Arterial Events In Patients Research Articles

Risk of venous thromboembolism and arterial events in patients with hypoalbuminemia: a comprehensive meta-analysis of more than 2 million patients

BackgroundAlbumin has antiplatelet and anticoagulant functions. Hypoalbuminemia, as defined by serum values of <3.5 g/dL, is associated with arterial thrombosis; its impact on venous thromboembolism (VTE) is unclear. ObjectivesThe objective of this meta-analysis is to assess the VTE risk in patients with hypoalbuminemia. MethodsMEDLINE and EMBASE were searched up to January 2024 for observational studies and randomized trials reporting data of interest. Primary outcome was the risk of VTE, while secondary outcomes were myocardial infarction and stroke risk in patients with hypoalbuminemia versus those without hypoalbuminemia. The risk of bias was evaluated using Newcastle–Ottawa scale and Cochrane tool. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated in a random-effects model. ResultsForty-three studies for a total of 2 531 091 patients (39 738 medical and 2 491 353 surgical) were included in primary analysis; 79.1% of the studies used 3.5 g/dL cut-off value for hypoalbuminemia definition. Follow-up duration was 30 days in 60.5% of studies. Patients with hypoalbuminemia had a higher risk of VTE (RR, 1.88; 95% CI, 1.66-2.13). RRs were similar in both medical (RR, 1.87; 95% CI, 1.53-2.27) and surgical patients (RR, 1.87; 95% CI, 1.61-2.16) and in patients with (RR, 1.86; 95% CI, 1.66-2.10) and without cancer (RR, 1.89; 95% CI, 1.47-2.44). Risk of myocardial infarction (RR, 1.88; 95% CI, 1.54-2.31) and stroke (RR, 1.77; 95% CI, 1.26-2.48) was higher in patients with hypoalbuminemia. ConclusionHypoalbuminemia is a risk factor for VTE in both medical and surgical patients irrespective of cancer coexistence. Serum albumin analysis may represent a simple and cheap tool to identify patients at VTE risk.

Intravenous high-dose anakinra drops venous thrombosis and acute coronary syndrome in severe and critical COVID-19 patients: a propensity score matched study

In our study, we aimed to evaluate the effect of high-dose intravenous anakinra treatment on the development of thrombotic events in severe and critical COVID-19 patients. This retrospective observational study was conducted at a tertiary referral center in Aksaray, Turkey. The study population consisted of two groups as follows; the patients receiving high-dose intravenous anakinra (anakinra group) added to background therapy and the patients treated with standard of care (SoC) as a historical control group. Age, gender, mcHIS scores, and comorbidities such as diabetes mellitus, hypertension, and coronary heart disease of the patients were determined as the variables to be matched. We included 114 patients in SoC and 139 patients in the Anakinra group in the study. Development of any thromboembolic event (5% vs 12.3%, p = 0.038; OR 4.3) and PTE (2.9% vs 9.6%, p = 0.023; OR 5.1) were lower in the Anakinra group than SoC. No patient experienced cerebrovascular accident and/or clinically evident deep venous thrombosis both in two arms. After 1:1 PS matching, 88 patients in SoC and 88 patients in the Anakinra group were matched and included in the analysis. In survival analysis, the development of any thromboembolic event, pulmonary thromboembolism, and acute coronary syndrome (ACS) were higher in SoC compared to Anakinra. Survival rate was also lower in patients with SoC arm than Anakinra in patients who had any thromboembolic event as well as ACS. In our study, the development of thrombosis was associated with hyperinflammation in patients with severe and critical COVID-19. Intravenous high-dose anakinra treatment decreases both venous and arterial events in patients with severe and critical COVID-19.

Incidence of Venous and Arterial Events in Patients Treated with Neoadjuvant Cisplatin-based Chemotherapy for Bladder Cancer and Predictability of Events using Khorana and Adapted HADVAS Score: a Large Retrospective Study across Three Centres in Scotland

Purpose: This study was designed to determine the incidence of venous and arterial thromboembolic events (TEEs) in patients with bladder cancer treated with neoadjuvant cisplatin-based chemotherapy and to analyse the prognostic baseline and treatment characteristics using Khorana and adapted HADVAS score in predicting TEE occurrences.

