-
1.
Comparison of a therapeutic-only versus prophylactic platelet transfusion policy for people with congenital or acquired bone marrow failure disorders
Malouf R, Ashraf A, Hadjinicolaou A V, Doree C, Hopewell S, Estcourt L J
The Cochrane Database of Systematic Reviews. 2018;5:CD012342.
-
-
-
Free full text
-
Full text
Abstract
BACKGROUND Bone marrow disorders encompass a group of diseases characterised by reduced production of red cells, white cells, and platelets, or defects in their function, or both. The most common bone marrow disorder is myelodysplastic syndrome. Thrombocytopenia, a low platelet count, commonly occurs in people with bone marrow failure. Platetet transfusions are routinely used in people with thrombocytopenia secondary to bone marrow failure disorders to treat or prevent bleeding. Myelodysplastic syndrome is currently the most common reason for receiving a platelet transfusion in some Western countries. OBJECTIVES To determine whether a therapeutic-only platelet transfusion policy (transfusion given when patient is bleeding) is as effective and safe as a prophylactic platelet transfusion policy (transfusion given to prevent bleeding according to a prespecified platelet threshold) in people with congenital or acquired bone marrow failure disorders. SEARCH METHODS We searched for randomised controlled trials (RCTs), non-RCTs, and controlled before-after studies (CBAs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2017, Issue 9), Ovid MEDLINE (from 1946), Ovid Embase (from 1974), PubMed (e-publications only), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 12 October 2017. SELECTION CRITERIA We included RCTs, non-RCTs, and CBAs that involved the transfusion of platelet concentrates (prepared either from individual units of whole blood or by apheresis any dose, frequency, or transfusion trigger) and given to treat or prevent bleeding among people with congenital or acquired bone marrow failure disorders.We excluded uncontrolled studies, cross-sectional studies, and case-control studies. We excluded cluster-RCTs, non-randomised cluster trials, and CBAs with fewer than two intervention sites and two control sites due to the risk of confounding. We included all people with long-term bone marrow failure disorders that require platelet transfusions, including neonates. We excluded studies of alternatives to platelet transfusion, or studies of people receiving intensive chemotherapy or a stem cell transplant. DATA COLLECTION AND ANALYSIS We used the standard methodological procedures outlined by Cochrane. Due to the absence of evidence we were unable to report on any of the review outcomes. MAIN RESULTS We identified one RCT that met the inclusion criteria for this review. The study enrolled only nine adults with MDS over a three-year study duration period. The trial was terminated due to poor recruitment rate (planned recruitment 60 participants over two years). Assessment of the risk of bias was not possible for all domains. The trial was a single-centre, single-blind trial. The clinical and demographic characteristics of the participants were never disclosed. The trial outcomes relevant to this review were bleeding assessments, mortality, quality of life, and length of hospital stay, but no data were available to report on any of these outcomes.We identified no completed non-RCTs or CBAs.We identified no ongoing RCTs, non-RCTs, or CBAs. AUTHORS' CONCLUSIONS We found no evidence to determine the safety and efficacy of therapeutic platelet transfusion compared with prophylactic platelet transfusion for people with long-term bone marrow failure disorders. This review underscores the urgency of prioritising research in this area. People with bone marrow failure depend on long-term platelet transfusion support, but the only trial that assessed a therapeutic strategy was halted. There is a need for good-quality studies comparing a therapeutic platelet transfusion strategy with a prophylactic platelet transfusion strategy; such trials should include outcomes that are important to patients, such as quality of life, length of hospital admission, and risk of bleeding.
Clinical Commentary
Xiangrong He, MD, PhD & Claudia S. Cohn, MD, PhD, both of University of Minnesota, Department of Laboratory Medicine and Pathology.
What is known?
Thrombocytopenia represents a common problem for patients withchronic bone marrow failure disorders, the most common of which are myelodysplastic syndrome (MDS) and anaplastic anemia (AA). In addition to thrombocytopenia, both morphologic and functional platelet abnormalities may be seen in these patients as well. Platelet transfusion support is the primary management option for thrombocytopenia and active bleeding in these patients. Platelets are usually transfused prophylactically at counts less than 10 x 109/L and with higher counts in patients with hemorrhage. As compared with no prophylaxis, prophylactic platelet transfusions have been shown to be superior in reducing moderate to severe bleeding, primarily in people with leukemia. However, the evidence of prophylactic use for platelet transfusions in people with chronic bone marrow failure is lacking. Meanwhile, platelets are a precious resource and platelet transfusion carries many risks. Thus, avoiding unnecessary prophylactic platelet transfusions will have significant financial and safety implications for health services.
What did this paper set out to examine?
The authors set out to to review in thrombocytopenic patients with chronic bone marrow failure, whether prophylactic transfusions are really necessary or whether these patients can be effectively supported with only therapeutic platelet transfusions given with the onset of bleeding. In particular, they wanted to show that a therapeutic-only platelet transfusion strategy is as effective and safe as a prophylactic platelet transfusion strategy for the prevention of clinically significant bleeding in thrombocytopenic patients with primary bone marrow failure disorders.
What did they show?
The review included all patients with MDS, acquired AA, or congenital bone marrow failure disorders that were not being actively treated with a stem cell transplant or intensive chemotherapy. To maximize the number of studies eligible for inclusion, not only randomized controlled trials (RCTs), but good quality non-RCTs, and controlled before-after studies were included. Only one trial met the inclusion criteria for this review. Unfortunately, the trial was incomplete due to an unexpected slow recruiting rate. Therefore, no results were provided by the trial authors. Although the review was unable to make any recommendations on prophylactic platelet transfusion policies for this patient population, it did identify an urgent need for good quality studies in this area.
What are the implications for practice and for future work?
Thrombocytopenia (platelet counts < 10 x 109/L) is one of the most common complications in patients with chronic bone marrow failure. For example, 40% to 65% of MDS patients have thrombocytopenia. Meanwhile, in some Western countries, bone marrow failure is one of the most common underlying reasons for receiving a prophylactic platelet transfusion. However, guidelines on a therapeutic platelet transfusion strategy versus a prophylactic platelet transfusion strategy in this population are still lacking. Due to the absence of relevant data, the current review was not able to reach any conclusions on the safety and efficacy of prophylactic platelet transfusion compared with therapeutic platelet transfusion for patients with chronic bone marrow failure. Nontheless, this review identified a major gap in the literature and underscored the urgency of prioritizing research in this area. In the meantime, platelet transfusions for people with bone marrow disorders should still be managed according to national transfusion guidelines.
