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Therapeutic Strategies in Traumatic Intracranial Hemorrhage and Outcomes
Singh A, Trivedi R, Ahmed N
Journal of neurological surgery. Part A, Central European neurosurgery. 2022
Abstract
BACKGROUND Traumatic intracranial hemorrhage (TICH) and its progression have historically resulted in poor prognosis and functional disability. Such outcomes can impact the daily lives and financial condition of patients' families as well as add burden to the health care system. This review examines the diverse therapeutic intervention that were observed in randomized clinical trials (RCT) on various outcomes. Many demographic and clinical risk factors have been identified for poor prognosis after a TICH. Among the many therapeutic strategies studied, few found to have some beneficial effect in minimizing the progression of hemorrhage and reducing the overall mortality. METHODS A literature review was conducted of all relevant sources using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to include articles that were RCTs for patients aged 18 years and above to include a total of 19 articles. RESULTS Across studies, many therapies have been assessed; however, only few findings including infusion of tranexamic acid (TXA), use of β-blocker, and early operative evacuation of TICH yielded favorable results. Use of steroid and blood transfusion to target higher hemoglobin levels showed evidence of adversely impacting the outcome. CONCLUSION Of the many therapeutic strategies available for TICH, very few therapies have proven to be beneficial.
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Evaluation of Direct Oral Anticoagulant Reversal Agents in Intracranial Hemorrhage: A Systematic Review and Meta-analysis
Chaudhary R, Singh A, Chaudhary R, Bashline M, Houghton DE, Rabinstein A, Adamski J, Arndt R, Ou NN, Rudis MI, et al
JAMA network open. 2022;5(11):e2240145
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Editor's Choice
Abstract
IMPORTANCE Direct oral anticoagulant (DOAC)-associated intracranial hemorrhage (ICH) has high morbidity and mortality. The safety and outcome data of DOAC reversal agents in ICH are limited. OBJECTIVE To evaluate the safety and outcomes of DOAC reversal agents among patients with ICH. DATA SOURCES PubMed, MEDLINE, The Cochrane Library, Embase, EBSCO, Web of Science, and CINAHL databases were searched from inception through April 29, 2022. STUDY SELECTION The eligibility criteria were (1) adult patients (age ≥18 years) with ICH receiving treatment with a DOAC, (2) reversal of DOAC, and (3) reported safety and anticoagulation reversal outcomes. All nonhuman studies and case reports, studies evaluating patients with ischemic stroke requiring anticoagulation reversal or different dosing regimens of DOAC reversal agents, and mixed study groups with DOAC and warfarin were excluded. DATA EXTRACTION AND SYNTHESIS Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used for abstracting data and assessing data quality and validity. Two reviewers independently selected the studies and abstracted data. Data were pooled using the random-effects model. MAIN OUTCOMES AND MEASURES The primary outcome was proportion with anticoagulation reversed. The primary safety end points were all-cause mortality and thromboembolic events after the reversal agent. RESULTS A total of 36 studies met criteria for inclusion, with a total of 1832 patients (967 receiving 4-factor prothrombin complex concentrate [4F-PCC]; 525, andexanet alfa [AA]; 340, idarucizumab). The mean age was 76 (range, 68-83) years, and 57% were men. For 4F-PCC, anticoagulation reversal was 77% (95% CI, 72%-82%; I2 = 55%); all-cause mortality, 26% (95% CI, 20%-32%; I2 = 68%), and thromboembolic events, 8% (95% CI, 5%-12%; I2 = 41%). For AA, anticoagulation reversal was 75% (95% CI, 67%-81%; I2 = 48%); all-cause mortality, 24% (95% CI, 16%-34%; I2 = 73%), and thromboembolic events, 14% (95% CI, 10%-19%; I2 = 16%). Idarucizumab for reversal of dabigatran had an anticoagulation reversal rate of 82% (95% CI, 55%-95%; I2 = 41%), all-cause mortality, 11% (95% CI, 8%-15%, I2 = 0%), and thromboembolic events, 5% (95% CI, 3%-8%; I2 = 0%). A direct retrospective comparison of 4F-PCC and AA showed no differences in anticoagulation reversal, proportional mortality, or thromboembolic events. CONCLUSIONS AND RELEVANCE In the absence of randomized clinical comparison trials, the overall anticoagulation reversal, mortality, and thromboembolic event rates in this systematic review and meta-analysis appeared similar among available DOAC reversal agents for managing ICH. Cost, institutional formulary status, and availability may restrict reversal agent choice, particularly in small community hospitals.
