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Drugs to reduce bleeding and transfusion in major open vascular or endovascular surgery: a systematic review and network meta-analysis
Beverly A, Ong G, Kimber C, Sandercock J, Dorée C, Welton NJ, Wicks P, Estcourt LJ
The Cochrane database of systematic reviews. 2023;2(2):Cd013649
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Abstract
BACKGROUND Vascular surgery may be followed by internal bleeding due to inadequate surgical haemostasis, abnormal clotting, or surgical complications. Bleeding ranges from minor, with no transfusion requirement, to massive, requiring multiple blood product transfusions. There are a number of drugs, given systemically or applied locally, which may reduce the need for blood transfusion. OBJECTIVES To assess the effectiveness and safety of anti-fibrinolytic and haemostatic drugs and agents in reducing bleeding and the need for blood transfusion in people undergoing major vascular surgery or vascular procedures with a risk of moderate or severe (> 500 mL) blood loss. SEARCH METHODS We searched: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL, and Transfusion Evidence Library. We also searched the WHO ICTRP and ClinicalTrials.gov trial registries for ongoing and unpublished trials. Searches used a combination of MeSH and free text terms from database inception to 31 March 2022, without restriction on language or publication status. SELECTION CRITERIA We included randomised controlled trials (RCTs) in adults of drug treatments to reduce bleeding due to major vascular surgery or vascular procedures with a risk of moderate or severe blood loss, which used placebo, usual care or another drug regimen as control. DATA COLLECTION AND ANALYSIS We used standard Cochrane methods. Our primary outcomes were units of red cells transfused and all-cause mortality. Our secondary outcomes included risk of receiving an allogeneic blood product, risk of reoperation or repeat procedure due to bleeding, risk of a thromboembolic event, risk of a serious adverse event and length of hospital stay. We used GRADE to assess certainty of evidence. MAIN RESULTS We included 22 RCTs with 3393 participants analysed, of which one RCT with 69 participants was reported only in abstract form, with no usable data. Seven RCTs evaluated systemic drug treatments (three aprotinin, two desmopressin, two tranexamic acid) and 15 RCTs evaluated topical drug treatments (drug-containing bioabsorbable dressings or glues), including fibrin, thrombin, collagen, gelatin, synthetic sealants and one investigational new agent. Most trials were conducted in high-income countries and the majority of the trials only included participants undergoing elective surgery. We also identified two ongoing RCTs. We were unable to perform the planned network meta-analysis due to the sparse reporting of outcomes relevant to this review. Systemic drug treatments We identified seven trials of three systemic drugs: aprotinin, desmopressin and tranexamic acid, all with placebo controls. The trials of aprotinin and desmopressin were small with very low-certainty evidence for all of our outcomes. Tranexamic acid versus placebo was the systemic drug comparison with the largest number of participants (2 trials; 1460 participants), both at low risk of bias. The largest of these included a total of 9535 individuals undergoing a number of different higher risk surgeries and reported limited information on the vascular subgroup (1399 participants). Neither trial reported the number of units of red cells transfused per participant up to 30 days. Three outcomes were associated with very low-certainty evidence due to the very wide confidence intervals (CIs) resulting from small study sizes and low number of events. These were: all-cause mortality up to 30 days; number of participants requiring an allogeneic blood transfusion up to 30 days; and risk of requiring a repeat procedure or operation due to bleeding. Tranexamic acid may have no effect on the risk of thromboembolic events up to 30 days (risk ratio (RR) 1.10, 95% CI 0.88 to 1.36; 1 trial, 1360 participants; low-certainty evidence due to imprecision). There is one large ongoing trial (8320 participants) comparing tranexamic acid versus placebo in people undergoing non-cardiac surgery who are at high risk of requiring a red cell transfusion. This aims to complete recruitment in April 2023. This trial has primary outcomes of proportion of participants transfused with red blood cells and incidence of venous thromboembolism (DVT or PE). Topical drug treatments Most trials of topical drug treatments were at high risk of bias due to their open-label design (compared with usual care, or liquids were compared with sponges). All of the trials were small, most were very small, and few reported clinically relevant outcomes in the postoperative period. Fibrin sealant versus usual care was the topical drug comparison with the largest number of participants (5 trials, 784 participants). The five trials that compared fibrin sealant with usual care were all at high risk of bias, due to the open-label trial design with no measures put in place to minimise reporting bias. All of the trials were funded by pharmaceutical companies. None of the