ANNALS OF EMERGENCY MEDICINE
APRIL 2015
Systematic Review Snapshot TAKE-HOME MESSAGE The use of tranexamic acid before surgery of hip or femur shaft fractures may reduce the need for blood transfusion; however, inferences are limited due to the small number of trials. METHODS DATA SOURCES In August 2012, authors searched resources, including the Cochrane Injuries Group Registrar, CENTRAL, MEDLINE, EMBASE, Conference Proceedings Citation Index - Science, Science Citation Index Expanded, Pfizer Web site, WHO Clinical Trials Registry Portal, and relevant trials. STUDY SELECTION Studies included were prospective randomized placebo-controlled trials comparing tranexamic acid with placebo or no tranexamic acid in adults undergoing emergency or urgent surgery, defined as surgery within 48 hours of hospitalization or if implicitly understood that patients’ conditions required emergency surgery. DATA EXTRACTION AND SYNTHESIS Two authors of the meta-analysis searched for studies that met inclusion criteria; included studies were all randomized controlled trials evaluating adult patients (>18 years) undergoing emergency or urgent surgeries who received tranexamic acid versus placebo or no tranexamic acid. A third author, blinded from the search, determined whether the
Volume 65, no. 4 : April 2015
Does Tranexamic Acid Improve Outcomes in Patients Undergoing Urgent or Emergency Surgery? EBEM Commentators
Jennifer Robertson, MD, MSEd Department of Emergency Medicine The Cleveland Clinic Cleveland, OH
Alex Koyfman, MD Department of Emergency Medicine UT Southwestern Medical Center/Parkland Memorial Hospital Dallas, TX
Results Outcomes in patients treated with tranexamic acid versus no tranexamic acid. No. of Studies
N
Outcome
Risk Ratio (95% CI)
3 3 2 1
260 260 191 57
All-cause mortality Need for transfusion Risk of deep venous thrombosis* Risk of stroke†
1.01 0.70 2.29 2.79
(0.14–7.30) (0.52–0.94) (0.68–7.66) (0.12–67.1)
I2, % 0 0 0
N¼total number of subjects. *Based on data by Zufferey et al2 and Pfizer.3 † Based on data by Zufferey et al.2
Five trials were included in the qualitative analysis, but only 3 (N¼260) met criteria for the quantitative meta-analysis. These trials by Sadeghi and Mehr-Aein,1 Zufferey et al,2 and Pfizer,3 compared tranexamic acid versus standard care without tranexamic acid in surgeries for hip or femur shaft fractures. All study participants received the minimum tranexamic acid bolus dose of 15 mg/kg intravenously at surgery. None of the participants were judged to have coagulopathies. The 3 trials were judged by the authors to be clinically and statistically homogeneous. The investigators judged the risk of bias
to be low or unclear and there were no disagreements. There was no effect of tranexamic acid on mortality (risk ratio approximately¼1); however, there was imprecision around this estimate (95% CI 0.14 to 7.30) according to the 3 trials. Alternatively, the use of tranexamic acid appeared to reduce the probability of requiring a blood transfusion by an estimated 30% but may have increased the risk of deep venous thrombosis or stroke.1,2 There were no reported myocardial infarctions or pulmonary emboli in any of the studies. Annals of Emergency Medicine 445
Systematic Review Snapshot
studies met the definitions for emergency or urgent surgery. The primary outcome was mortality. Secondary outcomes included need for transfusion, risk of deep venous thrombosis, pulmonary embolism, and stroke. Treatment effects were measured with risk ratios with 95% confidence intervals (CIs). Two authors assessed risk of bias with respect to allocation concealment, blinding, incomplete outcome reporting, and other sources. Heterogeneity was evaluated with I2 and results were pooled with a fixedeffect model.
Commentary Tranexamic acid was discovered in the 1950s as a potent antifibrinolytic agent.4 Since then, tranexamic acid has been shown to reduce the need for blood transfusions in gastrointestinal bleeding5 and elective surgeries6 and potentially reduce mortality in acute trauma.7 Although this meta-analysis did not show any direct mortality benefit, it did estimate a 30% (95% CI 6% to 48%) reduction in the need for transfusions in patients undergoing surgery for hip or femur shaft fractures. Although blood transfusions are considered to be quite safe, they carry a risk of infectious-, allergic-, and immunologicrelated reactions.8 Because of this, patients may indirectly benefit from tranexamic acid by negation of the need for transfusion and reduction of the chance of transfusion-related risks.
446 Annals of Emergency Medicine
However, there are significant limitations to the reviewed studies and the results should be interpreted with caution. Although the authors conducted a comprehensive search, the studies meeting the inclusion criteria were few and small. The 3 analyzed studies examined the effects of tranexamic acid only for surgery of the hip1,2 and femur shaft fractures3; no studies for other nonorthopedic urgent or emergency surgeries were identified. Additionally, the included studies examined the effect of tranexamic acid only when administered at surgery and so may not be directly relevant to management in the emergency department (ED). Although the authors of this metaanalysis determined that there was minimal statistical heterogeneity among the results of the 3 studies, there was considerable variation in terms of timing of tranexamic acid dosing, anesthesia and analgesic medications, deep venous thrombosis prophylaxis, transfusion thresholds, and type of surgery (arthroplasty versus osteosynthesis). The study by Zufferey et al2 also included a metaanalysis of previous studies of tranexamic acid on elective hip and knee arthroplasties, which further limits the applicability of their summary results to the ED setting. In conclusion, this meta-analysis reported a 30% reduction in the need for transfusions with the administration of tranexamic acid at the time of emergency hip and femur fracture surgery. However, given the multiple limitations of this systematic review, the benefits and potential harms of administration in the ED remain unknown.
