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Editor's Choice
  • Yassi N
  • Zhao H
  • Churilov L
  • Wu TY
  • Ma H
  • et al.
Lancet Neurol. 2024 Jun;23(6):577-587 doi: 10.1016/S1474-4422(24)00128-5.
POPULATION:

Patients with intracerebral haemorrhage treated within 2 hours of symptom onset, enrolled in the STOP-MSU trial conducted at 24 hospitals and one mobile stroke unit in Australia, Finland, New Zealand, Taiwan, and Viet Nam (n= 201).

INTERVENTION:

Tranexamic acid (n= 103).

COMPARISON:

Placebo (n= 98).

OUTCOME:

Haematoma growth occurred in 37 (38%) of 97 assessable participants in the placebo group and 43 (43%) of 101 assessable participants in the tranexamic acid group (adjusted odds ratio (aOR) 1.31; 95% CI [0.72, 2.40]). Major thromboembolic events occurred in one (1%) of 98 participants in the placebo group and three (3%) of 103 in the tranexamic acid group (risk difference 0.02 95% CI [-0.02, 0.06]). By 7 days, eight (8%) participants in the placebo group and eight (8%) in the tranexamic acid group had died (aOR 1.08 95% CI [0.35, 3.35]) and by 90 days, 15 (15%) participants in the placebo group and 19 (18%) in the tranexamic acid group had died (aOR 1.61; 95% CI [0.65, 3.98]).

BACKGROUND:

Tranexamic acid, an antifibrinolytic agent, might attenuate haematoma growth after an intracerebral haemorrhage. We aimed to determine whether treatment with intravenous tranexamic acid within 2 h of an intracerebral haemorrhage would reduce haematoma growth compared with placebo.

METHODS:

STOP-MSU was an investigator-led, double-blind, randomised, phase 2 trial conducted at 24 hospitals and one mobile stroke unit in Australia, Finland, New Zealand, Taiwan, and Viet Nam. Eligible participants had acute spontaneous intracerebral haemorrhage confirmed on non-contrast CT, were aged 18 years or older, and could be treated with the investigational product within 2 h of stroke onset. Using randomly permuted blocks (block size of 4) and a concealed pre-randomised assignment procedure, participants were randomly assigned (1:1) to receive intravenous tranexamic acid (1 g over 10 min followed by 1 g over 8 h) or placebo (saline; matched dosing regimen) commencing within 2 h of symptom onset. Participants, investigators, and treating teams were masked to group assignment. The primary outcome was haematoma growth, defined as either at least 33% relative growth or at least 6 mL absolute growth on CT at 24 h (target range 18-30 h) from the baseline CT. The analysis was conducted within the estimand framework with primary analyses adhering to the intention-to-treat principle. The primary endpoint and secondary safety endpoints (mortality at days 7 and 90 and major thromboembolic events at day 90) were assessed in all participants randomly assigned to treatment groups who did not withdraw consent to use any data. This study was registered with ClinicalTrials.gov, NCT03385928, and the trial is now complete.

FINDINGS:

Between March 19, 2018, and Feb 27, 2023, 202 participants were recruited, of whom one withdrew consent for any data use. The remaining 201 participants were randomly assigned to either placebo (n=98) or tranexamic acid (n=103; intention-to-treat population). Median age was 66 years (IQR 55-77), and 82 (41%) were female and 119 (59%) were male; no data on race or ethnicity were collected. CT scans at baseline or follow-up were missing or of inadequate quality in three participants (one in the placebo group and two in the tranexamic acid group), and were considered missing at random. Haematoma growth occurred in 37 (38%) of 97 assessable participants in the placebo group and 43 (43%) of 101 assessable participants in the tranexamic acid group (adjusted odds ratio [aOR] 1·31 [95% CI 0·72 to 2·40], p=0·37). Major thromboembolic events occurred in one (1%) of 98 participants in the placebo group and three (3%) of 103 in the tranexamic acid group (risk difference 0·02 [95% CI -0·02 to 0·06]). By 7 days, eight (8%) participants in the placebo group and eight (8%) in the tranexamic acid group had died (aOR 1·08 [95% CI 0·35 to 3·35]) and by 90 days, 15 (15%) participants in the placebo group and 19 (18%) in the tranexamic acid group had died (aOR 1·61 [95% CI 0·65 to 3·98]).