Celiprolol to prevent arterial events in patients with vascular Ehlers-Danlos and neither symptomatic nor silent arterial event. A retrospective cohort study from the French national reference center

Abstract Background Vascular Ehlers-Danlos syndrome (vEDS) is a rare inherited connective tissue disorder, leading to mainly arterial complications, caused by COL3A1 pathogenic variations. Ong et al. (Lancet 2010) showed that the introduction of celiprolol significantly reduced arterial events in a predominantly symptomatic population on arterial level. We reported the benefit of full dose of Celiprolol in longitudinal study to prevent arterial events in Frank et al. (JACC 2019). To our knowledge, there is no data regarding the benefit of celiprolol in patients without any arterial event. Purpose The aim of this study was to assess the occurrence of arterial events during follow-up in vEDS patients without arterial event. Methods All patients – probands and relatives – with a pathogenic variation in COL3A1 diagnosed at the Referral Centre for Rare Vascular Diseases since 2001 and at least one arterial tree assessment were included. We then focused on vEDS patients without any arterial event. We retrospectively analyzed the duration of follow-up, the occurrence of arterial events during follow-up, and the introduction and dose of celiprolol, especially at the time of occurrence of an arterial event. Results Among the 230 patients included, 144 (63%) had at least one symptomatic arterial event, 44 (19%) had only silent arterial event and 67 (29%) had no arterial event at the first arterial tree assessment event. Patients with no arterial event were significantly younger at this visit compared with the two other groups with a median age of 23 vs. 38 and 39 years (silent and symptomatic) (p&amp;lt;0.05). Patients with no arterial event were more frequently relatives (73%) than probands (27%) (p&amp;lt;10–3). Celiprolol was introduced in 48 (72%) of the 67 patients with no arterial event after positive genetic diagnosis disclosure or during one of the outpatient visit. During follow-up, 22 patients had a first arterial event at a median age of 29 years: 16 (33%) were receiving celiprolol and 6 (32%) were not. But the median follow-up duration was 4 years for the 48 treated patients vs. 2 years for the 19 untreated patients (p=0.03). Conclusions Genetic testing of the relatives of probands with vEDS remains of utmost importance as one quarter presented with symptomatic arterial event and one fifth had silent arterial event at initial arterial tree assessment. For patients with no arterial event, those without celiprolol have a similar incidence of arterial events than those with celiprolol, however their follow-up duration was twice shorter suggesting a higher incidence rate or arterial event in the absence of celiprolol. Funding Acknowledgement Type of funding sources: None.

Risk of Recurrent Acute Arterial Events Associated With Thiopurines and Anti-Tumor Necrosis Factor in Inflammatory Bowel Diseases

Patients with inflammatory bowel disease (IBD) are at increased risk of acute arterial events. Treatment with anti-tumor necrosis factor (anti-TNF) agents has been associated with a protective effect against the first occurrence of acute arterial events, but the impact of treatment with anti-TNF in patients with a previous history of acute arterial events remains unclear. We assessed the effect of anti-TNF and thiopurines on the risk of recurrent acute arterial events in patients with IBD in a nationwide cohort. Based on the French nationwide health insurance database, patients with IBD and a previous history of an acute arterial event were followed up from January 1, 2009, until December 31, 2018. The risk of acute arterial event recurrence associated with anti-TNF and thiopurine exposure was assessed using marginal structural Cox proportional hazard models adjusted for baseline and time-varying covariates. A total of 27,185 patients were included. During 121,822 person-years (median follow-up period, 4.0 y), 6865 recurrent acute arterial events occurred (incidence rate per 1000 person-years, 56.4; 95% CI, 55.0-57.7). Exposure to both anti-TNF and thiopurines were associated with a decreased risk of recurrent acute arterial events compared with the absence of exposure to either treatment (hazard ratio, 0.75; 95% CI, 0.63-0.90 and hazard ratio, 0.76; 95% CI, 0.66-0.88, respectively). In a nationwide cohort study of patients with IBD and a previous history of an acute arterial event, exposure to both anti-TNF and thiopurines were associated with a decreased risk of recurrent acute arterial events.

