Transfusion Evidence Alert and Round-Up

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The Transfusion Evidence Alert is a monthly overview of the top ten evidence-based publications in the field of transfusion medicine. The articles are selected for quality and relevance by clinical experts, supported by members of the Systematic Review Initiative.

The Transfusion Evidence Round-Up is a quarterly overview of the top 10 high quality studies about an internationally relevant subject in the field of transfusion medicine. The articles are selected by members from the International Society of Blood Transfusion and drawn from the Transfusion Evidence Library and, where relevant, Stem Cell Evidence.

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March 2024

New high-quality evidence publications
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
  • Koepsell SA
  • Stolla M
  • Sedjo RL
  • Carson J
  • Knudson M
  • et al.
Transfusion. 2024 Mar;64(3):457-465 doi: 10.1111/trf.17720.
POPULATION:

Participants with hypoproliferative thrombocytopenia requiring platelet transfusions, enrolled in the MiPLATE trial (n= 297).

INTERVENTION:

Mirasol-treated plasma-stored apheresis platelets (Mirasol group, n= 145).

COMPARISON:

Conventional plasma-stored apheresis platelets (Control group, n= 152).

OUTCOME:

The novel primary endpoint was days of ≥Grade 2 bleeding with a non-inferiority margin of 1.6. Participants in the Mirasol group had more days of grade ≥2 bleeding than participants in the Control group (RR 2.74; 95% CI [1.66, 4.53]), the primary endpoint. The secondary endpoints showed a similar proportion of participants in each group with days of grade ≥2 bleeding and no difference in red blood cell transfusion despite a higher rate of participants with platelets refractoriness, platelet transfusions, and lower corrected count increments in the Mirasol group.

BACKGROUND:

The Mirasol® Pathogen Reduction Technology System was developed to reduce transfusion-transmitted diseases in platelet (PLT) products.

STUDY DESIGN AND METHODS:

MiPLATE trial was a prospective, multicenter, controlled, randomized, non-inferiority (NI) study of the clinical effectiveness of conventional versus Mirasol-treated Apheresis PLTs in participants with hypoproliferative thrombocytopenia. The novel primary endpoint was days of ≥Grade 2 bleeding with an NI margin of 1.6.

RESULTS:

After 330 participants were randomized, a planned interim analysis of 297 participants (145 MIRASOL, 152 CONTROL) receiving ≥1 study transfusion found a 2.79-relative rate (RR) in the MIRASOL compared to the CONTROL in number of days with ≥Grade 2 bleeding (95% confidence interval [CI] 1.67-4.67). The proportion of subjects with ≥Grade 2 bleeding was 40.0% (n = 58) in MIRASOL and 30.3% (n = 46) in CONTROL (RR = 1.32, 95% CI 0.97-1.81, p = .08). Corrected count increments were lower (p < .01) and the number of PLT transfusion episodes per participant was higher (RR = 1.22, 95% CI 1.05-1.41) in MIRASOL. There was no difference in the days of PLT support (hazard ratio = 0.86, 95% CI 0.68-1.08) or total number of red blood cell transfusions (RR = 1.12, 95% CI 0.91-1.37) between MIRASOL versus CONTROL. Transfusion emergent adverse events were reported in 119 MIRASOL participants (84.4%) compared to 133 (82.6%) participants in CONTROL (p = NS).

DISCUSSION:

This study did not support that MIRASOL was non-inferior compared to conventional platelets using the novel endpoint number of days with ≥Grade 2 bleeding in MIRASOL when compared to CONTROL.

Editor's Choice
  • Donohue JK
  • Iyanna N
  • Lorence JM
  • Brown JB
  • Guyette FX
  • et al.
Trauma Surg Acute Care Open. 2024 Feb 17;9(1):e001346 doi: 10.1136/tsaco-2023-001346.
POPULATION:

Patients at risk for haemorrhage receiving tranexamic acid before hospitalization, enrolled in the Study of Tranexamic Acid During Air Medical and Ground Prehospital Transport (STAAMP) Trial (n= 903).

INTERVENTION:

Prehospital tranexamic acid (TXA) (n= 447).

COMPARISON:

Placebo (n= 456).

OUTCOME:

This study was a secondary analysis of the STAAMP trial, comparing patients that received thromboelastography (TEG) (YES-TEG, n= 837) and patients unable to be sampled (NO-TEG, n= 66) to analyze subgroups in which to investigate TEG differences. NO-TEG patients had lower prehospital systolic blood pressure (SBP) (100 (78, 140) vs. 125 (88, 147)), lower prehospital Glascow Coma Score (14 (3, 15) vs. 15 (12, 15)), greater rates of prehospital intubation (39.4% vs. 24.4%) and greater mortality at 30 days (36.4% vs. 6.8%). NO-TEG patients had a greater international normalized ratio relative to the YES-TEG subgroup (1.2 (1.1, 1.5) vs. 1.1 (1.0, 1.2)). Within a severe prehospital shock cohort (SBP< 70), TXA was associated with a significant decrease in clot lysis at 30 min on multivariate analysis (β= -27.6; 95% CI [-51.3, -3.9].

BACKGROUND:

Tranexamic acid (TXA) has been hypothesized to mitigate coagulopathy in patients after traumatic injury. Despite previous prehospital clinical trials demonstrating a TXA survival benefit, none have demonstrated correlated changes in thromboelastography (TEG) parameters. We sought to analyze if missing TEG data contributed to this paucity of findings.

METHODS:

We performed a secondary analysis of the Study of Tranexamic Acid During Air Medical and Ground Prehospital Transport Trial. We compared patients that received TEG (YES-TEG) and patients unable to be sampled (NO-TEG) to analyze subgroups in which to investigate TEG differences. TEG parameter differences across TXA intervention arms were assessed within subgroups disproportionately present in the NO-TEG relative to the YES-TEG cohort. Generalized linear models controlling for potential confounders were applied to findings with p<0.10 on univariate analysis.

RESULTS:

NO-TEG patients had lower prehospital systolic blood pressure (SBP) (100 (78, 140) vs 125 (88, 147), p<0.01), lower prehospital Glascow Coma Score (14 (3, 15) vs 15 (12, 15), p<0.01), greater rates of prehospital intubation (39.4% vs 24.4%, p<0.01) and greater mortality at 30 days (36.4% vs 6.8%, p<0.01). NO-TEG patients had a greater international normalized ratio relative to the YES-TEG subgroup (1.2 (1.1, 1.5) vs 1.1 (1.0, 1.2), p=0.04). Within a severe prehospital shock cohort (SBP<70), TXA was associated with a significant decrease in clot lysis at 30 min on multivariate analysis (β=-27.6, 95% CI (-51.3 to -3.9), p=0.02).

CONCLUSIONS:

Missing data, due to the logistical challenges of sampling certain severely injured patients, may be associated with a lack of TEG parameter changes on TXA administration in the primary analysis. Previous demonstration of TXA's survival benefit in patients with severe prehospital shock in tandem with the current findings supports the notion that TXA acts at least partially by improving clot integrity.

LEVEL OF EVIDENCE:

Level II.

Editor's Choice
  • Bus SR
  • de Haan RJ
  • Vermeulen M
  • van Schaik IN
  • Eftimov F
  • et al.
Cochrane Database Syst Rev. 2024 Feb 14;2(2):CD001797 doi: 10.1002/14651858.CD001797.pub4.
POPULATION:

People with chronic inflammatory demyelinating polyradiculoneuropathy (9 randomised controlled trials, n= 372).

INTERVENTION:

Intravenous immunoglobulin (IVIg).

COMPARISON:

Placebo; plasma exchange; corticosteroids (prednisolone and intravenous methylprednisolone (IVMP)).