INTERPRETATION:

Intravenous tranexamic acid did not reduce haematoma growth when administered within 2 h of intracerebral haemorrhage symptom onset. There were no observed effects on other imaging endpoints, functional outcome, or safety. Based on our results, tranexamic acid should not be used routinely in primary intracerebral haemorrhage, although results of ongoing phase 3 trials will add further context to these findings.

FUNDING:

Australian Government Medical Research Future Fund.

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
  • Balasubramanian H
  • Bhanushali M
  • Tripathi V
  • Srinivasan L
  • Sakharkar S
  • et al.
J Pediatr. 2024 Jun;269:114002 doi: 10.1016/j.jpeds.2024.114002.
POPULATION:

Infants born extremely preterm (n= 102).

INTERVENTION:

Restricted blood sampling approach (n= 52).

COMPARISON:

Conventional blood sampling approach (n= 50).

OUTCOME:

The primary outcome was the rate of early red blood cell (RBC) transfusions in the first six postnatal weeks. Fidelity to the sampling protocol was achieved in 95% of the infants. Sampling losses in the first six weeks were significantly lower in the restricted sampling group (16.8 ml/kg versus 23.6 ml/kg). The restricted sampling group had a significantly lower rate of early postnatal RBC transfusion (41% versus 73%, RR 0.56; 95% CI [0.39, 0.81]). The hazard of needing a transfusion during neonatal intensive care unit stay was reduced by 55% by restricted sampling. Mortality and neonatal morbidities were similar between the two groups.

OBJECTIVE:

To evaluate the effect of blood sampling stewardship on transfusion requirements among infants born extremely preterm.

STUDY DESIGN:

In this single-center, randomized controlled trial (RCT), infants born at <28 weeks of gestation and birth weight of <1000 g were randomized at 24 hours of age to two different blood sampling approaches: restricted sampling (RS) vs conventional sampling (CS). The stewardship intervention in the RS group included targeted reduction in blood sampling volume and frequency and point of care testing methods in the first 6 weeks after birth. Both groups received early recombinant erythropoietin from day three of age. Primary outcome was the rate of early red blood cell (RBC) transfusions in the first six postnatal weeks.

RESULTS:

A total of 102 infants (mean gestational age: 26 weeks; birth weight: 756 g) were enrolled. Fidelity to the sampling protocol was achieved in 95% of the infants. Sampling losses in the first 6 weeks were significantly lower in the RS group (16.8 ml/kg vs 23.6 ml/kg, P < .001). The RS group had a significantly lower rate of early postnatal RBC transfusions (41% vs 73%, RR: 0.56 [0.39-0.81], P = .001). The hazard of needing a transfusion during neonatal intensive care unit (NICU) stay was reduced by 55% by RS. Mortality and neonatal morbidities were similar between the two groups.

CONCLUSION:

Minimization of blood sampling losses by approximately one-third in the first 6 weeks after birth leads to substantial reduction in the early red blood cell transfusion rate in infants born extremely preterm and weighing <1000 g at birth.

TRIAL REGISTRATION:

http://www.ctri.nic.in (CTRI/2020/01/022  964).

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
  • van Beers EJ
  • Al-Samkari H
  • Grace RF
  • Barcellini W
  • Glenthøj A
  • et al.
Blood Adv. 2024 May 28;8(10):2433-2441 doi: 10.1182/bloodadvances.2023011743.
POPULATION:

Adults with pyruvate kinase deficiency not regularly transfused, enrolled in the phase 3 ACTIVATE clinical trial and long term extension (LTE) (n= 80).

INTERVENTION:

Mitapivat throughout ACTIVATE/LTE baseline to week (W) 96 (mitapivat-to-mitapivat M/M arm, n= 40).

COMPARISON:

Switched from placebo (baseline to W24) to mitapivat W24 to 96 (placebo-to-mitapivat P/M arm, n= 40).