PICO Summary
Population
Adult patients with intracranial hemorrhage receiving treatment with a direct oral anticoagulant (36 studies, n= 1,832).
Intervention
4-factor prothrombin complex concentrate (4F-PCC), (n= 967).
Comparison
Andexanet alfa (AA), (n= 525). Idarucizumab(n= 340).
Outcome
For 4F-PCC, anticoagulation reversal was 77% (95% CI 72% to 82%; I2 = 55%); all-cause mortality, 26% (95% CI 20% to 32%; I2 = 68%), and thromboembolic events, 8% (95% CI 5% to 12%; I2 = 41%). For AA, anticoagulation reversal was 75% (95% CI 67% to 81%; I2 = 48%); all-cause mortality, 24% (95% CI 16% to 34%; I2 = 73%), and thromboembolic events, 14% (95% CI 10% to 19%; I2 = 16%). Idarucizumab for reversal of dabigatran had an anticoagulation reversal rate of 82% (95% CI 55% to 95%; I2 = 41%), all-cause mortality, 11% (95% CI 8% to 15%, I2 = 0%), and thromboembolic events, 5% (95% CI 3% to 8%; I2 = 0%). A direct retrospective comparison of 4F-PCC and AA showed no differences in anticoagulation reversal, proportional mortality, or thromboembolic events.
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Early Outpatient Treatment for Covid-19 with Convalescent Plasma
Sullivan DJ, Gebo KA, Shoham S, Bloch EM, Lau B, Shenoy AG, Mosnaim GS, Gniadek TJ, Fukuta Y, Patel B, et al
The New England journal of medicine. 2022
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Editor's Choice
Abstract
BACKGROUND Polyclonal convalescent plasma may be obtained from donors who have recovered from coronavirus disease 2019 (Covid-19). The efficacy of this plasma in preventing serious complications in outpatients with recent-onset Covid-19 is uncertain. METHODS In this multicenter, double-blind, randomized, controlled trial, we evaluated the efficacy and safety of Covid-19 convalescent plasma, as compared with control plasma, in symptomatic adults (≥18 years of age) who had tested positive for severe acute respiratory syndrome coronavirus 2, regardless of their risk factors for disease progression or vaccination status. Participants were enrolled within 8 days after symptom onset and received a transfusion within 1 day after randomization. The primary outcome was Covid-19-related hospitalization within 28 days after transfusion. RESULTS Participants were enrolled from June 3, 2020, through October 1, 2021. A total of 1225 participants underwent randomization, and 1181 received a transfusion. In the prespecified modified intention-to-treat analysis that included only participants who received a transfusion, the primary outcome occurred in 17 of 592 participants (2.9%) who received convalescent plasma and 37 of 589 participants (6.3%) who received control plasma (absolute risk reduction, 3.4 percentage points; 95% confidence interval, 1.0 to 5.8; P = 0.005), which corresponded to a relative risk reduction of 54%. Evidence of efficacy in vaccinated participants cannot be inferred from these data because 53 of the 54 participants with Covid-19 who were hospitalized were unvaccinated and 1 participant was partially vaccinated. A total of 16 grade 3 or 4 adverse events (7 in the convalescent-plasma group and 9 in the control-plasma group) occurred in participants who were not hospitalized. CONCLUSIONS In participants with Covid-19, most of whom were unvaccinated, the administration of convalescent plasma within 9 days after the onset of symptoms reduced the risk of disease progression leading to hospitalization. (Funded by the Department of Defense and others; CSSC-004 ClinicalTrials.gov number, NCT04373460.).
PICO Summary
Population
Symptomatic adults who tested positive for severe acute respiratory syndrome coronavirus 2, at 23 trial sites in the United States (n= 1,225).
Intervention
Convalescent plasma transfusion (n= 610).
Comparison
Control plasma transfusion (n= 615).
Outcome
Covid-19-related hospitalization within 28 days after transfusion occurred in 17 of 592 patients (2.9%) who received convalescent plasma and 37 of 589 patients (6.3%) who received control plasma, which corresponded to a relative risk reduction of 54%. Evidence of efficacy in vaccinated patients could not be inferred. A total of 16 grade 3 or 4 adverse events (7 in the convalescent-plasma group and 9 in the control-plasma group) occurred in patients who were not hospitalized.
