BACKGROUND

Venous thromboembolism is common after major trauma. Strategies to prevent fatal pulmonary embolism (PE) are widely utilized, but the incidence and risk factors for fatal PE are poorly understood.

METHODS

Using linked data from the intensive care unit, trauma registry, Western Australian Death Registry, and post-mortem reports, the incidence and risk factors for fatal PE in a consecutive cohort of major trauma patients, admitted between 1994 and 2002, were assessed. Non-linear relationships between continuous predictors and risk of fatal PE were modelled by logistic regression.

RESULTS

Of the 971 consecutive trauma patients considered in the study, 134 (13.8%) died after their injuries. Fatal PE accounted for 11.9% of all deaths despite unfractionated heparin prophylaxis being used in 44% of these patients. Fatal PE occurred in those who were older (mean age 51- vs 37-yr-old, P=0.01), with more co-morbidities (Charlson's co-morbidity index 1.1 vs 0.2, P=0.01), had a larger BMI (31.8 vs 24.5, P=0.01), and less severe head and systemic injuries when compared with those who died of other causes. Sites of injuries were not significantly related to the risk of fatal PE. Fatal PE occurred much later than deaths from other causes (median 18 vs 2 days, P=0.01), and the estimated attributable mortality of PE was 49% (95% confidence interval 36-62%).

CONCLUSIONS

Fatal PE appeared to be a potential preventable cause of late mortality after major trauma. Severity of injuries, co-morbidity, and BMI were important risk factors for fatal PE after major trauma.

BACKGROUND

Elevated plasma levels of heparin-binding protein (HBP) are associated with risk of organ dysfunction and mortality in sepsis, but little is known about causality and mechanisms of action of HBP. The objective of the present study was to test the hypothesis that HBP is a key mediator of the increased endothelial permeability observed in sepsis and to test potential treatments that inhibit HBP-induced increases in permeability.

METHODS

Association between HBP at admission with clinical signs of increased permeability was investigated in 341 patients with septic shock. Mechanisms of action and potential treatment strategies were investigated in cultured human endothelial cells and in mice.

RESULTS

Following adjustment for comorbidities and Acute Physiology and Chronic Health Evaluation (APACHE) II, plasma HBP concentrations were weakly associated with fluid overload during the first 4 days of septic shock and the degree of hypoxemia (PaO2/FiO2) as measures of increased systemic and lung permeability, respectively. In mice, intravenous injection of recombinant human HBP induced a lung injury similar to that observed after lipopolysaccharide injection. HBP increased permeability of vascular endothelial cell monolayers in vitro, and enzymatic removal of luminal cell surface glycosaminoglycans (GAGs) using heparinase III and chondroitinase ABC abolished this effect. Similarly, unfractionated heparins and low molecular weight heparins counteracted permeability increased by HBP in vitro. Intracellular, selective inhibition of protein kinase C (PKC) and Rho-kinase pathways reversed HBP-mediated permeability effects.

CONCLUSIONS

HBP is a potential mediator of sepsis-induced acute lung injury through enhanced endothelial permeability. HBP increases permeability through an interaction with luminal GAGs and activation of the PKC and Rho-kinase pathways. Heparins are potential inhibitors of HBP-induced increases in permeability.

Venous thromboembolism (VTE) is common in patients with brain tumors, occurring in up to 30% of patients with high-grade glioma and up to 20% of those with brain metastasis and primary central nervous system (CNS) lymphoma. The risk is correlated with higher grade malignancies and is directly associated with the production of the potent procoagulant, tissue factor (TF). Upregulation of TF influences both the coagulation pathway and oncogenic signaling mechanisms important for cancer progression. The risk of intracranial hemorrhage with the use of anticoagulants complicates the management of VTE in patients with brain tumor. We discuss the recommended anticoagulants used for initial and long-term treatment of established VTE, including unfractionated heparin, low-molecular-weight heparin (LMWH), and warfarin. Therapeutic anticoagulation, particularly LMWH followed by secondary prophylaxis, is generally safe and effective in the treatment of VTE, including patients on antiangiogenic agents. Anticoagulation also reduces the risk of VTE during the perioperative period. However, despite the high risk of VTE throughout the course of disease, present data do not support routine thromboprophylaxis in brain tumor patients. Further investigation regarding the mechanisms underlying the hypercoagulable state of patients with brain tumors and the potential role of the factors and products of thrombogenesis as biomarkers for risk stratification will be useful in identification and management of patients at risk of developing VTE. Novel oral anticoagulants that directly inhibit thrombin such as dabigatran or factor Xa, including rivaroxaban and apixaban have several potential advantages; however, due to limited data in the cancer population, the use of these newer oral anticoagulants is not currently recommended for patients with malignancy and VTE. Recent studies have explored the role of anticoagulants as anticancer agents, which may contribute to cancer treatment in the future.

