Risk Of Vascular Occlusive Events Research Articles

Plasmin Inhibitor in Health and Diabetes: Role of the Protein as a Therapeutic Target.

The vascular obstructive thrombus is composed of a mesh of fibrin fibers with blood cells trapped in these networks. Enhanced fibrin clot formation and/or suppression of fibrinolysis are associated with an increased risk of vascular occlusive events. Inhibitors of coagulation factors and activators of plasminogen have been clinically used to limit fibrin network formation and enhance lysis. While these agents are effective at reducing vascular occlusion, they carry a significant risk of bleeding complications. Fibrin clot lysis, essential for normal hemostasis, is controlled by several factors including the incorporation of antifibrinolytic proteins into the clot. Plasmin inhibitor (PI), a key antifibrinolytic protein, is cross-linked into fibrin networks with higher concentrations of PI documented in fibrin clots and plasma from high vascular risk individuals. This review is focused on exploring PI as a target for the prevention and treatment of vascular occlusive disease. We first discuss the relationship between the PI structure and antifibrinolytic activity, followed by describing the function of the protein in normal physiology and its role in pathological vascular thrombosis. Subsequently, we describe in detail the potential use of PI as a therapeutic target, including the array of methods employed for the modulation of protein activity. Effective and safe inhibition of PI may prove to be an alternative and specific way to reduce vascular thrombotic events while keeping bleeding risk to a minimum. Key Points Plasmin inhibitor (PI) is a key protein that inhibits fibrinolysis and stabilizes the fibrin network.This review is focused on discussing mechanistic pathways for PI action, role of the molecule in disease states, and potential use as a therapeutic target.

Safety and Efficacy of 14-Day Cold Stored Platelets in Reversing Effects of Aspirin

Background: Aspirin is an antiplatelet therapy used to reduce the risk of vascular occlusive events. However, this therapy is associated with an increased risk of bleeding for which there is no antidote currently. Transfusion of 5-day room stored platelets (RSP) at 22°C can reverse the effect of aspirin but surprisingly, the recent randomized PATCH trial showed increased morbidity and mortality for patients who received RSP transfusion for intracranial hemorrhage while on aspirin. Prior studies have shown that cold stored platelets (CSP) at 4°C are mildly activated and may participate in clot formation immediately, thus may have the potential to reduce blood loss more rapidly than RSP in acutely bleeding patients. CSP also have the added advantages of decreased risk of bacterial contamination and longer shelf-life up to 14 days per current FDA variance. However, the function of 14-day CSP in plasma after transfusion is unclear and lacks high quality data. We aimed to evaluate the post-transfusion safety and efficacy of 14-day CSP in reversing the effects of aspirin therapy compared to that of 7-day RSP.Methods: Seven healthy human subjects were included in the analysis of this randomized, controlled, crossover study comparing transfusion of autologous 14-day CSP to 7-day RSP. Each subject participated in two study periods, which crossed over from one storage product to the other (CSP vs. RSP) according to randomization. For each study period, subjects underwent an apheresis platelet collection for autologous transfusion. Platelets were stored for either 14 days for CSP or 7 days for RSP. Subjects received a loading dose of aspirin 24 hours prior to transfusion. Blood was drawn at baseline, immediately pre-transfusion, at 1-hr, 4-hr, and 24-hr post-transfusion for an array of platelet function testing. After a washout period of 10-28 days, second study period commenced with similar sequence of events as the first study period using the other platelet storage product. The primary endpoint is the VerifyNOW Aspirin Reaction Units (ARU) at 1-hr after autologous transfusion. Secondary endpoints include ARU at 4-hr and 24-hr post transfusion, light transmission aggregometry in response to arachidonic acid and collagen, and the corrected count increment. Paired t-tests were used for statistical analysis between the two groups and, where appropriate, the change from pre-transfusion values were analyzed.Results: Transfusion of 14-day CSP and 7-day RSP units were well-tolerated by all subjects. Storage of platelets in the cold led to a non-significant trend for decreased platelet count, and the total platelet yield at the end of storage was significantly less in 14-day CSP compared to 7-day RSP (p=0.02). However, the corrected count increment did not differ significantly at 1-hr after transfusion. Platelet aggregation using the agonists, arachidonic acid 0.5mM and collagen 2.5ug/mL, did not reveal any significant difference between the two groups at any time points. The primary endpoint, platelet function testing by VerifyNOW, showed a larger change in platelet responsiveness at 1-hr post-transfusion in RSP than in CSP (p=0.03). Surprisingly, only RSP transfusion resulted in a significant change from the pre-transfusion VerifyNow measurements. Later time points showed a slight trend for improved platelet function as measured by VerifyNow with transfusion of both platelet products, but none were statistically significant.Conclusion: We report the first safety and efficacy data for 14-day cold stored platelets in in healthy humans. While prior in-vitro studies have demonstrated possible hemostatic superiority of cold stored over room temperature stored platelets, we observed inferior reversal of aspirin at early time points with CSP. This was in contrast to the results from our previous study, where 5 day-stored CSP were equivalent to RSP at early post transfusion time points. Further studies are needed to evaluate the maximal storage that provides functional equivalency between CSP and RSP. In addition, studies in actively bleeding patients are needed. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Effect of tranexamic acid by baseline risk of death in acute bleeding patients: a meta-analysis of individual patient-level data from 28 333 patients

