Definition of major bleeding: Prognostic classification.

BACKGROUND: In patients on anticoagulant treatment, the major bleeding (MB) definition released by the International Society of Thrombosis and Haemostasis (ISTH) is widely accepted. However, this definition identifies MBs with highly variable short-term risk of death. OBJECTIVES: The study aims were to derive and validate a classification of ISTH-defined MBs for the risk of short-term death. METHODS: Consecutive patients admitted for ISTH-defined MB occurring while on treatment with oral anticoagulants were included in the study and divided into a derivation and a validation cohort. Death within 30 days was the primary study outcome. RESULTS: Among 1077 patients with MB, 64/517 and 63/560 patients in the derivation and validation cohort died, respectively. In the derivation cohort, Glasgow coma scale (GCS) <14 and shock were predictors of death; critical site bleeding and hemoglobin decrease ≥2 g/dL, or transfusion ≥ 2 units were not. GCS <14 (hazard ratio [HR], 8.67; 95% confidence interval [CI], 3.93-19.13) was predictor of death in intracranial hemorrhage (ICH) and shock at admission (HR, 4.84; 95% CI, 2.01-11.70) and pericardial bleeding (HR, 11.37; 95% CI, 1.33-97.31) in non-ICH MBs. The predictive value of GCS <14 in ICH and shock and pericardial bleeding in non-ICH MBs was confirmed in the validation cohort. None of the patients with isolated ocular or articular bleeding died. A prognostic classification of ISTH-defined MBs for the risk of short-term death is proposed as "serious," "severe," and "life-threatening" (ICH with GCS <14 or non-ICH with shock) MBs. CONCLUSION: According to our study, ISTH-defined MBs can be stratified for the risk of death within 30 days.

Mortality in patients with intracerebral hemorrhage associated with antiplatelet agents, oral anticoagulants or no antithrombotic therapy.

The association between preceding treatment with antiplatelet agents (APs), vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) and mortality after intracerebral hemorrhage (ICH) remains unclear. The aim of this multicenter, prospective cohort study was to assess the risk for death after ICH in consecutive patients who were on treatment with APs, VKAs, DOACs, or no antithrombotic agent. The primary outcome was in-hospital death by day 30. ICH volume at admission and volume expansion were centrally assessed. Out of 598 study patients, in-hospital death occurred in 21% of patients who were on treatment with APs, 25% with VKAs, 30% with DOACs, and 13% with no antithrombotics. Crude death rate was higher in patients on antithrombotics as compared to patients receiving no antithrombotic agent. At multivariate analysis, age (HR 1.07; 95% CI 1.04-1.10), previous stroke (HR 1.83; 95% CI 1.14-2.93), GCS ≤8 at admission (HR 6.06; 95% CI 3.16-9.74) and GCS 9-12 (HR 3.38; 95% CI 1.81-6.33) were independent predictors of death. Treatment with APs (HR 1.29; 95% CI 0.61-2.76), VKAs (HR 1.42; 95% CI 0.70-2.88) or DOACs (HR 1.28; 95% CI 0.61-2.73) were not predictors of death in the overall study population, in non-trauma associated ICH as well as when GCS was not included in the model. ICH volume and volume expansion were independent predictors of death. In conclusion, preceding treatment with antithrombotic is associated with the severity of ICH. Age, previous stroke and clinical severity at presentation were independent predictors of in-hospital death in patients with ICH.

Carotid atherosclerosis and risk for ischemic stroke in patients with atrial fibrillation on oral anticoagulant treatment.