five trials reported the number of red cells transfused per participant up to 30 days or the number of participants requiring an allogeneic blood transfusion up to 30 days. The other three outcomes were associated with very low-certainty evidence with wide confidence intervals due to small sample sizes and the low number of events, these were: all-cause mortality up to 30 days; risk of requiring a repeat procedure due to bleeding; and risk of thromboembolic disease up to 30 days. We identified one large trial (500 participants) comparing fibrin sealant versus usual care in participants undergoing abdominal aortic aneurysm repair, which has not yet started recruitment. This trial lists death due to arterial disease and reintervention rates as primary outcomes. AUTHORS' CONCLUSIONS Because of a lack of data, we are uncertain whether any systemic or topical treatments used to reduce bleeding due to major vascular surgery have an effect on: all-cause mortality up to 30 days; risk of requiring a repeat procedure or operation due to bleeding; number of red cells transfused per participant up to 30 days or the number of participants requiring an allogeneic blood transfusion up to 30 days. There may be no effect of tranexamic acid on the risk of thromboembolic events up to 30 days, this is important as there has been concern that this risk may be increased. Trials with sample size targets of thousands of participants and clinically relevant outcomes are needed, and we look forward to seeing the results of the ongoing trials in the future.
PICO Summary
Population
Adults undergoing major vascular surgery or vascular procedures with a risk of moderate or severe blood loss (22 randomised controlled trials, n= 3,393).
Intervention
Drug treatments to reduce bleeding: anti-fibrinolytic and haemostatic drugs and agents.
Comparison
Placebo, usual care or another drug regimen.
Outcome
The primary outcomes were units of red blood cells transfused, all-cause mortality and thromboembolic events. There was too little data for a network meta-analysis. The reporting of outcomes was sparse. There was no evidence of increased risk of thromboembolic events with tranexamic acid [low certainty evidence]. The authors reported a need for larger trials with better reporting of post-surgical outcomes.
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The effect of perioperative antithrombin supplementation on blood conservation and postoperative complications after cardiopulmonary bypass surgery: A systematic review, meta-analysis and trial sequential analysis
Li, T., Bo, F., Meng, X., Wang, D., Ma, J., Dai, Z.
Heliyon. 2023;9(11):e22266
Abstract
STUDY OBJECTIVE Antithrombin (AT) activity is reduced during cardiopulmonary bypass (CPB) surgery. Guidelines has demonstrated that perioperative AT supplementation contributed to blood conservation and prevent perioperative thrombotic complications and target organ injury owing to its role in reducing thrombin generation. But these recommends is lack of support of meta-analysis in the guidelines. This meta-analysis aims to include all the relevant randomized controlled trails (RCT) on patients who experienced cardiac surgeries with CPB and investigate the effect of perioperative AT on blood conservation and complications after cardiac surgery. METHODS Standard published RCTs were searched from bibliographic databases to identify all evidence reporting perioperative AT supplementation for patients undergoing cardiovascular surgeries. The primary outcome was postoperative blood loss, the secondary outcomes were blood component transfusion (red blood cell (RBC), fresh frozen plasma (FFP), platelet and autologous blood), postoperative morbidity and in hospital mortality. The relative risk (RR) for dichotomous outcomes and the standardized mean difference (SMD) for continuous outcomes were estimated using a random-effects model. Trial sequential analysis (TSA) was performed using TSA software 0.9.5.10. RESULTS 13 RCTs with 996 participants undergoing different cardiovascular surgeries were included. Meta-analysis showed AT did not decrease postoperative blood loss (SMD -0.01, 95%CI -0.2 to 0.19). Subgroup analysis showed the effect of AT on postoperative blood loss was not associated with age, RCT type, surgery type, injection time of AT and AT deficiency. TSA further suggested that no additional studies were required for the stable result. Perioperative AT also did not reduce RBC ((SMD 0.10, 95%CI -0.66 to 0.85), (RR 0.99, 95%CI 0.83 to 1.19)), FFP ((SMD 0.11, 95%CI -0.19 to 0.41), (RR 1.30, 95%CI 0.90 to 1.87)), platelet (RR 1.10, 95%CI 0.83 to 1.46) and autologous blood (SMD 0.46, 95%CI -0.12 to 1.8504) transfusions. Perioperative AT significantly increased in hospital mortality (RR 2.53, 95%CI 1.02 to 6.28) and acute kidney injury (AKI) (RR 3.72, 95%CI 1.73 to 8.04) incidence. There was no significant difference in postoperative reexploration, thromboembolism, ECMO/IABP support, and stroke incidence between AT and non-AT group. CONCLUSIONS With the improvement of AT level and heparin sensitivity, perioperative AT has no significant effect on blood conservation. And it is noteworthy that the treatment increased in hospital mortality and the incidence of AKI after cardiac surgery.