OUTCOME:

The primary outcome was significant improvement in disability within six weeks after the start of treatment. There was low statistical heterogeneity between the trial results, and the overall risk of bias was low for all trials that contributed data to the analysis. IVIg compared with placebo increases the probability of significant improvement in disability within six weeks of the start of treatment (risk ratio (RR) 2.40; 95% confidence interval (CI) [1.72, 3.36]; number needed to treat for an additional beneficial outcome (NNTB) 4; 95% CI [3, 5]; 5 trials, 269 participants, high-certainty evidence). The trial comparing IVIg with plasma exchange reported none of our main outcomes. IVIg compared with prednisolone probably has little or no effect on the probability of significant improvement in disability four weeks after the start of treatment (RR 0.91; 95% CI [0.50, 1.68]; 1 trial, 29 participants, moderate-certainty evidence). IVIg compared with IVMP probably increases the likelihood of significant improvement in disability two weeks after starting treatment (RR 1.46; 95% CI [0.40, 5.38]; 1 trial, 45 participants, moderate-certainty evidence).

BACKGROUND:

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) causes progressive or relapsing weakness and numbness of the limbs, which lasts for at least two months. Uncontrolled studies have suggested that intravenous immunoglobulin (IVIg) could help to reduce symptoms. This is an update of a review first published in 2002 and last updated in 2013.

OBJECTIVES:

To assess the efficacy and safety of intravenous immunoglobulin in people with chronic inflammatory demyelinating polyradiculoneuropathy.

SEARCH METHODS:

We searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and two trials registers on 8 March 2023.

SELECTION CRITERIA:

We selected randomised controlled trials (RCTs) and quasi-RCTs that tested any dose of IVIg versus placebo, plasma exchange, or corticosteroids in people with definite or probable CIDP.

DATA COLLECTION AND ANALYSIS:

We used standard Cochrane methods. Our primary outcome was significant improvement in disability within six weeks after the start of treatment, as determined and defined by the study authors. Our secondary outcomes were change in mean disability score within six weeks, change in muscle strength (Medical Research Council (MRC) sum score) within six weeks, change in mean disability score at 24 weeks or later, frequency of serious adverse events, and frequency of any adverse events. We used GRADE to assess the certainty of evidence for our main outcomes.

MAIN RESULTS:

We included nine RCTs with 372 participants (235 male) from Europe, North America, South America, and Israel. There was low statistical heterogeneity between the trial results, and the overall risk of bias was low for all trials that contributed data to the analysis. Five trials (235 participants) compared IVIg with placebo, one trial (20 participants) compared IVIg with plasma exchange, two trials (72 participants) compared IVIg with prednisolone, and one trial (45 participants) compared IVIg with intravenous methylprednisolone (IVMP). We included one new trial in this update, though it contributed no data to any meta-analyses. IVIg compared with placebo increases the probability of significant improvement in disability within six weeks of the start of treatment (risk ratio (RR) 2.40, 95% confidence interval (CI) 1.72 to 3.36; number needed to treat for an additional beneficial outcome (NNTB) 4, 95% CI 3 to 5; 5 trials, 269 participants; high-certainty evidence). Since each trial used a different disability scale and definition of significant improvement, we were unable to evaluate the clinical relevance of the pooled effect. IVIg compared with placebo improves disability measured on the Rankin scale (0 to 6, lower is better) two to six weeks after the start of treatment (mean difference (MD) -0.26 points, 95% CI -0.48 to -0.05; 3 trials, 90 participants; high-certainty evidence). IVIg compared with placebo probably improves disability measured on the Inflammatory Neuropathy Cause and Treatment (INCAT) scale (1 to 10, lower is better) after 24 weeks (MD 0.80 points, 95% CI 0.23 to 1.37; 1 trial, 117 participants; moderate-certainty evidence). There is probably little or no difference between IVIg and placebo in the frequency of serious adverse events (RR 0.82, 95% CI 0.36 to 1.87; 3 trials, 315 participants; moderate-certainty evidence). The trial comparing IVIg with plasma exchange reported none of our main outcomes. IVIg compared with prednisolone probably has little or no effect on the probability of significant improvement in disability four weeks after the start of treatment (RR 0.91, 95% CI 0.50 to 1.68; 1 trial, 29 participants; moderate-certainty evidence), and little or no effect on change in mean disability measured on the Rankin scale (MD 0.21 points, 95% CI -0.19 to 0.61; 1 trial, 24 participants; moderate-certainty evidence). There is probably little or no difference between IVIg and prednisolone in the frequency of serious adverse events (RR 0.45, 95% CI 0.04 to 4.69; 1 cross-over trial, 32 participants; moderate-certainty evidence). IVIg compared with IVMP probably increases the likelihood of significant improvement in disability two weeks after starting treatment (RR 1.46, 95% CI 0.40 to 5.38; 1 trial, 45 participants; moderate-certainty evidence). IVIg compared with IVMP probably has little or no effect on change in disability measured on the Rankin scale two weeks after the start of treatment (MD 0.24 points, 95% CI -0.15 to 0.63; 1 trial, 45 participants; moderate-certainty evidence) or on change in mean disability measured with the Overall Neuropathy Limitation Scale (ONLS, 1 to 12, lower is better) 24 weeks after the start of treatment (MD 0.03 points, 95% CI -0.91 to 0.97; 1 trial, 45 participants; moderate-certainty evidence). The frequency of serious adverse events may be higher with IVIg compared with IVMP (RR 4.40, 95% CI 0.22 to 86.78; 1 trial, 45 participants, moderate-certainty evidence).

AUTHORS' CONCLUSIONS:

Evidence from RCTs shows that IVIg improves disability for at least two to six weeks compared with placebo, with an NNTB of 4. During this period, IVIg probably has similar efficacy to oral prednisolone and IVMP. Further placebo-controlled trials are unlikely to change these conclusions. In one large trial, the benefit of IVIg compared with placebo in terms of improved disability score persisted for 24 weeks. Further research is needed to assess the long-term benefits and harms of IVIg relative to other treatments.

Editor's Choice
  • Fussner LA
  • Flores-Suárez LF
  • Cartin-Ceba R
  • Specks U
  • Cox PG
  • et al.
Am J Respir Crit Care Med. 2024 Feb 12; 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 (ANCA)-associated vasculitis (AAV). The Plasma Exchange (PLEX) and Glucocorticoids (GC) in Severe AAV (PEXIVAS;NCT00987389) trial was the largest in AAV and first to enroll participants with DAH requiring mechanical ventilation.

OBJECTIVES:

Evaluate characteristics, treatment effects, outcomes for patients with AAV with and without DAH.

METHODS:

PEXIVAS randomized 704 participants to PLEX or no-PLEX and reduced or standard-dose GC. DAH status was defined at enrollment as no-DAH, non-severe, or severe (room air SpO2≤85% 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-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.

CONCLUSION:

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. Clinical trial registration available at www.

CLINICALTRIALS:

gov, ID: NCT00987389.

Editor's Choice
  • van Beers EJ
  • Al-Samkari H
  • Grace RF
  • Barcellini W
  • Glenthøj A
  • et al.
Blood Adv. 2024 Feb 8; 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 [W] 96; mitapivat-to-mitapivat [M/M] arm) or switched from placebo (baseline to W24) to mitapivat (W24 to 96; placebo-to-mitapivat [P/M] arm). 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 (n=40) from baseline to W24, sustained to W96. No improvements were observed in the P/M arm (n=40) 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 (LIC) by magnetic resonance imaging (MRI) 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). Mitapivat is the first disease-modifying pharmacotherapy shown to have beneficial effects on iron overload and ineffective erythropoiesis in patients with PK deficiency.

Editor's Choice
  • Vogel JP
  • Nguyen PY
  • Ramson J
  • De Silva MS
  • Pham MD
  • et al.
Am J Obstet Gynecol. 2024 Feb 7; doi: 10.1016/j.ajog.2024.01.012.
POPULATION:

Women experiencing vaginal birth or caesarean delivery (22 studies).

INTERVENTION:

Care bundles for postpartum haemorrhage (PPH) prevention and/or treatment.