BACKGROUND AND AIMS: Whether carotid atherosclerosis is associated with an increased risk for ischemic stroke in patients with atrial fibrillation (AF) on anticoagulant treatment is undefined. To explore this association, patients with AF on treatment with vitamin K antagonists were included in a multicenter, prospective study. METHODS: At inclusion in the study, patients underwent Doppler-ultrasonography for the assessment of carotid atherosclerosis and then were prospectively followed. Ischemic stroke or transient ischemic attack (TIA) were the primary study outcomes; death and its causes were reported. RESULTS: Overall, 587 patients were included in the study. At ultrasonography, 380 patients had carotid atherosclerosis (64.7%) and 45 internal carotid (ICA) stenosis ≥50% (7.7%). During a mean follow-up of 41 ±â€¯15 months, 30 patients had an ischemic stroke or TIA (1.49% per patient-year, 95% CI 0.96-2.03) and 81 patients died (4.01% per patient-year, 95% CI 3.16-4.86). Carotid atherosclerosis was associated with a significant increase in the risk for the composite of ischemic stroke or TIA or death after adjusting for CHA2DS2VASc (6.0% vs. 3.1% patient-year; HR 1.60, 95% CI 0.99-2.59; p = 0.05). ICA ≥50% was associated with a not significant increase in the risk of ischemic stroke or TIA (2.05% vs. 1.45% patient-year; HR 1.39, 95% CI 0.42-4.58) or all-cause death (6.1% vs. 3.8% patient-year; HR 1.66, 95% CI 0.83-3.32). CONCLUSIONS: In patients with AF, carotid atherosclerosis is a predictor for the composite of cerebrovascular events or death while on anticoagulant therapy. In patients with AF and carotid atherosclerosis, the clinical benefit of a more intense antithrombotic treatment should be evaluated.

Major bleeding with vitamin K antagonists or direct oral anticoagulants in real-life.

BACKGROUND: Limited data are available on major bleeding (MB) occurring during treatment with vitamin K (VKAs) or direct oral anticoagulants (DOACs) outside clinical trials. METHODS: Patients hospitalized for MB while on treatment with VKAs or DOACs were included in a multicenter study to compare clinical presentation, management and outcome of bleeding. The primary study outcome was death at 30days. RESULTS: Between September 2013 and September 2015, 806 patients were included in the study, 76% on VKAs and 24% on DOACs. MB was an intracranial hemorrhage in 51% and 21% patients on VKAs or DOACs, respectively (Odds Ratio [OR] 3.79; 95% confidence interval [CI] 2.59-5.54) a gastrointestinal bleeding in 46% and 25% patients on DOACs and VKAs, respectively (OR 2.62; 95% CI 1.87-3.68). Death at 30days occurred in 130 patients (16%), 18% and 9% of VKA and DOAC patients (HR 1.95; 95% CI 1.19-3.22, p=0.008). The rate of death at 30days was similar in VKA and DOAC patients with intracranial hemorrhage (26% and 24%; HR 1.05, 95% CI 0.54-2.02) and gastrointestinal bleeding (11% and 7%; HR 1.46, 95% CI 0.57-3.74) and higher in VKA than DOAC patients with other MBs (10% and 3%; HR 3.42, 95% CI 0.78-15.03). CONCLUSIONS: Admission for ICH is less frequent for DOAC patients compared with VKA patients. Admission for gastrointestinal MB is more frequent for DOAC as compared to VKA patients. Mortality seems lower in patients with MBs while on DOACs than VKAs but this finding varies across different types of MBs.

Long-term treatment of venous thromboembolism.

Long term treatment of venous thromboembolism is essential to complete therapy of the index episode and to reduce recurrences. Vitamin K antagonists are the mainstay for the long term treatment of venous thromboembolism for the majority of the patients as they allow oral administration. Low-molecular weight heparins are recommended for the long term treatment of cancer patients. The duration of long term anticoagulation depends on the features of the index venous thromboembolism and on the presence of associated risk factors. Patients at high risk for recurrence - mainly those who suffered unprovoked venous thromboembolism and those with cancer - should be evaluated for extended anticoagulation. The risk for major bleeding complications and the inconvenience for monitoring, dose adjustment and drug-food interactions are the main constraints for indefinite anticoagulant treatment. New anticoagulants with more favourable efficacy- safety profile and reduced need for monitoring could improve the feasibility of extended anticoagulation.

96 hours ECG monitoring for patients with ischemic cryptogenic stroke or transient ischaemic attack.

Atrial fibrillation (AF) is intermittent in 30% of patients with cardioembolic stroke and, therefore, might not be seen in a single standard ECG recording. The aim of this study was to evaluate if prolonged ECG monitoring (96 h) finds episodes of intermittent AF beyond the 24 h ECG monitoring in patients with cryptogenic stroke or transient ischemic attack (TIA). We prospectively evaluated consecutive patients affected by cryptogenic stroke or TIA who had sinus rhythm on a 12-lead ECG on admission, and during ECG monitoring performed in the acute phase (for at least 24 h). Patients had continuous 96 h Holter ECG monitoring within 30 days from stroke onset. 114 patients were included in the study (mean age 63.1 ± 15.1, 59 males). AF was found in 29 patients (24.3%). In 20 patients, AF was found in the first 24 h of recording, and in nine patients after 24 h. In addition, several other dysrhythmias such as supraventricular ectopic activity (33), ventricular tachycardia (10), sinus pause (4) and sinus-atrial block (1) were found. In patients with cryptogenic stroke or TIA, 96 h ECG monitoring detected a high rate of AF. One-third of AF was seen beyond 24 h of ECG monitoring.