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A Meta-Analysis of Using Protamine for Reducing the Risk of Hemorrhage During Carotid Recanalization: Direct Comparisons of Post-operative Complications
Pan Y, Zhao Z, Yang T, Jiao Q, Wei W, Ji J, Xin W
Frontiers in pharmacology. 2022;13:796329
Abstract
Background: Protamine can decrease the risk of hemorrhage during carotid recanalization. However, it may cause severe side effects. There is no consensus on the safety and efficacy of protamine during surgery. Thus, we conduct a comprehensive review and meta-analysis to compare the differences between the protamine and the no-protamine group. Method: We systematically obtained literature from Medline, Google Scholar, Cochrane Library, and PubMed electronic databases. All four databases were scanned from 1937 when protamine was first adopted as a heparin antagonist until February 2021. The reference lists of identified studies were manually checked to determine other eligible studies that qualify. The articles were included in this meta-analysis as long as they met the criteria of PICOS; conference or commentary articles, letters, case report or series, and animal observation were excluded from this study. The Newcastle-Ottawa Quality Assessment Scale and Cochrane Collaboration's tool are used to assess the risk of bias of each included observational study and RCT, respectively. Stata version 12.0 statistical software (StataCorp LP, College Station, Texas) was adopted as statistical software. When I (2) < 50%, we consider that the data have no obvious heterogeneity, and we conduct a meta-analysis using the fixed-effect model. Otherwise, the random-effect model was performed. Result: A total of 11 studies, consisting of 94,618 participants, are included in this study. Our analysis found that the rate of wound hematoma had a significant difference among protamine and no-protamine patients (OR = 0.268, 95% CI = 0.093 to 0.774, p = 0.015). Furthermore, the incidence of hematoma requiring re-operation (0.7%) was significantly lower than that of patients without protamine (1.8%). However, there was no significant difference in the incidence of stroke, wound hematoma with hypertension, transient ischemic attacks (TIA), myocardial infarction (MI), and death. Conclusion: Among included participants undergoing recanalization, the use of protamine is effective in reducing hematoma without increasing the risk of having other complications. Besides, more evidence-based performance is needed to supplement this opinion due to inherent limitations.
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Intraventricular fibrinolytic for the treatment of intraventricular hemorrhage: a network meta-analysis
Li M, Mu F, Han Q, Su D, Guo Z, Chen T
Brain Inj. 2020;:1-7
Abstract
OBJECTIVE To explore which intraventricular fibrinolytic agent - urokinase (UK) or recombinant tissue plasminogen activator (rt-PA) - combined with extraventricular drainage (EVD) is most suitable for patients with spontaneous intraventricular hemorrhage (IVH). PATIENTS AND METHODS We searched PubMed, MEDLINE, OVID, Embase, and Cochrane Library databases for relevant articles and assessed their quality and extracted statistical analyses using Stata 13.0 and Revman 5.3 software. RESULTS Compared with EVD alone, EVD combined with an agent causing intraventricular fibrinolysis (IVF) improved the survival and prognosis of patients with IVH. Regarding the patients' survival rates and prognoses, the treatments, from best to worst results were EVD + UK, EVD + rt-PA, EVD alone. The proportion of patients with serious disability also increased with these treatments, however, with the highest to lowest proportions being EVD + rt-PA, EVD + UK, EVD alone. In addition, EVD + IVF was associated with a higher risk of intracranial rebleeding (from lowest to highest incidence: EVD alone, EVD + rt-PA, EVD + UK). Finally, EVD + UK is associated with an increased risk of potential intracranial infection (from lowest to highest incidence: EVD + rt-PA, EVD alone, EVD + UK). CONCLUSIONS EVD + UK may be the best approach to improving patients' survival rate and prognosis. However, it also presents the highest risk of intracranial infection and rebleeding. EVD + IVF increased the proportion of patients with serious disability.