COMPARISON:

OUTCOME:

For prevention-only bundles (2 studies), low-certainty evidence suggests possible benefits in reducing blood loss, duration of hospitalization and intensive care unit stay, and maternal wellbeing. For treatment-only bundles (9 studies), high-certainty evidence shows that the E-MOTIVE intervention reduced risks of composite severe morbidity (RR 0.40; 95% CI [0.32, 0.50] as well as blood transfusion for bleeding, PPH, severe PPH, and mean blood loss. One non-randomized trial and seven uncontrolled studies suggest other PPH treatment bundles might reduce blood loss and severe PPH, but this is uncertain. For combined prevention/treatment bundles (11 studies), low-certainty evidence shows that the California Maternal Quality Care Collaborative (CMQCC) care bundle may reduce severe maternal morbidity (RR 0.64; 95% CI [0.57, 0.72]. Ten uncontrolled studies variably showed possible benefits, no effects, or harms for other bundle types.

OBJECTIVE:

Care bundles are a promising approach to reducing postpartum hemorrhage-related morbidity and mortality. We assessed the effectiveness and safety of care bundles for postpartum hemorrhage prevention and/or treatment.

DATA SOURCES:

We searched MEDLINE, Embase, Cochrane CENTRAL, Maternity and Infant Care Database, and Global Index Medicus (inception to June 9, 2023) and ClinicalTrials.gov and the International Clinical Trials Registry Platform (last 5 years) using a phased search strategy, combining terms for postpartum hemorrhage and care bundles.

STUDY ELIGIBILITY CRITERIA:

Peer-reviewed studies evaluating postpartum hemorrhage-related care bundles were included. Care bundles were defined as interventions comprising ≥3 components implemented collectively, concurrently, or in rapid succession. Randomized and nonrandomized controlled trials, interrupted time series, and before-after studies (controlled or uncontrolled) were eligible.

METHODS:

Risk of bias was assessed using RoB 2 (randomized trials) and ROBINS-I (nonrandomized studies). For controlled studies, we reported risk ratios for dichotomous outcomes and mean differences for continuous outcomes, with certainty of evidence determined using GRADE. For uncontrolled studies, we used effect direction tables and summarized results narratively.

RESULTS:

Twenty-two studies were included for analysis. For prevention-only bundles (2 studies), low-certainty evidence suggests possible benefits in reducing blood loss, duration of hospitalization, and intensive care unit stay, and maternal well-being. For treatment-only bundles (9 studies), high-certainty evidence shows that the E-MOTIVE intervention reduced risks of composite severe morbidity (risk ratio, 0.40; 95% confidence interval, 0.32-0.50) and blood transfusion for bleeding, postpartum hemorrhage, severe postpartum hemorrhage, and mean blood loss. One nonrandomized trial and 7 uncontrolled studies suggest that other postpartum hemorrhage treatment bundles might reduce blood loss and severe postpartum hemorrhage, but this is uncertain. For combined prevention/treatment bundles (11 studies), low-certainty evidence shows that the California Maternal Quality Care Collaborative care bundle may reduce severe maternal morbidity (risk ratio, 0.64; 95% confidence interval, 0.57-0.72). Ten uncontrolled studies variably showed possible benefits, no effects, or harms for other bundle types. Nearly all uncontrolled studies did not use suitable statistical methods for single-group pretest-posttest comparisons and should thus be interpreted with caution.

CONCLUSION:

The E-MOTIVE intervention improves postpartum hemorrhage-related outcomes among women delivering vaginally, and the California Maternal Quality Care Collaborative bundle may reduce severe maternal morbidity. Other bundle designs warrant further effectiveness research before implementation is contemplated.

Editor's Choice
  • Moulton SG
  • Hartwell MJ
  • Feeley BT
  • Moulton, S. G.
  • Hartwell, M. J.
  • et al.
Am J Sports Med. 2024 Feb 7;3635465231213039 doi: 10.1177/03635465231213039.
POPULATION:

Patients undergoing arthroscopic rotator cuff repair surgery with platelet-rich plasma (PRP) (25 studies).

INTERVENTION:

Systematic review to evaluate the presence of spin bias in the abstracts of systematic reviews and meta-analyses of PRP with rotator cuff repair surgery.

COMPARISON:

OUTCOME:

Each included study was evaluated for the 15 most common forms of spin. Correlations between spin types and study characteristics were evaluated. At least 1 form of spin bias was found in 56% (14/25) of the included studies. In regard to the 3 different categories of spin, a form of misleading interpretation was found in 56% (14/25) of the studies. A form of misleading reporting was found in 48% (12/25) of the studies. A form of inappropriate extrapolation was found in 16% (4/25) of the studies. A significant association was found between misleading interpretation and publication year (odds ratio (OR) 1.41 per year increase in publication; 95% CI [1.04, 1.92]) and misleading reporting and publication year (OR 1.41 per year increase in publication; 95% CI [1.02, 1.95]). An association was found between inappropriate extrapolation and journal impact factor (OR 0.21 per unit increase in impact factor; 95% CI [0.044, 0.99]).

BACKGROUND:

The use of platelet-rich plasma (PRP) in orthopaedics continues to increase. One common use of PRP is as an adjunct in rotator cuff repair surgery. Multiple systematic reviews and meta-analyses have summarized the data on PRP use in rotator cuff repair surgery. However, systematic reviews and meta-analyses are subject to spin bias, where authors' interpretations of results influence readers' interpretations.

PURPOSE:

To evaluate spin in the abstracts of systematic reviews and meta-analyses of PRP with rotator cuff repair surgery.

STUDY DESIGN:

Systematic review; Level of evidence, 3.

METHODS:

A PubMed and Embase search was conducted using the terms rotator cuff repair and PRP and systematic review or meta-analysis. After review of 74 initial studies, 25 studies met the inclusion criteria. Study characteristics were documented, and each study was evaluated for the 15 most common forms of spin and using the AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews, Version 2) rating system. Correlations between spin types and study characteristics were evaluated using binary logistic regression for continuous independent variables and a chi-square test or Fisher exact test for categorical variables.

RESULTS:

At least 1 form of spin was found in 56% (14/25) of the included studies. In regard to the 3 different categories of spin, a form of misleading interpretation was found in 56% (14/25) of the studies. A form of misleading reporting was found in 48% (12/25) of the studies. A form of inappropriate extrapolation was found in 16% (4/25) of the studies. A significant association was found between misleading interpretation and publication year (odds ratio [OR], 1.41 per year increase in publication; 95% CI, 1.04-1.92; P = .029) and misleading reporting and publication year (OR, 1.41 per year increase in publication; 95% CI, 1.02-1.95; P = .037). An association was found between inappropriate extrapolation and journal impact factor (OR, 0.21 per unit increase in impact factor; 95% CI, 0.044-0.99; P = .048).

CONCLUSION:

A significant amount of spin was found in the abstracts of systematic reviews and meta-analyses of PRP use in rotator cuff repair surgery. Given the increasing use of PRP by clinicians and interest among patients, spin found in these studies may have a significant effect on clinical practice.

Editor's Choice
  • Kim D
  • Bashrum BS
  • Kotlier JL
  • Mayfield CK
  • Thompson AA
  • et al.
Arthrosc Sports Med Rehabil. 2024 Jan 16;6(1):100851 doi: 10.1016/j.asmr.2023.100851.
POPULATION:

Patients with hip osteoarthritis (15 systematic reviews).

INTERVENTION:

Systematic review to describe the incidence and types of spin bias in systematic reviews of platelet-rich plasma injections for hip osteoarthritis and to determine whether patterns in study characteristics could be identified among studies with identifiable spin.

COMPARISON:

OUTCOME:

All studies contained at least two types of spin (range 2-9), with a median of 2. The most common type of spin was type 14 ("Failure to report a wide confidence interval of estimates"), which was observed in 10 studies. The second most common type of spin was type 13 ("Failure to specify the direction of the effect when it favors the control intervention"), found in 6 studies. Several associations were found between spin types and the study characteristics of AMSTAR 2 rating, Scopus CiteScore, journal impact factor, and PROSPERO preregistration.

