Anticoagulation versus placebo for heart failure in sinus rhythm.

BACKGROUND: People with chronic heart failure (HF) are at risk of thromboembolic events, including stroke, pulmonary embolism, and peripheral arterial embolism; coronary ischaemic events also contribute to the progression of HF. The use of long-term oral anticoagulation is established in certain populations, including people with HF and atrial fibrillation (AF), but there is wide variation in the indications and use of oral anticoagulation in the broader HF population. OBJECTIVES: To determine whether long-term oral anticoagulation reduces total deaths and stroke in people with heart failure in sinus rhythm. SEARCH METHODS: We updated the searches in CENTRAL, MEDLINE, and Embase in March 2020. We screened reference lists of papers and abstracts from national and international cardiovascular meetings to identify unpublished studies. We contacted relevant authors to obtain further data. We did not apply any language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCT) comparing oral anticoagulants with placebo or no treatment in adults with HF, with treatment duration of at least one month. We made inclusion decisions in duplicate, and resolved any disagreements between review authors by discussion, or a third party. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, and assessed the risks and benefits of antithrombotic therapy by calculating odds ratio (OR), accompanied by the 95% confidence intervals (CI). MAIN RESULTS: We identified three RCTs (5498 participants). One RCT compared warfarin, aspirin, and no antithrombotic therapy, the second compared warfarin with placebo in participants with idiopathic dilated cardiomyopathy, and the third compared rivaroxaban with placebo in participants with HF and coronary artery disease. We pooled data from the studies that compared warfarin with a placebo or no treatment. We are uncertain if there is an effect on all-cause death (OR 0.66, 95% CI 0.36 to 1.18; 2 studies, 324 participants; low-certainty evidence); warfarin may increase the risk of major bleeding events (OR 5.98, 95% CI 1.71 to 20.93, NNTH 17). 2 studies, 324 participants; low-certainty evidence). None of the studies reported stroke as an individual outcome. Rivaroxaban makes little to no difference to all-cause death compared with placebo (OR 0.99, 95% CI 0.87 to 1.13; 1 study, 5022 participants; high-certainty evidence). Rivaroxaban probably reduces the risk of stroke compared to placebo (OR 0.67, 95% CI 0.47 to 0.95; NNTB 101; 1 study, 5022 participants; moderate-certainty evidence), and probably increases the risk of major bleeding events (OR 1.65, 95% CI 1.17 to 2.33; NNTH 79; 1 study, 5008 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Based on the three RCTs, there is no evidence that oral anticoagulant therapy modifies mortality in people with HF in sinus rhythm. The evidence is uncertain if warfarin has any effect on all-cause death compared to placebo or no treatment, but it may increase the risk of major bleeding events. There is no evidence of a difference in the effect of rivaroxaban on all-cause death compared to placebo. It probably reduces the risk of stroke, but probably increases the risk of major bleedings. The available evidence does not support the routine use of anticoagulation in people with HF who remain in sinus rhythm.

Thromboembolism, bleeding and vascular death in nonvalvular atrial fibrillation patients with type 2 diabetes receiving rivaroxaban or warfarin.

BACKGROUND: Diabetes increases a patient's risk of developing atrial fibrillation by 49%. Patients with nonvalvular atrial fibrillation are at a fivefold increased risk of stroke and die more frequently from vascular causes. We sought to evaluate the effectiveness and safety of rivaroxaban versus warfarin in nonvalvular atrial fibrillation patients with type 2 diabetes. METHODS: This was an analysis of Optum® De-Identified electronic health record data from 11/2010 to 12/2019. We included adults with nonvalvular atrial fibrillation and type 2 diabetes, newly started on rivaroxaban or warfarin and with ≥ 12-months of prior electronic health record activity. Patients who were pregnant, had alternative indications for oral anticoagulation or valvular heart disease were excluded. We evaluated the incidence rate (%/year) of developing the composite outcome of stroke/systemic embolism or vascular death and major or clinically relevant nonmajor bleeding as well as each endpoint individually. Hazard ratios with 95% confidence intervals were calculated using propensity score-overlap weighted proportional hazards regression. RESULTS: We included 32,078 rivaroxaban (31% initiated on 15 mg dose) and 83,971warfarin users (time-in-therapeutic range = 47 ± 28%). Rivaroxaban was associated with a reduced risk of stroke/systemic embolism or vascular death (3.79 vs. 4.19; hazard ratio = 0.91, 95% confdience interval = 0.88-0.95), driven mostly by reductions in vascular death (2.81 vs 3.18, hazard ratio = 0.90, 95% confidence interval = 0.86-0.95) and systemic embolism (0.13 vs. 0.16; hazard ratio = 0.82, 95% confidence interval = 0.66-1.02). Major/clinically relevant nonmajor bleeding was less frequent with rivaroxaban versus warfarin (2.17 vs. 2.31; hazard ratio = 0.94, 95% confidence interval = 0.89-0.99) due to decreased critical organ bleeding (including intracranial hemorrhage) (0.35 vs. 0.54; hazard ratio = 0.63, 95% confidence interval = 0.55-0.72). CONCLUSIONS: In nonvalvular atrial fibrillation patients with type 2 diabetes, rivaroxaban was associated with an ~ 10% relative reduction in vascular mortality and fewer bleeding-related hospitalizations versus warfarin.