Previously, we demonstrated in a rat model of heparin-induced osteoporosis that low molecular weight heparin (LMWH) produces less bone loss than unfractionated heparin, and that only heparin increases osteoclast number and activity. In contrast, both heparin and LMWH were found to decrease osteoblast function to a similar extent, possibly because at the doses tested both agents produced maximal inhibition. To examine the relative effects of heparin and LMWH on osteoblast function more closely we used an in vitro bone nodule assay, together with measurements of alkaline phosphatase (ALP) activity. Both agents inhibited bone nodule formation and ALP activity in a concentration-dependent manner, but 6 to 8-fold higher concentrations of LMWH were required to achieve equivalent effects. The effect of heparin on osteoblast function was both chain-length and negative charge-dependent because the ability of defined heparin fragments to inhibit nodule formation correlated with their molecular weight (r = 0.98), and N-desulfated heparin was less inhibitory than heparin. In contrast, the effect of heparin on osteoblast function was pentasaccharide-independent because heparin with low affinity for antithrombin had similar activity to heparin with high antithrombin activity. These findings help to explain mounting clinical evidence that the risk of osteoporosis is lower with LMWH than with heparin.

OBJECTIVE

To determine the efficacy and safety of enoxaparin compared with unfractionated heparin during percutaneous coronary intervention.

METHODS

Systematic review and meta-analysis.

METHODS

Medline and Cochrane database of systematic reviews, January 1996 to May 2011.

METHODS

Randomised and non-randomised studies comparing enoxaparin with unfractionated heparin during percutaneous coronary intervention and reporting on both mortality (efficacy end point) and major bleeding (safety end point) outcomes.

METHODS

Sample size, characteristics, and outcomes, extracted independently and analysed.

RESULTS

23 trials representing 30,966 patients were identified, including 10,243 patients (33.1%) undergoing primary percutaneous coronary intervention for ST elevation myocardial infarction, 8750 (28.2%) undergoing secondary percutaneous coronary intervention after fibrinolysis, and 11,973 (38.7%) with non-ST elevation acute coronary syndrome or stable patients scheduled for percutaneous coronary intervention. A total of 13,943 patients (45.0%) received enoxaparin and 17,023 (55.0%) unfractionated heparin. Enoxaparin was associated with significant reductions in death (relative risk 0.66, 95% confidence interval 0.57 to 0.76; P<0.001), the composite of death or myocardial infarction (0.68, 0.57 to 0.81; P<0.001), and complications of myocardial infarction (0.75, 0.6 to 0.85; P<0.001), and a reduction in incidence of major bleeding (0.80, 0.68 to 0.95; P=0.009). In patients who underwent primary percutaneous coronary intervention, the reduction in death (0.52, 0.42 to 0.64; P<0.001) was particularly significant and associated with a reduction in major bleeding (0.72, 0.56 to 0.93; P=0.01).

CONCLUSIONS

Enoxaparin seems to be superior to unfractionated heparin in reducing mortality and bleeding outcomes during percutaneous coronary intervention and particularly in patients undergoing primary percutaneous coronary intervention for ST elevation myocardial infarction.