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Ulinastatin reduces postoperative bleeding and red blood cell transfusion in patients undergoing cardiac surgery: A PRISMA-compliant systematic review and meta-analysis
Yao YT, Fang NX, Liu DH, Li LH
Medicine. 2020;99(7):e19184
Abstract
BACKGROUND Ulinastatin is a type of glycoprotein and a nonspecific wide-spectrum protease inhibitor like antifibrinolytic agent aprotinin. Whether Ulinastatin has similar beneficial effects on blood conservation in cardiac surgical patients as aprotinin remains undetermined. Therefore, a systematic review and meta-analysis were performed to evaluate the effects of Ulinastatin on perioperative bleeding and transfusion in patients who underwent cardiac surgery. METHODS Electronic databases were searched to identify all clinical trials comparing Ulinastatin with placebo/blank on postoperative bleeding and transfusion in patients undergoing cardiac surgery. Primary outcomes included perioperative blood loss, blood transfusion, postoperative re-exploration for bleeding. Secondary outcomes include perioperative hemoglobin level, platelet counts and functions, coagulation tests, inflammatory cytokines level, and so on. For continuous variables, treatment effects were calculated as weighted mean difference (WMD) and 95% confidential interval (CI). For dichotomous data, treatment effects were calculated as odds ratio and 95% CI. Statistical significance was defined as P < .05. RESULTS Our search yielded 21 studies including 1310 patients, and 617 patients were allocated into Ulinastatin group and 693 into Control (placebo/blank) group. There was no significant difference in intraoperative bleeding volume, postoperative re-exploration for bleeding incidence, intraoperative red blood cell transfusion units, postoperative fresh frozen plasma transfusion volumes and platelet concentrates transfusion units between the 2 groups (all P > .05). Ulinastatin reduces postoperative bleeding (WMD = -0.73, 95% CI: -1.17 to -0.28, P = .001) and red blood cell (RBC) transfusion (WMD = -0.70, 95% CI: -1.26 to -0.14, P = .01), inhibits hyperfibrinolysis as manifested by lower level of postoperative D-dimer (WMD = -0.87, 95% CI: -1.34 to -0.39, P = .0003). CONCLUSION This meta-analysis has found some evidence showing that Ulinastatin reduces postoperative bleeding and RBC transfusion in patients undergoing cardiac surgery. However, these findings should be interpreted rigorously. Further well-conducted trials are required to assess the blood-saving effects and mechanisms of Ulinastatin.
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The effect of levosimendan on postoperative bleeding and blood transfusion in cardiac surgical patients: a PRISMA-compliant systematic review and meta-analysis
Yao YT, He LX, Zhao YY
Perfusion. 2020;:267659120963909
Abstract
BACKGROUND Levosimendan (LEVO), is an inotropic agent which has been shown to be associated with better myocardial performance, and higher survival rate in cardiac surgical patients. However, preliminary clinical evidence suggested that LEVO increased the risk of post-operative bleeding in patients undergoing valve surgery. Currently, there has been no randomized controlled trials (RCTs) designed specifically on this issue. Therefore, we performed present systemic review and meta-analysis. METHODS Electronic databases were searched to identify all RCTs comparing LEVO with Control (placebo, blank, dobutamine, milrinone, etc). Primary outcomes include post-operative blood loss and re-operation for bleeding. Secondary outcomes included post-operative transfusion of red blood cells (RBC), fresh frozen plasma (FFP) and platelet concentrates (PC). For continuous variables, treatment effects were calculated as weighted mean difference (WMD) and 95% confidential interval (CI). For dichotomous data, treatment effects were calculated as odds ratio (OR) and 95% CI. RESULTS Search yielded 15 studies including 1,528 patients. Meta-analysis suggested that, LEVO administration was not associated with increased risk of reoperation for bleeding post-operatively (OR = 1.01; 95%CI: 0.57 to 1.79; p = 0.97) and more blood loss volume (WMD = 28.25; 95%CI: -19.21 to 75.72; p = 0.24). Meta-analysis also demonstrated that, LEVO administration did not increase post-operative transfusion requirement for RBC (rate: OR = 0.97; 95%CI: 0.72 to 1.30; p = 0.83 and volume: WMD = 0.34; 95%CI: -0.55 to 1.22; p = 0.46), FFP (volume: WMD = 0.00; 95%CI: -0.10 to 0.10; p = 1.00) and PC (rate: OR = 1.01; 95%CI: 0.41 to 2.50; p = 0.98 and volume: WMD = 0.00; 95%CI: -0.05 to 0.04; p = 0.95). CONCLUSION This meta-analysis suggested that, peri-operative administration of LEVO was not associated with increased risks of post-operative bleeding and blood transfusion requirement in cardiac surgical patients.