Antiplatelet and anticoagulant agents for secondary prevention of stroke and other thromboembolic events in people with antiphospholipid syndrome.

BACKGROUND: Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by arterial or venous thrombosis (or both), and/or pregnancy morbidity in association with the presence of antiphospholipid antibodies. The prevalence of APS is estimated at 40 to 50 cases per 100,000 people. The most common sites of thrombosis are cerebral arteries and deep veins of the lower limbs. People with a definite APS diagnosis have an increased lifetime risk of recurrent thrombotic events. OBJECTIVES: To assess the effects of antiplatelet (AP) or anticoagulant agents, or both, for the secondary prevention of recurrent thrombosis, particularly ischemic stroke, in people with APS. SEARCH METHODS: We last searched the MEDLINE, Embase, CENTRAL, Cochrane Stroke Group Trials Register, and ongoing trials registers on 22 November 2019. We checked reference lists of included studies, systematic reviews, and practice guidelines. We also contacted experts in the field. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that evaluated any anticoagulant or AP agent, or both, in the secondary prevention of thrombosis in people with APS, according to the criteria valid when the study took place. We did not include studies specifically addressing women with obstetrical APS. DATA COLLECTION AND ANALYSIS: Pairs of review authors independently worked on each step of the review, following Cochrane methods. We summarized the evidence using the GRADE approach. MAIN RESULTS: We identified eight studies including 811 participants that compared different AP or anticoagulant agents. NOAC (non-VKA oral anticoagulant: rivaroxaban 15 or 20 mg/d) versus standard-dose VKA (vitamin K antagonist: warfarin at moderate International Normalized Ratio [INR] - 2.5) or adjusted [INR 2.0-3.0] dose): In three studies there were no differences in any thromboembolic event (including death) and major bleeding (moderate-certainty evidence), but an increased risk of stroke (risk ratio [RR] 14.13, 95% confidence interval [CI] 1.87 to 106.8; moderate-certainty evidence). One of the studies reported a small benefit of rivaroxaban in terms of quality of life at 180 days measured as health state on Visual Analogue Scale (mean difference [MD] 7 mm, 95% CI 2.01 to 11.99; low-certainty evidence), but not measured as health utility on a scale from 0 to 1 (MD 0.04, 95% CI -0.02 to 0.10; low-certainty evidence). High-dose VKA (warfarin with a target INR of 3.1 to 4.0 [mean 3.3] or 3.5 [mean 3.2]) versus standard-dose VKA (warfarin with a target INR of 2.0 to 3.0 [mean 2.3] or 2.5 [mean 2.5]): In two studies there were no differences in the rates of thrombotic events and major bleeding (RR 2.22, 95% CI 0.79 to 6.23, low-certainty evidence), but an increased risk of minor bleeding in one study during a mean of 3.4 years (standard deviation [SD] 1.2) of follow-up (RR 2.55, 95% CI 1.07 to 6.07). In both trials there was evidence of a higher risk of any bleeding (hazard ratio [HR] 2.03 95% CI 1.12 to 3.68; low-certainty evidence) in the high-dose VKA group, and for this outcome (any bleeding) the incidence is not different, only the time to event is showing an effect. Standard-dose VKA plus a single AP agent (warfarin at a target INR of 2.0 to 3.0 plus aspirin 100 mg/d) versus standard-dose VKA (warfarin at a target INR of 2.0 to 3.0): One high-risk-of-bias study showed an increased risk of any thromboembolic event with combined treatment (RR 2.14, 95% CI 1.04 to 4.43; low-certainty evidence) and reported on major bleeding with five cases in the combined treatment group and one case in the standard-dose VKA treatment group, resulting in RR 7.42 (95% CI 0.91 to 60.7; low-certainty evidence) and no differences for secondary outcomes (very low- to low-certainty evidence). Single/dual AP agent and standard-dose VKA (pooled results): Two high-risk-of-bias studies compared a combination of AP and VKA (aspirin 100 mg/d plus warfarin or unspecified VKA at a target INR of 2.0 to 3.0 or 2.0 to 2.5) with a single AP agent (aspirin 100 mg/d), but did not provide any conclusive evidence regarding the effects of those drugs in people with APS (very low-certainty evidence). One of the above-mentioned studies was a three-armed study that compared a combination of AP and VKA (aspirin 100 mg/d plus warfarin at a target INR of 2.0 to 2.5) with dual AP therapy (aspirin 100 mg/d plus cilostazol 200 mg/d) and dual AP therapy (aspirin 100 mg/d plus cilostazol 200 mg/d) versus a single AP treatment (aspirin 100 mg/d). This study reported on stroke (very low-certainty evidence) but did not report on any thromboembolic events, major bleeding, or any secondary outcomes. We identified two ongoing studies and three studies are awaiting classification. AUTHORS' CONCLUSIONS: The evidence identified indicates that NOACs compared with standard-dose VKAs may increase the risk of stroke and do not appear to alter the risk of other outcomes (moderate-certainty evidence). Using high-dose VKA versus standard-dose VKA did not alter the risk of any thromboembolic event or major bleeding but may increase the risk of any form of bleeding (low-certainty evidence). Standard-dose VKA combined with an AP agent compared with standard-dose VKA alone may increase the risk of any thromboembolic event and does not appear to alter the risk of major bleeding or other outcomes (low-certainty evidence). The evidence is very uncertain about the benefit or harm of using standard-dose VKA plus AP agents versus single or dual AP therapy, or dual versus single AP therapy, for the secondary prevention of recurrent thrombosis in people with APS (very low-certainty evidence).