BackgroundEarly administration of the antifibrinolytic drug tranexamic acid reduces death from bleeding in trauma and postpartum haemorrhage. We examined how the effectiveness and safety of antifibrinolytic drugs varies by the baseline risk of death as a result of bleeding. MethodsWe performed an individual patient-level data meta-analysis of randomised trials including more than 1000 patients that assessed antifibrinolytics in acute severe bleeding. We identified trials performed between January 1, 1946 and July 5, 2018 (PROSPERO, number 42016052155). ResultsTwo randomised trials were selected where 28 333 patients received tranexamic acid treatment within 3 h after the onset of acute bleeding. Baseline characteristics to estimate the risk of death as a result of bleeding were divided into four categories: Low (0–5%), intermediate (6–10%), high (11–20%), and very high (>20%). Most patients had a low baseline risk of death as a result of bleeding (23 008 [81%]). Deaths as a result of bleeding occurred in all baseline risk categories with 240 (1%), 202 (8%), 232 (14%), and 357 (30%) deaths in the low-, intermediate-, high-, and very high-risk categories, respectively. The effectiveness of tranexamic acid did not vary by baseline risk when given within 3 h after bleeding onset (P=0.51 for interaction term). There was no increased risk of vascular occlusive events with tranexamic acid and it did not vary by baseline risk categories (P=0.25). ConclusionsTranexamic acid appears to be safe and effective regardless of baseline risk of death. Because many deaths are in patients at low and intermediate risk, tranexamic acid use should not be restricted to the most severely injured or bleeding patients.

Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial

SummaryBackgroundTranexamic acid reduces surgical bleeding and decreases mortality in patients with traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury (TBI) and can cause brain herniation and death. We aimed to assess the effects of tranexamic acid in patients with TBI.MethodsThis randomised, placebo-controlled trial was done in 175 hospitals in 29 countries. Adults with TBI who were within 3 h of injury, had a Glasgow Coma Scale (GCS) score of 12 or lower or any intracranial bleeding on CT scan, and no major extracranial bleeding were eligible. The time window for eligibility was originally 8 h but in 2016 the protocol was changed to limit recruitment to patients within 3 h of injury. This change was made blind to the trial data, in response to external evidence suggesting that delayed treatment is unlikely to be effective. We randomly assigned (1:1) patients to receive tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was head injury-related death in hospital within 28 days of injury in patients treated within 3 h of injury. We prespecified a sensitivity analysis that excluded patients with a GCS score of 3 and those with bilateral unreactive pupils at baseline. All analyses were done by intention to treat. This trial was registered with ISRCTN (ISRCTN15088122), ClinicalTrials.gov (NCT01402882), EudraCT (2011-003669-14), and the Pan African Clinical Trial Registry (PACTR20121000441277).ResultsBetween July 20, 2012, and Jan 31, 2019, we randomly allocated 12 737 patients with TBI to receive tranexamic acid (6406 [50·3%] or placebo [6331 [49·7%], of whom 9202 (72·2%) patients were treated within 3 h of injury. Among patients treated within 3 h of injury, the risk of head injury-related death was 18·5% in the tranexamic acid group versus 19·8% in the placebo group (855 vs 892 events; risk ratio [RR] 0·94 [95% CI 0·86–1·02]). In the prespecified sensitivity analysis that excluded patients with a GCS score of 3 or bilateral unreactive pupils at baseline, the risk of head injury-related death was 12·5% in the tranexamic acid group versus 14·0% in the placebo group (485 vs 525 events; RR 0·89 [95% CI 0·80–1·00]). The risk of head injury-related death reduced with tranexamic acid in patients with mild-to-moderate head injury (RR 0·78 [95% CI 0·64–0·95]) but not in patients with severe head injury (0·99 [95% CI 0·91–1·07]; p value for heterogeneity 0·030). Early treatment was more effective than was later treatment in patients with mild and moderate head injury (p=0·005) but time to treatment had no obvious effect in patients with severe head injury (p=0·73). The risk of vascular occlusive events was similar in the tranexamic acid and placebo groups (RR 0·98 (0·74–1·28). The risk of seizures was also similar between groups (1·09 [95% CI 0·90–1·33]).InterpretationOur results show that tranexamic acid is safe in patients with TBI and that treatment within 3 h of injury reduces head injury-related death. Patients should be treated as soon as possible after injury.FundingNational Institute for Health Research Health Technology Assessment, JP Moulton Charitable Trust, Department of Health and Social Care, Department for International Development, Global Challenges Research Fund, Medical Research Council, and Wellcome Trust (Joint Global Health Trials scheme).TranslationsFor the Arabic, Chinese, French, Hindi, Japanese, Spanish and Urdu translations of the abstract see Supplementary Material.

PS1188 AN UPDATED META‐ANALYSIS OF THE RISKS OF ARTERIAL AND VENOUS OCCLUSIVE EVENTS WITH NEW GENERATION BCR‐ABL TKIS IN PATIENTS WITH CHRONIC MYELOID LEUKAEMIA

Background:A prior meta‐analysis demonstrated that 3 of the new generation BCR‐ABL tyrosine kinase inhibitors (TKIs) (i.e. dasatinib, nilotinib and ponatinib) are associated with an increased risk of vascular occlusive events compared with imatinib. Additional analyses demonstrate that this risk is mainly driven by the occurrence of arterial events. At the time of these analyses, few clinical data were available on bosutinib (only one study included with few events in each arms), inducing a low statistical power to compute the risk of vascular occlusive events with this treatment. Recent clinical data comparing bosutinib to imatinib have been published and need to be incorporated in the meta‐analysis.Aims:To update the meta‐analysis on the risk of arterial and venous occlusive events in patients with Ph+ CML treated with new generation BCR‐ABL TKIs in randomized clinical trials (RCTs), particularly to assess the cardiovascular safety of bosutinib.Methods:The literature search (data lock point: January, 25th, 2019) was conducted according to a registered protocol (PROSPERO 2014:CRD42014014147). All RCTs comparing a new generation BCR‐ABL TKI versus imatinib in patients with Ph+ CML were included. Two independent investigators screened the literature, reviewed and extracted the data using standard forms. The statistical analyses were performed using a random (REM) and a fixed (FEM) effect model according to the characteristics of the included studies. ORs with 95% CIs were computed using the Peto method. Statistical heterogeneity was quantified using the I2 value, and publication bias was assessed by funnel plots.Results:Among the 385 abstracts identified, 13 studies fulfilled the established criteria and were included in the statistical analysis. Overall, 7.93% (197/2,484) of patients treated with a new generation BCR‐ABL TKIs developed a vascular occlusive event compared with 2.61% (56/2,149) when treated with imatinib (REM ORPETO: 2.81; 95%CI: 2.09 to 3.80). The update does not change the increased risk of vascular occlusive events with ponatinib (REM ORPETO: 3.47; 95%CI: 1.23 to 9.78), nilotinib (REM ORPETO: 3.55; 95%CI: 2.29 to 5.51) and dasatinib (REM ORPETO: 2.87; 95%CI: 1.48 to 5.55) compared with imatinib. The addition of the results from the BFORE trial (NCT02130557) improve the statistical power of the analysis and demonstrate a non‐significant trend towards an increased risk of vascular events with this treatment (REM ORPETO: 1.67; 95%CI: 0.91 to 3.05). In accordance with the results on ponatinib, nilotinib and dasatinib, this risk is mainly driven by the occurrence of arterial occlusive events. Arterial occlusive events occur in 7.08% (176/2,487) of patients treated with bosutinib whereas only 0.85% (21/2,484) of patients treated with bosutinib report a venous occlusive event. Funnel plots demonstrate no evidences of publication bias, and the I2 statistic specifies no heterogeneity among studies.Limitations of this meta‐analysis include the absence of a time‐to‐event analysis and the inconsistent report of cardiovascular events in the literature. However, the use of a clinical trial register aimed to decrease this heterogeneity.Summary/Conclusion:This updated meta‐analysis confirmed the risk of arterial occlusive events with new generation BCR‐ABL TKIs. The addition of the results from the BFORE trial increases the statistical power of the bosutinib sub‐analysis and reduce the interval confidence of the analysis. Further investigations are needed to confirm the apparently safer profile of bosutinib in regard to cardiovascular occlusive events.