-
2.
Reversal of trauma-induced coagulopathy using first-line coagulation factor concentrates or fresh frozen plasma (RETIC): a single-centre, parallel-group, open-label, randomised trial
Innerhofer P, Fries D, Mittermayr M, Innerhofer N, von Langen D, Hell T, Gruber G, Schmid S, Friesenecker B, Lorenz IH, et al
The Lancet. Haematology. 2017;4((6):):e258-e271.. e258
-
-
-
Full text
Abstract
BACKGROUND Effective treatment of trauma-induced coagulopathy is important; however, the optimal therapy is still not known. We aimed to compare the efficacy of first-line therapy using fresh frozen plasma (FFP) or coagulation factor concentrates (CFC) for the reversal of trauma-induced coagulopathy, the arising transfusion requirements, and consequently the development of multiple organ failure. METHODS This single-centre, parallel-group, open-label, randomised trial was done at the Level 1 Trauma Center in Innsbruck Medical University Hospital (Innsbruck, Austria). Patients with trauma aged 18-80 years, with an Injury Severity Score (ISS) greater than 15, bleeding signs, and plasmatic coagulopathy identified by abnormal fibrin polymerisation or prolonged coagulation time using rotational thromboelastometry (ROTEM) were eligible. Patients with injuries that were judged incompatible with survival, cardiopulmonary resuscitation on the scene, isolated brain injury, burn injury, avalanche injury, or prehospital coagulation therapy other than tranexamic acid were excluded. We used a computer-generated randomisation list, stratification for brain injury and ISS, and closed opaque envelopes to randomly allocate patients to treatment with FFP (15 mL/kg of bodyweight) or CFC (primarily fibrinogen concentrate [50 mg/kg of bodyweight]). Bleeding management began immediately after randomisation and continued until 24 h after admission to the intensive care unit. The primary clinical endpoint was multiple organ failure in the modified intention-to-treat population (excluding patients who discontinued treatment). Reversal of coagulopathy and need for massive transfusions were important secondary efficacy endpoints that were the reason for deciding the continuation or termination of the trial. This trial is registered with ClinicalTrials.gov, number NCT01545635. FINDINGS Between March 3, 2012, and Feb 20, 2016, 100 out of 292 screened patients were included and randomly allocated to FFP (n=48) and CFC (n=52). Six patients (four in the FFP group and two in the CFC group) discontinued treatment because of overlooked exclusion criteria or a major protocol deviation with loss of follow-up. 44 patients in the FFP group and 50 patients in the CFC group were included in the final interim analysis. The study was terminated early for futility and safety reasons because of the high proportion of patients in the FFP group who required rescue therapy compared with those in the CFC group (23 [52%] in the FFP group vs two [4%] in the CFC group; odds ratio [OR] 25.34 [95% CI 5.47-240.03], p<0.0001) and increased needed for massive transfusion (13 [30%] in the FFP group vs six [12%] in the CFC group; OR 3.04 [0.95-10.87], p=0.042) in the FFP group. Multiple organ failure occurred in 29 (66%) patients in the FFP group and in 25 (50%) patients in the CFC group (OR 1.92 [95% CI 0.78-4.86], p=0.15). INTERPRETATION Our results underline the importance of early and effective fibrinogen supplementation for severe clotting failure in multiple trauma. The available sample size in our study appears sufficient to make some conclusions that first-line CFC is superior to FFP. FUNDING None.
Clinical Commentary
What is known?
The management of major trauma haemorrhage has changed significantly over the last two decades, and the use of haemostatic resuscitation (the transfusion of red cells and FFP early and in high ratio to mitigate/treat clotting abnormalities that arise from severe trauma haemorrhage) is now standard practice. There are attendant risks from the transfusion of blood components (TRALI, TACO, increased rates of multiple organ failure (MOF) in trauma) and the potential to use clotting factor concentrates (CFCs) such as prothrombin complex concentrate, factor XIII and fibrinogen in place of FFP may confer advantages.
What did this paper set out to examine?
The RETIC study was a single centre, open-label, RCT evaluating the effects of FFP vs. coagulation factor concentrates (CFCs) as treatment for major bleeding after injury in adult trauma patients (age 18 80). The primary endpoint was the development of MOF during ICU stay, as defined by the SOFA score. Secondary endpoints were numerous and included transfusion use, changes to clotting parameters, thromboembolic complications and mortality. The study was designed to detect a difference in MOF between groups notably the publication did not specify the difference expected and 292 patients were required for 80% power.
What did they show?
The study recruited 100 patients (48 FFP and 52 CFC) between March 2012 Feb 2016. Six patients were later excluded. 44FFP and 50 CFC patients were analysed. The baseline characteristics in each arm were balanced. The study was terminated early for safety 52% patients in FFP arm required rescue therapy (double dose therapy followed by switching to the other treatment to stop the bleeding) compared to 4% CFC group (OR: 25.34 [95% CI 5.47 240.03], p < 0.0001). Additionally more FFP patients received massive transfusion; OR 3.04 [0.95 10.87], p = 0.042.
Primary endpoint results were provided using a modified ITT population (patients randomised but did not complete therapy were removed). The study showed no significant difference in MOF between arms: 66% FFP arm vs. 50% CFC arm; OR 1.92 [95%CI 0.78 4.86], p = 0.15. Post-hoc logistic regression analysis showed a significant difference in MOF development in the FFP arm for patients who had higher injury severity and worse brain injury; OR 3.13 [1.19-8.88], p = 0.025. The CFC patients were more likely to have coagulopathy reversed OR 25.34 [5.47-240.03], p <0.0001. (Defined by: FIBTEM A10 >8mm, EXTEM CT < 78 secs and no clinical bleeding). Seven patients died 5 CFC and 2 FFP, most due to severe brain injury and no patient died from exsanguination.
What are the implications for practice and for future work?
