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Editor's Choice
  • Brown AN
  • Yendluri A
  • Lawrence KW
  • Cordero JK
  • Moucha CS
  • et al.
J Am Acad Orthop Surg. 2024 Jun 1;32(11):508-515 doi: 10.5435/JAAOS-D-23-00503.
POPULATION:

Patients undergoing orthopaedic surgery (108 randomised controlled trials).

INTERVENTION:

Tranexamic acid (TXA).

COMPARISON:

Placebo/control; other antifibrinolytic/clotting agents; TXA with a different dose or route of administration.

OUTCOME:

A total of 192 outcomes were reported across the 108 included studies. The median fragility index (FI) of the 192 outcomes was 4 (IQR= 2, 5) with an associated fragility quotient (FQ) of 0.03 (IQR= 0.019, 0.050). 45 outcomes were reported as statistically significant with a median FI of 1 (IQR= 1, 5) and associated FQ of 0.02 (IQR= 0.011, 0.034). 147 outcomes were reported as nonsignificant with a median reverse fragility index of 4 (IQR= 3, 5) and associated FQ of 0.04 (IQR= 0.023, 0.051). The adult reconstruction, trauma, and spine subspecialties had a median FI of 4. Sports had a median FI of 3. Shoulder and elbow and foot and ankle had median FIs of 6.

INTRODUCTION:

Randomized controlled trials (RCTs) represent the highest level of evidence in orthopaedic surgery literature, although the robustness of statistical findings in these trials may be unreliable. We used the fragility index (FI), reverse fragility index (rFI), and fragility quotient (FQ) to evaluate the statistical stability of outcomes reported in RCTs that assess the use of tranexamic acid (TXA) across orthopaedic subspecialties.

METHODS:

PubMed, EMBASE, and MEDLINE were queried for RCTs (2010-present) reporting dichotomous outcomes with study groups stratified by TXA administration. The FI and rFI were defined as the number of outcome event reversals needed to alter the significance level of significant and nonsignificant outcomes, respectively. FQ was determined by dividing the FI or rFI by sample size. Subgroup analyses were conducted based on orthopaedic subspecialty.

RESULTS:

Six hundred five RCTs were screened with 108 studies included for analysis comprising 192 total outcomes. The median FI of the 192 outcomes was 4 (IQR 2 to 5) with an associated FQ of 0.03 (IQR 0.019 to 0.050). 45 outcomes were reported as statistically significant with a median FI of 1 (IQR 1 to 5) and associated FQ of 0.02 (IQR 0.011 to 0.034). 147 outcomes were reported as nonsignificant with a median rFI of 4 (IQR 3 to 5) and associated FQ of 0.04 (IQR 0.023 to 0.051). The adult reconstruction, trauma, and spine subspecialties had a median FI of 4. Sports had a median FI of 3. Shoulder and elbow and foot and ankle had median FIs of 6.

DISCUSSION:

Statistical outcomes reported in RCTs on the use of TXA in orthopaedic surgery are fragile. Reversal of a few outcomes is sufficient to alter statistical significance. We recommend reporting FI, rFI, and FQ metrics to aid in interpreting the outcomes reported in comparative trials.

Editor's Choice
  • Liu CW
  • Anih J
  • Lebedeva V
  • Gungor A
  • Wang C
  • et al.
J Clin Anesth. 2024 Jun;94:111417 doi: 10.1016/j.jclinane.2024.111417.
POPULATION:

Patients undergoing non-obstetric surgery (300 trials, n= 53,085).

INTERVENTION:

Intravenous tranexamic acid.

COMPARISON:

Placebo or usual care without tranexamic acid.