BACKGROUND

(18)F-fluorodeoxyglucose (FDG) PET plays an important role in the detection of cardiac involvement sarcoidosis (CS). However, diffuse left ventricle (LV) wall uptake sometimes makes it difficult to distinguish between positive uptake and physiological uptake. The aims of this study were to evaluate the effects of 18-h fasting with low-carbohydrate diet (LCD) vs a minimum of 6-h fasting preparations on diffuse LV FDG uptake and free fatty acid (FFA) levels in patients with suspected CS.

METHODS

Eighty-two patients with suspected CS were divided into 2 preparation protocols: one with a minimum 6-h fast without LCD preparation (group A, n = 58) and the other with a minimum 18-h fast with LCD preparation (group B, n = 24). All patients also received intravenous unfractionated heparin (UFH; 50 IU/kg) before the injection of FDG.

RESULTS

Group A showed a higher percentage of diffuse LV uptake than did group B (27.6 vs 0.0%, P = .0041). Group B showed higher FFA levels (1159.1 ± 393.0, 650.5 ± 310.9 μEq/L, P < .0001) than did group A. Patients with diffuse LV uptake (n = 16) showed lower FFA levels than did other patients (n = 66) (432.1 ± 296.1, 888.4 ± 381.4 μEq/L, P < .0001). UFH administration significantly increased FFAs in both groups, even in the patients with diffuse LV FDG uptake.

CONCLUSIONS

The 18-h fast with LCD preparation significantly reduced diffuse LV uptake and increased FFA levels. In particular, the FFA level was significantly lower in patients with LV diffuse uptake than in patients without LV diffuse uptake. Acutely increasing plasma FFA through the use of UFH may not have a significant role in reducing physiological LV FDG uptake.

Heparin fractions of differing Mr (7800-18 800) prepared from commercial heparin by gel filtration and affinity chromatography on immobilized anti-thrombin III had specific activities when determined by anti-Factor Xa and anti-thrombin assays that ranged from 228 to 448 units/mg. The anti-Factor Xa activity of these fractions could be readily and totally neutralized by increasing concentrations of platelet factor 4 (PF4). That these fractions bound to immobilized PF4 was indicated by the complete binding under near physiological conditions of 3H-labelled unfractionated commercial heparin. An anti-thrombin III-binding oligosaccharide preparation (containing predominantly eight to ten saccharide units), prepared by degradation of heparin with HNO2 had high (800 units/mg) anti-Factor Xa, but negligible anti-thrombin, specific activity. The anti-Factor Xa activity of this material could not be readily neutralized by PF4, and the 3H-labelled oligosaccharides did not completely bind to immobilized PF4. A heterogeneous anti-thrombin III-binding preparation containing upwards of 16 saccharides had anti-thrombin specific activity of just less than one-half the anti-Factor Xa specific activity. This material was completely bound to immobilized PF4 and was eluted with similar concentrations of NaCl to those that were required to elute unfractionated heparins from these columns. Furthermore, increasing concentrations of PF4 neutralized the anti-Factor Xa activity of this material in a manner similar to that of unfractionated heparin. It is concluded that heparin oligosaccharides require saccharide units in addition to the anti-thrombin III-binding sequence in order to fully interact with PF4.

The mechanism of elimination of blood borne heparin was studied. To this end unfractionated heparin (UFH) was tagged with FITC, which served as both a visual marker and a site of labeling with (125)I-iodine. UFH labeled in this manner did not alter the anticoagulant activity or binding specificity of the glycosaminoglycan. Labeled heparin administered intravenously to rats (0.1 IU/kg) had a circulatory t(1/2) of 1.7 min, which was increased to 16 min upon coinjection with unlabeled UFH (100 IU/kg). At 15 min after injection, 71% of recovered radioactivity was found in liver. Liver cell separation revealed the following relative uptake capacity, expressed per cell: liver sinusoidal endothelial cell (LSEC)-parenchymal cell-Kupffer cell = 15:3.6:1. Fluorescence microscopy on liver sections showed accumulation of FITC-UFH only in cells lining the liver sinusoids. No fluorescence was detected in parenchymal cells or endothelial cells lining the central vein. Fluorescence microscopy of cultured LSECs following binding of FITC-UFH at 4 degrees C and chasing at 37 degrees C, showed accumulation of the probe in vesicles located at the periphery of the cells after 10 min, with transfer to large, evenly stained vesicles in the perinuclear region after 2 h. Immunogold electron microscopy of LSECs to probe the presence of FITC following injection of FITC-UFH along with BSA-gold to mark lysosomes demonstrated colocalization of the probe with the gold particles in the lysosomal compartment. Receptor-ligand competition experiments in primary cultures of LSECs indicated the presence of a specific heparin receptor, functionally distinct from the hyaluronan/scavenger receptor (Stabilin2). The results suggest a major role for LSECs in heparin elimination.