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7.
Meta-Analysis of Effects of Bivalirudin Versus Heparin on Myocardial Ischemic and Bleeding Outcomes After Percutaneous Coronary Intervention
Barria Perez, A. E., Rao, S. V., Jolly, S. J., Pancholy, S. B., Plourde, G., Rimac, G., Poirier, Y., Costerousse, O., Bertrand, O. F.
The American Journal of Cardiology. 2016;117(8):1256-66
Abstract
Bivalirudin is an alternative to unfractionated heparin (UFH) anticoagulation during percutaneous coronary intervention. Previously, we have reported clinical benefit on major bleeding in favor of bivalirudin compared with UFH monotherapy but inconclusive results on mortality. Controversial data have been reported in the last 2 years. We conducted an updated meta-analysis including randomized trials and observational studies, which evaluated ischemic and bleeding outcomes for bivalirudin compared with UFH-only during percutaneous coronary intervention. We included 18 observational studies and 12 randomized trials published from 2003 to 2015. Primary outcomes were major adverse cardiovascular events within 30 days including death, myocardial infarction, and urgent revascularization and stent thrombosis, major bleeding, and transfusion. Overall, we found a significant risk reduction with bivalirudin for major bleeding (odds ratio [OR] 0.59, 95% confidence interval [CI] 0.49 to 0.71, p <0.0001) and for transfusion (OR 0.79, 95% CI 0.66 to 0.95, p = 0.01) and similar risk for major adverse cardiovascular events (OR 0.98, 95% CI 0.86 to 1.12, p = 0.80). However, there was a substantial increased risk of stent thrombosis associated with bivalirudin (OR 1.52, 95% CI 1.11 to 2.08, p = 0.009). No impact on mortality was found. Meta-regression analyses on major bleeding suggested that bivalirudin was more effective than UFH at doses >60 IU/kg and independent of radial access. In conclusion, compared with UFH monotherapy, bivalirudin remains associated with less bleeding risk but higher stent thrombosis risk. Further study remains required to define its role in current antithrombotic armamentarium.
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Blood loss after cardiopulmonary bypass, standard vs titrated protamine: a meta-analysis
Wang, J., Ma, H. P., Zheng, H.
The Netherlands Journal of Medicine. 2013;71(3):123-7
Abstract
BACKGROUND The aim of this meta-analysis was to determine whether standard or titrated dosing of protamine is more effective in facilitating haemostasis after cardiac surgery with cardiopulmonary bypass (CPB). METHODS We searched MEDLINE, and Biomedical Central using the terms 'cardiopulmonary bypass and heparin and protamine'. Studies were included in the meta-analysis if they were randomised controlled trials (RCTs), controlled clinical studies, or cohort studies with designs comparing the postoperative volume of bleeding between the study group (titrated dose) and the control group (standard dose) for protamine reversal of surgical anticoagulation in CPB procedures. The primary outcome of interest was postoperative blood loss. RESULTS There were 219 studies identified in the initial search; four of these were included in the meta-analysis. All studies were RCTs, involving a total of 507 patients. Postoperative blood loss was lower in the study group (range: 625-839 ml) compared with the control group (range: 765-995 ml) in all four studies. Transfusion of packed red blood cells was also lower in the study group compared with the control group in all four studies. There was no evidence of significant heterogeneity in postoperative blood loss among the four studies (Q=4.224, I2=28.98%, p=0.238); hence, a fixed-effects model of analysis was used. The overall/combined standardised difference in means of postoperative blood loss volume significantly favoured study treatment over control treatment (-0.562±0.322, p<0.001). CONCLUSION These findings suggest that titrated protamine dosing is more effective than standard protamine dosing for reducing postoperative bleeding after CPB.