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Standard-Volume Plasma Exchange Improves Outcomes in Patients With Acute Liver Failure: A Randomized Controlled Trial
Maiwall R, Bajpai M, Singh A, Agarwal T, Kumar G, Bharadwaj A, Nautiyal N, Tevethia H, Jagdish RK, Vijayaraghavan R, et al
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2022;20(4):e831-e854
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Abstract
BACKGROUND High volume plasma-exchange (HVPE) improves survival in patients with acute liver failure (ALF), but apprehension regarding volume overload and worsening of cerebral edema remain. METHODS In an open-label randomized controlled trial, 40 consecutive patients of ALF were randomized 1:1 to either standard medical treatment (SMT) or SMT with standard-volume plasma-exchange (SVPE). SVPE was performed using centrifugal apheresis [target volume of 1.5 to 2.0 plasma volumes per session] until desired response was achieved. Cerebral edema was assessed by brain imaging. Results were analyzed in an intention-to-treat analysis. Primary outcome was 21-day transplant-free survival. The levels of cytokines, damage-associated molecular patterns (DAMPs) and endotoxins were analyzed at baseline and day 5. RESULTS ALF patients [aged 31.5 ± 12.2 years, 60% male, 78% viral, 83% hyperacute, 70% with SIRS were included. At day 5, SVPE [mean sessions 2.15 ± 1.42, median plasma volume replaced 5.049 L] compared to SMT alone, resulted in higher lactate clearance (p = .02), amelioration of SIRS (84% vs. 26%; P = .02), reduction in ammonia levels [(221.5 ± 96.9) vs.(439 ± 385.6) μg/dl, P = .02) and SOFA scores [9.9(±3.3) vs. 14.6(±4.8); P = .001]. There were no treatment related deaths. SVPE was associated with a higher 21-day transplant free-survival [75% vs. 45%; P = .04, HR 0.30, 95%CI 0.01-0.88]. A significant decrease in levels of pro-inflammatory cytokines and an increase in anti-inflammatory cytokines along with a decrease in endotoxin and DAMPs was seen with SVPE. CONCLUSION In ALF patients with cerebral edema, SVPE is safe and effective and improves survival possibly by a reduction in cytokine storm and ammonia. CLINICALTRIAL gov (identifier: NCT02718079).
PICO Summary
Population
Patients with acute liver failure (n= 40).
Intervention
Standard medical treatment with standard volume plasma exchange (SVPE), (n= 20).
Comparison
Standard medical treatment (n= 20).
Outcome
Compared to standard medical treatment alone, at day five SVPE resulted in higher lactate clearance, amelioration of systemic inflammatory response syndrome (84% vs. 26%), reduction in ammonia levels [(221.5 ± 96.9) vs. (439 ± 385.6) μg/dl] and sequential organ failure assessment scores [9.9(±3.3) vs. 14.6(±4.8)]. There were no treatment related deaths. SVPE was associated with a higher 21-day transplant free-survival (75% vs. 45%). A significant decrease in levels of pro-inflammatory cytokines and an increase in anti-inflammatory cytokines along with a decrease in endotoxin and damage-associated molecular patterns was seen with SVPE.
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Randomized Controlled Trial of Early Outpatient COVID-19 Treatment with High-Titer Convalescent Plasma
Sullivan DJ, Gebo KA, Shoham S, Bloch EM, Lau B, Shenoy AG, Mosnaim GS, Gniadek TJ, Fukuta Y, Patel B, et al
medRxiv : the preprint server for health sciences. 2021
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Editor's Choice
Abstract
BACKGROUND The efficacy of polyclonal high titer convalescent plasma to prevent serious complications of COVID-19 in outpatients with recent onset of illness is uncertain. METHODS This multicenter, double-blind randomized controlled trial compared the efficacy and safety of SARS-CoV-2 high titer convalescent plasma to placebo control plasma in symptomatic adults ≥18 years positive for SARS-CoV-2 regardless of risk factors for disease progression or vaccine status. Participants with symptom onset within 8 days were enrolled, then transfused within the subsequent day. The measured primary outcome was COVID-19-related hospitalization within 28 days of plasma transfusion. The enrollment period was June 3, 2020 to October 1, 2021. RESULTS A total of 1225 participants were randomized and 1181 transfused. In the pre-specified modified intention-to-treat analysis that excluded those not transfused, the primary endpoint occurred in 37 of 589 (6.3%) who received placebo control plasma and in 17 of 592 (2.9%) participants who received convalescent plasma (relative risk, 0.46; one-sided 95% upper bound confidence interval 0.733; P=0.004) corresponding to a 54% risk reduction. Examination with a model adjusting for covariates related to the outcome did not change the conclusions. CONCLUSION Early administration of high titer SARS-CoV-2 convalescent plasma reduced outpatient hospitalizations by more than 50%. High titer convalescent plasma is an effective early outpatient COVID-19 treatment with the advantages of low cost, wide availability, and rapid resilience to variant emergence from viral genetic drift in the face of a changing pandemic. TRIAL REGISTRATION ClinicalTrials.gov number, NCT04373460 .