Overall, given these limitations, there will be debate about the implications of this trial for practice. The findings regarding reversal of coagulopathy are intriging there is a clear agreement between reversal of coagulopathy i.e. a FIBTEM A10 >8mm, and an EXTEM CT < 78 secs and reduced bleeding. This is the first time, in an RCT setting, that improved ROTEM parameters have been linked to clinical reduction of bleeding and these findings are important. One particular area for further research might be to validate whether the ROTEM parameters are effective thresholds for bleeding treatment and importantly linking the thresholds with hard clinical outcomes such as mortality or significant reduction in transfusion therapy.
-
3.
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.
-
-
-
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
-
4.
Efficacy and safety of fibrinogen concentrate in surgical patients: a meta-analysis of randomized controlled trials
Fominskiy E, Nepomniashchikh VA, Lomivorotov VV, Monaco F, Vitiello C, Zangrillo A, Landoni G
Journal of Cardiothoracic and Vascular Anesthesia. 2016;30((5):):1196-204.
-
-
-
Full text
Abstract
OBJECTIVES To investigate the efficacy and safety of fibrinogen concentrate (FC) in surgical patients. DESIGN Meta-analysis of randomized controlled studies (RCTs). SETTING Perioperative. PARTICIPANTS Adult and pediatric surgical patients. INTERVENTIONS A search of PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials, Transfusion Evidence Library, Google Scholar, and the proceedings from major international anesthesiology meetings up to February 1, 2016 for RCTs that compared FC with placebo or other comparators. MEASUREMENTS AND MAIN RESULTS The primary outcome was all-cause mortality. Pooled risk ratios and mean differences (MDs) were computed with either fixed-effects or random-effects models. The study included 14 RCTs comprising 1,035 patients; the majority of patients underwent cardiac surgery. All-cause mortality was lower in the fibrinogen group (4/432 [0.9%] v 15/430 [3.5%]; risk ratio 0.26; 95% confidence interval [CI] 0.09-0.78; p = 0.02; heterogeneity statistic (l2) = 0%). The use of FC was associated with reduced bleeding (MD -127 mL; 95% CI -207 to -47; p = 0.002; I2= 54%) and a lower number of red blood cells units transfused versus comparator (MD -0.9; 95% CI -1.3 to -0.5; p<0.001; I2 = 42%). There were no differences in the rates of thrombotic events and myocardial infarction. CONCLUSIONS In surgical patients, FC was associated with reduced bleeding and a lower number of red blood cell units transfused, and it also might reduce mortality. However, none of the analyzed trials was powered for estimation of survival and adverse events with FC use. Half of the included studies were of high or moderate risk of bias. The evidence primarily came from cardiac surgery settings.
Clinical Commentary
Dr. MJR Desborough, Haematology/Transfusion Medicine, NHS Blood and Transplant, Oxford, UK.
What is known?
Bleeding is an important and potentially preventable adverse event associated with surgery. Prevention, or treatment, of bleeding must be balanced against the risk of arterial or venous thrombotic events. Fibrin, which is formed from fibrinogen, is a key part of blood clot formation. In situations where a patient’s fibrinogen concentration is low, fibrinogen concentrate (or another source of fibrinogen such as cryoprecipitate) is often administered. However it is less clear whether fibrinogen concentrate is effective and safe for patients with a normal baseline fibrinogen level.
An alternate, or adjuvant approach, is the use of anti-fibrinolytic agents (which prevent fibrin from being broken down) such as tranexamic acid and epsilon aminocaproic acid. These drugs are increasingly used to prevent peri-operative blood loss and do not appear to be associated with significant adverse events.
A systematic review and meta-analysis published in 2013 on fibrinogen concentrate in surgical patients found no difference in mortality but found a significant reduction in the incidence of red cell transfusion (Wikkelsø et al. Cochrane Database Syst Rev 2013;8:CD008864).
What did this paper set out to examine?
The authors set out to compare efficacy and safety of fibrinogen concentrate in surgical patients in a systematic review and meta-analysis. Randomised controlled trials including adult or paediatric surgery were included. Trials were included if they compared fibrinogen concentrate to placebo or another haemostatic therapy (fresh frozen plasma, platelets, cryoprecipitate or coagulation factor concentrates). The only exclusion was congenital (inherited) fibrinogen deficiency.
The primary outcome was all-cause mortality. Secondary outcomes were blood loss; proportion of patients who received a red cell transfusion; number of red cell units used; surgical revisions for bleeding; and thrombotic complications.
What did they show?
The authors identified 14 randomised controlled trials with 1035 patients. The majority of trials were in the setting of cardiac surgery. There was a high level of variation in the comparators that were used, the trigger for infusion of fibrinogen concentrate; prophylactic or therapeutic use; the timing of administration; and the dose of fibrinogen concentrate. The authors reported that half of the included studies were at high or moderate risk of bias.
The risk of all-cause mortality was significantly lower in the group treated with fibrinogen concentrate. The event rate for mortality was very low with the majority of trials having no deaths in either arm. The meta-analysis included an unpublished paper and exclusion of this paper form the meta-analysis resulted in a non-significant difference in mortality (Mengoli et al. J Cardiothorac Vasc Anesth 2017;31:e33-5).
Blood loss; number of red cell units transfused; and proportion of patients who received a red cell transfusion were significantly lower for those treated with fibrinogen concentrate. No difference was found in the risk of surgical revisions for bleeding or thrombotic complications.
What are the implications for practice and for future work?
This meta-analysis suggests that fibrinogen concentrate may reduce peri-operative mortality, bleeding and transfusion requirements. However the considerable variation in triggers, comparators and settings suggests that further randomised controlled trial data will be necessary to demonstrate efficacy in this setting. It is unclear whether anti-fibrinolytic drugs such as tranexamic acid or epsilon aminocaproic acid were used in the trials included in this meta-analysis. Now that these agents have been widely adopted into clinical guidelines, the efficacy and risk profile of fibrinogen concentrate may differ and this should be taken into account in future randomised controlled trials.
References
Fibrinogen/*therapeutic use Humans Perioperative Care/*methods Randomized Controlled Trials as Topic *Surgical Procedures, Operative Treatment Outcome efficacy fibrinogen hemorrhage safety surgery
-
5.
