1.
Does tranexamic acid prevent postpartum haemorrhage? A systematic review of randomised controlled trials
Ker K, Shakur H, Roberts I
Bjog : an International Journal of Obstetrics and Gynaecology. 2016;123((11):):1745-52.
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Abstract
BACKGROUND Postpartum haemorrhage is the leading cause of maternal mortality. Tranexamic acid (TXA) reduces surgical haemorrhage and the risk of death in bleeding trauma patients. OBJECTIVES To assess the effects of TXA on risk of postpartum haemorrhage and other clinically relevant outcomes. SEARCH STRATEGY We searched the MEDLINE, CENTRAL, EMBASE, PubMed, ClinicalTrials.gov and WHO ICTRP electronic databases to May 2015. SELECTION CRITERIA Randomised controlled trials comparing TXA with no TXA or placebo in women giving birth vaginally or by caesarean section. DATA COLLECTION AND ANALYSIS Two authors extracted data and assessed the risk of bias for each trial. Because of data concerns we did not conduct a meta-analysis. MAIN RESULTS We found 26 trials including a total of 4191 women. Examination of the trial reports raised concerns about the quality of the data. Eight trial reports contained identical or similar text and there were important data inconsistencies in several trials. Two trials did not have ethics committee approval. Meta-analysis of baseline variables suggested that randomisation was inadequate in many trials. CONCLUSIONS There is no reliable evidence that TXA prevents postpartum haemorrhage during childbirth. Many of the trials conducted to date are small, low quality and contain serious flaws. TWEETABLE ABSTRACT No evidence that TXA prevents postpartum haemorrhage. Existing trials are unreliable, with serious flaws.
Clinical Commentary
What is known?
Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide with about 50,000 deaths each year. In those women who survive PPH, hysterectomy is sometimes necessary to stop the haemorrhage, depriving many women of their ability to bear additional children. Tranexamic acid (TXA) reduces bleeding by inhibiting fibrinolysis. TXA is an inexpensive, widely available drug that has been proven to reduce bleeding in surgery and reduce the risk of death in bleeding trauma patients. TXA given at delivery could potentially prevent severe postpartum bleeding.
What did this paper set out to examine?
The authors conducted a systematic review of randomised controlled trials (RCTs) to assess the effects of TXA on the risk of PPH as well as other clinically relevant outcomes. They searched MEDLINE, CENTRAL, EMBASE, PubMed, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform electronic databases for reviews published as of May 2015. Selection criteria included RCTs comparing TXA with no TXA or placebo in women giving birth vaginally or by caesarean section (CS).
What did they show?
The authors found 31 reports describing 26 trials involving 4191 women published between 2001 and 2015. Eight reports contained identical or similar data and there were important clinical inconsistencies in several trials. Two trials did not have ethics committee approval and meta-analysis showed that randomization was inadequate in many trials. The median sample size was 120 patients (74-740). All but one were single centre trials. Trials were conducted in China (3), Egypt (2), India (9), Iran (5), Malaysia (1), Pakistan (2), Turkey (3) and Ukraine (1). Twenty-two trials focused on the effects of TXA on women giving birth by CS and four in women delivering vaginally.
TXA was given within 30 minutes prior to incision in all of the CS trials except one (given at delivery of anterior shoulder). TXA was given at delivery of anterior shoulder in 3 and at delivery of placenta in the remaining vaginal births. The TXA dose ranged from 0.5 g to 1 g. Women receiving TXA were compared to those given placebo in 13 reports and with those in a no-TXA group in the remaining 13 trials.
The number of patients assigned to each group was not reported in one trial, rendering the data unusable. Frequency of PPH was reported in 13 of the trials (50%), blood loss in 24 (92%), thromboembolic events in 16 (62%), death in six (23%), surgical intervention in five (19%) and transfusion of blood products in 10 (38%). No trial reported on maternal well-being or quality of life. A major problem when comparing these studies is that even the definition of what constitutes PPH varied; four trials classified PPH as blood loss = 1000 mL after CS and = 500 mL after vaginal delivery. The remaining trials used other, lower thresholds such as = 500 mL after CS and = 400 mL after vaginal delivery.
Because of the authors’ concerns about the quality of the trials and data reliability, they chose not to perform a meta-analysis. They instead calculated effect estimates and 95% CI’s were presented as Forest plots. They concluded that, in all trials, fewer women in the TXA group developed PPH than in the control group. Additionally, from the data of the trials where blood loss was evaluated, the effect estimates were consistent with less blood loss in the TXA group; the difference was statistically significant in all but one trial. In the trials detailing blood product transfusion data, where products were transfused (7), fewer women in the TXA group received a blood transfusion than in the control group. In studies reporting adverse outcomes, there were no deaths, surgical interventions, myocardial infarctions, strokes or pulmonary embolisms.
What are the implications for practice and for future work?
This publication provided valuable data in its description of the scale and nature of deficiencies in the studies evaluating the effect of TXA in preventing PPH. Unless the problems with these studies are brought to the attention of the maternal fetal medicine and transfusion medicine leaders, treatment decisions may be based on unsound evidence putting women at risk. The information provided by the authors should serve to guide future trial developers such that conclusions are based on the highest quality research possible.
Based on the studies reviewed by the authors, it is clear that large, multicentre randomized control trials with clinically relevant endpoints must be developed before widespread clinical guidelines endorsing TXA in preventing PPH are implemented. It should be noted that the data from the WOMAN trial was not available at the time of this study.