Risk of arterial and venous occlusive events in chronic myeloid leukemia patients treated with new generation BCR-ABL tyrosine kinase inhibitors: a systematic review and meta-analysis

ABSTRACTBackground: A previous meta-analysis demonstrated that 3 of the new-generation BCR-ABL tyrosine kinase inhibitors (TKIs) (dasatinib, nilotinib and ponatinib) are associated with an increased risk of vascular occlusive events in patients with Ph+ chronic myeloid leukemia compared with imatinib. This meta-analysis of randomized controlled trials aims at assessing these risks separately.Methods: The literature search was performed by two independent reviewers following the previous protocol (PROSPERO 2014:CRD42014014147). A random-effects model and a fixed-effect model were used according to the characteristics of the included studies. Peto odds ratios with 95%CI were computed.Results: Overall, 4.78% of patients developed arterial occlusive events with new generation TKIs compared with 0.96% with imatinib. Ponatinib (ORPETO:3.26; 95%CI:1.12 to 9.50), nilotinib (ORPETO: 3.69; 95%CI:2.29 to 5.95) and dasatinib (ORPETO:3.32; 95%CI:1.37 to 8.01) are all associated with a higher risk of arterial occlusive events than imatinib. Venous occlusive events occur in 0.72% of patients treated with new generation TKIs and in 0.27% of imatinib-treated patients. Overall, a trend toward an increase of the rate of venous occlusive events with new-generation TKIs (ORPETO:2.17; 95%CI:0.90 to 5.25) was highlighted but stratifications by treatment gave nonsignificant results.Conclusions: Vascular occlusive events associated with new-generation BCR-ABL TKIs are driven by arterial occlusive events.

Association Between BCR-ABL Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia and Cardiovascular Events, Major Molecular Response, and Overall Survival: A Systematic Review and Meta-analysis.

A phase 3 trial with ponatinib in patients with chronic myeloid leukemia (CML) was interrupted due to an important increase of vascular occlusive events. A similar risk was also suspected with nilotinib, another BCR-ABL tyrosine kinase inhibitor (TKI) used in patients with CML. To assess the risk of vascular occlusive events in patients with CML treated by new generations of TKIs and provide an overall assessment of the clinical benefit. Two independent reviewers selected studies from PubMed, Scopus, and the Cochrane library database from their inception to October 21, 2014. Abstracts published during the past 3 years at international congresses and a trial register were also searched. Two independent reviewers screened abstracts and titles against inclusion and exclusion criteria published previously in the PROSPERO 2014 protocol: CRD42014014147. Among the 249 abstracts identified, 10 studies fulfilled the established criteria. Two investigators independently extracted data using a standard form. Information extracted included study and patients characteristics, type of intervention and data on vascular occlusive events, overall survival, and major molecular response (MMR). The meta-analysis was performed using a fixed-effects model. Odds ratios (ORs) with 95% CIs were computed using the Peto method. Ten randomized clinical trials (3043 patients) were analyzed. Risk of vascular occlusive events was increased with dasatinib (OR, 3.86; 95% CI, 1.33-11.18), nilotinib (OR, 3.42; 95% CI, 2.07-5.63), and ponatinib (OR, 3.47; 95% CI, 1.23-9.78) compared with imatinib in patients with CML. No significant difference was found with bosutinib (OR, 2.77; 95% CI, 0.39-19.77). New-generation TKIs increased the rate of MMR at 1 year compared with imatinib (overall OR, 2.22; 95% CI, 1.87 to 2.63). No statistical difference in overall survival at 1 year was found (overall OR, 1.20; 95% CI, 0.63-2.29). Inaccessibility to individual data and time-to-event data and differences in evaluation criteria between studies could have introduced bias. Dasatinib, nilotinib, and ponatinib increase vascular occlusive events. New-generation TKIs improve MMR but not the overall survival at 1 year in patients with CML.