OUTCOME:

Changes from baseline in markers of iron overload and erythropoiesis were assessed to W96. Improvements in hepcidin (mean [95% confidence interval (CI)] 4770.0 ng/L [-1532.3, 11,072.3]), erythroferrone (-9834.9 ng/L [-14,328.4, -5341.3]), soluble transferrin receptor (-56.0 nmol/L [-84.8, -27.2]), and erythropoietin (-32.85 IU/L [-54.65, -11.06]) were observed in the M/M arm from baseline to W24, sustained to W96. No improvements were observed in the P/M arm to W24; however, upon transitioning to mitapivat, improvements similar to the M/M arm were seen. Mean (95% CI) changes from baseline in liver iron concentration by magnetic resonance imaging at W96 were -2.0 mg Fe/g dry weight (dw) (-4.8, -0.8; M/M arm) and -1.8 mg Fe/g dw (-4.4, 0.80; P/M arm).

Pyruvate kinase (PK) deficiency is a rare, hereditary disease characterized by chronic hemolytic anemia. Iron overload is a common complication regardless of age, genotype, or transfusion history. Mitapivat, an oral, allosteric PK activator, improves anemia and hemolysis in adult patients with PK deficiency. Mitapivat's impact on iron overload and ineffective erythropoiesis was evaluated in adults with PK deficiency who were not regularly transfused in the phase 3 ACTIVATE trial and long-term extension (LTE) (#NCT03548220/#NCT03853798). Patients in the LTE received mitapivat throughout ACTIVATE/LTE (baseline to week 96; mitapivat-to-mitapivat [M/M] arm) or switched from placebo (baseline to week 24) to mitapivat (week 24 to week 96; placebo-to-mitapivat [P/M] arm). Changes from baseline in markers of iron overload and erythropoiesis were assessed to week 96. Improvements in hepcidin (mean, 4770.0 ng/L; 95% confidence interval [CI], -1532.3 to 11 072.3), erythroferrone (mean, -9834.9 ng/L; 95% CI, -14 328.4 to -5341.3), soluble transferrin receptor (mean, -56.0 nmol/L; 95% CI, -84.8 to -27.2), and erythropoietin (mean, -32.85 IU/L; 95% CI, -54.65 to -11.06) were observed in the M/M arm (n = 40) from baseline to week 24, sustained to week 96. No improvements were observed in the P/M arm (n = 40) to week 24; however, upon transitioning to mitapivat, improvements similar to those observed in the M/M arm were seen. Mean changes from baseline in liver iron concentration by magnetic resonance imaging at week 96 in the M/M arm and the P/M arm were -2.0 mg Fe/g dry weight (dw; 95% CI, -4.8 to -0.8) and -1.8 mg Fe/g dw (95% CI, -4.4 to 0.80), respectively. Mitapivat is the first disease-modifying pharmacotherapy shown to have beneficial effects on iron overload and ineffective erythropoiesis in patients with PK deficiency. This trial was registered at www.ClinicalTrials.gov as #NCT03548220 (ACTIVATE) and #NCT03853798 (LTE).

Editor's Choice
  • Tabish M
  • Agarwal S
  • Gopi S
  • Rana R
  • Ahmed S
  • et al.
Am J Gastroenterol. 2024 May 14; doi: 10.14309/ajg.0000000000002775.
POPULATION:

Patients with cirrhosis and iron deficiency anaemia following variceal bleed (n= 92).

INTERVENTION:

Intravenous ferric-carboxymaltose (IV-FCM) (n= 48).

COMPARISON:

Oral carbonyl iron (n= 44).

OUTCOME:

The primary outcome was change in haemoglobin at 3 months. The median increase in haemoglobin at 3 months in the intravenous and oral arm were 3.65 gm/dl (IQR= 2.55, 5.25) and 1.10 gm/dl (IQR= 0.05, 2.90) respectively. Iron stores normalized in 84.6% and 21% of the intravenous and oral arms, respectively. Anaemia improved in 50% and 21.9% in the intravenous and oral arms, respectively. Patients in the intravenous arm showed a significant improvement in all domains of chronic liver disease quality of life. Liver related adverse events were comparable in both arms. Transient mild/moderate hypophosphataemia developed in 43% of patients receiving IV-FCM.