Impact of body mass index on real-world outcomes of rivaroxaban treatment in Japanese patients with non-valvular atrial fibrillation.

This sub-analysis of the XAPASS, a prospective, single-arm, observational study, aimed to evaluate relationships between body mass index (BMI) and safety (major bleeding and all-cause mortality) and effectiveness [stroke/non-central nervous system (non-CNS) systemic embolism (SE)/myocardial infarction (MI)] outcomes in Japanese patients with non-valvular atrial fibrillation (NVAF) receiving rivaroxaban. Patients were categorized according to BMI (kg/m2) as underweight (< 18.5), normal weight (18.5 to < 25), overweight (25 to < 30), or obese (≥ 30). In total, 9578 patients with NVAF completed the 1-year follow-up and were evaluated; of these, 7618 patients had baseline BMI data. Overall, 542 (5.7%), 4410 (46.0%), 2167 (22.6%), and 499 (5.2%) patients were underweight, normal weight, overweight, and obese, respectively. Multivariable Cox regression analysis demonstrated that none of the BMI categories were independent predictors of major bleeding whereas being underweight was independently associated with increased all-cause mortality [hazard ratio (HR) 3.56, 95% confidence interval (CI) 2.40-5.26, p < 0.001]. The incidence of stroke/non-CNS SE/MI was higher in patients who were underweight than in those of normal weight (HR 2.11, 95% CI 1.20-3.70, p = 0.009). However, in multivariable analyses, being underweight was not identified as an independent predictor of stroke/non-CNS SE/MI (HR 1.64, 95% CI 0.90-2.99, p = 0.104). In conclusion, the high incidence of thromboembolic events and all-cause mortality in patients who were underweight highlights that thorough evaluation of disease status and comorbidities may be required in this population.

A Controlled Trial of Rivaroxaban after Transcatheter Aortic-Valve Replacement.