PURPOSE:

To describe the incidence and types of spin in systematic reviews of platelet-rich plasma (PRP) injections for hip osteoarthritis (OA) and to determine whether patterns in study characteristics could be identified among studies with identifiable spin.

METHODS:

The PubMed, Scopus, and SPORTDiscus databases were queried. Inclusion criteria were systematic reviews or meta-analyses that included an assessment of intra-articular PRP injections as a stand-alone treatment for hip OA. Two authors independently assessed the presence of spin in the included studies and recorded general study characteristics. The prevalence of the 15 different categories of spin was quantified using descriptive statistics.

RESULTS:

Fifteen studies met inclusion criteria for this study. All studies contained at least two types of spin (range 2-9), with a median of 2. The most common type of spin was type 14 ("Failure to report a wide confidence interval of estimates"), which was observed in 10 studies. The second most common type of spin was type 13 ("Failure to specify the direction of the effect when it favors the control intervention"), found in 6 studies.

CONCLUSIONS:

Spin is highly prevalent in abstracts of systematic reviews of PRP in the treatment of hip OA. Several associations were found between spin types and the study characteristics of AMSTAR 2 rating, Scopus CiteScore, journal impact factor, and PROSPERO preregistration. When present, spin in the abstracts of reviewed studies tended to favor the use of PRP in hip osteoarthritis.

CLINICAL RELEVANCE:

It is important to understand the prevalence of spin in published abstracts, especially in areas of great impact or interest, so authors and readers can have a greater awareness of this potential form of bias.

Editor's Choice
  • Al-Otaibi T
  • Nagib AM
  • Halim MA
  • Abo-Atya H
  • Mahmoud T
  • et al.
Exp Clin Transplant. 2024 Jan;22(Suppl 1):323-331 doi: 10.6002/ect.MESOT2023.P112.
POPULATION:

Adult kidney transplant recipients with stable graft function (n= 247).

INTERVENTION:

Targeted haemoglobin of 11 to 12 g/dL with the use of erythropoietin-stimulating agents (ESA) (group 1, n= 183)

COMPARISON:

Targeted haemoglobin of 13 to 15 g/dL with ESA (group 2, n= 64)

OUTCOME:

Patients underwent monthly clinical and laboratory evaluations of kidney graft function. Quality of life and echocardiography were assessed at study start and at 12 months. In group 2, there were comparable post-transplant complications, but better graft function at 6 months and better cardiac indexes at 1 year of the study. At 12 months, quality of life had improved after full correction of post-transplant anaemia in the renal transplant recipients who received erythropoietin-stimulating agents.

OBJECTIVES:

Posttransplant anemia might be associated with cardiovascular morbidity and increased mortality. To our knowledge, the debate on anemia correction has neither been revisited nor decided definitively. We aimed to assess the effects of full correction of posttransplant anemia on the cardiovascular system and quality of life among renal transplant recipients with stable graft function who were using erythropoietin-stimulating agents.

MATERIALS AND METHODS:

We enrolled 247 kidney recipients with stable graft function to be assessed for anemia. Eligible patients were randomized to achieve targeted hemoglobin of 11 to 12 g/dL (group 1, n = 183) or of 13 to 15 g/dL (group 2, n = 64) with the use of erythropoietin-stimulating agents. Patients underwent monthly clinical and laboratory evaluations of kidney graft function. Quality of life and echocardiography were assessed at study start and at 12 months.

RESULTS:

The 2 groups were comparable regarding pretransplant characteristics. In group 2, we observed comparable posttransplant complications (P > .05) but better graft function at 6 months and better cardiac indexes at 1 year of the study (P < .05). At 12 months, quality of life had improved after full correction of posttransplant anemia in the renal transplant recipients who received erythropoietinstimulating agents.

CONCLUSIONS:

Full correction of posttransplant anemia in renal transplant recipients was associated with improved quality of life and cardiac indexes without an effect on cardiovascular comorbidity.

Transfusion Evidence Round-Up: World Kidney Day - 14 March 2024
Editor's Choice
  • Dixon A
  • Kenny JE
  • Buzzard L
  • Holcomb J
  • Bulger E
  • et al.
J Trauma Acute Care Surg. 2024 Feb 1;96(2):319-325 doi: 10.1097/TA.0000000000004096.
POPULATION:

Trauma patients 15 years of age or older, enrolled in the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial, in 12 Level I trauma centers across North America (n= 629).

INTERVENTION:

Plasma, platelets, and red blood cells administered in a 1:1:1 ratio (n= 321).

COMPARISON:

Plasma, platelets, and red blood cells administered in a 1:1:2 ratio (n= 308).

OUTCOME:

This is a secondary analysis of the PROPPR trial. Syndecan-1, soluble thrombomodulin (sTM), and receptor for advanced glycation end products (RAGE) were quantified for each treatment group on admission and at 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, and 72 hours. Patients were excluded if they did not survive longer than 3 hours or had data from fewer than two time points. Three hundred eight patients in the 1:1:1 group and 291 in the 1:1:2 group were analyzed. There were no statistically significant differences in syndecan-1, sTM, or RAGE between treatment groups at any time point. Patients who developed acute respiratory distress syndrome, acute kidney injury, and death had significantly elevated biomarker expression at most time points when compared with patients who did not develop these sequelae.

BACKGROUND:

Disruption of the vascular endothelium and endothelial glycocalyx (EG) has been described after severe trauma. Plasma has been suggested to restore microvascular integrity by preservation and repair of the EG. We sought to evaluate whether plasma administered in a 1:1:1 ratio was associated with less endothelial marker circulation than a 1:1:2 ratio.

METHODS:

This is a secondary analysis of the PROPPR trial, which investigated post-traumatic resuscitation with platelets, plasma, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. Syndecan-1, soluble thrombomodulin (sTM), and receptor for advanced glycation end products (RAGE) were quantified for each treatment group on admission and at 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, and 72 hours. Patients were excluded if they did not survive longer than 3 hours or had data from fewer than two time points.

RESULTS:

Three hundred eight patients in the 1:1:1 group and 291 in the 1:1:2 group were analyzed. There were no statistically significant differences in syndecan-1, sTM, or RAGE between treatment groups at any time point ( p > 0.05). Patients who developed acute respiratory distress syndrome, acute kidney injury, and death had significantly elevated biomarker expression at most time points when compared with patients who did not develop these sequelae ( p < 0.05).

CONCLUSION:

Administration of FFP in a 1:1:1 ratio does not consistently affect circulation of endothelial biomarkers following significant trauma when compared with a 1:1:2 ratio. The development of post-traumatic ARDS, AKI, and death was associated with increased endothelial biomarker circulation.

LEVEL OF EVIDENCE:

Therapeutic/Care Management; Level III.

Editor's Choice
  • Miao J
  • Krisanapan P
  • Tangpanithandee S
  • Thongprayoon C
  • Cheungpasitporn W
  • et al.
Blood Purif. 2024;53(1):1-9 doi: 10.1159/000534102.
POPULATION:

Cryoglobulinemic vasculitis (CV) patients with renal involvement (63 case reports and 13 case series, n= 154).

INTERVENTION:

Different therapeutic apheresis (TA) modalities: plasma exchange (PE), plasmapheresis (PP), and cryofiltration (CF).

COMPARISON:

OUTCOME:

A total of 154 patients experiencing 170 episodes of serious events that necessitated TA, were included in this systematic review. The CV type was classified as 15 type I cases, 97 type II cases, and 13 type III cases, while the remaining patients exhibited mixed (n= 17) or undetermined CV types (n= 12). Among the treatment modalities, PE, PP, and CF were performed in 85 (56%), 52 (34%), and 17 patients (11%), respectively, with no identical protocol for TA treatment. The overall response rate for TA was 78%, with response rates of 84%, 77%, and 75% observed in type I, II, and III patients respectively. Most patients received steroids, immunosuppressants, and treatment targeting the underlying causative disease. The overall long-term renal outcome rate was 77%, with type I, II, and III patients experiencing response rates of 89%, 76%, and 90%, respectively. The renal outcomes in patients receiving PE, PP, and CF were comparable, with rates of 78%, 76%, and 81%, respectively.