BCR-ABL Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: A Systematic Review and Meta-Analysis on the Risk of Cardiovascular Events, Major Molecular Response and Overall Survival

Introduction:Ponatinib is a BCR-ABL tyrosine kinase inhibitor (TKI) indicated in adult patients suffering from chronic myeloid leukemia (CML) or “Philadelphia-chromosome positive” (Ph+) acute lymphoblastic leukemia resistant or intolerant to dasatinib or nilotinib. A high incidence of arterial events including peripheral artery occlusive diseases has been observed with ponatinib during the clinical development. A similar risk was also suspected with nilotinib, another BCR-ABL TKI used in CML. To date, no signal of increased risk of vascular thrombosis and embolism was found in clinical trials with imatinib and dasatinib. However, some cases were reported post-marketing.Aim:To perform a meta-analysis to assess the risk of vascular occlusive events (VOE) with novel generation BCR-ABL TKI (i.e. bosutinib, dasatinib, nilotinib and ponatinib) in CML patients compared with standard of care (i.e. imatinib). Stratifications by BCR-ABL TKI are performed to provide product specific risk assessment. Data on the overall survival and the major molecular response were also extracted to provide global benefit-risk evaluation.Methods:Study selection was performed in two stages. Initially, two independent reviewers screened abstracts and titles against inclusion and exclusion criteria (see protocol at PROSPERO 2014:CRD42014014147). Then, both reviewers assessed potentially relevant papers in their entirety, deciding on inclusion. Studies included all randomized controlled trials (RCT), comparing BCR-ABL TKI versus the reference therapy. Data on major molecular response, overall survival and VOE were extracted. The meta-analysis was performed using a fixed-effect model. Odds ratios (OR) with 95% confidence intervals (CI) were computed using the Peto method. Statistical heterogeneity across the various trials was tested using the Cochran's Q statistic and quantified by the I2 value. Funnel plot asymmetry was assessed by the method of Egger's linear regression, the Begg and Mazumbar rank correlation and the Owrin's fail safe N tests.Results:Among the 10 studies included, 3 studies did not report overall survival and 9 studies reported VOE and the major molecular response. Risk of VOE was increased with dasatinib (OR 3.86; 95%CI: 1.33 to 11.18), nilotinib (OR: 3.45; 95%CI: 2.07 to 5.63) and ponatinib (OR: 3.47; 95%CI: 1.23 to 9.78) compared to imatinib in patients with Ph+ CML (Figure 1). No significant difference was found with bosutinib (OR: 2.77; 95%CI: 0.39 to 19.77) probably due to a lack of power, but a trend was also demonstrated (Figure 1). Novel generation TKI increased the rate of major molecular response at 1 year compared to imatinib (overall OR: 2.22; 95%CI: 1.87 to 2.63) (Figure 2). No statistical difference in term of overall survival at one year was found (overall OR: 1.23; 95%CI: 0.67 to 2.23) (Figure 3). Unfortunately, the inaccessibility to individual data and to the time-to-event along with the fact that the evaluation criteria were not similar between studies can introduce a bias in the analysis. However, neither heterogeneity nor publication bias were found, supporting the robustness of our results.The risk of VOE is likely to be dose-related; however, currently available data on dose-efficacy and dose-toxicity relationship are not sufficient to make a formal recommendation on dose reduction, since there is a risk that lower doses might have reduced efficacy. However, safety and efficacy data concerning dose reduction following major cytogenetic response have been included in the EU-SmPC of Iclusig¨ (ponatinib) as a risk minimization measure.Conclusion:Dasatinib, nilotinib and ponatinib increase VOE. Novel generation TKI improve major molecular response but not the overall survival at one year. Further dose-ranging studies are required to define the dose regimen of each BCR-ABL TKI that will provide the best benefit-risk profile. Monitoring the response at the individual level might be of utmost importance to reduce the risk of VOE while keeping the benefit in term of major molecular response. [Display omitted] [Display omitted] [Display omitted] DisclosuresGraux:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Antifibrinolytic drugs for acute traumatic injury.