BACKGROUND: Whether the direct factor Xa inhibitor rivaroxaban can prevent thromboembolic events after transcatheter aortic-valve replacement (TAVR) is unclear. METHODS: We randomly assigned 1644 patients without an established indication for oral anticoagulation after successful TAVR to receive rivaroxaban at a dose of 10 mg daily (with aspirin at a dose of 75 to 100 mg daily for the first 3 months) (rivaroxaban group) or aspirin at a dose of 75 to 100 mg daily (with clopidogrel at a dose of 75 mg daily for the first 3 months) (antiplatelet group). The primary efficacy outcome was the composite of death or thromboembolic events. The primary safety outcome was major, disabling, or life-threatening bleeding. The trial was terminated prematurely by the data and safety monitoring board because of safety concerns. RESULTS: After a median of 17 months, death or a first thromboembolic event (intention-to-treat analysis) had occurred in 105 patients in the rivaroxaban group and in 78 patients in the antiplatelet group (incidence rates, 9.8 and 7.2 per 100 person-years, respectively; hazard ratio with rivaroxaban, 1.35; 95% confidence interval [CI], 1.01 to 1.81; P = 0.04). Major, disabling, or life-threatening bleeding (intention-to-treat analysis) had occurred in 46 and 31 patients, respectively (4.3 and 2.8 per 100 person-years; hazard ratio, 1.50; 95% CI, 0.95 to 2.37; P = 0.08). A total of 64 deaths occurred in the rivaroxaban group and 38 in the antiplatelet group (5.8 and 3.4 per 100 person-years, respectively; hazard ratio, 1.69; 95% CI, 1.13 to 2.53). CONCLUSIONS: In patients without an established indication for oral anticoagulation after successful TAVR, a treatment strategy including rivaroxaban at a dose of 10 mg daily was associated with a higher risk of death or thromboembolic complications and a higher risk of bleeding than an antiplatelet-based strategy. (Funded by Bayer and Janssen Pharmaceuticals; GALILEO ClinicalTrials.gov number, NCT02556203.).

Successful COMPASS, Disappointing COMMANDER HF, What Have We Learned From These Two Trials?

Despite considerable progress in the field of heart failure about drugs and device therapy, the mortality rate of patients with heart failure remains high. Studies have shown that thromboembolism and stroke are associated with high mortality in patients with heart failure. Although warfarin therapy reduces the rate of ischemic stroke in patients with heart failure, the overall benefit from warfarin in this population seems to be offset by the increased bleeding risk. Thus, whether patients with chronic heart failure might benefit from anticoagulation, especially in patients with sinus rhythm, is still controversial. Rivaroxaban, a new oral anticoagulant, is a selective direct factor Xa inhibitor that is used to reduce thrombin generation, which may bring hope to anticoagulation in patients with heart failure. However, the COMPASS trial and recently published COMMANDER HF trial presented different results. By carefully analyzing 2 clinical trials, we think several factors might explain this different outcome.

Safety and effectiveness of a prothrombin complex concentrate in approved and off-label indications.

OBJECTIVE: To evaluate the effectiveness and safety of prothrombin complex concentrates (PCCs) in approved and off-label indications. BACKGROUND: PCCs are approved for the urgent reversal of vitamin K antagonists (VKAs). Data concerning the efficacy, safety and dosing for off-label indications are limited, but they are included in massive bleeding protocols. METHODS: This was a retrospective review of cases treated with four-factor PCCs (4F-PCCs) between January 2009 and 2016. Efficacy end-points include: (i) VKA reversal efficacy assessed by international normalised ratio (INR) normalisation (<1·5) and (ii) clinical efficacy as bleeding cessation and/or decreased number of transfused blood components and 24-h mortality in bleeding coagulopathy. The safety end-point is the incidence of thromboembolic events. RESULTS: A total of 328 patients were included (51·8% male, median age 78 years old). Indications were as follows: VKA reversal (66·6%), bleeding coagulopathy (30·5%) and direct anticoagulant (DOAC) reversal due to bleeding (2·5%). VKA reversal was effective in 97·1% of patients, and 76·5% demonstrated complete reversal (INR < 1·5); only 34·3% patients needed hemoderivatives. Prior to emergency procedures, PCCs achieved global responses in 83% of patients, with no bleeding complication during intervention. DOAC reversal was effective in 88·9% of patients. Bleeding cessation was associated with the dose administered (P = 0·002). In coagulopathy bleeding, haemorrhage cessation, established by the International Society of Thrombosis and Haemostais (ISTH) definition, occurred in 56·7% of massive bleeding events and in 42·5% of other coagulopathies; 24-h mortality was 30%, mainly related to active bleeding. Ten thrombotic episodes were observed (3·1%). CONCLUSION: 4F-PCC was effective as adjuvant treatment with an acceptable safety profile, not only for the emergent reversal of VKAs but also for refractory coagulopathy associated with major bleeding.

Multimodality Imaging for Best Dealing With Patients in Atrial Arrhythmias.

The management of atrial fibrillation (AF) is not only a clinical challenge but also an imaging challenge. The role of different imaging modalities to estimate the thromboembolic risk in AF is a key clinical question. The present review summarizes the advances of myocardial imaging in the stratification of thromboembolic risk, diagnosis, and management of left atrial thrombosis in patients with AF. These imaging techniques are also important for understanding arrhythmias and their consequences. It is becoming fundamental for guiding therapy. Still, large studies are required, but be sure that left atrial imaging will become more and more clinically fundamental.