INTRODUCTION:

Limited evidence exists on the optimal strategy to correct iron deficiency anemia after variceal bleeding (VB) in cirrhosis. This trial compared the efficacy and safety of intravenous ferric carboxymaltose (IV-FCM) with those of oral iron therapy in this cohort.

METHODS:

In this open-label, single-center, randomized controlled trial, eligible patients with hemoglobin <10 g/dL and iron deficiency (ferritin <100 ng/mL) after VB received either IV-FCM (1,500-2,000 mg) divided into 2 doses (n = 48) or oral carbonyl iron (100 mg elemental iron/day) (n = 44) for 3 months. The primary outcome was change in hemoglobin at 3 months. Secondary outcomes included improvement in anemia (last hemoglobin >12 g/dL), normalization of iron stores (ferritin >100 ng/mL), liver-related adverse events, adverse drug reactions, and changes in quality of life (CLDQOL questionnaire).

RESULTS:

Baseline characteristics, including median Child-Turcotte-Pugh score 7 (interquartile range [IQR] 6-9), Model for End-Stage Liver Disease score 12 (IQR 10-17), blood hemoglobin (8.25 ± 1.06 g/dL), and ferritin (30.00 ng/mL [15.00-66.50]), were comparable in both arms. The median increase in hemoglobin at 3 months in the IV and oral arms was 3.65 g/dL (IQR 2.55-5.25) and 1.10 g/dL (IQR 0.05-2.90 g/dL) ( P < 0.001), respectively. Iron stores normalized in 84.6% and 21% of the IV and oral arms, respectively ( P < 0.001). Anemia improved in 50% and 21.9% in the IV and oral arms, respectively ( P < 0.009). Patients in the IV arm showed a significant improvement in all domains of CLDQOL. Liver-related adverse events were comparable in both arms. Transient mild/moderate hypophosphatemia developed in 43% of patients receiving IV-FCM.

DISCUSSION:

Intravenous iron replacement is efficacious and safe to treat iron deficiency anemia after VB in patients with cirrhosis.

Editor's Choice
  • Amin AM
  • Ali K
  • Elbenawi H
  • Saber A
  • Abuelazm M
  • et al.
Coron Artery Dis. 2024 May 1;35(3):239-251 doi: 10.1097/MCA.0000000000001349.
POPULATION:

Patients with acute myocardial infarction and anaemia (4 randomised controlled trials, n= 4,325).

INTERVENTION:

Restrictive blood transfusion strategy (n= 2,170).

COMPARISON:

Liberal blood transfusion strategy (n= 2,155).

OUTCOME:

There was no significant difference between both groups regarding major adverse cardiovascular events whether at 30 days (risk ratio (RR) 0.93; 95% CI [0.57, 1.51]) or ≥ six months (RR 1.17; 95% CI [0.95, 1.45]), all-cause mortality at 30 days (RR 1.16; 95% CI [0.95, 1.40]) or ≥ six months (RR 1.16; 95% CI [0.88, 1.53]). The liberal strategy was significantly associated with increased haemoglobin level change (mean difference: -1.44; 95% CI [-1.68, -1.20]). The restrictive strategy was significantly associated with a lower incidence of acute lung injury (RR 0.11; 95% CI [0.02, 0.60].

BACKGROUND:

Blood transfusion strategies in patients with acute myocardial infarction (AMI) and anemia are yet to be conclusively identified. Thus, we aim to assess the efficacy and safety of restrictive versus liberal blood transfusion strategies for AMI and anemia.

METHODS:

A systematic review and meta-analysis of randomized controlled trials (RCTs) retrieved from PubMed, web of science, SCOPUS, EMBASE, and Cochrane Central Register of Controlled Trials were performed through November 2023. We used RevMan V. 5.4 to pool dichotomous data using risk ratio (RR) and continuous data using mean difference (MD) with a 95% confidence interval (CI). (PROSPERO): ID: CRD42023490692.