Use of platelet transfusions prior to lumbar punctures or epidural anaesthesia for the prevention of complications in people with thrombocytopenia
Estcourt LJ, Ingram C, Doree C, Trivella M, Stanworth SJ
The Cochrane Database of Systematic Reviews. 2016;((5)):CD011980.
-
-
-
Free full text
-
Full text
Abstract
BACKGROUND People with a low platelet count (thrombocytopenia) often require lumbar punctures or an epidural anaesthetic. Lumbar punctures can be diagnostic (haematological malignancies, epidural haematoma, meningitis) or therapeutic (spinal anaesthetic, administration of chemotherapy). Epidural catheters are placed for administration of epidural anaesthetic. Current practice in many countries is to correct thrombocytopenia with platelet transfusions prior to lumbar punctures and epidural anaesthesia, in order to mitigate the risk of serious procedure-related bleeding. However, the platelet count threshold recommended prior to these procedures varies significantly from country to country. This indicates significant uncertainty among clinicians of the correct management of these patients. The risk of bleeding appears to be low but if bleeding occurs it can be very serious (spinal haematoma). Therefore, people may be exposed to the risks of a platelet transfusion without any obvious clinical benefit. OBJECTIVES To assess the effects of different platelet transfusion thresholds prior to a lumbar puncture or epidural anaesthesia in people with thrombocytopenia (low platelet count). SEARCH METHODS We searched for randomised controlled trials (RCTs) in CENTRAL (The Cochrane Library 2016, Issue 3), MEDLINE (from 1946), EMBASE (from 1974), the Transfusion Evidence Library (from 1950) and ongoing trial databases to 3 March 2016. SELECTION CRITERIA We included RCTs involving transfusions of platelet concentrates, prepared either from individual units of whole blood or by apheresis, and given to prevent bleeding in people of any age with thrombocytopenia requiring insertion of a lumbar puncture needle or epidural catheter. We only included RCTs published in English. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. MAIN RESULTS We identified no completed or ongoing RCTs in English. We did not exclude any completed or ongoing RCTs because they were published in another language. AUTHORS' CONCLUSIONS There is no evidence from RCTs to determine what is the correct platelet transfusion threshold prior to insertion of a lumbar puncture needle or epidural catheter. There are no ongoing registered RCTs assessing the effects of different platelet transfusion thresholds prior to the insertion of a lumbar puncture or epidural anaesthesia in people with thrombocytopenia. Any future RCT would need to be very large to detect a difference in the risk of bleeding. We would need to design a study with at least 47,030 participants to be able to detect an increase in the number of people who had major procedure-related bleeding from 1 in 1000 to 2 in 1000.
Clinical Commentary
Richard Kaufman MD, Brigham and Women’s Hospital, Boston
What is known?
In rare cases, bleeding complicates lumbar punctures and epidural anesthesia. The clinical consequences of bleeding in this setting range from trivial (traumatic tap detectable by cerebrospinal fluid cell count only) to devastating (spinal hematoma/paralysis). Most cases of spinal hematoma following lumbar puncture have been reported in patients with platelet counts below 50 X 109 cells/Lalthough other risk factors for bleeding were present in nearly all of these cases.1 Platelet transfusions are often administered prophylactically to thrombocytopenic patients having a lumbar puncture or epidural anesthesia. But what constitutes a safe minimum platelet count to perform these procedures is unclear, and clinical practices and published practice guidelines vary widely. This is an important topic because: (1) lumbar punctures and epidural anesthesia are performed commonly; (2) these procedures have rare but serious risks; (3) platelet transfusions carry a range of infectious and noninfectious risks; and (4) platelet units are expensive and limited in availability.
What did this paper set out to examine?
The authors conducted a systematic review of the literature aimed at evaluating the risks and benefits of different platelet transfusion thresholds before a lumbar puncture or epidural anesthesia in thrombocytopenic patients. This was an update of a 2016 Cochrane Review.
What did they show?
The authors found that the published literature on this topic remains extremely limited. They identified no high-quality studies. After rigorously screening 999 published reports, the authors included in their analysis only three retrospective cohort studies describing participants who received or did not receive lumbar puncture. One study was in adults; the other two were in children. No study compared different platelet count thresholds before a procedure. No major bleeding complications occurred in the two studies reporting this outcome (150 participants). There was no difference in minor bleeding (traumatic taps) among pediatric or adult patients who received or did not receive platelet transfusion pre-procedure. The authors concluded that no clinical study evidence exists on which to base a correct platelet transfusion threshold before lumbar puncture or epidural anesthesia.
At this time, it is impossible to make firm recommendations on whether platelet transfusions should be administered before lumbar puncture or epidural anesthesia in thrombocytopenic children or adults. A safe minimum platelet count for performing these procedures cannot be identified based on the existing data. Until stronger data allow us to better understand the risks and benefits of platelet transfusion before lumbar puncture or epidural anesthesia, practices will vary among clinicians and will remain a matter of clinical judgment.
What are the implications for practice and for future work?
What are the implications for future research?Because bleeding complication rates are so low in the setting of lumbar puncture and epidural anesthesia, the authors estimate that performing a randomized trial would require more than 47,000 participants. Utilizing large electronic patient registries/databases thus appears to be the only realistic way that our understanding in this area could be improved moving forward.
Predicting bleeding in the setting of any invasive procedure has proven to be remarkably difficult. Hemostasis is complex; bleeding from most procedures is rare; and the tools that we have to assess bleeding risk are crude. Platelet counts tell us nothing about platelet hemostatic function. Other variables, including medications, coagulation factor activity, tissue integrity, and disease state may predominate in determining a patient’s bleeding risk. Platelet counts are easy to measure, but hopefully in the future we will discover better ways to determine whether a platelet transfusion should be given.
What are the implications for future practice? At this time, it is impossible to make firm recommendations on whether platelet transfusions should be administered before lumbar puncture or epidural anesthesia in thrombocytopenic children or adults. A safe minimum platelet count for performing these procedures cannot be identified based on the existing data. Until stronger data allow us to better understand the risks and benefits of platelet transfusion before lumbar puncture or epidural anesthesia, practices will vary among clinicians and will remain a matter of clinical judgment.