Role of rivaroxaban in the management of atrial fibrillation: insights from clinical practice.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and it leads to significant morbidity and mortality, predominantly from ischemic stroke. Vitamin K antagonists, mainly warfarin, have been used for decades to prevent ischemic stroke in AF, but their use is limited due to interactions with food and other drugs, as well as the requirement for regular monitoring of the international normalized ratio. Rivaroxaban, a direct factor Xa inhibitor and the most commonly used non-vitamin K oral anticoagulant, avoids many of these challenges and is being prescribed with increasing frequency for stroke prevention in non-valvular AF. Randomized controlled trial (RCT) data from the ROCKET-AF(Rivaroxaban once daily oral direct Factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation) trial have shown rivaroxaban to be non-inferior to warfarin in preventing ischemic stroke and systemic embolism and to have comparable overall bleeding rates. Applicability of the RCT data to real-world practice can sometimes be limited by complex clinical scenarios or multiple comorbidities not adequately represented in the trials. Available real-world evidence in non-valvular AF patients with comorbidities - including renal impairment, acute coronary syndrome, diabetes mellitus, malignancy, or old age - supports the use of rivaroxaban as safe and effective in preventing ischemic stroke in these subgroups, though with some important considerations required to reduce bleeding risk. Patient perspectives on rivaroxaban use are also considered. Real-world evidence indicates superior rates of drug adherence with rivaroxaban when compared with vitamin K antagonists and with alternative non-vitamin K oral anticoagulants - perhaps, in part, due to its once-daily dosing regimen. Furthermore, self-reported quality of life scores are highest among patients compliant with rivaroxaban therapy. The generally high levels of patient satisfaction with rivaroxaban therapy contribute to overall favorable clinical outcomes.

Efficacy and safety of aspirin combined with warfarin after acute coronary syndrome : A meta-analysis.

A comprehensive meta-analysis was performed to investigate whether the combination of high-/low-dose of aspirin and various intensities of warfarin (W) offer greater benefit than aspirin (ASA) alone. A total of 14 randomized clinical trials (RCTs) having 26,916 patients with acute coronary syndrome (ACS) met inclusion criteria. The efficacy and safety of all outcomes which included myocardial infarction (MI), all-cause death, stroke, and bleeding were calculated. The overall outcomes analysis showed there was no significant difference in the risk of MI (relative ratio [RR] 0.959, 95 % confidence interval [CI] 0.78-1.04, P = 0.308), stroke (RR 0.789, 95 % CI 0.57-1.09, P = 0.145), and all-cause death (RR 1.007, 95 % CI 0.93-1.09, P = 0.87) between the combination group and ASA group. The subgroup analysis suggested that ASA (≤100 mg/day) plus W (mean international normalized ratio [INR] 2.0-3.0) decreased the risk rate of stroke (RR 0.660, 95 % CI 0.50-0.87, P = 0.003). There was a lower risk of MI (RR 0.605, 95 % CI 0.47-0.77, P < 0.0001) as well as stroke (RR 0.594, 95 % CI 0.45-0.79, P < 0.0001) between W (INR 2.0-3.0) combined with ASA (mean dose ≥100 mg/day) and ASA. However, the risk of major bleeding (RR 1.738, 95 % CI 1.45-2.08, P < 0.0001) and minor bleeding (RR 2.767, 95 % CI 2.12-3.61, P < 0.0001) was almost doubled in the combined groups. Compared with ASA, high-dose aspirin with moderate-intensity warfarin (INR 2.0-3.0) may better reduce the risk of MI and stroke but confer an increased risk of bleeding.

Thromboembolic, Bleeding, and Mortality Risks of Rivaroxaban and Dabigatran in Asians With Nonvalvular Atrial Fibrillation.