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Are batroxobin agents effective for perioperative hemorrhage in thoracic surgery? A systematic review of randomized controlled trials
Zeng Z, Xiao P, Chen J, Wei Y
Blood Coagulation & Fibrinolysis. 2009;20((2):):101-7.
Abstract
The objective of the present study was to evaluate the effect of batroxobin agents on perioperative hemorrhage in thoracic surgery.We systematically searched Cochrane Library, Pubmed, EMBASE and the China Biological Medicine CD-ROM Databases up to August 2007. Reference lists of all included studies and of reviews related to the topic of the present systematic review were manually searched. Two reviewers independently identified the eligible studies, assessed their methodological quality and extracted data. Results of relevant outcomes were pooled together whenever possible, using RevMan software.Five randomized controlled trials involving 678 patients were included. Three trials were for pneumonectomy and two for cardiac surgery with cardiopulmonary bypass. The quality of the identified studies was generally poor. All the trials claimed randomized allocation, but allocation concealment was unclear. Blinding was not mentioned. Two trials found that batroxobin agents decreased intraoperative blood loss for pneumonectomy. Mean differences between the batroxobin agents group and the no-treatment group were -182.20 ml [95% confidence interval (CI), -207.48 to -156.92] and -131.32 ml (95% CI, -142.95 to -119.69), respectively, for these two trials. All included trials reported less drainage volume favoring the batroxobin agents group. Mean differences at different time points after operation ranged from -15 ml (95% CI, -31.77 to 1.77) to -150.60 ml (95% CI, -179.26 to -121.94). Although most of the differences between the batroxobin agents group and the no treatment group were statistically significant, clinical value was limited.There is not enough evidence supporting any benefit of batroxobin agents for hemorrhage during thoracic surgery.
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10.
Desmopressin reduces transfusion needs after surgery: a meta-analysis of randomized clinical trials
Crescenzi G, Landoni G, Biondi-Zoccai G, Pappalardo F, Nuzzi M, Bignami E, Fochi O, Maj G, Calabro MG, Ranucci M, et al
Anesthesiology. 2008;109((6):):1063-76.
Abstract
BACKGROUND Perioperative pathologic microvascular bleeding is associated with increased morbidity and mortality and could be reduced by hemostatic drugs. At the same time, safety concerns regarding existing hemostatic agents include excess mortality. Numerous trials investigating desmopressin have lacked power to detect a beneficial effect on transfusion of blood products. The authors performed a meta-analysis of 38 randomized, placebo-controlled trials (2,488 patients) investigating desmopressin in surgery and indicating at least perioperative blood loss or transfusion of blood products. METHODS Pertinent studies were searched in BioMed Central, CENTRAL, and PubMed (updated May 1, 2008). Further hand or computerized searches involved recent (2003-2008) conference proceedings. RESULTS In most of the included studies, 0.3 microg/kg desmopressin was used prophylactically over a 15- to 30-min period. In comparison with placebo, desmopressin was associated with reduced requirements of blood product transfusion (standardized mean difference = -0.29 [-0.52 to -0.06] units per patient; P = 0.01), which were more pronounced in the subgroup of noncardiac surgery and were without a statistically significant increase in thromboembolic adverse events (57/1,002 = 5.7% in the desmopressin group vs. 45/979 = 4.6% in the placebo group; P = 0.3). CONCLUSIONS Desmopressin slightly reduced blood loss (almost 80 ml per patient) and transfusion requirements (almost 0.3 units per patient) in surgical patients, without reduction in the proportion of patients who received transfusions. This meta-analysis suggests the importance of further large, randomized controlled studies using desmopressin in patients with or at risk of perioperative pathologic microvascular bleeding.