Venous thromboembolism after laparoscopic cholecystectomy: clinical burden and prevention.

BACKGROUND: The clinical benefit of prophylaxis for venous thromboembolism (VTE) in laparoscopic cholecystectomy is unclear. This study aimed to assess the clinical burden of VTE and the efficacy and safety of antithrombotic prophylaxis during laparoscopic cholecystectomy. METHODS: Data sources and study selection studies were searched in MEDLINE and Embase using the terms "cholecystectomy and venous thrombosis" and "cholecystectomy and venous thromboembolism." Studies were considered for a systematic review and a metaanalysis if they reported on the methods of antithrombotic prophylaxis and on the incidence of objectively confirmed VTE in patients who had undergone laparoscopic cholecystectomy. Overall, 15 studies of patients who had undergone laparoscopic cholecystectomy were included in the systematic review. RESULTS: The incidence of VTE was lower after laparoscopic cholecystectomy than after open cholecystectomy [odds ratio (OR), 0.47; 95 % confidence interval (CI), 0.40-0.56]. No statistically significant reduction in VTE was observed in patients receiving heparin prophylaxis after laparoscopic cholecystectomy (OR, 0.86; 95 % CI, 0.12-5.82). CONCLUSIONS: The rate of VTE after laparoscopic cholecystectomy seems to be relatively low. The clinical benefit of heparin prophylaxis for patients undergoing laparoscopic cholecystectomy remains unclear.

Venous thromboembolism after laparoscopic bariatric surgery for morbid obesity: clinical burden and prevention.

BACKGROUND: The clinical benefit of prophylaxis for venous thromboembolism (VTE) in laparoscopic bariatric surgery is unclear. Our objective was to assess the clinical burden of VTE after laparoscopic bariatric surgery. METHODS: We performed a systematic review and meta-analysis. Studies were considered for the review if they reported on the methods used for antithrombotic prophylaxis and on the incidence of objectively confirmed VTE in patients who had undergone laparoscopic bariatric surgery. RESULTS: Overall, 19 studies were included in the analysis. The weighted mean incidence (WMI) of pulmonary embolism was .5% (12 events in 3991 patients, 12 studies; 95% confidence interval [CI] .2-.9%; I(2) 38%) with unfractionated heparin (5000 UI twice or 3 times daily) or low-molecular-weight heparin (30 mg twice daily or 40 mg once daily). The WMI of major bleeding as originally reported in 7 of these studies was 3.6% (2741 patients; 95% CI .9-7.95; I(2) 94%). The WMI of screened VTE in 3 high-quality studies with different regimens of heparin prophylaxis was 2.0% (8 events in 458 patients; 95% CI .9-3.5%; I(2) 0%). The WMI of symptomatic VTE was .6% (4 studies; 7 events in 1328 patients; 95% CI .3-1.1%; I(2) 0%) and that of major bleeding was 2.0% (95% CI 1.0-3.4%; I(2) 55%), with weight-adjusted doses of heparin prophylaxis. CONCLUSION: The rate of VTE after laparoscopic bariatric surgery seems to be relatively low with standard regimens for antithrombotic prophylaxis. The incidence of major bleeding seems to increase using weight-adjusted doses of heparin with no advantage in terms of VTE reduction.

Risk factors for cerebral ischemic events in patients with atrial fibrillation on warfarin for stroke prevention.