INTRODUCTION:

Therapeutic apheresis (TA) is commonly used for cryoglobulinemic vasculitis (CV) patients, but its efficacy remains uncertain. This systematic review aimed to assess the efficacy of different TA modalities, such as plasma exchange (PE), plasmapheresis (PP), and cryofiltration (CF), in treating CV patients with renal involvement.

METHODS:

Literature search of MEDLINE, EMBASE, and Cochrane Databases was conducted up to December 2022. Studies that reported the outcomes of TA in adult CV patients with renal involvement were assessed. The protocol for this systematic review has been registered with PROSPERO (No. CRD42023417727). The quality of each study was evaluated by the investigators using the validated methodological index for non-randomized studies (minors) quality score.

RESULTS:

154 patients who encountered 170 episodes of serious events necessitating TA were evaluated across 76 studies. Among them, 51% were males, with a mean age ranging from 49 to 58 years. The CV types included 15 type I, 97 type II, and 13 type III, while the remaining patients exhibited mixed (n = 17) or undetermined CV types (n = 12). Among the treatment modalities, PE, PP, and CF were performed in 85 (56%), 52 (34%), and 17 patients (11%), respectively, with no identical protocol for TA treatment. The overall response rate for TA was 78%, with response rates of 84%, 77%, and 75% observed in type I, II, and III patients respectively. Most patients received steroids, immunosuppressants, and treatment targeting the underlying causative disease. The overall long-term renal outcome rate was 77%, with type I, II, and III patients experiencing response rates of 89%, 76%, and 90%, respectively. The renal outcomes in patients receiving PE, PP, and CF were comparable, with rates of 78%, 76%, and 81%, respectively.

CONCLUSIONS:

This study presents compelling evidence that combination of TA with other treatments, especially immunosuppressive therapy, is a successful strategy for effectively managing severe renal involvement in CV patients. Among the TA modalities studied, including PE, PP, and CF, all demonstrated efficacy, with PE being the most frequently employed approach.

Editor's Choice
  • Damarlapally N
  • Thimmappa V
  • Irfan H
  • Sikandari M
  • Madhu K
  • et al.
Cureus. 2023 Oct 21;15(10):e47430 doi: 10.7759/cureus.47430.
POPULATION:

Patients with chronic kidney disease regardless of their dialysis status, who also exhibited anaemia (19 randomised controlled trials, n= 22,151).

INTERVENTION:

Hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs): roxadustat, daprodustat, and vadadustat (n= 11,234).

COMPARISON:

Erythropoiesis-stimulating agents (ESA) (n= 10,917).

OUTCOME:

HIF-PHI yielded a slight but significant increase in change in mean haemoglobin levels (MD 0.06; 95% CI [0.00, 0.11]), with the maximum significant increase shown in roxadustat followed by daprodustat as compared to ESA. There was a significant decrease in efficacy outcomes such as change in mean iron (MD -1.54; 95% CI [-3.01, -0.06]), change in mean hepcidin (MD -21.04; 95% CI [-28.92, -13.17]), change in mean ferritin (MD -16.45; 95% CI [-27.17, -5.73]) with roxadustat showing maximum efficacy followed by daprodustat.

Hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs) are a novel group of drugs used to treat renal anemia, but their benefits vary among different trials. Our meta-analysis aims to assess the safety and efficacy of HIF-PHI versus erythropoiesis-stimulating agents (ESA) in managing anemia among patients with chronic kidney disease (CKD), regardless of their dialysis status. PubMed, Embase, and Google Scholar were queried to discover eligible randomized controlled trials (RCTs). To quantify the specific effects of HIF-PHI, we estimated pooled mean differences (MDs) and relative risks (RR) with 95% CIs. Our meta-analysis involved 22,151 CKD patients, with 11,234 receiving HIF-PHI and 10,917 receiving ESA from 19 different RCTs. The HIF-PHI used included roxadustat, daprodustat, and vadadustat. HIF-PHI yielded a slight but significant increase in change in mean hemoglobin (Hb) levels (MD: 0.06, 95% CI (0.00, 0.11); p = 0.03), with the maximum significant increase shown in roxadustat followed by daprodustat as compared to ESA. There was a significant decrease in efficacy outcomes such as change in mean iron (MD: -1.54, 95% CI (-3.01, -0.06); p = 0.04), change in mean hepcidin (MD: -21.04, 95% CI (-28.92, -13.17); p < 0.00001), change in mean ferritin (MD: -16.45, 95% CI (-27.17,-5.73); p = 0.03) with roxadustat showing maximum efficacy followed by daprodustat. As for safety, HIF-PHI showed significantly increased incidence in safety outcomes such as diarrhea (MD: 1.3, 95% CI (1.11, 1.51); p = 0.001), adverse events leading to withdrawal (MD: 2.03, 95% CI (1.5, 2.74), p = 0.00001) among 25 various analyzed outcomes. This meta-analysis indicates that HIF-PHIs present a potentially safer and more effective alternative to ESAs, with increased Hb levels and decreased iron usage in CKD patients without significantly increasing adverse events. Therefore, in these patients, we propose HIF-PHI alongside renal anemia treatment.

Editor's Choice
  • Hariri G
  • Collet L
  • Duarte L
  • Martin GL
  • Resche-Rigon M
  • et al.
Crit Care. 2023 Sep 12;27(1):354 doi: 10.1186/s13054-023-04640-1.
POPULATION:

Adult patients undergoing cardiac surgery such as coronary artery bypass grafting and/or valve surgery (86 randomised controlled trials (RCTs) n= 25,855).

INTERVENTION:

Non-pharmacological interventions to reduce the incidence of cardiac surgery-associated acute kidney injury (CSA-AKI): Goal directed perfusion (GDP), pulsatile flow during cardiopulmonary bypass (CPB), minimally invasive extracorporeal circulation (MECC), epidural analgesia, remote ischemic preconditioning (RIPc), tight glycemic control, kidney disease improving global outcomes care bundle, hyperoxia during CPB, restrictive transfusion strategy, high target arterial pressure.

COMPARISON:

Usual care.

OUTCOME:

No intervention had high-quality evidence to reduce CSA-AKI. From the included studies, the most frequent intervention was RIPc (31 RCTs, n= 7,738), MECC, (14 RCTs, n= 1,617) and pulsatile blood flow during CPB (10 RCTs, n= 1,993). Three interventions were associated with a significantly reduced risk of CSA-AKI: GDP, RIPc and pulsatile flow during CPB.

BACKGROUND:

Cardiac surgery-associated acute kidney injury (CSA-AKI) is frequent. While two network meta-analyses assessed the impact of pharmacological interventions to prevent CSA-AKI, none focused on non-pharmacological interventions. We aim to assess the effectiveness of non-pharmacological interventions to reduce the incidence of CSA-AKI.

METHODS:

We searched PubMed, Embase, Central and clinical trial registries from January 1, 2004 (first consensus definition of AKI) to July 1, 2023. Additionally, we conducted manual screening of abstracts of major anesthesia and intensive care conferences over the last 5 years and reference lists of relevant studies. We selected all randomized controlled trials (RCTs) assessing a non-pharmacological intervention to reduce the incidence of CSA-AKI, without language restriction. We excluded RCTs of heart transplantation or involving a pediatric population. The primary outcome variable was CSA-AKI. Two reviewers independently identified trials, extracted data and assessed risk of bias. Random-effects meta-analyses were conducted to calculate risk ratios (RRs) with 95% confidence intervals (CIs). We used the Grading of Recommendations Assessment, Development, and Evaluation to assess the quality of evidence.