Uncontrolled bleeding is an important cause of death in trauma victims. Antifibrinolytic treatment has been shown to reduce blood loss following surgery and may also be effective in reducing blood loss following trauma. To assess the effect of antifibrinolytic drugs in patients with acute traumatic injury. We ran the most recent search in January 2015. We searched the Cochrane Injuries Group's Specialised Register, The Cochrane Library, Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase Classic+Embase (OvidSP), PubMed and clinical trials registries. Randomised controlled trials of antifibrinolytic agents (aprotinin, tranexamic acid [TXA], epsilon-aminocaproic acid and aminomethylbenzoic acid) following acute traumatic injury. From the results of the screened electronic searches, bibliographic searches, and contacts with experts, two authors independently selected trials meeting the inclusion criteria, and extracted data. One review author assessed the risk of bias for key domains.Outcome measures included: mortality at end of follow-up (all-cause); adverse events (specifically vascular occlusive events [myocardial infarction, stroke, deep vein thrombosis or pulmonary embolism] and renal failure); number of patients undergoing surgical intervention or receiving blood transfusion; volume of blood transfused; volume of intracranial bleeding; brain ischaemic lesions; death or disability.We rated the quality of the evidence as 'high', 'moderate', 'low' or 'very low' according to the GRADE approach. Three trials met the inclusion criteria.Two trials (n = 20,451) assessed the effect of TXA. The larger of these (CRASH-2, n = 20,211) was conducted in 40 countries and included patients with a variety of types of trauma; the other (n = 240) restricted itself to those with traumatic brain injury (TBI) only.One trial (n = 77) assessed aprotinin in participants with major bony trauma and shock.The pooled data show that antifibrinolytic drugs reduce the risk of death from any cause by 10% (RR 0.90, 95% CI 0.85 to 0.96; P = 0.002) (quality of evidence: high).This estimate is based primarily on data from the CRASH-2 trial of TXA, which contributed 99% of the data.There is no evidence that antifibrinolytics have an effect on the risk of vascular occlusive events (quality of evidence: moderate), need for surgical intervention or receipt of blood transfusion (quality of evidence: high). There is no evidence for a difference in the effect by type of antifibrinolytic (TXA versus aprotinin) however, as the pooled analyses were based predominantly on trial data concerning the effects of TXA, the results can only be confidently applied to the effects of TXA. The effects of aprotinin in this patient group remain uncertain.There is some evidence from pooling data from one study (n = 240) and a subset of data from CRASH-2 (n = 270) in patients with TBI which suggest that TXA may reduce mortality although the estimates are imprecise, the quality of evidence is low, and uncertainty remains. Stronger evidence exists for the possibility of TXA reducing intracranial bleeding in this population. TXA safely reduces mortality in trauma patients with bleeding without increasing the risk of adverse events. TXA should be given as early as possible and within three hours of injury, as further analysis of the CRASH-2 trial showed that treatment later than this is unlikely to be effective and may be harmful. Although there is some promising evidence for the effect of TXA in patients with TBI, substantial uncertainty remains.Two ongoing trials being conducted in patients with isolated TBI should resolve these remaining uncertainties.