Risk Factors of Arterial Events in Patients with Venous Thromboembolism: A Systematic Review and Meta-Analysis.

If recent studies suggested that arterial ischemic events in patients with venous thromboembolism (VTE) are more frequent than in the general population without VTE, whether patients with VTE have different risk factors of arterial events than classic known cardiovascular risk factors remain undefined. Through this systematic review and meta-analysis, we aimed to identify risk factors of arterial ischemic events in patients with VTE. We searched PubMed, EMBASE, and Cochrane databases to identify cohort studies published between January 1, 2000, and December 31, 2020, reporting risk factors of arterials ischemic events in patients with VTE. Random-effect models meta-analysis served to get the pooled hazard ratio (HR) and 95% confidence interval (CI) of each risk factor identified. We screened 1,467 records of which 18 were finally included in systematic review and 10 in meta-analyses. Adjusted HR for 9 factors were included in meta-analysis. Male gender (HR: 1.38; 95% CI: 1.28-1.49), diabetes (HR: 1.65; 95% CI: 1.28-2.12), hypertension (HR: 1.38; 95% CI: 1.04-1.84), previous atherothrombotic event (HR: 3.22; 95% CI: 1.12-9.23), chronic kidney disease (HR: 1.41; 95% CI: 1.05-1.88), cancer (HR: 1.72; 95% CI: 1.41-2.09), and unprovoked VTE (HR: 1.88; 95% CI: 1.37-2.57) were the identified risk factors of arterial events in VTE population after meta-analysis. Risk factors of arterial events in patients with VTE include usual cardiovascular risk factors and other risk factors that are related to VTE such as cancer and unprovoked VTE.

Frequency and incidence of arterial events in patients with venous thromboembolism compared to the general population: A systematic review and meta-analysis of cohort studies

BackgroundRecent literature hypothesized that patients with venous thromboembolism (VTE) are at increased risk of developing arterial ischemic events than general population without VTE. However, data summarizing the epidemiology of arterial events among VTE population compared to the general population are lacking. MethodsWe conducted a systematic review and meta-analysis from current literature. PubMed, EMBASE, and Cochrane databases were searched between Jan 1, 2000, and December 31, 2020. Eligible studies were observational cohort studies published in English on arterial ischemic events in patients with VTE. Pooled effect size estimates and their 95% confidence intervals were obtained through random-effect models meta-analysis. ResultsTwenty-eight observational studies enrolling 352,014 patients were identified and included. The pooled frequency of all arterial events was 6.1% (95% CI: 3.7–9.1) in patients with VTE and was significantly higher than the pooled frequency of 5.0% (95% CI: 3.1–7.2) found in controls, with a pooled risk ratio (RR) of 1.20 (95% CI: 1.01–1.44; p = 0.0422). The pooled incidence of all arterial events in patients with VTE was 11.3‰ per patient-year (95% CI: 4.6–18.0), and was significantly higher than the 9.2‰ per patient-year (95% CI: 2.0–16.4) obtained in controls (Incidence rate ratio, IRR: 1.32; 95% CI: 1.08–1.61; p = 0.0103). The pooled frequency and pooled incidence of arterial events were also higher in patients with unprovoked VTE than in patients with provoked VTE (RR: 2.12; 95% CI: 1.38–3.24; p = 0.0042; and IRR: 2.26, 95% CI: 1.45–3.49; p = 0.0032). ConclusionThe frequency and incidence of arterial events in patients with VTE are considerably higher than in the general population, without VTE. Further studies are urgently needed to understand these differences and reduce the burden related to these diseases. FundingNone.