RESULTS:

We included 86 trials (25,855 patients) evaluating 10 non-pharmacological interventions to reduce the incidence of CSA-AKI. No intervention had high-quality evidence to reduce CSA-AKI. Two interventions were associated with a significant reduction in CSA-AKI incidence, with moderate quality of evidence: goal-directed perfusion (RR, 0.55 [95% CI 0.40-0.76], I2 = 0%; Phet = 0.44) and remote ischemic preconditioning (RR, 0.86 [0.78-0.95]; I2 = 23%; Phet = 0.07). Pulsatile flow during cardiopulmonary bypass was associated with a significant reduction in CSA-AKI incidence but with very low quality of evidence (RR = 0.69 [0.48; 0.99]; I2 = 53%; Phet < 0.01). We found high quality of evidence for lack of effect of restrictive transfusion strategy (RR, 1.02 [95% CI 0.92; 1.12; Phet = 0.67; I2 = 3%) and tight glycemic control (RR, 0.86 [95% CI 0.55; 1.35]; Phet = 0.25; I2 = 26%).

CONCLUSIONS:

Two non-pharmacological interventions are likely to reduce CSA-AKI incidence, with moderate quality of evidence: goal-directed perfusion and remote ischemic preconditioning.

Editor's Choice
  • Kang ZY
  • Ma S
  • Liu W
  • Liu C
Transpl Immunol. 2023 Jun;78:101801 doi: 10.1016/j.trim.2023.101801.
POPULATION:

Kidney transplant recipients (11 studies, n= 19,543).

INTERVENTION:

Kidney transplantation with blood transfusion (n= 6,191).

COMPARISON:

Kidney transplantation without blood transfusion (n= 13,352).

OUTCOME:

The authors assessed the pooled associations between blood transfusion and occurrence of de novo donor-specific antibodies (dnDSA) and clinical outcomes. Blood transfusion was strongly correlated with the development of dnDSA (relative risk (RR) 1.40; 95% confidence interval (CI) [1.17, 1.67]). Patients with blood transfusion had a higher risk of developing anti-human leukocyte antigen (HLA) class I dnDSA than non-transfused patients (RR 1.75; 95% CI [1.14, 2.69]) as well as significantly higher rates of antibody-mediated rejection (RR 1.41; 95% CI [1.21, 2.35]) and graft loss (RR 1.75; 95% CI [1.30, 2.35]). There were no statistically significant differences between the two groups in the development of anti-HLA antibodies, anti-HLA class II dnDSA, and anti-HLA class I and II dnDSA; delayed graft function; T cell-mediated rejection; acute rejection; borderline rejection; or patient death.

The relationship between blood transfusion following kidney transplantation (KT) and the development of de novo donor-specific antibodies (dnDSA) is controversial. This was investigated by conducting a meta-analysis of studies on patients who underwent KT with or without blood transfusion, and by evaluating the effect of post-KT blood transfusion on clinical outcomes of kidney transplant recipients. Relevant studies in the PubMed, EMBASE, and Cochrane Library databases were identified from inception to July 1, 2022. Two reviewers independently extracted data from the selected articles and estimated study quality. A fixed effects or random effects model was used to pool data according to the heterogeneity among studies. Data included in the meta-analysis were derived from 11 studies with a total of 19,543 patients including 6191 with and 13,352 without blood transfusion post-KT. We assessed the pooled associations between blood transfusion and occurrence of dnDSA and clinical outcomes of transplant recipients. Blood transfusion was strongly correlated with the development of dnDSA (relative risk [RR] = 1.40, 95% confidence interval [CI]: 1.17-1.67; P < 0.05). Patients with blood transfusion had a higher risk of developing anti-human leukocyte antigen (HLA) class I dnDSA than non-transfused patients (RR = 1.75, 95% CI: 1.14-2.69; P < 0.05) as well as significantly higher rates of antibody-mediated rejection (AMR) (RR = 1.41, 95% CI: 1.21-2.35; P < 0.05) and graft loss (RR = 1.75, 95% CI: 1.30-2.35; P < 0.05). There were no statistically significant differences between the two groups in the development of anti-HLA antibodies, anti-HLA class II dnDSA, and anti-HLA class I and II dnDSA; delayed graft function; T cell-mediated rejection; acute rejection; borderline rejection; or patient death. Our results suggest that blood transfusion was associated with dnDSA development in KT recipients. The findings of this systematic review also suggest that post-KT blood transfusion recipients have a higher risk of AMR, and graft loss compared with non-transfused patients. Evidence from this meta-analysis indicates that the use of blood transfusion post-KT is associated with a significantly higher risk of immunological sensitization. More and higher quality results from large randomized controlled trials are still needed to inform clinical practice.

Editor's Choice
  • Liu Y
  • Deng X
  • Wen Z
  • Huang J
  • Wang C
  • et al.
Front Oncol. 2023 Feb 16;13:1092734 doi: 10.3389/fonc.2023.1092734.
POPULATION:

Renal cell carcinoma patients undergoing nephrectomy (10 retrospective studies, n= 19,240).

INTERVENTION:

Systematic review and meta-analysis to demonstrate whether perioperative blood transfusion affected postoperative survival.

COMPARISON:

OUTCOME:

Perioperative blood transfusion was significantly associated with the decline of overall survival (HR 2.62; 95% CI [1,98, 3.46]), recurrence-free survival (HR 2.55; 95% CI [1.74, 3.75]), and cancer-specific survival (HR 3.15; 95% CI [2.3, 4.31]) values. There was high heterogeneity among the study results due to the retrospective nature and the low quality of the included studies. Subgroup analysis findings suggested that the heterogeneity of this study might be caused by different tumor stages in the included articles.

BACKGROUND:

The effect of perioperative blood transfusion (PBT) on postoperative survival in RCC patients who underwent partial nephrectomy (PN) or radical nephrectomy (RN) remains controversial. Two meta-analyses in 2018 and 2019 reported the postoperative mortality of PBT patients with RCC, but they did not investigate the effect on the survival of patients. We performed a systematic review and meta-analysis of relevant literature to demonstrate whether PBT affected postoperative survival in RCC patients who received nephrectomy.

METHODS:

Pubmed, Web of Science, Cochrane, and Embase databases were searched. Studies comparing RCC patients with or without PBT following either RN or PN were included in this analysis. Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the included literature, and hazard ratios (HRs) of overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival (CSS), as well as 95% confidence intervals, were considered as effect sizes. All data were processed using Stata 15.1.

RESULTS:

Ten retrospective studies involving 19,240 patients were included in this analysis, with the publication dates ranging from 2014 to 2022. Evidence revealed that PBT was significantly associated with the decline of OS (HR, 2.62; 95%CI: 1,98-3.46), RFS (HR, 2.55; 95%CI: 1.74-3.75), and CSS (HR, 3.15; 95%CI: 2.3-4.31) values. There was high heterogeneity among the study results due to the retrospective nature and the low quality of the included studies. Subgroup analysis findings suggested that the heterogeneity of this study might be caused by different tumor stages in the included articles. Evidence implied that PBT had no significant influence on RFS and CSS with or without robotic assistance, but it was still linked to worse OS (combined HR; 2.54 95% CI: 1.18, 5.47). Furthermore, the subgroup analysis with intraoperative blood loss lower than 800 ML revealed that PBT had no substantial impact on OS and CSS of postoperative RCC patients, whereas it was correlated with poor RFS (1.42, 95% CI: 1.02-1.97).

CONCLUSIONS:

RCC patients undergoing PBT after nephrectomy had poorer survival.

SYSTEMATIC REVIEW REGISTRATION:

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022363106.

Editor's Choice
  • El-Shaer W
  • Haggag MS
  • Elshaer A
  • Shaboob I
  • Kandeel W
  • et al.
Int J Urol. 2022 Dec;29(12):1535-1542 doi: 10.1111/iju.15036.
POPULATION:

Patients undergoing percutaneous nephrolithotomy (PCNL) (n= 140).

INTERVENTION:

PCNL after tract infiltration with norepinephrine (NE) (NE-PCNL group, n= 70).

COMPARISON:

PCNL after tract infiltration with normal saline (S-PCNL group, n= 70).