References
1. Van Veen JJ, Nokes TJ, Makris M. The risk of spinal haematoma following neuraxial anaesthesia or lumbar puncture in thrombocytopenic individuals. Br J Haematol. 148(1):15-25.
-
6.
Transfusion-related adverse events in the Platelet Dose study
Kaufman RM, Assmann SF, Triulzi DJ, Strauss RG, Ness P, Granger S, Slichter SJ
Transfusion. 2015;55((1):):144-53.
-
-
-
Free full text
-
Abstract
BACKGROUND How platelet (PLT) product characteristics such as dose, source (whole blood derived [WBD] vs. apheresis), storage duration, and ABO matching status affect the risks of transfusion-related adverse events (TRAEs) is unclear. Similarly, more information is needed to define how recipient characteristics affect the frequency of TRAEs after PLT transfusion. STUDY DESIGN AND METHODS In the multicenter Platelet Dose ("PLADO") study, pediatric and adult hematology-oncology patients with hypoproliferative thrombocytopenia were randomized to receive low-dose (LD), medium-dose (MD), or high-dose (HD) PLT prophylaxis for a pretransfusion PLT count of not more than 10x10(9) /L. All PLT units (apheresis or WBD) were leukoreduced. Post hoc analyses of PLADO data were performed using multipredictor models. RESULTS A total of 5034 PLT transfusions to 1102 patients were analyzed. A TRAE occurred with 501 PLT transfusions (10.0%). The most common TRAEs were fever (6.6% of transfusions), allergic or hypersensitivity reactions (1.9%), and sinus tachycardia (1.8%). Patients assigned HD PLTs were more likely than LD or MD patients to experience any TRAE (odds ratio for HD vs. MD, 1.50; 95% confidence interval, 1.10-2.05; three-group comparison p=0.02). PLT source and ABO matching status were not significantly related to overall TRAE risk. Compared to a patient's first PLT transfusion, subsequent PLT transfusions were less likely to have a TRAE reported, primarily due to a lower risk of allergic or hypersensitivity reactions. CONCLUSION The most important PLT unit characteristic associated with TRAEs was PLT dose per transfusion. HD PLTs may increase the risk of TRAEs, and LD PLTs may reduce the risk.Copyright 2014 AABB.
Clinical Commentary
What is known?
Patients with severe thrombocytopenia (very low platelet count) due to a hypoproliferative bone marrow (markedly reduced platelet production) receive prophylactic (given to prevent bleeding) platelet transfusions. This usually occurs when the platelet count drops below a certain threshold (the current standard is a platelet count of 10 x 109/l). Platelet transfusions are known to be associated with risks. Mild to moderate reactions to platelet transfusions include rigors (severe shivering accompanied by a feeling of coldness), fever, and urticaria (hives). These reactions are not life-threatening but can be extremely distressing for the patient. Rarer, but more serious side effects include: transfusion-transmitted infections (bacterial and viral infections) and transfusion-related acute lung injury (TRALI).
What did this paper set out to examine?
This is a secondary analysis of the PLADO Study (Slichter et al, 2010). The authors set out to show whether the characteristics of the patient receiving the platelet transfusion (patient’s age, sex, type of treatment, number of previous platelet transfusions) or of the platelet component itself (whether the platelets were ABO matched with the patient, how the platelet component had been produced, number of platelets within the transfusion, number of days the platelets had been stored for) affected the frequency of transfusion-related adverse events (TRAEs) after platelet transfusions. In this study TRAEs were any event that occurred within 4 hours of the platelet transfusion irrespective of whether medical staff at the time thought the event was related to the transfusion. TRAEs consisted of at least one of the following: allergic or hypersensitivity reaction; slow or fast heart rate; high or low blood pressure; shortness of breath; low oxygen levels; wheezing; cough; rigors or chills, fever, infection, or haemolysis (breakdown of red blood cells). The severity of TRAEs were graded. Multivariable analyses were carried out that compared any TRAE versus none, any TRAE of Grade 2 or above versus none, and any TRAE of Grade 3 or above versus none. As well as analyses of specific TRAEs that occurred in at least 50 (1%) of transfusions in the analysis.
What did they show?
Fever (6.6%) and allergic reactions (1.9%) were the most common TRAEs. A multipredictor logistic regression model for any TRAE versus no TRAE, which adjusted for all other variables in the model and for within-person correlation. This study found that a high number of platelets within the component increased the risk of a TRAE (odds ratio for high platelet number vs. intermediate platelet number, 1.50; 95% confidence interval, 1.10-2.05). This effect was no longer seen when only grade 2 or above TRAEs were considered, however this may be due to the small number of episodes observed. Compared to a patient’s first platelet transfusion, participants who had more than five platelet transfusions were less likely to have a TRAE reported during subsequent transfusions. This was primarily due to a lower risk of allergic or hypersensitivity reactions.
What are the implications for practice and for future work?
The primary publication of the PLADO study showed that a large number of platelets within a transfusion does not decrease the risk of WHO grade 2 or above bleeding, and does not reduce the number of transfusion episodes compared to an intermediate number of platelets within a component. This study now shows that platelet components that contain a large number of platelets may put patients at a higher risk of developing a TRAE. This study provides an additional reason why platelet components that contain a high number of platelets should not be used routinely.
-
7.
Transfusion of fresh-frozen plasma in critically ill patients with a coagulopathy before invasive procedures: a randomized clinical trial (CME)
Muller MC, Arbous MS, Spoelstra-de Man AM, Vink R, Karakus A, Straat M, Binnekade JM, de Jonge E, Vroom MB, Juffermans NP
Transfusion. 2015;55((1):):26-35.