The chemokine platelet factor 4 (PF4) undergoes conformational changes when complexing with polyanions. This can induce the antibody-mediated adverse drug effect of heparin-induced thrombocytopenia (HIT). Understanding why the endogenous protein PF4 becomes immunogenic when complexing with heparin is important for the development of other negatively charged drugs and may also hint toward more general mechanisms underlying the induction of autoantibodies to other proteins. By circular dichroism spectroscopy, atomic force microscopy, and isothermal titration calorimetry we characterized the interaction of PF4 with unfractionated heparin (UFH), its 16-, 8-, and 6-mer subfractions, low-molecular-weight heparin (LMWH), and the pentasaccharide fondaparinux. To bind anti-PF4/heparin antibodies, PF4/heparin complexes require (1) an increase in PF4 antiparallel β-sheets exceeding ∼30% (achieved by UFH, LMWH, 16-, 8-, 6-mer), (2) formation of multimolecular complexes (UFH, 16-, 8-mer), and (3) energy (needed for a conformational change), which is released by binding of ≥11-mer heparins to PF4, but not by smaller heparins. These findings may help to synthesize safer heparins. Beyond PF4 and HIT, the methods applied in the current study may be relevant to unravel mechanisms making other endogenous proteins more vulnerable to undergo conformational changes with little energy requirement (eg, point mutations and post-translational modifications) and thereby predisposing them to become immunogenic.

BACKGROUND

The global EINSTEIN DVT and PE studies compared rivaroxaban (15 mg twice daily for 3 weeks followed by 20 mg once daily) with enoxaparin/vitamin K antagonist therapy and demonstrated non-inferiority for efficacy and superiority for major bleeding. Owing to differences in targeted anticoagulant intensities in Japan, Japanese patients were not enrolled into the global studies. Instead, a separate study of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in Japanese patients was conducted, which compared the Japanese standard of care with a reduced dose of rivaroxaban.

METHODS

We conducted an open-label, randomized trial that compared 3, 6, or 12 months of oral rivaroxaban alone (10 mg twice daily or 15 mg twice daily for 3 weeks followed by 15 mg once daily) with activated partial thromboplastin time-adjusted intravenous unfractionated heparin (UFH) followed by warfarin (target international normalized ratio 2.0; range 1.5-2.5) in patients with acute, objectively confirmed symptomatic DVT and/or PE. Patients were assessed for the occurrence of symptomatic recurrent venous thromboembolic events or asymptomatic deterioration and bleeding.

RESULTS

Eighty-one patients were assigned to rivaroxaban and 19 patients to UFH/warfarin. Three patients were excluded because of serious non-compliance issues. The composite of symptomatic venous thromboembolic events or asymptomatic deterioration occurred in 1 (1.4%) rivaroxaban patient and in 1 (5.3%) UFH/warfarin patient (absolute risk difference, 3.9% [95% confidence interval, -3.4-23.8]). No major bleeding occurred during study treatment. Clinically relevant non-major bleeding occurred in 6 (7.8%) patients in the rivaroxaban group and 1 (5.3%) patient in the UFH/warfarin group.

CONCLUSIONS

The findings of this study in Japanese patients with acute DVT and/or PE suggest a similar efficacy and safety profile with rivaroxaban and control treatment, consistent with that of the worldwide EINSTEIN DVT and PE program.