OUTCOME:

From all the included studies, 45,958 participants (86.6%) were enrolled in 228 trials (76.0%) that explicitly excluded patients with kidney disease. Definitions of kidney diseased used for exclusion varied widely. Most were non-specific and some corresponded to mild disease. Only 5 trials adjusted dosing for kidney function. Meta-analysis of two large trials found tranexamic acid unlikely to substantially increase or decrease the occurrence of thrombotic events in patients with estimated glomerular filtration rate <60 mL/min/1.73m(2) (RR 0.95; 95% CI [0.83, 1.07]) or ≥ 60 mL/min/1.73m(2) (RR 1.00; 95% CI [0.91, 1.11], but both trials excluded patients with severe kidney disease. No analysis could be performed regarding seizure risk. One large trial in non-cardiac surgery reported similar reduction in bleeding across subgroups of kidney function but excluded patients with creatinine clearance <30 mL/min.

STUDY OBJECTIVE:

To assess how kidney disease is handled in randomized trials evaluating the safety and efficacy of perioperative tranexamic acid, and to evaluate its effects across levels of kidney function.

DESIGN:

Systematic review and meta-analysis of randomized controlled trials.

SETTING:

We screened studies from a previous comprehensive systematic review, and updated its search of PubMed, Embase, and Cochrane CENTRAL to July 31, 2023.

PATIENTS:

Patients undergoing non-obstetric surgery.

INTERVENTIONS:

Intravenous tranexamic acid compared to placebo or usual care without tranexamic acid.

MEASUREMENT:

We summarized the handling of kidney disease in eligibility criteria, dose adjustments for kidney function, and effects of tranexamic acid on thrombotic events, seizures, and bleeding by subgroups of kidney function.

MAIN RESULTS:

We evaluated 300 trials with 53,085 participants; 45,958 participants (86.6%) were enrolled in 228 trials (76.0%) that explicitly excluded patients with kidney disease. Definitions of kidney diseased used for exclusion varied widely. Most were non-specific and some corresponded to mild disease. Only 5 trials adjusted dosing for kidney function. Meta-analysis of two large trials found tranexamic acid unlikely to substantially increase or decrease the occurrence of thrombotic events in patients with eGFR <60 mL/min/1.73m2 (RR, 0.95; 95% CI: 0.83 to 1.07) or ≥ 60 mL/min/1.73m2 (RR, 1.00; 95% CI, 0.91 to 1.11; P for subgroup difference = 0.47), but both trials excluded patients with severe kidney disease. No analysis could be performed regarding seizure risk. One large trial in noncardiac surgery reported similar reduction in bleeding across subgroups of kidney function but excluded patients with creatinine clearance <30 mL/min.

CONCLUSIONS:

The large evidence base supporting perioperative tranexamic acid suffers from broad and unjustified exclusion of patients with kidney disease. Typical perioperative dosing of tranexamic acid is likely safe and effective in patients with creatinine clearance >30 mL/min, but effects in more severe kidney disease are unknown.

Editor's Choice
  • Elmenawi KA
  • Mohamed FAE
  • Poilvache H
  • Prokop LJ
  • Abdel MP
  • et al.
J Arthroplasty. 2024 Apr 16; doi: 10.1016/j.arth.2024.04.033.
POPULATION:

Patients undergoing total hip and knee arthroplasty (6 studies n= >2million).

INTERVENTION:

Tranexamic acid (TXA).

COMPARISON:

No TXA.

OUTCOME:

Among 2,098,469 arthroplasties, TXA utilization was associated with an overall lower risk of periprosthetic joint infection (PJI) (OR 0.63; 95% CI [0.42, 0.96]) and a 0.4% lower incidence of PJI (RD -0.0038; 95% CI [-0.005, -0.002]). When sub-grouping the studies according to length of follow-up, TXA was associated with a lower risk of PJI (OR 0.43; 95% CI [0.35, 0.53]) and a 1% lower incidence of PJI (RD -0.0095; 95% CI [-0.013, -0.005]) in patients followed for more than 90 days.

BACKGROUND:

The purpose of this study was to perform a systematic review and meta-analysis to evaluate the association between tranexamic acid (TXA) use during primary total hip arthroplasty (THA) and primary total knee arthroplasty (TKA), and the risk of developing periprosthetic joint infection (PJI) after these procedures.