-
-
-
Abstract
BACKGROUND Prophylactic use of fresh-frozen plasma (FFP) is common practice in patients with a coagulopathy undergoing an invasive procedure. Evidence that FFP prevents bleeding is lacking, while risks of transfusion-related morbidity after FFP have been well demonstrated. We aimed to assess whether omitting prophylactic FFP transfusion in nonbleeding critically ill patients with a coagulopathy who undergo an intervention is noninferior to a prophylactic transfusion of FFP. STUDY DESIGN AND METHODS A multicenter randomized open-label trial with blinded endpoint evaluation was performed in critically ill patients with a prolonged international normalized ratio (INR; 1.5-3.0). Patients undergoing placement of a central venous catheter, percutaneous tracheostomy, chest tube, or abscess drainage were eligible. Patients with clinically overt bleeding, thrombocytopenia, or therapeutic use of anticoagulants were excluded. Patients were randomly assigned to omitting or administering a prophylactic transfusion of FFP (12mL/kg). Outcomes were occurrence of postprocedural bleeding complications, INR correction, and occurrence of lung injury. RESULTS Due to slow inclusion, the trial was stopped before the predefined target enrollment was reached. Eighty-one patients were randomly assigned, 40 to FFP and 41 to no FFP transfusion. Incidence of bleeding did not differ between groups, with a total of one major and 13 minor bleedings (p=0.08 for noninferiority). FFP transfusion resulted in a reduction of INR to less than 1.5 in 54% of transfused patients. No differences in lung injury scores were observed. CONCLUSION In critically ill patients undergoing an invasive procedure, no difference in bleeding complications was found regardless whether FFP was prophylactically administered or not.Copyright 2014 AABB.
Clinical Commentary
Dr Simon Stanworth, NHS Blood & Transplant, Oxford, UK
What is known?
Audits continue to document that a common reason for transfusion of plasma is to non-bleeding critically ill patients with laboratory measures of abnormal coagulopathy and prior to invasive procedures. Although the broader observational literature argues against benefit for this practice, evidence from randomized controlled trials is very limited.
What did this paper set out to examine?
This paper describes a multi-centred randomized open-label trial in adult critically ill patients to determine whether FFP transfusion could be safely omitted prior to invasive procedures. The patients admitted to critical care were prospectively screened between 2010 and 2013 for prolongation of the INR. Patients fulfilling the inclusion criteria were randomly assigned to receive or not to receive a single dose of 12mg of FFP prior to defined invasive procedures which included insertion of a central venous catheter, for thoracocentesis, percutaneous tracheostomy, drainage of abscess or fluid collection. The primary outcome of the study was procedure related bleeding occurring within 24 hours after the procedure. Bleeding was assessed using a tool previously validated and published in the critically ill population. For this tool, major bleeding was defined if bleeding accompanied by any of the following; a decrease in Hb by more that 2g/dL in the absence of another course of bleeding, transfusion of two or more units of red cells without an increase in Hb, a decrease in systolic blood pressure by more that 20mmHg, an increase in heart rate or wound related bleeding requiring specific intervention.
What did they show?
Due to slow patient accrual the trial was stopped before the predefined target enrolment was reached which was indicated to be a sample size in each arm of 198 patients. 81 patients were randomly assigned, 42 FFP and 41 to no FFP transfusion. The incidence of bleeding did not differ between the two study group arms. One major bleed was reported but although this event rate was consistent with the prediction of the researchers, the lower event rate was considered too small to complete a planned inferiority analysis. There were 13 minor bleeds recorded but there is some uncertainty about these numbers given that the clinical significance of these events is unclear. It was also noted that transfusion resulted in a reduction of INR to less than 1.5 in 54% of the transfused patients. No differences were reported in lung injuries scores between the arms.
What are the implications for practice and for future work?
The researchers are to be commended for attempting to address a clinical important research question: that of the role of plasma transfusion prior to invasive procedures in critically ill patients. Unfortunately the trial failed to recruit to target and the findings are not able to provide the level of evidence required to refute a clinical role for plasma in this setting. There is a need for research to address the best diagnostic tests as well as the optimal role of plasma or other pro-haemostatic coagulation factors. Arguably another lesson from this trial is the value of pilot trials ahead of a larger trial which might, for example, identify issues with recruitment.
-
8.
Blood transfusion after percutaneous coronary intervention and risk of subsequent adverse outcomes: a systematic review and meta-analysis
Kwok CS, Sherwood MW, Watson SM, Nasir SB, Sperrin M, NolanJ, Kinnaird T, Kiatchoosakun S, Ludman PF, de Belder MA, et al
JACC: Cardiovascular Interventions. 2015;8((3):):436-46.
-
-
-
Free full text
Abstract
OBJECTIVES This study sought to define the prevalence and prognostic impact of blood transfusions in contemporary percutaneous coronary intervention (PCI) practice. BACKGROUND Although the presence of anemia is associated with adverse outcomes in patients undergoing PCI, the optimal use of blood products in patients undergoing PCI remains controversial. METHODS A search of EMBASE and MEDLINE was conducted to identify PCI studies that evaluated blood transfusions and their association with major adverse cardiac events (MACE) and mortality. Two independent reviewers screened the studies for inclusion, and data were extracted from relevant studies. Random effects meta-analysis was used to estimate the risk of adverse outcomes with blood transfusions. Statistical heterogeneity was assessed by considering the I(2) statistic. RESULTS Nineteen studies that included 2,258,711 patients with more than 54,000 transfusion events were identified (prevalence of blood transfusion 2.3%). Crude mortality rate was 6,435 of 50,979 (12.6%, 8 studies) in patients who received a blood transfusion and 27,061 of 2,266,111 (1.2%, 8 studies) in the remaining patients. Crude MACE rates were 17.4% (8,439 of 48,518) in patients who had a blood transfusion and 3.1% (68,062 of 2,212,730) in the remaining cohort. Meta-analysis demonstrated that blood transfusion was independently associated with an increase in mortality (odds ratio: 3.02, 95% confidence interval: 2.16 to 4.21, I(2) = 91%) and MACE (odds ratio: 3.15, 95% confidence interval: 2.59 to 3.82, I(2) = 81%). Similar observations were recorded in studies that adjusted for baseline hematocrit, anemia, and bleeding. CONCLUSIONS Blood transfusion is independently associated with increased risk of mortality and MACE events. Clinicians should minimize the risk for periprocedural transfusion by using available bleeding-avoidance strategies and avoiding liberal transfusion practices.Copyright 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Clinical Commentary
What is known?
Allogenic red cell transfusion is associated with adverse clinical outcomes in many clinical settings.
What did this paper set out to examine?