Editor’s Note: The source for this systematic review snapshot is: Perel P, Ker K, Morales Uribe CH, et al. Tranexamic acid for reducing mortality in emergency and urgent surgery. Cochrane Database Syst Rev. 2013;http://dx.doi.org/10.1002/ 14651858.CD010245.pub2. 1. Sadeghi M, Mehr-Aein A. Does a single bolus dose of tranexamic acid reduce blood loss and transfusion requirements during hip fracture surgery? a prospective randomized double blind study in 67 patients. Acta Med Iran. 2007;45:437-442. 2. Zufferey PJ, Miquet M, Quenet S, et al. Tranexamic acid in hip fracture surgery: a randomized controlled trial. Br J Anaesth. 2010;104:23-30. 3. Pfizer. Prospective randomised phase IV open label comparative study of tranexamic acid plus standard care for the reduction of blood loss in subjects undergoing surgery for long bone fracture. Available at: http://clinicaltrials. gov/show/NCT00824564. Updated June 6, 2011. Accessed July 25, 2014. 4. Okamoto S, Okamoto U. Amino-methylcyclohexane-carbolic acid: AMCHA. A new potent inhibitor of fibrinolysis. Keio J Med. 1962;11:105-115. 5. Von Holstein C, Erikkson S, Kallen R. Tranexamic acid as an aid to reducing blood transfusion requirements in gastric and duodenal bleeding. BMJ. 1987;294:7-10. 6. Ker K, Edwards P, Perel P, et al. Effect of tranexamic acid on surgical bleeding: systemic review and cumulative metaanalysis. BMJ. 2012;344:e3054. 7. Shakur H, Roberts I, Bautista R, et al, CRASH2 Trial Collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376:23-32. 8. Shander A, Goodnough LT. Update on transfusion medicine. Pharmacotherapy. 2007;27(9 pt 2):57S-68S.
Michael Brown, MD, MSc, Alan Jones, MD, and David Newman, MD, serve as editors of the SRS series.
Volume 65, no. 4 : April 2015
APRIL 2015
Systematic Review Snapshot TAKE-HOME MESSAGE The use of tranexamic acid before surgery of hip or femur shaft fractures may reduce the need for blood transfusion; however, inferences are limited due to the small number of trials. METHODS DATA SOURCES In August 2012, authors searched resources, including the Cochrane Injuries Group Registrar, CENTRAL, MEDLINE, EMBASE, Conference Proceedings Citation Index - Science, Science Citation Index Expanded, Pfizer Web site, WHO Clinical Trials Registry Portal, and relevant trials. STUDY SELECTION Studies included were prospective randomized placebo-controlled trials comparing tranexamic acid with placebo or no tranexamic acid in adults undergoing emergency or urgent surgery, defined as surgery within 48 hours of hospitalization or if implicitly understood that patients’ conditions required emergency surgery. DATA EXTRACTION AND SYNTHESIS Two authors of the meta-analysis searched for studies that met inclusion criteria; included studies were all randomized controlled trials evaluating adult patients (>18 years) undergoing emergency or urgent surgeries who received tranexamic acid versus placebo or no tranexamic acid. A third author, blinded from the search, determined whether the
Volume 65, no. 4 : April 2015
Does Tranexamic Acid Improve Outcomes in Patients Undergoing Urgent or Emergency Surgery? EBEM Commentators
Jennifer Robertson, MD, MSEd Department of Emergency Medicine The Cleveland Clinic Cleveland, OH
Alex Koyfman, MD Department of Emergency Medicine UT Southwestern Medical Center/Parkland Memorial Hospital Dallas, TX
Results Outcomes in patients treated with tranexamic acid versus no tranexamic acid. No. of Studies
N
Outcome
Risk Ratio (95% CI)
3 3 2 1
260 260 191 57
All-cause mortality Need for transfusion Risk of deep venous thrombosis* Risk of stroke†
1.01 0.70 2.29 2.79
(0.14–7.30) (0.52–0.94) (0.68–7.66) (0.12–67.1)
I2, % 0 0 0
N¼total number of subjects. *Based on data by Zufferey et al2 and Pfizer.3 † Based on data by Zufferey et al.2
Five trials were included in the qualitative analysis, but only 3 (N¼260) met criteria for the quantitative meta-analysis. These trials by Sadeghi and Mehr-Aein,1 Zufferey et al,2 and Pfizer,3 compared tranexamic acid versus standard care without tranexamic acid in surgeries for hip or femur shaft fractures. All study participants received the minimum tranexamic acid bolus dose of 15 mg/kg intravenously at surgery. None of the participants were judged to have coagulopathies. The 3 trials were judged by the authors to be clinically and statistically homogeneous. The investigators judged the risk of bias
to be low or unclear and there were no disagreements. There was no effect of tranexamic acid on mortality (risk ratio approximately¼1); however, there was imprecision around this estimate (95% CI 0.14 to 7.30) according to the 3 trials. Alternatively, the use of tranexamic acid appeared to reduce the probability of requiring a blood transfusion by an estimated 30% but may have increased the risk of deep venous thrombosis or stroke.1,2 There were no reported myocardial infarctions or pulmonary emboli in any of the studies. Annals of Emergency Medicine 445
Systematic Review Snapshot
studies met the definitions for emergency or urgent surgery. The primary outcome was mortality. Secondary outcomes included need for transfusion, risk of deep venous thrombosis, pulmonary embolism, and stroke. Treatment effects were measured with risk ratios with 95% confidence intervals (CIs). Two authors assessed risk of bias with respect to allocation concealment, blinding, incomplete outcome reporting, and other sources. Heterogeneity was evaluated with I2 and results were pooled with a fixedeffect model.