METHODS:

A systematic review was carried out from inception to October 17, 2022. There were 6 studies that were ultimately included in the meta-analysis. The association between the development of PJI and TXA was analyzed using odds ratios (ORs) with 95% confidence intervals (CIs) and estimates of risk difference (RD). Subgroup analysis was performed to evaluate only studies reporting out to 90 days of follow-up versus more than 90 days of follow-up.

RESULTS:

Among 2,098,469 arthroplasties, TXA utilization was associated with an overall lower risk of PJI (OR = 0.63 [95% CI 0.42 to 0.96], P < .001) and a 0.4% lower incidence of PJI (RD = -0.0038, 95% CI [-0.005 to -0.002], P < .001). When subgrouping the studies according to length of follow-up, TXA was associated with a lower risk of PJI (OR = 0.43 [95% CI 0.35 to 0.53], P < .001) and a 1% lower incidence of PJI (RD = -0.0095 [95% CI -0.013 to -0.005], P < .001) in patients followed for more than 90 days.

CONCLUSIONS:

This meta-analysis demonstrates that TXA use is associated with a reduced risk of PJI, with our RD analysis identifying an approximately 0.4% reduction in PJI rates with TXA use. These findings provide even more data to support the routine use of TXA during primary THA and primary TKA.

Editor's Choice
  • Zhang Y
  • Li J
  • Li X
  • Geng Q
  • Xie Y
  • et al.
Syst Rev. 2024 Apr 4;13(1):101 doi: 10.1186/s13643-024-02515-2.
POPULATION:

Patients with severe aplastic anaemia (16 studies, n= 2,148).

INTERVENTION:

Immunosuppressive therapy (IST) combined with eltrombopag (EPAG).

COMPARISON:

Immunosuppressive therapy.

OUTCOME:

The IST combined with the EPAG group had higher overall response rate (ORR) than the IST group at 3 months (pooled OR 2.10; 95% CI [1.58, 2.79]) and 6 months (pooled OR 2.13; 95% CI [1.60, 2.83]), but the difference between the two groups became statistically insignificant at 12 months (pooled OR 1.13; 95% CI [0.75, 1.72]). The results of complete response rate (pooled OR at 3 months 2.73; 95% CI [1.83, 4.09], 6 months 2.76; 95% CI [2.08, 3.67] and 12 months 1.38; 95% CI [0.85, 2.23]) were similar to ORR. Compared with the IST group, the IST combined with the EPAG group had better overall survival rate (pooled OR 1.70; 95% CI [1.15, 2.51]), but there were no statistically significant differences in event-free survival rate (pooled OR 1.40; 95% CI [0.93, 2.13]), clonal evolution rate (pooled OR 0.68; 95% CI [0.46, 1.00]) and other adverse events between the two groups.

BACKGROUND AND OBJECTIVE:

Immunosuppressive therapy (IST) is the first choice for severe aplastic anemia (SAA) patients with hematopoietic stem cell transplantation (HSCT) limitation, and the main factor limiting its efficacy is too few residual hematopoietic stem/progenitor cells (HSPC). Eltrombopag (EPAG), as a small molecule thrombopoietin receptor agonist, can stimulate the proliferation of residual HSPC and restore the bone marrow hematopoietic function of patients. In recent years, many studies have observed the efficacy and safety of IST combined with EPAG in the treatment of SAA, but the results are still controversial. The aim of this study is to systematically evaluate the efficacy and safety of IST combined with or without EPGA in the treatment of SAA.

METHODS:

We conducted a systematic review of all relevant literature published up to January 19, 2024. Pooled odds ratio (OR) was calculated to compare the rates, along with 95% confidence intervals (CI) and p value to assess whether the results were statistically significant by Review Manager 5.4.1. The p values for the interactions between each subgroup were calculated by Stata 15.1. The Newcastle-Ottawa Scale and the Cochrane bias risk assessment tools were respectively used to evaluate the quality of the literature with cohort studies and randomized controlled trials. The Review Manager 5.4.1 and Stata 15.1 were used to assess bias risk and perform the meta-analysis.