The authors conducted a systematic review of the evidence that relates to the relationship between red cell transfusion and adverse clinical outcomes in patients undergoing percutaneous coronary interventions (PCI). The study is timely because the increasingly elderly population referred for PCI are at increased risk of anaemia and acute haemorrhage, the two key indications for red cell transfusion.
What did they show?
The authors conducted a robust and well described systematic review of relevant databases. They identified 19 observational analyses that included 2,258,711 patients met their eligibility criteria; reporting of transfusions, death and Major Adverse Cardiac Events (MACE). The included studies were of mixed quality and showed differences in their design, definitions of primary and secondary exposures, duration of follow up, and type of analyses. Pooled effect estimates demonstrated strong associations between transfusion, mortality and MACE, although these analyses also demonstrated significant heterogeneity. Sub group analyses that included only studies with longer follow-up, or that contained adjustment for confounders such as transfusion volume or anaemia showed consistent associations between transfusion and harm, with some reduction in heterogeneity.
What are the implications for practice and for future work?
Implications for future research: The authors conclude that their data cannot demonstrate a causal relationship between transfusion and adverse outcomes in these patients. However they do discuss the possible pathological effects of transfusion and conclude that their data should support more restrictive transfusion practice. Implications for future practice: This study generates the hypothesis that reduced exposure to red cells may have benefits in these high risk patients. This hypothesis should be tested in a randomised controlled clinical trial. It is premature to suggest that the evidence presented here makes a case for restrictive practice.
-
9.
Single dose intravenous tranexamic acid as effective as continuous infusion in primary total knee arthroplasty: a randomised clinical trial
Hourlier H, Reina N, Fennema P
Archives of Orthopaedic & Trauma Surgery. 2015;135((4):):465-71.
-
-
-
Full text
Abstract
INTRODUCTION A randomised, double-blind clinical trial was conducted comparing the efficacy of tranexamic acid (TXA) as a single intravenous bolus or a continuous infusion to patients undergoing total knee arthroplasty (TKA). Study hypothesis was that a second dose of TXA would not offer any clinical benefits over the single infusion. MATERIALS AND METHODS One hundred and six patients were randomised to a single intraoperative dose of 30 mg/kg tranexamic acid (OS group, n = 54), or to a loading dose of 10 mg/kg tranexamic acid followed 2 h later by a continuous 2 mg/kg/h infusion for 20 h (OD group, n = 52). The primary outcome was blood loss calculated from haematological values and perioperative transfusions. Secondary outcomes included the occurrence of major complications within the first postoperative year. RESULTS All patients completed tranexamic acid therapy without adverse events. The mean blood loss was 1,148 +/- 585 ml in group OS and 1,196 +/- 614 ml in group OD (p = 0.68). No patients received a transfusion. There were no occurrences of major complications up to 6-weeks follow-up. CONCLUSIONS The study demonstrated that a single bolus of tranexamic acid 30 mg/kg is as effective as a continuous infusion in patients undergoing tranexamic acid. The single application of tranexamic acid as part of routine care is recommended.
Clinical Commentary
Dr Antony Palmer, University of Oxford.
Tranexamic Acid for Reducing Blood Loss and Transfusion Rates in Total Knee Arthroplasty - commentary on 3 papers: 1) Hourlier H, Reina N, Fennema P. Single dose intravenous tranexamic acid as effective as continuous infusion in primary total knee arthroplasty: a randomised clinical trial. Archives of Orthopaedic & Trauma Surgery 2015, 135(4): 465-71; 2) Shemshaki H, Nourian SM, Nourian N, Dehghani M, Mokhtari M, Mazoochian F. One step closer to sparing total blood loss and transfusion rate in total knee arthroplasty: a meta-analysis of different methods of tranexamic acid administration. Archives of Orthopaedic & Trauma Surgery 2015, 135(4): 573-88; 3) Wu Q, Zhang HA, Liu SL, Meng T, Zhou X, Wang P. Is tranexamic acid clinically effective and safe to prevent blood loss in total knee arthroplasty? A meta-analysis of 34 randomized controlled trials. European Journal of Orthopaedic Surgery & Traumatologie 2015, 25(3): 525-41.
What is known?
Total Knee Arthroplasty (TKA) represents the mainstay of treatment for severe osteoarthritis with over 80,000 procedures performed in the UK last year. TKA gives rise to significant blood loss and tranexamic acid is proposed as a strategy for blood conservation. Tranexamic acid is a synthetic lysine analogue that competitively inhibits plasminogen activation and acts as an anti-fibrinolytic. It is increasingly used in elective surgery, supported by a number of studies that demonstrate a reduction in blood loss and transfusion rates. However, studies often reach conflicting conclusions as to the safety and efficacy of this agent. In addition, the optimal dosing strategy and route of delivery for TKA remains unknown.
What did this paper set out to examine?
These three publications include two meta-analyses of randomised controlled trials that compare tranexamic acid treatment to no treatment or placebo in patients undergoing unilateral TKA. Each meta-analysis includes data from over 30 trials. Outcomes include total blood loss, transfusion rate, and the incidence of vascular occlusive events. The authors also compare outcomes of intravenous and intraarticular tranexamic acid delivery. The third publication is a randomised controlled trial comparing the efficacy of a single intravenous bolus of tranexamic acid versus a continuous infusion in 106 patients undergoing unilateral TKA.
What did they show?
The meta-analyses conclude that tranexamic acid reduces total blood loss associated with TKA when given intravenously or intraarticularly. The effect is considered clinically relevant given there is also a reduction in blood transfusion rates (relative risk <0.5), although the authors did identity a high level of statistical heterogeneity between studies. There was no apparent increase in the risk of DVT (deep vein thrombosis) or PE (pulmonary embolism) in patients receiving tranexamic acid. When comparing intravenous and intraarticular delivery, there was no significant difference in outcomes. Results from the randomised controlled trial suggest that a single intraoperative bolus of tranexamic acid is as effective as a continuous infusion. There were no adverse events and no patient required a blood transfusion.
What are the implications for practice and for future work?