OUTCOME:

The primary outcome was procedure-related blood loss. The median blood loss was 378 ml (IQR= 252, 504) in the NE-PCNL group versus 592 ml (IQR= 378, 756) in the S-PCNL group. Haemoglobin and haematocrit deficits were lower in NE-PCNL. Patients in the NE-PCNL group had a higher immediate stone-free rate (80%) compared with those of the S-PCNL group (70%). No statistical differences were found in the final stone free rate. The reported overall complications between the two groups were similar. Bleeding-related complications were 1 (1.4%) versus 10 (14.3%) for NE-PCNL and S-PCNL, respectively.

PURPOSE:

To determine the efficacy and safety of trajectory infiltration with 1:150 000 Norepinephrine (NE) in reducing blood loss during percutaneous nephrolithotomy (PCNL).

MATERIALS AND METHODS:

This is a prospective randomized double-blinded placebo-controlled trial. In all, 140 consecutive patients underwent PCNL for the management of large renal calculi. They were randomly assigned (1:1) to one of either study groups, the NE-PCNL group (70 patients whose PCNL-trajectory was infiltrated by NE) or the Placebo group (saline PCNL) (70 patients whose PCNL tracts were infiltrated by normal saline). Procedure-related blood loss (the primary outcome) was assessed and statistically analyzed. Also, all other procedure-related events and complications were recorded and compared.

RESULTS:

The median blood loss was 378 ml (IQR: 252-504) in the NE-PCNL group versus 592 ml (IQR: 378-756) in the S-PCNL group (p < 0.0001). In addition, Hemoglobin and Hematocrit deficits were lower in NE-PCNL (p < 0.05). Patients who were randomized to the NE-PCNL group had a higher immediate stone-free rate (SFR) (80%) compared with those of the S-PCNL group (70%) (p = 0.034). However, no statistical differences were found in the final SFR. The reported overall complications between the 2 groups were similar (p > 0.05). Indeed, bleeding-related complications were 1 (1.4%) versus 10 (14.3%) for NE-PCNL and S-PCNL, respectively (p = 0.009).

CONCLUSIONS:

Trajectory infiltration of PCNL tracts by NE was found to be effective and safe in mitigation of PCNL-related blood loss. This step is a timeless and cost-effective as NE is readily available in surgical theaters and of very low cost.

Editor's Choice
  • Li L
  • Zheng X
  • Deng J
  • Zhou J
  • Ou J
  • et al.
Ren Fail. 2022 Dec;44(1):1112-1122 doi: 10.1080/0886022X.2022.2094273.
POPULATION:

Chronic kidney disease (CKD) patients with hyperphosphataemia and anaemia (16 randomised controlled trials, n= 1,754).

INTERVENTION:

Ferric citrate treatment.

COMPARISON:

Control drugs, including placebo and positive drugs.

OUTCOME:

The meta-analysis showed that ferric citrate could significantly reduce the serum phosphorus in CKD patients compared to the placebo control groups (MD -1.76 mg/dL; 95% CI [-2.78, -0.75]). The difference between ferric citrate treatment and active controls, such as non-iron-based phosphate binders, sevelamer, calcium carbonate, lanthanum carbonate and sodium ferrous citrate, was not statistically significant (MD -0.09 mg/dL; 95% CI [-0.35, 0.17]). Ferric citrate could effectively improve haemoglobin levels when compared to the active drug (MD 0.43 g/dL; 95% CI [0.04, 0.82]) and placebo groups (MD 0.39 g/dL; 95% CI [0.04, 0.73]). According to eight studies, ferric citrate was found to be cost-effective treatment in comparison to control drugs. Most of the adverse events following ferric citrate treatment were mild at most.

BACKGROUND:

Hyperphosphatemia and anemia, which are common complications of chronic kidney disease (CKD), can independently contribute to cardiovascular events. Several previous studies have found that the iron-based phosphate binder, ferric citrate (FC), could be beneficial to both hyperphosphatemia and anemia.

METHODS:

Relevant literature from PUBMED, EMBASE, the Cochrane Central Register of Controlled Trials (CCRCT) and MEDLINE databases were searched up to 21 February 2022, in order to conduct a meta-analysis to investigate the efficacy, safety and economic benefits of ferric citrate treatment in CKD patients with hyperphosphatemia and anemia. The meta-analysis was conducted independently by two reviewers using the RevMan software (version 5.3).

RESULTS:

In total, this study included 16 randomized clinical trials (RCT) involving 1754 participants. The meta-analysis showed that ferric citrate could significantly reduce the serum phosphorus in CKD patients compared to the placebo control groups (MD -1.76 mg/dL, 95% CI (-2.78, -0.75); p = 0.0007). In contrast, the difference between ferric citrate treatment and active controls, such as non-iron-based phosphate binders, sevelamer, calcium carbonate, lanthanum carbonate and sodium ferrous citrate, was not statistically significant (MD - 0.09 mg/dL, 95% CI (-0.35, 0.17); p = 0.51). However, ferric citrate could effectively improve hemoglobin levels when compared to the active drug (MD 0.43 g/dL, 95% CI (0.04, 0.82); p = 0.03) and placebo groups (MD 0.39 g/dL, 95% CI (0.04, 0.73); p = 0.03). According to eight studies, ferric citrate was found to be cost-effective treatment in comparison to control drugs. Most of the adverse events (AE) following ferric citrate treatment were mild at most.

CONCLUSION:

Collectively, our review suggests that iron-based phosphate binder, ferric citrate is an effective and safe treatment option for CKD patients with hyperphosphatemia and anemia. More importantly, this alternative treatment may also less expensive. Nevertheless, more scientific studies are warranted to validate our findings.

Editor's Choice
  • Jayne D
  • Walsh M
  • Merkel PA
  • Peh CA
  • Szpirt W
  • et al.
Health Technol Assess. 2022 Sep;26(38):1-60 doi: 10.3310/PNXB5040.
POPULATION:

Patients with severe anti-neutrophil cytoplasm antibody-associated vasculitis, enrolled in the Plasma Exchange In VASculitis (PEXIVAS) trial in 95 hospitals in Europe, North America, Australia/New Zealand and Japan (n= 704).

INTERVENTION:

[Two-by-two factorial design] Adjunctive plasma exchange (n= 352). Reduced glucocorticoid dosing regimen (n= 353).

COMPARISON:

No plasma exchange (n= 352). Standard glucocorticoid dosing regimen (n= 351).

OUTCOME:

The primary outcome was a composite of all-cause mortality and end-stage renal disease at a common close-out when the last patient had completed 10 months in the trial. Ninety-nine patients died and 138 developed end-stage renal disease, with the primary end point occurring in 209 out of 704 (29.7%) patients: 100 out of 352 (28%) in the plasma exchange group and 109 out of 352 (31%) in the no plasma exchange group (adjusted hazard ratio 0.86; 95% confidence interval (CI) [0.65, 1.13]). In the per-protocol analysis for the non-inferiority glucocorticoid comparison, the primary end point occurred in 92 out of 330 (28%) patients in the reduced-dose group and 83 out of 325 (26%) patients in the standard-dose group (partial-adjusted risk difference 0.023; 95% CI [0.034, 0.08]). Serious infections in the first year occurred in 96 out of 353 (27%) patients in the reduced-dose group and in 116 out of 351 (33%) patients in the standard-dose group. The rate of serious infections at 1 year was lower in the reduced-dose group than in the standard-dose group (incidence rate ratio 0.69, 95% CI [0.52, 0.93]).

BACKGROUND:

Anti-neutrophil cytoplasm antibody-associated vasculitis is a multisystem, autoimmune disease that causes organ failure and death. Physical removal of pathogenic autoantibodies by plasma exchange is recommended for severe presentations, along with high-dose glucocorticoids, but glucocorticoid toxicity contributes to morbidity and mortality. The lack of a robust evidence base to guide the use of plasma exchange and glucocorticoid dosing contributes to variation in practice and suboptimal outcomes.