Frequency of Arterial Thromboemobolic Events in Patients with Cancer Associated Venous Thromboembolism

Background:Patients with cancer are at high risk of both venous thromboembolism (VTE) and arterial events, however, little is known about the association between venous and arterial thromboembolic events in patients with cancer. In this study, we evaluated the incidence and relative risk of subsequent arterial thromboembolism in patients with a confirmed diagnosis of acute cancer-associated VTE. Methods:We conducted a retrospective cohort study at the Cleveland Clinic Taussig Cancer Institute of cancer patients with confirmed VTE who were referred to a centralized thrombosis clinic between January 2017-October 2019 with at least 6 months of follow-up. Arterial thrombotic events (ATE), including myocardial infarction, peripheral arterial thrombosis, and ischemic stroke, were identified by manual review of electronic medical records. The cumulative incidence rate of each ATE event was calculated. Results:The study population comprised 294 patients with a median age of (63.5) years (range 27-90), and 49.7 % were male. The cumulative incidence rate of overall ATE during the 6-month, 1-year, and 2-year follow-up period was 3.07%, 3.42%, and 3.42%, respectively. A total of 10 patients who experienced arterial events of whom 7 had ischemic stroke, 2 had myocardial infarction, 2 had peripheral arterial thrombosis where one patient had two arterial events of myocardial infarction and peripheral arterial thrombosis(Table 1 shows the incidence rates of arterial events). Amongst patients with ATE, 30 % were active smokers (n=3), 90% had hypertension (n=9), 20% had diabetes mellitus (n=2), 50% had a family history of coronary artery disease (n=5), 40% were on statin and daily aspirin use (n=4), 40% were obese with BMI &amp;gt;30 (n=4). 40% of ATE patients(n=4) were on a therapeutic anticoagulant therapy at the time of arterial thrombotic event (3 on enoxaparin, 1 on apixaban) Conclusion:Cancer patients with acute VTE have a substantial increased risk of subsequent arterial thromboembolism particularly in the first six months after VTE. Ischemic stroke was the most frequent arterial event and ATE events occured despite therapeutic anticoagulation in a large subset of our cohort. Further prospective studies are needed to better understand the risk of ATE in cancer patients, and further studies should be designed to mitigate the risk of arterial events in this patient population. Disclosures McCrae: Momenta Pharmaceuticals:Consultancy;Novartis:Honoraria;Rigel:Consultancy;Dova:Consultancy.Khorana:Pharmacyclics:Honoraria;Pharmacyte:Honoraria;Seattle Genetics:Honoraria;Leo Pharma:Honoraria;Medscape:Honoraria;Sanofi:Honoraria;Pfizer:Honoraria;Bayer:Honoraria;Janssen:Honoraria;Array:Other: Research funding (to institution);Merck:Research Funding;BMS:Honoraria, Research Funding;Leap:Research Funding.

Risk of acute arterial events associated with treatment of inflammatory bowel diseases: nationwide French cohort study

ObjectivePatients with IBD are at increased risk of acute arterial events. Antitumour necrosis factor (TNF) agents and thiopurines may, via their anti-inflammatory properties, lower the risk of acute arterial events....

Acute arterial cardiovascular events risk in patients with primary membranous nephropathy.

Venous thromboembolism is a well established risk in patients with primary membranous nephropathy (MN) due to deficiency in natural anti-coagulants. Recent studies suggested a higher risk of arterial thrombotic events as well in this group. To identify that risk in our cohort. We reviewed the data of all patients who had biopsy proven primary MN at our institute between 2003 and 2013. Clinical data were retrospectively reviewed until November 2016. The cardiovascular (CV) events, including acute coronary syndromes and strokes were determined and included only if occurred after the diagnosis of the nephropathy. A total of 204 patients had biopsy proven MN. Follow up information was available for 166 patients. Thirty-one patients (18.6%) developed CV events during follow up. Thirty-eight per cent of total events occurred within 1 year of MN diagnosis. Forty-two per cent of those who developed CV events were not on anti-thrombotic medications and 60% were not on statin therapy. Male gender, age, diabetes and absence of statins therapy were associated with higher rates of CV events in this group. There is an increased risk of arterial events in patients with primary MN. This risk is greatest in the first year of diagnosis. The risk should be highlighted in this group of patients and anti-platelets and statin therapy should be considered especially during the initial phase of the disease.