RESULTS:

We included four RCTs with 4.325 patients. There was no significant difference between both groups regarding MACE whether at 30 days (RR: 0.93 with 95% CI [0.57-1.51], P  = 0.76) or ≥ six months (RR: 1.17 with 95% CI [0.95-1.45], P  = 0.14), all-cause mortality at 30 days (RR: 1.16 with 95% CI [0.95-1.40], P  = 0.14) or ≥ six months (RR: 1.16 with 95% CI [0.88-1.53], P  = 0.28). However, the liberal strategy was significantly associated with increased hemoglobin level change (MD: -1.44 with 95% CI [-1.68 to -1.20], P  < 0.00001). However, the restrictive strategy was significantly associated with a lower incidence of acute lung injury (RR: 0.11 with 95% CI [0.02-0.60], P  = 0.01).

CONCLUSION:

There was no significant difference between the restrictive blood transfusion strategy and the liberal blood transfusion strategy regarding the clinical outcomes. However, restrictive blood transfusion strategy was significantly associated with a lower incidence of acute lung injury than liberal blood transfusion strategy.

Editor's Choice
  • Fussner LA
  • Flores-Suárez LF
  • Cartin-Ceba R
  • Specks U
  • Cox PG
  • et al.
Am J Respir Crit Care Med. 2024 May 1;209(9):1141-1151 doi: 10.1164/rccm.202308-1426OC.
POPULATION:

Patients with severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis including glomerulonephritis and/or diffuse alveolar hemorrhage (DAH), enrolled in the PEXIVAS trial (n= 704).

INTERVENTION:

Plasma exchange (PLEX) and standard glucocorticoid (GC) (n= 176). PLEX and reduced GC (n= 176).

COMPARISON:

No PLEX and standard GC (n= 175). No PLEX and reduced GC (n= 177).

OUTCOME:

At enrollment, 191 (27.1%) participants had DAH and were younger, more frequently relapsing, proteinase 3-ANCA positive, and had lower serum creatinine but were more frequently dialyzed than participants without DAH (n= 513 (72.9%)). Among those with DAH, 8/95 (8.4%) receiving PLEX died within one year vs. 15/96 (15.6%) with no-PLEX (HR 0.52; CI [0.21, 1.24]), while 13/96 (13.5%) receiving reduced-GC died vs. 10/95 (10.5%) with standard-GC (HR 1.33; CI [0.57, 3.13]). When ventilated, ventilator-free days were similar with PLEX vs. no-PLEX (medians 25; IQR 22, 26 vs. 22, 27), fewer with reduced-GC (23 [20, 25]) vs. standard-GC (26 [25, 28]). Treatment effects on mortality did not vary by presence or severity of DAH. Overall, 23/191 (12.0%) with DAH died within one year vs. 34/513 (6.6%) without DAH. End-stage kidney disease and serious infections did not differ by DAH status or treatments.

Rationale: Diffuse alveolar hemorrhage (DAH) is a life-threatening manifestation of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The PEXIVAS (Plasma Exchange and Glucocorticoids in Severe Antineutrophil Cytoplasmic Antibody-Associated Vasculitis) (NCT00987389) trial was the largest in AAV and the first to enroll participants with DAH requiring mechanical ventilation. Objectives: Evaluate characteristics, treatment effects, and outcomes for patients with AAV with and without DAH. Methods: PEXIVAS randomized 704 participants to plasma exchange (PLEX) or no-PLEX and reduced or standard-dose glucocorticoids (GC). DAH status was defined at enrollment as no-DAH, nonsevere, or severe (room air oxygen saturation of ⩽ 85% as measured by pulse oximetry, or use of mechanical ventilation). Measurements and Main Results: At enrollment, 191 (27.1%) participants had DAH (61 severe, including 29 ventilated) and were younger, more frequently relapsing, PR3 (proteinase 3)-ANCA positive, and had lower serum creatinine but were more frequently dialyzed than participants without DAH (n = 513; 72.9%). Among those with DAH, 8/95 (8.4%) receiving PLEX died within 1 year versus 15/96 (15.6%) with no-PLEX (hazard ratio, 0.52; confidence interval [CI], 0.21-1.24), whereas 13/96 (13.5%) receiving reduced GC died versus 10/95 (10.5%) with standard GC (hazard ratio, 1.33; CI, 0.57-3.13). When ventilated, ventilator-free days were similar with PLEX versus no-PLEX (medians, 25; interquartile range [IQR], 22-26 vs. 22-27) and fewer with reduced GC (median, 23; IQR, 20-25) versus standard GC (median, 26; IQR, 25-28). Treatment effects on mortality did not vary by presence or severity of DAH. Overall, 23/191 (12.0%) with DAH died within 1 year versus 34/513 (6.6%) without DAH. End-stage kidney disease and serious infections did not differ by DAH status or treatments. Conclusions: Patients with AAV and DAH differ from those without DAH in multiple ways. Further data are required to confirm or refute a benefit of PLEX or GC dosing on mortality. Original clinical trial registered with www.clinicaltrials.gov (NCT00987389).