Commentary Tranexamic acid was discovered in the 1950s as a potent antifibrinolytic agent.4 Since then, tranexamic acid has been shown to reduce the need for blood transfusions in gastrointestinal bleeding5 and elective surgeries6 and potentially reduce mortality in acute trauma.7 Although this meta-analysis did not show any direct mortality benefit, it did estimate a 30% (95% CI 6% to 48%) reduction in the need for transfusions in patients undergoing surgery for hip or femur shaft fractures. Although blood transfusions are considered to be quite safe, they carry a risk of infectious-, allergic-, and immunologicrelated reactions.8 Because of this, patients may indirectly benefit from tranexamic acid by negation of the need for transfusion and reduction of the chance of transfusion-related risks.
446 Annals of Emergency Medicine
However, there are significant limitations to the reviewed studies and the results should be interpreted with caution. Although the authors conducted a comprehensive search, the studies meeting the inclusion criteria were few and small. The 3 analyzed studies examined the effects of tranexamic acid only for surgery of the hip1,2 and femur shaft fractures3; no studies for other nonorthopedic urgent or emergency surgeries were identified. Additionally, the included studies examined the effect of tranexamic acid only when administered at surgery and so may not be directly relevant to management in the emergency department (ED). Although the authors of this metaanalysis determined that there was minimal statistical heterogeneity among the results of the 3 studies, there was considerable variation in terms of timing of tranexamic acid dosing, anesthesia and analgesic medications, deep venous thrombosis prophylaxis, transfusion thresholds, and type of surgery (arthroplasty versus osteosynthesis). The study by Zufferey et al2 also included a metaanalysis of previous studies of tranexamic acid on elective hip and knee arthroplasties, which further limits the applicability of their summary results to the ED setting. In conclusion, this meta-analysis reported a 30% reduction in the need for transfusions with the administration of tranexamic acid at the time of emergency hip and femur fracture surgery. However, given the multiple limitations of this systematic review, the benefits and potential harms of administration in the ED remain unknown.
Editor’s Note: The source for this systematic review snapshot is: Perel P, Ker K, Morales Uribe CH, et al. Tranexamic acid for reducing mortality in emergency and urgent surgery. Cochrane Database Syst Rev. 2013;http://dx.doi.org/10.1002/ 14651858.CD010245.pub2. 1. Sadeghi M, Mehr-Aein A. Does a single bolus dose of tranexamic acid reduce blood loss and transfusion requirements during hip fracture surgery? a prospective randomized double blind study in 67 patients. Acta Med Iran. 2007;45:437-442. 2. Zufferey PJ, Miquet M, Quenet S, et al. Tranexamic acid in hip fracture surgery: a randomized controlled trial. Br J Anaesth. 2010;104:23-30. 3. Pfizer. Prospective randomised phase IV open label comparative study of tranexamic acid plus standard care for the reduction of blood loss in subjects undergoing surgery for long bone fracture. Available at: http://clinicaltrials. gov/show/NCT00824564. Updated June 6, 2011. Accessed July 25, 2014. 4. Okamoto S, Okamoto U. Amino-methylcyclohexane-carbolic acid: AMCHA. A new potent inhibitor of fibrinolysis. Keio J Med. 1962;11:105-115. 5. Von Holstein C, Erikkson S, Kallen R. Tranexamic acid as an aid to reducing blood transfusion requirements in gastric and duodenal bleeding. BMJ. 1987;294:7-10. 6. Ker K, Edwards P, Perel P, et al. Effect of tranexamic acid on surgical bleeding: systemic review and cumulative metaanalysis. BMJ. 2012;344:e3054. 7. Shakur H, Roberts I, Bautista R, et al, CRASH2 Trial Collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376:23-32. 8. Shander A, Goodnough LT. Update on transfusion medicine. Pharmacotherapy. 2007;27(9 pt 2):57S-68S.
Michael Brown, MD, MSc, Alan Jones, MD, and David Newman, MD, serve as editors of the SRS series.
Volume 65, no. 4 : April 2015