PF638 VENOUS AND ARTERIAL THROMBOTIC EVENTS IN MYELOMA PATIENTS TREATED WITH IXAZOMIB, LENALIDOMIDE AND DEXAMETHASONE (IRD) OR LENALIDOMIDE AND DEXAMETHASONE (RD)

Background: Patients with multiple myeloma (MM) are at increased risk of venous thromboembolism (VTE). Immunomodulatory agents (IMiDs) are known to contribute to this increased VTE risk. Less is known about the risk of arterial thrombosis. Combining proteasome inhibitors (PI) or monoclonal antibodies to IMiDs improves clinical outcomes and is now a standard of care. Addition of the oral PI (Ixazomib) to Lenalidomide Dexamethasone (RD) significantly improves progression-free survival in patients with relapsed / refractory MM (RRMM), with no significant difference in VTE and arterial events with addition of Ixazomib to RD. Aims: To compare the incidence of VTE and arterial events in patients with RRMM treated with RD and IRD, with reference to previous VTE history, cardiovascular (CV) risk factors and use of thromboprophylaxis (TP). Methods: A retrospective review of patient records noting prior venous thrombosis and arterial risk factors in patients treated with RD or IRD. To avoid bias in patient selection, we reviewed RRMM patients treated with RD alone (July 2014 to February 2016) or after we routinely used Ixazomib with RD (IRD, February 2016 to July 2018). VTE and arterial events whilst receiving RD or IRD were noted. Results: Each group consisted of 88 patients (176 in total). Baseline patient characteristics were: median age 65 years in both groups (Range: 32–85 for IRD, 30–88 for RD); 54% male in both groups; median number of prior lines of therapy was 3 (range 1–5); median number cycles delivered 7 (range 1–32, IRD) and 7.5 (range 1–48, RD); 8 (9%) patients were still on treatment in the RD and 35 (40%) in IRD patients at the time of data collection. Prior VTEs were higher in the IRD group; 13 (15%) patients, compared to the RD group 8 (9%) patients. Potential arterial risk factors were higher in the RD group; 31 (35%) patients, compared to the IRD group, 20 (23%) patients. The commonest arterial risk factor was hypertension; 16 (52% of those with CV risk factors) on RD and 11 (55% of those with CV risk factors) on IRD patients. Four (5%) patients in each cohort had a prior CVA/TIA. Obesity (Body Mass Index ≥ 30) was higher in the RD group: 26 (30%) patients compared to the IRD group 18 (21%) patients. Aspirin VTE TP was given in 60 (62%) and 68 (77%) IRD and RD patients respectively. More DOAC prescriptions were noted in the IRD group (12 patients, 13%), vs RD (2 patients, 2%). In those patients receiving IRD; 5 (5.7%) VTEs (3 PE, 1 venous sinus thrombosis, 1 DVT). Four VTEs occurred on aspirin, the other on rivaroxaban TP. For RD there were 3 (3.4%) VTEs (1 PE and 2 DVT), all on aspirin TP. Two patients (2.3%) had arterial events whilst receiving IRD (TIA after 6 months with no risk factors; stroke after 3 months, hypertension only risk factor), 1 RD patient (1.1%) developed a stroke 11 months after starting RD (known hypertensive and diabetic). Summary/Conclusion: VTEs occur at a lower rate than reported; between 3 and 6%, compared to 8–11% in the Touramaline MM1 trial, however we note VTEs of potential clinical concern (PE or venous sinus thrombosis), 4 events in the IRD and 1 in the RD group. VTEs still occurred despite thromboprophylaxis. The IRD group had more previous VTEs, but a lower obesity rate. This requires further exploration. Arterial events occur at a similar rate to that reported (1–2%), and occur early in treatment, despite aspirin TP and in the absence of other risk factors. Strategies to prevent this are urgently needed.

Clinical activity is an independent risk factor of ischemic heart and cerebrovascular arterial disease in patients with inflammatory bowel disease.