BACKGROUND

Clinicaltrials.gov: NCT01516840 and NCT01516814.

BACKGROUND

Lifelong oral anticoagulation (OAC) therapy is required for the prevention of thromboembolic events after implantation of an artificial heart valve. Thromboembolism and anticoagulant-related bleedings account for approximately 75% of all complications experienced by heart valve recipients (2-9% of patients per year). The present study investigated the efficacy of dabigatran, a new direct thrombin inhibitor for oral use, as compared to unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) in preventing thrombus formation on mechanical heart valves in vitro.

METHODS

Blood (230 ml) from healthy young male volunteers was anticoagulated either by dabigatran (1 micromol/l), UFH (150 IU), or LMWH (100 IU). Mechanical heart valve prostheses were placed in an in vitro thrombosis tester and exposed to the anticoagulated blood samples under continuous circulation at a rate of 75 beats per minute.

RESULTS

In whole blood with no anticoagulant, the apparatus completely clotted in 15-20 minutes. When blood was treated with dabigatran, the mean thrombus weight was 164+/-55 mg, in the UFH group 159+/-69 mg, and in the LMWH group 182+/-82 mg (p-value: 0.704). Electron microscopy showed no significant difference in thrombus formation in any group.

CONCLUSIONS

Dabigatran was as effective as UFH and LMWH in preventing thrombus formation on mechanical heart valves in our in vitro investigation. Thus, we hypothesize that dabigatran etexilate might potentially be a useful and competitive orally administered alternative to UFH and LMWH for recipients of alloplastic heart valve prostheses.

Many cancer patients reportedly have a hypercoagulable state, with recurrent thrombosis due to the impact of cancer cells and chemotherapy on the coagulation cascade. Studies have demonstrated that unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) interferes with various processes involved in tumor growth and metastasis. These processes might include fibrin formation, binding of heparin to angiogenic growth factors such as basic fibroblast growth factor and vascular endothelial growth factor, modulation of tissue factor, and other mechanisms. Clinical trials have indicated a clinically relevant effect of LMWH as compared with UFH on the survival of cancer patients with deep vein thrombosis. Similarly, the impact of warfarin on the survival of cancer patients with thromboembolic disorders was demonstrated. Recent studies from our laboratory defined the role of an LMWH (tinzaparin), warfarin, anti-factor VIIa, and recombinant tissue factor pathway inhibitor in the modulation of angiogenesis, tumor growth, and tumor metastasis.

OBJECTIVE

In preparation for a pediatric randomized controlled trial on thromboprophylaxis, we determined the frequency of catheter-related thrombosis in children. We also systematically reviewed the pediatric trials on thromboprophylaxis to evaluate its efficacy and to identify possible pitfalls in the conduct of these trials.

METHODS

We searched MEDLINE, EMBASE, Web of Science and the Cochrane Central Register for Controlled Trials for articles published until December 2013. We included cohort studies and trials on patients aged 0-18 years with central venous catheters who underwent active surveillance for thrombosis with radiologic imaging. We estimated the pooled frequency of thrombosis and the pooled risk ratio (RR) with thromboprophylaxis by using a random effects model.

RESULTS

From 2651 articles identified, we analyzed 37 articles with 3128 patients. The pooled frequency of thrombosis was 0.20 (95% confidence interval [CI] 0.16-0.24). In 10 trials, we did not find evidence that heparin-bonded catheters (RR 0.34; 95%CI 0.01-7.68), unfractionated heparin (RR 0.93; 95% CI 0.57-1.51), low molecular weight heparin (RR 1.13; 95% CI 0.51-2.50), warfarin (RR 0.85; 95%CI 0.34-2.17), antithrombin concentrate (RR 0.76; 95% CI 0.38-1.55) or nitroglycerin (RR 1.53; 95%CI 0.57-4.10) reduced the risk of thrombosis. Most of the trials were either not powered for thrombosis or were powered to detect large, probably unachievable, reductions in thrombosis. Missing data on thrombosis also limited these trials.