The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients

Among trauma patients who survive to reach hospital, exsanguination is a common cause of death. A widely practicable treatment that reduces blood loss after trauma could prevent thousands of premature deaths each year. The CRASH-2 trial aimed to determine the effect of the early administration of tranexamic acid on death and transfusion requirement in bleeding trauma patients. In addition, the effort of tranexamic acid on the risk of vascular occlusive events was assessed. Tranexamic acid (TXA) reduces bleeding in patients undergoing elective surgery. We assessed the effects and cost-effectiveness of the early administration of a short course of TXA on death, vascular occlusive events and the receipt of blood transfusion in trauma patients. Randomised placebo-controlled trial and economic evaluation. Randomisation was balanced by centre, with an allocation sequence based on a block size of eight, generated with a computer random number generator. Both participants and study staff (site investigators and trial co-ordinating centre staff) were masked to treatment allocation. All analyses were by intention to treat. A Markov model was used to assess cost-effectiveness. The health outcome was the number of life-years (LYs) gained. Cost data were obtained from hospitals, the World Health Organization database and UK reference costs. Cost-effectiveness was measured in international dollars ($) per LY. Deterministic and probabilistic sensitivity analyses were performed to test the robustness of the results to model assumptions. Two hundred and seventy-four hospitals in 40 countries. Adult trauma patients (n = 20,211) with, or at risk of, significant bleeding who were within 8 hours of injury. Tranexamic acid (loading dose 1 g over 10 minutes then infusion of 1 g over 8 hours) or matching placebo. The primary outcome was death in hospital within 4 weeks of injury, and was described with the following categories: bleeding, vascular occlusion (myocardial infarction, stroke and pulmonary embolism), multiorgan failure, head injury and other. Patients were allocated to TXA (n = 10,096) and to placebo (n = 10,115), of whom 10,060 and 10,067 patients, respectively, were analysed. All-cause mortality at 28 days was significantly reduced by TXA [1463 patients (14.5%) in the TXA group vs 1613 patients (16.0%) in the placebo group; relative risk (RR) 0.91; 95% confidence interval (CI) 0.85 to 0.97; p = 0.0035]. The risk of death due to bleeding was significantly reduced [489 patients (4.9%) died in the TXA group vs 574 patients (5.7%) in the placebo group; RR 0.85; 95% CI 0.76 to 0.96; p = 0.0077]. We recorded strong evidence that the effect of TXA on death due to bleeding varied according to the time from injury to treatment (test for interaction p < 0.0001). Early treatment (≤ 1 hour from injury) significantly reduced the risk of death due to bleeding [198 out of 3747 patients (5.3%) died in the TXA group vs 286 out of 3704 patients (7.7%) in the placebo group; RR 0.68; 95% CI 0.57 to 0.82; p < 0.0001]. Treatment given between 1 and 3 hours also reduced the risk of death due to bleeding [147 out of 3037 patients (4.8%) died in the TXA group vs 184 out of 2996 patients (6.1%) in the placebo group; RR 0.79; 95% CI 0.64 to 0.97; p = 0.03]. Treatment given after 3 hours seemed to increase the risk of death due to bleeding [144 out of 3272 patients (4.4%) died in the TXA group vs 103 out of 3362 patients (3.1%) in the placebo group; RR 1.44; 95% CI1.12 to 1.84; p = 0.004]. We recorded no evidence that the effect of TXA on death due to bleeding varied by systolic blood pressure, Glasgow Coma Scale score or type of injury. Administering TXA to bleeding trauma patients within 3 hours of injury saved an estimated 755 LYs per 1000 trauma patients in the UK. The cost of giving TXA to 1000 patients was estimated at $30,830. The incremental cost of giving TXA compared with not giving TXA was $48,002. The incremental cost per LY gained of administering TXA was $64. Early administration of TXA safely reduced the risk of death in bleeding trauma patients and is highly cost-effective. Treatment beyond 3 hours of injury is unlikely to be effective. Future work [the Clinical Randomisation of an Antifibrinolytic in Significant Head injury-3 (CRASH-3) trial] will evaluate the effectiveness and safety of TXA in the treatments of isolated traumatic brain injury (http://crash3.lshtm.ac.uk/). Current Controlled Trials ISRCTN86750102, ClinicalTrials.gov NCT00375258 and South African Clinical Trial Register DOH-27-0607-1919. The project was funded by the Bupa Foundation, the J P Moulton Charitable Foundation and the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 10. See HTA programme website for further project information.

Risk factors for vascular occlusive events and death due to bleeding in trauma patients; an analysis of the CRASH-2 cohort.