Background and aimsIn inflammatory bowel disease (IBD), the impact of established cardiovascular risk factors and disease-related factors on the risk of acute arterial events is still unclear. We aimed to identify risk factors of acute arterial events in patients with IBD.MethodsAll consecutive patients followed at Saint-Antoine Hospital between 1996 and 2015 with subsequent occurrence of acute arterial events (acute coronary syndrome or ischemic stroke) were identified. Traditional cardiovascular risk factors, treatment exposure, systemic inflammation (mean serum CRP level greater than or equal to 5 mg/L) and IBD clinical activity were assessed. A nested case-control study was performed including cases and controls without arterial ischemic event, matched on age, gender, and disease extent.ResultsA total of 30 patients (median age at acute vascular event occurrence: 42 years (interquartile range: 25–59)) developed acute coronary syndrome (n = 22) or ischemic stroke (n = 8). In univariate analysis, clinical disease activity and the persistence of systemic inflammation, diabetes, dyslipidemia and hypertension were significantly associated with an increased risk of acute arterial events. Neither protective nor aggravating effects associated with treatment exposure were identified. In multivariate analysis, the presence of diabetes (Odds ratio (OR): 14.5, 95% confidence interval (CI): 1.1–184.7) and clinical disease activity (OR: 10.4, 95% CI: 2.1–49.9) remained significantly associated with the risk of acute arterial event.ConclusionDisease activity may have an independent impact on the risk of acute arterial events in patients with IBD. These findings may highlight new potential benefits of optimizing anti-inflammatory treatment in patients with persisting clinical activity.

Celiprolol: A Unique Selective Adrenoceptor Modulator.

Celiprolol is a β-blocker with a unique pharmacologic profile: it is a β1-andrenoceptor antagonist with partial β2 agonist activity. Given this combination of effects, celiprolol may be better described as a selective adrenoreceptor modulator. It has antihypertensive and antianginal properties and is indicated for those uses in various countries around the world. In the United States, however, the proposed indication for this drug will be for the treatment of vascular type Ehlers–Danlos syndrome, a rare connective tissue disorder characterized by fragile arterial structure and an increased risk of life-threatening vascular complications. By reducing heart rate and pulsatile pressure, celiprolol may reduce the mechanical stress on collagen fibers within the arterial wall and be of benefit in patients with vascular type Ehlers–Danlos syndrome. The largest investigation of celiprolol in vascular Ehlers–Danlos syndrome was prematurely terminated due to significant benefit with celiprolol in reducing arterial events in patients with this condition. Celiprolol, therefore, represents a β-blocker that is unique from others in its class in both its pharmacology and clinical applications.

Arterial Events in Patients with Chronic Myeloid Leukemia Receiving Treatment with Second Generation Tyrosine Kinase Inhibitors

Target therapy of chronic myeloid leukemia (CML) by tyrosine kinase inhibitors (TKI) allows to achieve high rates of the overall survival in CML. The choice of TKI treatment in every particular case should be based on individual CML patient’s characteristics, including comorbidities and the risk of adverse events (AE). Every TKI has a particular toxicity profile depending on off-target action spectrum. A probability of arterial AEs on TKI therapy is comparatively low but they may be life threatening. It is highly important to evaluate this kind of AEs during a long period of vascular TKI exposure. The age-specific increased incidence of cardiovascular and respiratory diseases is an additional factor in these patients with high overall survival on TKI therapy. The article is devoted to the analysis of frequency, mechanisms, particular features, methods of diagnostics and treatment of arterial AEs emerging on second generation TKI (nilotinib and dasatinib) therapy. The detailed characteristics of arterial occlusive events on nilotinib therapy and pulmonary arterial hypertension on dasatinib are presented. Special attention is paid to the analysis of risk factors of vascular AEs and the ways to correct modified risk factors. Timely assessment of clinical symptoms of cardiopulmonary, ischemic diseases/complications, and metabolic disorders helps to find specialized medical care (by a cardiologist, pulmonologist, endocrinologist), to prescribe an adequate therapy, provide prevention of complications and make decision about TKI dose adjustment/switching to alternative TKI being a true foundation of safe personalized treatment in CML patients.

