94. CONCLUSION In conclusion, the use of TXA in upper GI bleeding appears to have a beneficial effect in terms of decreasing the risk of re-bleeding and decreasing the need for surgery. However, we could not find a statistically significant effect on need for blood transfusions, risk of thromboembolic events, or effect on mortality. Future randomised controlled trials may elucidate these outcomes.
PICO Summary
Population
Patients with upper gastrointestinal (GI) bleeding (8 studies, n= 12,994).
Intervention
Meta-analysis to synthesise available evidence of the effect of tranexamic acid (TXA) on upper GI bleeding.
Comparison
Outcome
All studies reported on the effect of TXA on mortality, and the risk ratio was 0.95; however, this was not statistically significant. 6 of the studies reported on rebleeding rate, the risk ratio was 0.64, and this was statistically significant. 3 of the studies reported on the risk of adverse thromboembolic events, and the risk ratio was 0.93; however, was not statistically significant. 7 of the studies reported on the need for surgery, and the risk ratio was 0.59 and was statistically significant.
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Efficacy and safety of tranexamic acid in acute upper gastrointestinal bleeding: meta-analysis of randomised controlled trials
Kamal F, Khan MA, Lee-Smith W, Sharma S, Imam Z, Jowhar D, Petryna E, Marella HK, Aksionav P, Iqbal U, et al
Scandinavian journal of gastroenterology. 2020;:1-8
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Editor's Choice
Abstract
BACKGROUND Studies evaluating the role of tranexamic acid in acute upper GI bleeding (UGIB) have reported conflicting results. In this systematic review, we have evaluated the efficacy and safety of tranexamic acid in UGIB. METHODS We searched several databases from inception to June 6, 2020 to identify randomised controlled trials (RCTs) that compared tranexamic acid and placebo in UGIB. Our outcomes of interest were mortality, rebleeding, all thromboembolic events, venous thromboembolic events, need for transfusion, endoscopic intervention and surgery. Pooled risk ratios (RR) with 95% confidence intervals (CI) were calculated using fixed effect model. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework to assess the certainty of evidence. RESULTS We included 12 RCTs comprising 14,100 patients. We found no significant difference in mortality, pooled RR (95% CI) 0.87 (0.74-1.01), rebleeding, pooled RR (95% CI) 0.90 (0.79-1.02), need for surgery, pooled RR (95% CI) 0.86 (0.73-1.02), need for transfusion, pooled RR (95% CI) 1.00 (0.99-1.01) or thromboembolic events, RR (95% CI) 1.16 (0.87-1.56) between treatments. We found an increased risk of venous thromboembolic events with tranexamic acid, pooled RR (95% CI) 1.94 (1.23-3.05). Certainty of evidence based on the GRADE framework for the different outcomes ranged from low to very low. CONCLUSIONS Tranexamic acid does not improve outcomes in UGIB and may increase the risk of venous thromboembolic events.
PICO Summary
Population
Patients with acute upper gastrointestinal bleeding bleeding (12 studies, n= 14,100).
Intervention
Tranexamic acid (n= 7101).
Comparison
Placebo (n= 6999).
Outcome
No significant difference in mortality, rebleeding, need for surgery, need for transfusion, or thromboembolic events, between treatments was found. However, there was an increased risk of venous thromboembolic events with tranexamic acid.