BackgroundVascular occlusive events can complicate recovery following trauma. We examined risk factors for venous and arterial vascular occlusive events in trauma patients and the extent to which the risk of vascular occlusive events varies with the severity of bleeding.Methods and FindingsWe conducted a cohort analysis using data from a large international, double-blind, randomised, placebo-controlled trial (The CRASH-2 trial) [1]. We studied the association between patient demographic and physiological parameters at hospital admission and the risk of vascular occlusive events. To assess the extent to which risk of vascular occlusive events varies with severity of bleeding, we constructed a prognostic model for the risk of death due to bleeding and assessed the relationship between risk of death due to bleeding and risk of vascular occlusive events. There were 20,127 trauma patients with outcome data including 204 (1.01%) patients with a venous event (pulmonary embolism or deep vein thrombosis) and 200 (0.99%) with an arterial event (myocardial infarction or stroke). There were 81 deaths due to vascular occlusive events. Increasing age, decreasing systolic blood pressure, increased respiratory rates, longer central capillary refill times, higher heart rates and lower Glasgow Coma Scores (all p<0.02) were strong risk factors for venous and arterial vascular occlusive events. Patients with more severe bleeding as assessed by predicted risk of haemorrhage death had a greatly increased risk for all types of vascular occlusive event (all p<0.001).ConclusionsPatients with severe traumatic bleeding are at greatly increased risk of venous and arterial vascular occlusive events. Older age and blunt trauma are also risk factors for vascular occlusive events. Effective treatment of bleeding may reduce venous and arterial vascular occlusive complications in trauma patients.

Tranexamic acid: less bleeding and less thrombosis?

The early administration of tranexamic acid (TXA) to bleeding trauma patients reduces all-cause mortality without increasing the risk of vascular occlusive events. Indeed, the risk of arterial thrombosis appears to be reduced with TXA. In this commentary we hypothesize that TXA has an antithrombotic effect and explore potential mechanisms. These include inhibition of the inflammatory effects of plasmin, effects on platelets and effects on factors V and VIII. If proven, these antithrombotic effects would have major implications for the systemic use of TXA in surgical patients, where TXA has been clearly shown to reduce bleeding.

Uremic medium increases cytokine-induced PAI-1 secretion by cultured endothelial cells

The overall fibrinolytic activity is depressed in patients with chronic renal failure where a prothrombotic state is described, thereby enhancing the risk of vascular occlusive events. The mechanism responsible for fibrinolysis derangement has not yet been elucidated. To evaluate the effect of the uremic environment on the fibrinolytic activity of endothelial cells, we studied plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) production by human umbilical vein endothelial cells (HUVEC) in culture, exposed either to uremic or normal sera, before and after cytokine stimulation. Twenty uremics were studied: 11 were on conservative dietary treatment and nine were on maintenance hemodialysis. Eight healthy subjects served as controls. Before cytokine stimulation, no difference in the HUVEC supernatant concentration of t-PA and PAI-1 was found among the groups studied. After stimulation with interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha, the HUVEC supernatant levels of PAI-1 in the uremics were higher than in the controls, whereas the supernatant levels of t-PA did not differ. Our data provide evidence that uremic serum, in concert with IL-1 or TNF-alpha, can enhance PAI-1 secretion by endothelial cells, thereby depressing the fibrinolytic system. This impaired endothelial fibrinolytic response to hypercoagulation could favor vascular events, which are the major cause of morbidity and mortality in patients with chronic uremia.

Thromboxane biosynthesis and metabolism in relation to cardiovascular risk factors

Enhanced platelet biosynthesis of thromboxane A 2 is associated with several cardiovascular risk factors, as a consequence of a direct effect on platelet biochemistry and/or some form of endothelial dysfunction. Moreover, episodic increases in thromboxane biosynthesis occur in acute coronary and cerebral ischemic syndromes. Thromboxane-dependent platelet activation represents an important mechanism that amplifies the consequences of acute vascular lesions as well as those of longstanding metabolic or hemodynamic disturbances, and results in increased risk of vascular occlusive events.

Thromboxane biosynthesis and metabolism in relation to cardiovascular risk factors.

Enhanced platelet biosynthesis of thromboxane A2 is associated with several cardiovascular risk factors, as a consequence of a direct effect on platelet biochemistry and/or some form of endothelial dysfunction. Moreover, episodic increases in thromboxane biosynthesis occur in acute coronary and cerebral ischemic syndromes. Thromboxane-dependent platelet activation represents an important mechanism that amplifies the consequences of acute vascular lesions as well as those of long-standing metabolic or hemodynamic disturbances, and results in increased risk of vascular occlusive events.