C0119: Subsequent Arterial Events in Patients with Acute Venous Thromboembolism. Findings from the Riete Registry

E. Bonet, L. Martos, L.A. Ramon, F. Ferrando, A. Vaya, Y. Mira, S. Bonanad, A. Estelles, R.M. Bertina, H.L. Vos, F. Espana, P. Medina, S. Navarro Rosales. Haemostasis, Thrombosis, Arteriosclerosis and Vascular Biology Group. La Fe University and Polytechnic Hospital La Fe. Valencia, Spain; Hemotology Service. La Fe University and Polytechnic Hospital. Valencia, Spain; Leiden University Medical Centre. Leiden, The Netherlands

Risk of arterial events in patients with primary APS

Risk of arterial events in patients with primary APS

Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia

Recombinant factor VIIa (rFVIIa) is licensed for use in patients with haemophilia and inhibitory allo-antibodies and for prophylaxis and treatment of patients with congenital factor VII deficiency. It is also used for off-license indications to prevent bleeding in operations where blood loss is likely to be high, and/or to stop bleeding that is proving difficult to control by other means. This is the third version of the 2007 Cochrane review on the use of recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia, and has been updated to incorporate recent trial data. To assess the effectiveness of rFVIIa when used therapeutically to control active bleeding or prophylactically to prevent (excessive) bleeding in patients without haemophilia. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and other medical databases up to 23 March 2011. Randomised controlled trials (RCTs) comparing rFVIIa with placebo, or one dose of rFVIIa with another, in any patient population (except haemophilia). Outcomes were mortality, blood loss or control of bleeding, red cell transfusion requirements, number of patients transfused and thromboembolic adverse events. Two authors independently assessed potentially relevant studies for inclusion, extracted data and examined risk of bias. We considered prophylactic and therapeutic rFVIIa studies separately. Twenty-nine RCTs were included: 28 were placebo-controlled, double-blind RCTs and one compared different doses of rFVIIa. In the 'Risk of bias' assessment, most studies were found to have some threats to validity although therapeutic RCTs were found to be less prone to bias than prophylactic RCTs.Sixteen trials involving 1361 participants examined the prophylactic use of rFVIIa; 729 received rFVIIa. There was no evidence of mortality benefit (risk ratio (RR) 1.04; 95% confidence interval (CI) 0.55 to 1.97). There was decreased blood loss (mean difference (MD) -297 mL; 95% CI -416 to -178) and decreased red cell transfusion requirements (MD -261 mL; 95% CI -367 to -154) with rFVIIa treatment; however, these values were likely overestimated due to the inability to incorporate data from trials (four RCTs in the outcome of blood loss and three RCTs in the outcome of transfusion requirements) showing no difference of rFVIIa treatment compared to placebo. There was a trend in favour of rFVIIa in the number of participants transfused (RR 0.85; 95% CI 0.72 to 1.01). However, there was a trend against rFVIIa with respect to thromboembolic adverse events (RR 1.35; 95% CI 0.82 to 2.25).Thirteen trials involving 2929 participants examined the therapeutic use of rFVIIa; 1878 received rFVIIa. There were no outcomes where any observed advantage or disadvantage of rFVIIa over placebo could not have been observed by chance alone. There was a trend in favour of rFVIIa for reducing mortality (RR 0.91; 95% CI 0.78 to 1.06). However, there was a trend against rFVIIa for increased thromboembolic adverse events (RR 1.14; 95% CI 0.89 to 1.47).When all trials were pooled together to examine the risk of thromboembolic events, a significant increase in total arterial events was observed (RR 1.45; 95% CI 1.02 to 2.05). The effectiveness of rFVIIa as a more general haemostatic drug, either prophylactically or therapeutically, remains unproven. The results indicate increased risk of arterial events in patients receiving rFVIIa. The use of rFVIIa outside its current licensed indications should be restricted to clinical trials.