References
Adult Antifibrinolytic Agents/*administration & dosage Delivery, Obstetric/*adverse effects Female Humans Parturition/*drug effects Postpartum Hemorrhage/etiology/*prevention & control Pregnancy Randomized Controlled Trials as Topic Tranexamic Acid/*administration & dosage Treatment Outcome Postpartum haemorrhage systematic review tranexamic acid
2.
Pre-emptive treatment with fibrinogen concentrate for postpartum haemorrhage: randomized controlled trial
Wikkelso AJ, Edwards HM, Afshari A, Stensballe J, Langhoff-Roos J, Albrechtsen C, Ekelund K, Hanke G, Secher EL, Sharif HF, et al
British Journal of Anaesthesia. 2015;114((4):):623-33.
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Abstract
BACKGROUND In early postpartum haemorrhage (PPH), a low concentration of fibrinogen is associated with excessive subsequent bleeding and blood transfusion. We hypothesized that pre-emptive treatment with fibrinogen concentrate reduces the need for red blood cell (RBC) transfusion in patients with PPH. METHODS In this investigator-initiated, multicentre, double-blinded, parallel randomized controlled trial, we assigned subjects with severe PPH to a single dose of fibrinogen concentrate or placebo (saline). A dose of 2 g or equivalent was given to all subjects independent of body weight and the fibrinogen concentration at inclusion. The primary outcome was RBC transfusion up to 6 weeks postpartum. Secondary outcomes were total blood loss, total amount of blood transfused, occurrence of rebleeding, haemoglobin <58 g litre(-1), RBC transfusion within 4 h, 24 h, and 7 days, and as a composite outcome of 'severe PPH', defined as a decrease in haemoglobin of >40 g litre(-1), transfusion of at least 4 units of RBCs, haemostatic intervention (angiographic embolization, surgical arterial ligation, or hysterectomy), or maternal death. RESULTS Of the 249 randomized subjects, 123 of 124 in the fibrinogen group and 121 of 125 in the placebo group were included in the intention-to-treat analysis. At inclusion the subjects had severe PPH, with a mean blood loss of 1459 (sd 476) ml and a mean fibrinogen concentration of 4.5 (sd 1.2) g litre(-1). The intervention group received a mean dose of 26 mg kg(-1) fibrinogen concentrate, thereby significantly increasing fibrinogen concentration compared with placebo by 0.40 g litre(-1) (95% confidence interval, 0.15-0.65; P=0.002). Postpartum blood transfusion occurred in 25 (20%) of the fibrinogen group and 26 (22%) of the placebo group (relative risk, 0.95; 95% confidence interval, 0.58-1.54; P=0.88). We found no difference in any predefined secondary outcomes, per-protocol analyses, or adjusted analyses. No thromboembolic events were detected. CONCLUSIONS We found no evidence for the use of 2 g fibrinogen concentrate as pre-emptive treatment for severe PPH in patients with normofibrinogenaemia. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov: http://clinicaltrials.gov/show/NCT01359878. Published protocol: http://www.trialsjournal.com/content/pdf/1745-6215-13-110.pdf.Copyri ght The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Clinical Commentary
Dr Akshay Shah, Adult Intensive Care Unit, John Radcliffe Hospital, Oxford
What is known?
Post-partum haemorrhage (PPH) is a leading cause of maternal morbidity and mortality worldwide. Fibrinogen is an essential component of haemostasis and fibrinogen levels of <2 g.L-1, in patients with PPH, have been shown to predict further severe bleeding and requirement for blood and blood products. Current guidelines recommend using fibrinogen concentrate to correct acquired hypofibrinogenaemia although high quality evidence for this is lacking. A recent Cochrane review demonstrated weak evidence for fibrinogen concentrate in reducing transfusion requirements in bleeding patients undergoing elective cardiac surgery.
What did this paper set out to examine?
This was a multicentre randomised placebo-controlled study aimed to assess the efficacy of pre-emptive treatment with fibrinogen concentrate early in PPH without any laboratory evidence of hypofibrinogenaemia. This is different to previous studies that have examined the use of fibrinogen concentrate once coagulopathy and a fibrinogen deficit have been established. Patients aged >18 years with a PPH, defined as bleeding from the uterus and/or birth canal with 24 hours of delivery were randomised to receive a fixed dose of 2g of fibrinogen concentrate or placebo (isotonic saline). The primary outcome was red blood cell (RBC) transfusion during a 6-week follow-up period postpartum.
What did they show?
Data from 244 patients were available for final analysis; 123 in the fibrinogen group and 121 in the placebo group. There was no difference in the primary outcome RBC transfusion was given to 25 patient (20.3%) in the fibrinogen group and 26 patients (21.5%) in the placebo group. There was also no difference in clinically important secondary outcomes such as estimated blood loss, adverse effects and progression to severe PPH between both groups. An important limitation of this study is that patients who may stand to benefit the most from fibrinogen therapy were either under-represented or not included only 2.2% of patients had a critical fibrinogen level of <2 g.L-1 and 46 patients 15% of the bleeding population in this study, could not be randomised because they were bleeding too heavily and therefore informed consent could not be obtained. Furthermore, the difference in fibrinogen concentrate between the treated and placebo group was only 0.4 g.L-1 which suggests that a larger dose may be required.
What are the implications for practice and for future work?
This study highlights the lack of benefit of fibrinogen concentrate in patients with early PPH and a normal fibrinogen level, which may help, limits it use. Future research should be directed towards developing fast and accurate tests for measuring fibrinogen levels and developing 'goal-directed’ therapy towards patients who may benefit the most such as those with severe PPH and/or acquired hypofibrinogenaemia.