RESULTS:

A total of 16 studies involving 2148 patients were included. The IST combined with the EPAG group had higher overall response rate (ORR) than the IST group at 3 months (pooled OR = 2.10, 95% CI 1.58-2.79, p < 0.00001) and 6 months (pooled OR = 2.13, 95% CI 1.60-2.83, p < 0.00001), but the difference between the two groups became statistically insignificant at 12 months (pooled OR = 1.13, 95% CI 0.75-1.72, p = 0.55). The results of complete response rate (CRR) (pooled OR at 3 months = 2.73, 95% CI 1.83-4.09, p < 0.00001, 6 months = 2.76, 95% CI 2.08-3.67, p < 0.00001 and 12 months = 1.38, 95% CI 0.85-2.23, p = 0.19) were similar to ORR. Compared with the IST group, the IST combined with the EPAG group had better overall survival rate (OSR) (pooled OR = 1.70, 95% CI 1.15-2.51, p = 0.008), but there were no statistically significant differences in event-free survival rate (EFSR) (pooled OR = 1.40, 95% CI 0.93-2.13, p = 0.11), clonal evolution rate (pooled OR = 0.68, 95% CI 0.46-1.00, p = 0.05) and other adverse events between the two groups. The results of subgroup analysis showed that different ages were a source of heterogeneity, but different study types and different follow-up times were not. Moreover, all p-values for the interactions were greater than 0.05, suggesting that the treatment effect was not influenced by subgroup characteristics.

CONCLUSION:

EPAG added to IST enables patients to achieve earlier and faster hematologic responses with a higher rate of complete response. Although it had no effect on overall EFSR, it improved OSR and did not increase the incidence of clonal evolution and other adverse events.

Editor's Choice
  • Provinciatto H
  • Barbalho ME
  • da Câmara PM
  • Donadon IB
  • Fonseca LM
  • et al.
Can J Anaesth. 2024 Apr;71(4):465-478 doi: 10.1007/s12630-024-02715-3.
POPULATION:

Patients undergoing caesarean delivery (38 randomised controlled trials, n= 22,940).

INTERVENTION:

Postpartum haemorrhage (PPH) prophylaxis with tranexamic acid (TXA).

COMPARISON:

Placebo or no treatment.

OUTCOME:

The main outcomes were PPH, blood transfusion, need for additional uterotonics, and adverse events. Patients treated with TXA had significantly fewer cases of PPH (risk ratio (RR) 0.51; 95% confidence interval (CI) [0.38, 0.69]); less blood transfusion (RR 0.43; 95% CI [0.30, 0.61]), and less use of additional uterotonics (RR 0.52; 95% CI [0.40, 0.68]). No significant differences were found between the groups in terms of adverse effects and thromboembolic events.

PURPOSE:

Postpartum hemorrhage (PPH) is a leading cause of maternal mortality worldwide. Although several studies on the prophylactic use of tranexamic acid (TXA) in parturients undergoing Cesarean delivery have been published, conflicting results raise questions regarding its use. Thus, we aimed to investigate the safety and efficacy of PPH prophylaxis with TXA.

SOURCE:

We searched PubMed®, Embase, Cochrane Central, and ClinicalTrials.gov for randomized controlled trials (RCTs) comparing prophylactic TXA with placebo or no treatment in parturients undergoing Cesarean delivery. Our main outcomes were PPH, any blood transfusion, need for additional uterotonics, and adverse events. We performed a trial sequential analysis (TSA) of all outcomes to investigate the reliability and conclusiveness of findings.