Platelet function tests and resistance to antiplatelet therapy

The clinical efficacy of antiplatelet therapy (aspirin, P2Y12 and glycoprotein IIb/IIIa receptor antagonists) to prevent occlusive arterial events in patients with atherothrombotic disease is well established. Despite the proven benefits of antiplatelet therapy, many patients continue to experience arterial events. Many factors may influence the response of platelets to antiplatelet therapy and some patients with adequate compliance to the treatment may exhibit failure of platelet inhibition as determined by ex vivo laboratory tests, a phenomenon termed "resistance" to antiplatelet therapy. Platelet function can be measured by numerous platelet function tests, with which various parameters of platelet activation, secretion, adhesion and aggregation can be determined. These tests include light transmission (optical) and whole blood aggregometry, point-of-care devices, such as platelet function analyzers PFA-100, and VerifyNow, flow cytometry, serum thromboxane B2 and urinary levels of the thromboxane B2 metabolite 11-dehyro-thromboxane B2. Other tests, such as whole blood platelet aggregation measured by platelet counting, thrombelastography and devices such as the cone and plate(let) analyzer, Plateletworks and thrombotic status analyzer have also been used to determine platelet inhibition by antiplatelet drugs, but their use is not widespread and therefore experience is limited. Further studies need to be carried out to answer basic questions on the clinical utility and cost-effectiveness of laboratory monitoring of antiplatelet therapy before it can be recommended in clinical practice.

Haemorrhagic stroke during anti-platelet therapy

Drugs that inhibit platelet function are widely used to decrease the risk of occlusive arterial events in patients with atherosclerosis. There are three families of anti-platelet agents with proven clinical efficacy: (1) cyclo-oxygenase inhibitors, such as aspirin; (2) adenosine diphosphate receptor antagonists, such as the thienopyridine compounds ticlopidine and clopidogrel; and (3) glycoprotein IIb/IIIa antagonists. All these drugs are used during coronary interventions and in the medical management of acute coronary syndromes, while only aspirin and thienopyridine compounds are used in the long-term prevention of cardiovascular and cerebrovascular events in patients at risk. Despite the good risk-to-benefit ratio of anti-platelet agents, the risk of severe bleeding complications, including cerebral haemorrhage, is slightly increased, albeit to a much lesser extent than that associated with the use of other antithrombotic drugs, such as anticoagulants or thromobolytic agents. In addition, it must be noted that the increased incidence of haemorrhagic stroke is usually outweighed by a significant decrease in the incidence of ischaemic strokes. The combination of aspirin and vitamin K antagonists may be associated with the heightened risk of cerebral haemorrhage, compared to treatment with either drug alone.

Arterial Thrombosis in Mice with Factor V Leiden Mutation

The factor V Leiden (FVL) mutation has been demonstrated to be associated with the development of venous thrombosis in humans. Whether such a propensity also exists in the arterial circulation remains controversial. In an effort to minimize the variability that clouds the clinical study of arterial thrombosis, we studied FVL-associated arterial thrombosis in an experimental model of homozygous, heterozygous, and wild-type mice. Heterozygous FVL mice were crossbred to C57BL/6J mice over several generations. The genotypes of the resulting three genotype groups (wild type, heterozygous FVL, and homozygous FVL) were blinded to the investigators. Arterial injury was produced with the injection of ferric chloride into an isolated segment of carotid artery. Arterial thrombosis was assessed with an ultrasonic flow probe and the time to occlusion (TTO) was recorded. The carotid artery occluded within 60 minutes of injury in 72 of the animals studied (97.3%). The carotid artery remained patent at 60 minutes in the remaining two animals, both of whom were subsequently found to be genotypically wild type. There was a statistically significant relationship between TTO and genotype (p = .002). TTO was greatest in the wild-type mice (p < .001 vs heterozygous, < .001 vs homozygous) and least in the homozygotes (p < .001 vs heterozygotes). Increased thrombogenicity is present in mice with the FVL mutation and is more prolonged in homozygotes than heterozygotes. These findings provide some corroboration to the clinical studies that suggest an increased risk of arterial events in patients with the FVL mutation.