BACKGROUND: It is unclear whether the non-vitamin K antagonist oral anticoagulant agents rivaroxaban and dabigatran are superior to warfarin for efficacy and safety outcomes in Asians with nonvalvular atrial fibrillation (NVAF). OBJECTIVES: The aim of this study was to compare the risk for thromboembolic events, bleeding, and mortality associated with rivaroxaban and dabigatran versus warfarin in Asians with NVAF. METHODS: A nationwide retrospective cohort study was conducted of consecutive patients with NVAF taking rivaroxaban (n = 3,916), dabigatran (n = 5,921), or warfarin (n = 5,251) using data collected from the Taiwan National Health Insurance Research Database between February 1, 2013 and December 31, 2013. The propensity score weighting method was used to balance covariates across study groups. Patients were followed until the first occurrence of any study outcome or the study end date (December 31, 2013). RESULTS: A total of 3,425 (87%) and 5,301 (90%) patients were taking low-dose rivaroxaban (10 to 15 mg once daily) and dabigatran (110 mg twice daily), respectively. Compared with warfarin, both rivaroxaban and dabigatran significantly decreased the risk for ischemic stroke or systemic embolism (p = 0.0004 and p = 0.0006, respectively), intracranial hemorrhage (p = 0.0007 and p = 0.0005, respectively), and all-cause mortality (p < 0.0001 and p < 0.0001, respectively) during the short follow-up period. In comparing the 2 non-vitamin K antagonist oral anticoagulant agents with each other, no differences were found regarding risk for ischemic stroke or systemic embolism, intracranial hemorrhage, myocardial infarction, or mortality. Rivaroxaban carried a significantly higher risk for hospitalization for gastrointestinal bleeding than dabigatran (p = 0.0416), but on-treatment analysis showed that the risk for hospitalized gastrointestinal bleeding was similar between the 2 drugs (p = 0.5783). CONCLUSIONS: In real-world practice among Asians with NVAF, both rivaroxaban and dabigatran were associated with reduced risk for ischemic stroke or systemic embolism, intracranial hemorrhage, and all-cause mortality without significantly increased risk for acute myocardial infarction or hospitalization for gastrointestinal bleeding compared with warfarin.

Efficacy and safety of rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome: Rationale and design of the Trial on Rivaroxaban in AntiPhospholipid Syndrome (TRAPS) trial.

BACKGROUND: New oral anticoagulants may simplify long-term therapy in conditions requiring anticoagulation. Rivaroxaban is a direct factor Xa inhibitor that has been extensively studied and is now approved for the prevention and therapy of a number of thromboembolic conditions. OBJECTIVE AND METHODS: This is a multicentre, randomized, open-label, study that will evaluate if Rivaroxaban 20 mg od (or 15 mg od in patients with moderate renal insufficiency) is non-inferior to warfarin (INR target 2.5), for the prevention of thromboembolic events, major bleeding and death in high risk (triple positive) patients with antiphospholipid syndrome. Secondary endpoints will assess the incidence of any individual component of the composite end point. An external adjudication committee will evaluate all suspected outcome events. This will be a unique trial, as it will enrol the biggest homogenous cohort of high risk APS individuals. CONCLUSION: The methods and the study design should be appropriate to achieve study results that are both scientifically valid and relevant to clinical practice.

Spontaneous neonatal arterial thromboembolism: infants at risk, diagnosis, treatment, and outcomes.

Neonatal spontaneous arterial thromboembolism is a rare phenomenon with a high risk of morbidity and mortality. Currently, there is little information regarding common risk factors, diagnostic strategies, therapeutic interventions, and outcomes of this condition. The objective was to nucleate the best evidence regarding the disorder in order to facilitate early detection and treatment recommendations and document adverse outcomes. Web of Science, PubMed, Medline, CINAHL, Cochrane Databases, DARE, and OVID databases were searched using the following keywords: 'arterial' AND 'thrombus' OR 'thrombosis' OR 'thromboembolism' OR 'embolism' AND 'spontaneous' AND 'at birth' OR 'newborn' OR 'neonatal' OR 'fetal' AND 'umbilical cord' OR 'umbilical wall necrosis' AND 'coagulation abnormality' OR 'placenta bits' OR 'ischemic limbs'. The search yielded 172 articles, all of which were case series or single case descriptions. Twenty-seven met inclusion criteria, with a total of 53 newborns and 30 newborn pathology reports. Ultrasound was the preferred method of diagnosis and thromboembolic locations varied with the most common site being umbilical, resulting in embolism and vascular compromise. Treatment interventions and drug dosages were not standardized and ranged from use of anticoagulants to surgery and hyperbaric oxygen. The reported mortality rate was 32.8%. Recurring etiological features facilitated identification of possible sequences of events contributing to the disorder. The literature lacks empirical evidence to affirm causes and predisposing risk factors for timely diagnosis and effective treatment of spontaneous neonatal arterial thromboembolism. Further research is needed to clearly establish the causes and the efficacy of specific treatment options.

What is the optimum strategy for thromboembolic prophylaxis following extrapleural pneumonectomy in patients with malignant pleural mesothelioma?