PRINCIPAL FINDINGS:

We included 38 RCTs including 22,940 parturients, 11,535 (50%) of whom were randomized to receive prophylactic TXA. Patients treated with TXA had significantly fewer cases of PPH (risk ratio [RR], 0.51; 95% confidence interval [CI], 0.38 to 0.69; P < 0.001); less blood transfusion (RR, 0.43; 95% CI, 0.30 to 0.61; P < 0.001), and less use of additional uterotonics (RR, 0.52; 95% CI, 0.40 to 0.68; P < 0.001). No significant differences were found between the groups in terms of adverse effects and thromboembolic events.

CONCLUSION:

Prophylactic TXA administration for parturients undergoing Cesarean delivery significantly reduced blood loss, without increasing adverse events, supporting its use as a safe and effective strategy for reducing PPH in this population.

STUDY REGISTRATION:

PROSPERO (CRD42023422188); first submitted 27 April 2023.

Editor's Choice
  • Zhang M
  • Liu T
Am J Emerg Med. 2024 Mar 13;80:35-43 doi: 10.1016/j.ajem.2024.03.005.
POPULATION:

Adults with traumatic brain injury (11 randomised controlled trials, n= 11,299).

INTERVENTION:

Tranexamic acid (TXA) (n= 5,876).

COMPARISON:

Placebo (n= 5,423).

OUTCOME:

The primary outcome was mortality, poor clinical outcomes, haemorrhagic expansion and mean haemorrhage volume. TXA had no effect on mortality (risk ratio (RR) 0.93 [95% confidence interval 0.86, 1.00]), poor clinical outcomes (RR 0.92 [0.78, 1.09]), adverse events (RR 0.94 [0.83, 1.07]), vascular occlusive events (RR 0.85 [0.68, 1.06]), pulmonary embolism (RR 0.76 [0.47, 1.22]), seizure (RR 1.11 [0.92, 1.35]) and haemorrhagic complications (RR 0.78 [0.55, 1.09]). TXA might reduce the rate of haemorrhagic expansion (RR 0.83 [0.70, 0.99]) and mean haemorrhage volume (standardized mean difference (SMD) -0.39 [-0.60, -0.18]). When the time interval from symptom onset to treatment was <3 h, TXA reduced mean haemorrhage volume (SMD -0.51 [-0.81, -0.20]).

INTRODUCTION:

Tranexamic acid (TXA) holds a pivotal role in the therapeutic approach to traumatic conditions. Nevertheless, its precise influence on diminishing mortality and limiting the progression of intracranial hemorrhage (ICH) during the treatment of traumatic brain injury (TBI) remains indeterminate.

METHODS:

PubMed, EMBASE, Cochrane Library, and Web of Science were searched for randomized controlled trials that compared TXA and a placebo in adults with TBI up to September 31, 2023. Two authors independently abstracted the data and assessed the quality of evidence. Additionally, subgroup analyses were performed to assess outcomes with low heterogenety.

RESULTS:

Our search strategy yielded 11,299 patients from 11 studies. The result showed that TXA had no effect on mortality (RR 0.93 [0.86, 1.00], p = 0.06; I2: 0%, p = 0.79), poor clinical outcomes (RR 0.92 [0.78, 1.09], p = 0.34; I2: 0%, p = 0.40), adverse events (RR 0.94 [0.83, 1.07], p = 0.34; I2: 48%, p = 0.10), vascular occlusive events (RR 0.85 [0.68, 1.06], p = 0.16; I2: 32%, p = 0.22), pulmonary embolism (RR 0.76 [0.47, 1.22], p = 0.26; I2: 0%, p = 0.83), seizure (RR 1.11 [0.92, 1.35], p = 0.27; I2: 0%, p = 0.49) and hemorrhagic complications (RR 0.78 [0.55, 1.09], p = 0.14; I2: 0%, p = 0.42). TXA might reduce the rate of hemorrhagic expansion (RR 0.83 [0.70, 0.99], p = 0.03; I2: 18%, p = 0.29) and mean hemorrhage volume (SMD -0.39 [-0.60, -0.18], p <0.001; I2: 44%, p = 0.13).When the time interval from symptom onset to treatment was <3 h, TXA reduced mean hemorrhage volume (SMD -0.51 [-0.81, -0.20], p = 0.001; I2: 0%, p = 0.94).