Tranexamic acid administration at the time of TKA appears safe and effective at reducing blood loss and the need for transfusion. An increasing body of evidence now supports its use in clinical practice, however, the optimal dose and route of administration remains unclear. Although outcomes do not appear to differ between intravenous and intraarticular delivery, intraarticular tranexamic acid may overcome systemic contraindications such as renal insufficiency. The finding that a single intravenous bolus is as effective as a continuous infusion warrants further investigation. Future research would benefit from a standardised protocol for tranexamic acid administration as a comparator for novel dosing regimes. Sources of heterogeneity that must be taken into consideration include surgical and anaesthetic technique, concurrent use of other pharmaceutical agents, transfusion thresholds, and the method of diagnosing adverse events. In addition, it is important that studies address patient reported outcome measures pertaining to joint function and quality of life.
-
10.
Is tranexamic acid clinically effective and safe to prevent blood loss in total knee arthroplasty? A meta-analysis of 34 randomized controlled trials
Wu Q, Zhang HA, Liu SL, Meng T, Zhou X, Wang P
European Journal of Orthopaedic Surgery & Traumatologie. 2015;25((3):):525-41.
-
-
-
Full text
Abstract
BACKGROUND Tranexamic acid (TXA) is well established as a versatile intraarticular and intravenous (IV) antifibrinolytic agent that has been successfully used to control bleeding after total knee arthroplasty (TKA). The present meta-analysis aimed at assessing the effectiveness and safety of TXA in reducing blood loss and transfusion in TKA. METHODS We searched the PubMed, Medline, Embase, Cochrane Central Register of Controlled Trials, and Google Scholar databases from 1966 to December 2013. Only randomized controlled trials (RCTs) were included in the present study. Two independent reviewers identified the eligible studies, assessed their methodological quality, and extracted data. The data were using fixed-effects or random-effects models with standard mean differences and risk ratios for continuous and dichotomous variables, respectively. Subgroup analysis was performed according to the IV or intraarticular administration of TXA. RESULTS Thirty-four RCTs encompassing 2,594 patients met the inclusion criteria for our meta-analysis. Our meta-analysis indicated that when compared with the control group, the IV or intraarticular use of TXA significantly reduced total blood loss, postoperative blood loss, Hb loss, and transfusion rate as well as blood units transfused per patient after primary TKA, but did not reduce intraoperative blood loss. No significant difference in deep vein thrombosis (DVT), pulmonary embolism, or other adverse events among the study groups. CONCLUSIONS IV or intraarticular use of TXA for patients undergoing TKA is effective and safe for the reduction blood loss and blood transfusion requirements, yet does not increase the risk of postoperative DVT. LEVEL OF EVIDENCE Level II.
Clinical Commentary
Dr Antony Palmer, University of Oxford.
Tranexamic Acid for Reducing Blood Loss and Transfusion Rates in Total Knee Arthroplasty - commentary on 3 papers: 1) Hourlier H, Reina N, Fennema P. Single dose intravenous tranexamic acid as effective as continuous infusion in primary total knee arthroplasty: a randomised clinical trial. Archives of Orthopaedic & Trauma Surgery 2015, 135(4): 465-71; 2) Shemshaki H, Nourian SM, Nourian N, Dehghani M, Mokhtari M, Mazoochian F. One step closer to sparing total blood loss and transfusion rate in total knee arthroplasty: a meta-analysis of different methods of tranexamic acid administration. Archives of Orthopaedic & Trauma Surgery 2015, 135(4): 573-88; 3) Wu Q, Zhang HA, Liu SL, Meng T, Zhou X, Wang P. Is tranexamic acid clinically effective and safe to prevent blood loss in total knee arthroplasty? A meta-analysis of 34 randomized controlled trials. European Journal of Orthopaedic Surgery & Traumatologie 2015, 25(3): 525-41.
What is known?
Total Knee Arthroplasty (TKA) represents the mainstay of treatment for severe osteoarthritis with over 80,000 procedures performed in the UK last year. TKA gives rise to significant blood loss and tranexamic acid is proposed as a strategy for blood conservation. Tranexamic acid is a synthetic lysine analogue that competitively inhibits plasminogen activation and acts as an anti-fibrinolytic. It is increasingly used in elective surgery, supported by a number of studies that demonstrate a reduction in blood loss and transfusion rates. However, studies often reach conflicting conclusions as to the safety and efficacy of this agent. In addition, the optimal dosing strategy and route of delivery for TKA remains unknown.
What did this paper set out to examine?
These three publications include two meta-analyses of randomised controlled trials that compare tranexamic acid treatment to no treatment or placebo in patients undergoing unilateral TKA. Each meta-analysis includes data from over 30 trials. Outcomes include total blood loss, transfusion rate, and the incidence of vascular occlusive events. The authors also compare outcomes of intravenous and intraarticular tranexamic acid delivery. The third publication is a randomised controlled trial comparing the efficacy of a single intravenous bolus of tranexamic acid versus a continuous infusion in 106 patients undergoing unilateral TKA.
What did they show?
The meta-analyses conclude that tranexamic acid reduces total blood loss associated with TKA when given intravenously or intraarticularly. The effect is considered clinically relevant given there is also a reduction in blood transfusion rates (relative risk <0.5), although the authors did identity a high level of statistical heterogeneity between studies. There was no apparent increase in the risk of DVT (deep vein thrombosis) or PE (pulmonary embolism) in patients receiving tranexamic acid. When comparing intravenous and intraarticular delivery, there was no significant difference in outcomes. Results from the randomised controlled trial suggest that a single intraoperative bolus of tranexamic acid is as effective as a continuous infusion. There were no adverse events and no patient required a blood transfusion.
What are the implications for practice and for future work?
Tranexamic acid administration at the time of TKA appears safe and effective at reducing blood loss and the need for transfusion. An increasing body of evidence now supports its use in clinical practice, however, the optimal dose and route of administration remains unclear. Although outcomes do not appear to differ between intravenous and intraarticular delivery, intraarticular tranexamic acid may overcome systemic contraindications such as renal insufficiency. The finding that a single intravenous bolus is as effective as a continuous infusion warrants further investigation. Future research would benefit from a standardised protocol for tranexamic acid administration as a comparator for novel dosing regimes. Sources of heterogeneity that must be taken into consideration include surgical and anaesthetic technique, concurrent use of other pharmaceutical agents, transfusion thresholds, and the method of diagnosing adverse events. In addition, it is important that studies address patient reported outcome measures pertaining to joint function and quality of life.