PICO Summary
Population
SARS-CoV-2 positive adults within 8 days of symptom onset (n= 1,225).
Intervention
High titre convalescent plasma (n= 592).
Comparison
ABO compatible control plasma (n= 589).
Outcome
A total of 1,181 patients were transfused. In the pre-specified modified intention-to-treat analysis that excluded those not transfused, the primary endpoint occurred in 37 of 589 (6.3%) patients who received ABO compatible control plasma and in 17 of 592 (2.9%) patients who received convalescent plasma corresponding to a 54% risk reduction.
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A Comparative Study on Therapeutic Efficacy of Autologous Platelet Rich Fibrin Matrix Versus Zinc Oxide And Phenytoin Paste in Non Healing Ulcers
Singh A, Chahar YS, Chhabra S
Indian journal of dermatology. 2021;66(6):620-624
Abstract
CONTEXT A non-healing ulcer occurs due to multiple causes and possesses a great impact on the quality of life. Autologous platelet-rich fibrin and the application of a triple combination paste (zinc oxide, phenytoin, and mupirocin ointment) have emerged with a good response in the treatment of non-healing ulcers. AIMS To compare the therapeutic efficacy of autologous platelet-rich fibrin matrix versus the triple combination paste (zinc oxide, phenytoin, and mupirocin ointment) in non-healing ulcers. SETTINGS AND DESIGN Hospital-based interventional comparative study. MATERIALS AND METHOD Twenty-four patients with non-healing ulcers were randomly divided into two groups. One group received platelet-rich fibrin (PRF) therapy every week for up to 5 weeks and the second group applied triple combination paste (zinc oxide, phenytoin, and mupirocin ointment) again for 5 weeks. In the end, the ulcer area was measured. STATISTICAL ANALYSIS USED Student's paired t-test was used to evaluate the correlations between variables. A P-value of < 0.05 was considered significant. RESULTS Group A showed a mean reduction in the ulcer area by 8.26 mm(2) (75.99%). Group B showed a mean reduction in the ulcer area by 4.799 mm(2) (47.75%), which was statistically significant with a P-value of 0.004. CONCLUSION We conclude that autologous platelet-rich fibrin matrix is much more effective than the triple combination paste (zinc oxide, phenytoin, and mupirocin ointment) in the treatment of non-healing ulcers.
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Impact of higher hemoglobin targets on blood pressure and clinical outcomes: a secondary analysis of CHOIR
Inrig JK, Sapp S, Barnhart H, Patel UD, Reddan D, Singh A, Califf RM, Szczech L
Nephrology Dialysis Transplantation. 2012;27((9):):3606-14.
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BACKGROUND Targeting a higher hemoglobin in patients with chronic kidney disease leads to adverse cardiovascular outcomes, yet the reasons remain unclear. Herein, we sought to determine whether changes in erythropoiesis-stimulating agent (ESA) dose and in hemoglobin were predictive of changes in blood pressure (BP) and whether these changes were associated with cardiovascular outcomes. METHODS In this secondary analysis of 1421 Correction of Hemoglobin and Outcomes in Renal Disease (CHOIR) participants, mixed model analyses were used to describe monthly changes in ESA dose and hemoglobin with changes in diastolic BP (DBP) and systolic BP (SBP). Poisson modeling was performed to determine whether changes in hemoglobin and BP were associated with the composite end point of death or cardiovascular outcomes. RESULTS Monthly average DBP, but not SBP, was higher in participants in the higher hemoglobin arm. Increases in ESA doses and in hemoglobin were significantly associated with linear increases in DBP, but not consistently with increases in SBP. In models adjusted for demographics and comorbid conditions, increases in ESA dose (>0 U) and larger increases in hemoglobin (>1.0 g/dL/month) were associated with poorer outcomes [event rate ratio per 1000 U weekly dose per month increase 1.05, (1.02-1.08), P = 0.002 and event rate ratio 1.70 (1.02-2.85), P = 0.05, respectively]. However, increasing DBP was not associated with adverse outcomes [event rate ratio 1.01 (0.98-1.03), P = 0.7]. CONCLUSION Among CHOIR participants, higher hemoglobin targets, increases in ESA dose and in hemoglobin were associated both with increases in DBP and with higher event rates; however, increasing DBP was not associated with adverse outcomes.