CONCLUSIONS:

TXA did not elevate the risk of adverse event, however, the lack of reduction in mortality and the poor clinical outcomes constrain the value of clinical application. Early administration of TXA (within 3 h) may significantly decrease the likelihood of ICH growth in patients with TBI.

Editor's Choice
  • Wang M
  • Che JX
  • Chen L
  • Song TT
  • Qu JT
Chin Med Sci J. 2024 Mar;39(1):54-68 doi: 10.24920/004294.
POPULATION:

Patients undergoing spine surgery (21 randomised controlled trials, n= 1,388).

INTERVENTION:

Dexmedetomidine (Dex).

COMPARISON:

Saline.

OUTCOME:

This meta-analysis revealed a negative effect of Dex on haemodynamics. Dex increased the risk of hypotension and bradycardia during spine surgery, while it did not reduce intraoperative blood loss. The risk of hypotension and bradycardia was higher with the use of a loading dose in combination with a maintenance dose than using a maintenance dose alone. Dex was more likely to cause severe hypotension rather than mild hypotension. In terms of heart rate reduction, the incidence of both mild and severe bradycardia increased.

Objective Dexmedetomidine (Dex) is a highly selective α2 adrenoceptor agonist that reduces blood pressure and heart rate. However, its ability to provide stable hemodynamics and a clinically significant reduction in blood loss in spine surgery is still a matter of debate. This study aimed to investigate the effects of Dex on intraoperative hemodynamics and blood loss in patients undergoing spine surgery.Methods The Web of Science, MEDLINE, EMBASE, and the Cochrane Library were searched up to February 2023 for randomized controlled trials (RCTs) including patients undergoing spine surgeries under general anaesthesia and comparing Dex and saline. A fixed- or random-effect model was used depending on heterogeneity.Results Twenty-one RCTs, including 1388 patients, were identified. Dex added the overall risk of intraoperative hypotension (odds ratio [OR]: 2.11; 95% confidence interval [CI]: 1.24 - 3.58; P=0.006) and bradycardia (OR: 2.48; 95%CI: 1.57 - 3.93; P=0.0001). The use of a loading dose of Dex led to significantly increased risks of intraoperative hypotension (OR: 2.00; 95%CI: 1.06 - 3.79; P=0.03) and bradycardia (OR: 2.28; 95%CI: 1.42 - 3.66; P=0.0007). For patients receiving total intravenous anesthesia, there was an increased risk of hypotension (OR: 2.90; 95%CI: 1.24 - 6.82; P=0.01) and bradycardia (OR: 2.66; 95%CI: 1.53 - 4.61; P=0. 0005). For patients in the inhalation anesthesia group, only an increased risk of bradycardia (OR: 4.95; 95%CI: 1.41 - 17.37; P=0.01) was observed. No significant increase in the risk of hypotension and bradycardia was found in the combined intravenous-inhalation anesthesia group. The incidence of severe hypotension (OR: 2.57; 95%CI: 1.05 - 6.32; P=0.04), but not mild hypotension, was increased. Both mild (OR: 2.55; 95%CI: 1.06 - 6.15; P=0.04) and severe (OR: 2.45; 95%CI: 1.43 - 4.20; P=0.001) bradycardia were associated with a higher risk. The overall analyses did not reveal significant reduction in intraoperative blood loss. However, a significant decrease in blood loss was observed in total inhalation anesthesia subgroup (mean difference [MD]: -82.97; 95%CI: -109.04 - -56.90; P<0.001).Conclusions Dex increases the risks of intraoperative hypotension and bradycardia in major spine surgery. The administration of a loading dose of Dex and the utilization of various anesthesia maintenance methods may potentially impact hemodynamic stability and intraoperative blood loss.