Malignant pleural mesothelioma (MPM) increases the risk of venous thromboembolic (VTE) events. This risk is higher following extrapleural pneumonectomy (EPP) as part of trimodality therapy, where VTE can be catastrophic. In our series, the impact of warfarin in preventing a pulmonary embolus (PE) after neoadjuvant chemotherapy and EPP for MPM was analysed. A retrospective analysis of 21 consecutive patients undergoing EPP for MPM was conducted. The first 10 patients (Group A) had VTE prophylaxis by subcutaneous enoxaparin and compression stockings commenced a day prior to surgery, intraoperative pneumatic calf compression and early post-operative mobilization. Enoxaparin was continued for 30 days postoperatively. The following 11 patients (Group B) had the same VTE prophylaxis, together with warfarin, started prior to hospital discharge and continued for 6 months postoperatively. All patients had a computed tomography pulmonary angiogram within 8 weeks after surgery and a full examination at 1, 3, 6 and 12 months. Both groups were comparable for characteristics. Three patients in Group A suffered a PE at 4, 6 and 16 weeks postoperatively. One PE was fatal. No patient in Group B suffered VTE (P = 0.05, χ(2) test) or haemorrhagic complications. Warfarin anticoagulation following EPP is feasible and safe, and is associated with a significant reduction in VTE complications.

Antiplatelet effects of Spatholobus suberectus via inhibition of the glycoprotein IIb/IIIa receptor.

ETHNOPHARMACOLOGICAL RELEVANCE: The vine stem of Spatholobus suberectus is a widely used blood-activating and stasis-dispelling medicine for the treatment of diseases related to blood stasis syndrome in traditional medicine in Korea, Japan, and China. AIM OF THE STUDY: To demonstrate the clinical effects of Spatholobus suberectus against blood stasis syndromes using in vitro and in vivo platelet aggregation studies and to investigate its exact mechanisms. MATERIALS AND METHODS: We extracted vine stems of Spatholobus suberectus, using 95% EtOH (SSE) and investigated its antiplatelet activity on platelet aggregation induced by collagen and ADP in human platelet-rich plasma (PRP). For the mechanism study, a glycoprotein IIb/IIIa (GP IIb/IIIa) assay using flow cytometric analysis and a thromboxane A(2) (TXA(2)) assay were performed. In addition, we investigated the effects of SSE in a thromboembolic mouse model. RESULTS: SSE significantly inhibited ADP- and collagen-induced platelet aggregation in human PRP concentration-dependently without affecting plasma clotting time. It also significantly inhibited fibrinogen binding to the GP IIb/IIIa receptor and partly inhibited the formation of TXA(2). In the in vivo study, oral administration of SSE dose-dependently suppressed the death of thromboembolism model mice induced by intravenous injection of collagen plus epinephrine. CONCLUSIONS: SSE showed antiplatelet activity without anticoagulant effects mainly through the inhibition of fibrinogen binding to the GP IIb/IIIa receptor. Our current results support the clinical usage of SSE in the East Asian region treating atherothrombotic diseases and may represent a new natural source to develop antiplatelet agents.

Digitalis: a dangerous drug in atrial fibrillation? An analysis of the SPORTIF III and V data.

OBJECTIVE: In heart failure, digitalis increases exercise capacity and reduces morbidity, but has no effect on survival. This raises the suspicion that the inotropic benefits of digitalis may be counteracted by serious adverse effects. Patients with atrial fibrillation (AF) were studied to clarify this. DESIGN: In the Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation (SPORTIF) III and V studies, 7329 patients with AF at moderate-to-high risk were randomised to preventive treatment of thromboembolism, either with warfarin or the oral direct thrombin inhibitor ximelagatran. The survival of users and non-users of digitalis was investigated. RESULTS: At baseline, 53.4% of the study population used digitalis, and these patients had a higher mortality than non-users (255/3911 (6.5%) vs 141/3418 (4.1%), p<0.001; hazard ratio (HR) = 1.58 (95% CI 1.29 to 1.94)). Digitalis users also had more baseline risk factors. After multivariate risk factor adjustment, the increased mortality persisted (p<0.001; HR = 1.53 (95% CI 1.22 to 1.92 vs 1.23 to 1.92)). CONCLUSIONS: The results suggest that digitalis, like other inotropic drugs, may increase mortality. This may be concealed in heart failure, but be revealed in patients with AF, who need the rate-reducing effect of digitalis, but do not benefit much from an increased inotropy. Cautious interpretation of the data is mandatory since the patients were not randomised with respect to digitalis use.

Surgery for chronic thromboembolic pulmonary hypertension--inclusive experience from a national referral center.