BACKGROUND AND PURPOSES: Patients with atrial fibrillation (AF) on treatment with oral anticoagulants may still suffer ischemic cerebrovascular events. The aim of this study was to evaluate the risk factors for cerebral ischemic events in warfarin-treated AF patients with an International Normalized Ratios (INR) above 1.8 on admission. METHODS: In a case-control study, cases were consecutive patients with AF who were on warfarin and who were admitted to four Italian hospitals after an acute cerebrovascular ischemic event (ischemic stroke or transient ischemic attack) with an INR above 1.8. Controls were selected from a single anticoagulation clinic and were patients with AF on adequate warfarin treatment who did not suffer cerebrovascular events. RESULTS: Cases were identified among 4785 consecutive patients with an ischemic cerebral event. 148 cases (3.1%, 21 with transient ischemic events and 127 with ischemic strokes) had AF and were taking warfarin with an INR above 1.8 on admission. On multivariate analysis, diabetes (OR 3.8; 95% CI 1.09-13.82, p=0.025), hyperlipidemia (OR 4.5; 95% CI 1.11-18.23, p=0.035) and carotid/vertebral atherosclerosis on ultrasound (OR 3.0; 95% CI 1.13-8.41, p=0.028) were independent predictors for ischemic cerebral events. The use of statins was inversely correlated with an ischemic event (OR 0.1; 95% CI 0.06-0.47. p=0.001). CONCLUSIONS: Carotid/vertebral atherosclerosis, diabetes and hyperlipidemia are associated with an increased risk for ischemic events in patients with AF on adequate warfarin treatment. Statins significantly reduce the risk of ischemic events.

Bosentan for chronic thromboembolic pulmonary hypertension: findings from a systematic review and meta-analysis.

BACKGROUND: After acute pulmonary embolism, chronic thromboembolic pulmonary hypertension (CTEPH) is diagnosed in about 1% of patients. We performed a systematic review and meta-analysis aimed at assessing the effects of bosentan therapy in patients with CTEPH. METHODS: We searched in MEDLINE and Embase using the terms 'pulmonary hypertension' AND 'bosentan'. Papers were included in this review if they reported on patients with objectively confirmed CTEPH treated with bosentan. Efficacy measures were the improvement in NYHA class, in 6 minute walking distance (6 mwd) and in hemodynamics (cardiac index, pulmonary artery pressure, pulmonary vascular resistance). Mortality and safety were also assessed. RESULTS: Overall, 543 papers were found. Eight single-arm cohort studies (175 patients), one randomized double-blind study, one case-control study and one case report were included in the analysis. A 35.9 meters weighted mean increase in 6 minute walking distance was observed after 3-6 months of treatment (9 studies, 208 patients) (95% CI 33.6 to 38.2; p<0.001) and an additional increase of 21 meters after one year (4 studies, 80 patients). About 25% of patients had an improvement on functional NYHA class at 3-6 months. Data on hemodynamics were available in seven studies, 185 patients. The mean weighted increase in cardiac index at 3-6 months was 0.23 l/min/m2 (95% CI 0.22 to 0.25); the mean weighted decrease in pulmonary artery pressure at 3-6 months was 2.62 mmHg (95% CI 2.44 to 2.80). Three patient died within 3-6 months (1.4%) and 3 additional patients died within one year. CONCLUSIONS: Bosentan therapy is associated with an improvement of hemodynamics and probably exercise capacity in patients with CTEPH. Controlled data on mortality and time to clinical worsening in patients with CTEPH are needed.

[Determinants of prognosis in acute pulmonary embolism: the role of serum troponins]. / Marcatori prognostici nell'embolia polmonare acuta: il ruolo delle troponine.

In-hospital mortality in patients with acute pulmonary embolism ranges between about 1% and over 30%. Due to a particularly high mortality, hemodynamically unstable patients with pulmonary embolism should receive thrombolytic treatment. The role of thrombolytic treatment in hemodynamically stable patients with pulmonary embolism is controversial and should be restricted to those at high risk for in-hospital mortality. Prognostic stratification is crucial in hemodynamically stable patients as mortality in this group ranges between 1 and 10%. Serum troponin levels have been shown to be associated with in-hospital mortality and clinical deterioration. Studies on the prognostic value of serum troponin in patients with acute pulmonary embolism have been included in a meta-analysis that shows a 5-fold in hospital mortality in patients with high troponin compared to those with normal troponin levels. The prognostic value of elevated serum troponin levels have also been shown in studies including only hemodynamically stable patients with pulmonary embolism. Future studies will evaluate the clinical benefit of thrombolytic treatment in hemodynamically stable patients with acute pulmonary embolism at high risk for adverse outcome.