Editor's Choice
  • Saraf SL
  • Hagar RW
  • Idowu M
  • Osunkwo I
  • Cruz K
  • et al.
Blood Adv. 2024 Apr 19; doi: 10.1182/bloodadvances.2023012467.
POPULATION:

Patients with sickle cell disease (SCD) (n= 36).

INTERVENTION:

Single dose cohort: etavopivat 700mg (n= 5); placebo (n= 2). Multiple ascending doses (MAD) cohort: etavopivat 300mg (MAD1, n= 8); etavopivat 600mg (MAD2, n= 8); placebo (n= 4). Open label (OL) cohort: etavopitat 400mg (n= 15).

COMPARISON:

OUTCOME:

The single dose portion of the study was conducted to confirm the safety and pharmacokinetic/pharmacodynamic response to 700-mg. All patients in the single dose and MAD cohorts completed the study. Fourteen of 15 patients in the OL cohort (including 6 patients from the MAD cohorts who elected to roll over) completed the study; 1 withdrew due to an adverse event (AE). Increases in ATP and decreases in 2, 3 diphosphoglycerate were observed and sustained over 12 weeks' treatment. This translated clinically to an increase in haemoglobin (mean maximal increase 1.6 [range= 0.8, 2.8] g/dL), with >1 g/dL increase in 11 (73%) patients during treatment. Additionally, oxygen tension at which haemoglobin is 50% saturated was reduced with concomitant shift in point-of-sickling to lower oxygen tension in oxygen-gradient ektacytometry. Haemolysis markers decreased from baseline, along with matrix metalloproteinase-9 and erythropoietin. In the OL cohort, adverse events were mostly grade 1/2, consistent with underlying SCD; 5 patients had serious AEs. Vaso-occlusive pain episode was the most common treatment-emergent AE (n= 7) in the OL cohort.

Etavopivat is an investigational, once-daily, oral, selective erythrocyte pyruvate kinase (PKR) activator. A multicenter, randomized, placebo-controlled, double-blind, 3-part, phase 1 study (https://clinicaltrials.gov/study/NCT03815695) was conducted to characterize the safety and clinical activity of etavopivat. Thirty-six patients with sickle cell disease (SCD) were enrolled into 4 cohorts: one single-dose; two multiple ascending doses; one open-label [OL]. In the OL cohort, 15 patients (median age 33.0 [range, 17‒55] years received 400-mg etavopivat once daily for 12 weeks; 14 completed treatment. Consistent with the mechanism of PKR activation, increases in ATP and decreases in 2,3 diphosphoglycerate were observed and sustained over 12 weeks' treatment. This translated clinically to an increase in hemoglobin (mean maximal increase 1.6 [range, 0.8‒2.8] g/dL), with >1 g/dL increase in 11 (73%) patients during treatment. Additionally, oxygen tension at which hemoglobin is 50% saturated was reduced (P=.0007) with concomitant shift in point-of-sickling (P=.0034) to lower oxygen tension in oxygen-gradient ektacytometry. Hemolysis markers (absolute reticulocyte count, indirect bilirubin, lactate dehydrogenase) decreased from baseline, along with matrix metalloproteinase-9 and erythropoietin. In the OL cohort, adverse events (AEs) were mostly grade 1/2, consistent with underlying SCD; 5 patients had serious AEs. Vaso-occlusive pain episode was the most common treatment-emergent AE (n=7) in the OL cohort. In this first study of etavopivat in SCD, 400 mg once daily for 12 weeks was well-tolerated, resulting in rapid and sustained increases in hemoglobin, improved RBC physiology, and decreased hemolysis.

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.