BACKGROUND: Chronic thromboembolic pulmonary hypertension represents a unique form of pulmonary hypertension amenable to curative intervention with a pulmonary thromboendarterectomy (PTE). Canada's first successful and sustainable program for PTE surgery was established at the University of Ottawa Heart Institute in 1995. Inclusive results from similarly sized programs are not readily available owing to selective reporting, therefore making it difficult to benchmark outcomes. The purpose of this report is to provide a review of the inclusive results from our moderately sized national program for all PTE, with a particular emphasize on the aspects of the learning curve in terms of patient management. METHODS: Since 1995, 180 patients have been referred for consideration of PTE, and 106 patients have undergone surgery with a perioperative 30-day mortality rate of 9.4%. RESULTS: There was a significant improvement in all hemodynamic parameters except right ventricular ejection fraction in nonsurvivors (mean pulmonary artery pressure pre 47 +/- 12 mm Hg versus post 28 +/- 9 mm Hg, p < 0.0001; pulmonary vascular resistance pre 814 +/- 429 dynes x sec(-1) x cm(-5), post 224 +/- 145 dynes x sec(-1) x cm(-5), p < 0.0001; cardiac index pre 2.0 +/- 0.7 L x min(-1) x m(-2), post 3.2 +/- 0.7 L x min(-1) x m(-2), p < 0.0001). A postoperative pulmonary vascular resistance of 500 dynes x sec(-1) x cm(-5) or more was associated with increased perioperative mortality (odds ratio, 12 +/- 8.7; p = 0.001). On average, these procedures were associated with significant resource use involving operating room time (610 +/- 243 minutes), intensive care unit and hospital days (11.2 +/- 13.7 and 19.5 +/- 15.6 days), and ventilation time (7.8 +/- 10.0 days). There was no significant change in hospital or intensive care unit length of stay, or the mortality rate during this first decade. CONCLUSIONS: PTE programs are resource-intensive surgical specialty services that demand excellence in cardiothoracic expertise. The initial decade reflected an expanding referral basis and likely parallel increases in patient complexity and expertise. The current results at a national referral center have emphasized the importance of centralization of resources to optimize patient outcome.

Longitudinal study of survival and causes of death in patients with thalassemia major in Greece.

Iron-induced organ degeneration is the main factor of mortality in patients with thalassemia major. Since chelation therapy is at a turning point, from the laborious parenteral route to the use of new promising oral agents, we investigated the current status of survival of these patients to present reliable data that will be useful in future comparative studies. Survival probabilities were estimated by the Kaplan-Meier method, and results were compared by the log-rank test in a total of 647 thalassemic patients (pts) (52% males) born between 1/1/58 and 1/2/04. Terminal follow-up was 1/12/04. All transfusion-dependent pts monitored in our center, or in frequent contact if they had moved elsewhere, were strictly selected, excluding all rarely transfused or intermediate cases. Pts born before 1/1/75 were classified in group A (n = 366), while pts born later were included in group B (n = 281). According to the last 5 years' mean serum ferritin level, pts were divided into three hemosiderosis groups: (1) mild (<2000 microg/L) 49%, (2) moderate (2000-4000 microg/L) 28%, and (3) severe (>4000 microg/L) 23%. Of the 647 pts, 115 died (mean age: 22.6 +/- 6.2 years), most frequently by heart failure (71.3%) followed by sepsis (7.8%). Life expectancy in the entire population was up to 59% at 46 years. Survival was higher for pts born after 1975 than those before (P < .001). Statistically significantly different survival probabilities were found between groups with mild, moderate, or severe hemosiderosis (P < .001). Effective management with improved chelation therapy could lead to better results.

Antihaemostatic and antithrombotic effect of some antiplatelet agents isolated from Chinese herbs.

Five antiplatelet agents have been isolated from Chinese herbs. Apigenin and magnolol are inhibitors of thromboxane synthesis, while osthole, protopine and norathyriol are inhibitiors of phosphoinositide breakdown. Thirty min after intraperitoneal (i.p.) administration of these drugs, tail bleeding time of mice was prolonged markedly in a dose-dependent manner by norathyriol, protopine, osthole and magnolol, but not by apigenin. However, the antiplatelet agents (up to 200 mg kg-1, i.p.) could not prevent acute thromboembolic death in mice. In endotoxin-induced experimental disseminated intravascular coagulation in rats, norathyriol (50-100 mg kg-1, i.p.) prevented the decrease in platelet counts and fibrinogen, and the prolongation of plasma prothrombin time. Norathyriol (100 mg kg-1, i.p.) also suppressed ex-vivo platelet aggregation induced by collagen and ADP in rat plasma.