OBJECTIVES:

We aimed to determine the clinical efficacy of plasma exchange in addition to immunosuppressive therapy and glucocorticoids with respect to death and end-stage renal disease in patients with severe anti-neutrophil cytoplasm antibody-associated vasculitis. We also aimed to determine whether or not a reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen with respect to death and end-stage renal disease.

DESIGN:

This was an international, multicentre, open-label, randomised controlled trial. Patients were randomised in a two-by-two factorial design to receive either adjunctive plasma exchange or no plasma exchange, and either a reduced or a standard glucocorticoid dosing regimen. All patients received immunosuppressive induction therapy with cyclophosphamide or rituximab.

SETTING:

Ninety-five hospitals in Europe, North America, Australia/New Zealand and Japan participated.

PARTICIPANTS:

Participants were aged ≥ 16 years with a diagnosis of granulomatosis with polyangiitis or microscopic polyangiitis, and either proteinase 3 anti-neutrophil cytoplasm antibody or myeloperoxidase anti-neutrophil cytoplasm antibody positivity, and a glomerular filtration rate of < 50 ml/minute/1.73 m2 or diffuse alveolar haemorrhage attributable to active anti-neutrophil cytoplasm antibody-associated vasculitis.

INTERVENTIONS:

Participants received seven sessions of plasma exchange within 14 days or no plasma exchange. Oral glucocorticoids commenced with prednisolone 1 mg/kg/day and were reduced over different lengths of time to 5 mg/kg/day, such that cumulative oral glucocorticoid exposure in the first 6 months was 50% lower in patients allocated to the reduced-dose regimen than in those allocated to the standard-dose regimen. All patients received the same glucocorticoid dosing from 6 to 12 months. Subsequent dosing was at the discretion of the treating physician.

PRIMARY OUTCOME:

The primary outcome was a composite of all-cause mortality and end-stage renal disease at a common close-out when the last patient had completed 10 months in the trial.

RESULTS:

The study recruited 704 patients from June 2010 to September 2016. Ninety-nine patients died and 138 developed end-stage renal disease, with the primary end point occurring in 209 out of 704 (29.7%) patients: 100 out of 352 (28%) in the plasma exchange group and 109 out of 352 (31%) in the no plasma exchange group (adjusted hazard ratio 0.86, 95% confidence interval 0.65 to 1.13; p = 0.3). In the per-protocol analysis for the non-inferiority glucocorticoid comparison, the primary end point occurred in 92 out of 330 (28%) patients in the reduced-dose group and 83 out of 325 (26%) patients in the standard-dose group (partial-adjusted risk difference 0.023, 95% confidence interval 0.034 to 0.08; p = 0.5), thus meeting our non-inferiority hypothesis. Serious infections in the first year occurred in 96 out of 353 (27%) patients in the reduced-dose group and in 116 out of 351 (33%) patients in the standard-dose group. The rate of serious infections at 1 year was lower in the reduced-dose group than in the standard-dose group (incidence rate ratio 0.69, 95% confidence interval 0.52 to 0.93; p = 0.016).

CONCLUSIONS:

Plasma exchange did not prolong the time to death and/or end-stage renal disease in patients with anti-neutrophil cytoplasm antibody-associated vasculitis with severe renal or pulmonary involvement. A reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen and was associated with fewer serious infections.

FUTURE WORK:

A meta-analysis examining the effects of plasma exchange on kidney outcomes in anti-neutrophil cytoplasm antibody-associated vasculitis is planned. A health-economic analysis of data collected in this study to examine the impact of both plasma exchange and reduced glucocorticoid dosing is planned to address the utility of plasma exchange for reducing early end-stage renal disease rates. Blood and tissue samples collected in the study will be examined to identify predictors of response to plasma exchange in anti-neutrophil cytoplasm in antibody-associated vasculitis. The benefits associated with reduced glucocorticoid dosing will inform future studies of newer therapies to permit further reduction in glucocorticoid exposure. Data from this study will contribute to updated management recommendations for anti-neutrophil cytoplasm antibody-associated vasculitis.

LIMITATIONS:

This study had an open-label design which may have permitted observer bias; however, the nature of the end points, end-stage renal disease and death, would have minimised this risk. Despite being, to our knowledge, the largest ever trial in anti-neutrophil cytoplasm antibody-associated vasculitis, there was an insufficient sample size to assess clinically useful benefits on the separate components of the primary end-point: end-stage renal disease and death. Use of a fixed-dose plasma exchange regimen determined by consensus rather than data-driven dose ranging meant that some patients may have been underdosed, thus reducing the therapeutic impact. In particular, no biomarkers have been identified to help determine dosing in a particular patient, although this is one of the goals of the biomarker plan of this study.

TRIAL REGISTRATION:

This trial is registered as ISRCTN07757494, EudraCT 2009-013220-24 and Clinicaltrials.gov NCT00987389.

FUNDING:

This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 38. See the NIHR Journals Library website for further project information.

Editor's Choice
  • Sepah YJ
  • Nguyen QD
  • Yamaguchi Y
  • Otsuka T
  • Majikawa Y
  • et al.
Kidney Int Rep. 2022 Jan 19;7(4):763-775 doi: 10.1016/j.ekir.2022.01.1045.
POPULATION:

Patients with anaemia of chronic kidney disease (CKD), (2 randomised controlled trials: CL-0307 (n= 302 dialysis-dependent (DD) patients) and CL-310 (n= 262 non-DD patients)).

INTERVENTION:

Roxadustat (CL-0307, n= 150); (CL-310, n= 131).

COMPARISON:

Darbepoetin alfa (DA) (CL-0307, n= 152); (CL-310, n= 131).

OUTCOME:

Ophthalmic imaging and assessments of visual acuity were performed up to week 24 or at study discontinuation. Proportions of DD patients with new or worsening retinal hemorrhages (RHs) in the roxadustat group and DA group were 32.4% (46 of 142) and 36.6% (53 of 145), respectively. Proportions of non-DD patients with CKD with new or worsening RH in the roxadustat and DA groups were 31.4% (38 of 121) and 39.8% (51 of 128), respectively. Similar trends were apparent in subgroup analyses: patients with/without RH at baseline and with/without diabetes mellitus at baseline. In both studies, there were no differences in retinal thickness, visual acuity, presence of hard exudates or cotton wool spots, or presence of intra- and subretinal fluid between groups, at any given time point.

INTRODUCTION:

Roxadustat is an orally administered hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that represents a novel therapeutic option for patients with anemia of chronic kidney disease (CKD).

METHODS:

Conducted in Japan, CL-0307 (NCT02952092) and CL-310 (NCT02988973) were phase 3, darbepoetin alfa (DA)-controlled studies conducted in dialysis-dependent (DD) and non-DD (NDD) patients with CKD, respectively, where patients were randomized to receive roxadustat or DA. Ophthalmic imaging and assessments of visual acuity were performed up to week 24 or at study discontinuation. Ophthalmic imaging was centrally evaluated by independent readers masked to the study treatment.

RESULTS:

In CL-0307, 302 patients (roxadustat, n = 150; DA, n = 152) received ≥1 dose of the study drug and were included in this analysis. In CL-0310, 262 patients (roxadustat, n = 131; DA, n = 131) received ≥1 dose of the study drug and were included in this analysis. Proportions of DD patients with new or worsening retinal hemorrhages (RHs) in the roxadustat group and DA group were 32.4% (46 of 142) and 36.6% (53 of 145), respectively. Proportions of NDD patients with CKD with new or worsening RH in the roxadustat and DA groups were 31.4% (38 of 121) and 39.8% (51 of 128), respectively. Similar trends were apparent in subgroup analyses: patients with/without RH at baseline and with/without diabetes mellitus at baseline. In both studies, there were no differences in retinal thickness, visual acuity, presence of hard exudates or cotton wool spots, or presence of intra- and subretinal fluid between groups, at any given time point.

CONCLUSION:

In these studies, roxadustat, compared with DA, was not associated with an increased risk of adverse ophthalmologic events in these cohorts.