CONCLUSIONS

Catheter-related thrombosis is common in children. An adequately powered multicenter trial that can detect a modest, clinically significant reduction in thrombosis is critically needed. Missing outcome data should be minimized in this trial.

Physicochemical and anticoagulant characteristics of 27 samples from recent batches of commercially produced unfractionated heparin have been determined as part of the process of establishment of the 5th International Standard Unfractionated Heparin. They have been compared with current heparin standards (European Pharmacopoeia, United States Pharmacopoeia, Chinese), with the 4th International Standard Unfractionated Heparin. and with the three predecessor International Standards. The results indicate that the 4th International Standard Unfractionated Heparin, established in 1982, has significantly lower molecular weight and specific activity than recently produced heparin; this is also true of all preceding International Standard Heparins and of the United States Pharmacopoeial standard. The composition of commercial unfractionated heparin may therefore have changed over time; reasons for this are discussed.

BACKGROUND

Perioperative antithrombotic treatment for gastric cancer patients receiving chronic anticoagulation and/or antiplatelet agents requires an understanding of potential bleeding and thromboembolic risks. However, no study has examined the safety aspects of perioperative antithrombotic treatment during radical gastrectomy. This study sought to evaluate postoperative bleeding and thromboembolic complications after radical gastrectomy in patients undergoing perioperative antithrombotic treatment.

METHODS

The medical records of patient treated by radical gastrectomy from January 2006 to December 2010 were retrospectively reviewed. Those in the thromboprophylaxis group had received one of three regimens of perioperative antithrombotic treatment according to the clinical indications of chronic anticoagulation and/or antiplatelet agents and several published evidence-based recommendations: (1) bridging therapy with unfractionated heparin; (2) continuation of aspirin; or (3) both 1 and 2. multivariate analysis was used to identify risk factors for postoperative bleeding complications after radical gastrectomy.

RESULTS

During the study period, 340 patients underwent radical gastrectomy. Of these, 62 patients received perioperative antithrombotic treatment; this thromboprophylaxis group had a significantly higher postoperative bleeding rate (8.1 vs. 0.7 %, P = 0.003). However, other complications, including thromboembolic events, were similar in the two study groups. Multivariate analysis revealed that perioperative antithrombotic treatment was the only independent risk factor of postoperative bleeding complications after radical gastrectomy (odds ratio, 8.53; 95 % confidence interval, 1.47-49.39; P = 0.017).

CONCLUSIONS

Perioperative antithrombotic treatment is an independent risk factor of postoperative bleeding complications in patients with gastric cancer undergoing radical gastrectomy, although such treatment was effective in preventing postoperative thromboembolic events.

In two randomized double-blind studies perioperative bleeding complications and thromboembolic events were assessed in 189 patients (pts) undergoing elective visceral surgery after subcutaneous administration of a low molecular weight (LMW) heparin fragment (KABI fragment 2165) or unfractionated (UF) heparin. The first study comparing 1 X 7'500 anti-factor Xa IU LMW heparin daily with 2 X 5'000 IU UF heparin was interrupted because of excessive bleeding complications (LMW heparin: 11/23 pts, UF heparin: 2/20 pts, p less than 0.01). In the second study (146 pts) the dose of LMW heparin was reduced to 1 X 2'500 anti-factor Xa IU. Bleeding complications (LMW heparin: 14.9%, UF heparin: 15.3%) and thromboembolic events (LMW heparin: 2.86%, UF heparin: 2.94%) were equal among the two groups. 2'500 anti-factor Xa IU/day of this LMW heparin fragment, corresponding to 15 mg/day, is the lowest dose of a LMW heparin used in a randomized clinical trial and was found to be a safe and efficient regimen in perioperative thrombosis prophylaxis. An advantage of LMW heparin over UF heparin is its once daily administration.

BACKGROUND

There is substantial published evidence that warfarin reduces the risk of stroke in patients with atrial fibrillation (AF). However, the current literature suggests that not all patients who could benefit from warfarin receive the drug.

OBJECTIVE

To evaluate patient-related demographic and clinical factors that could influence warfarin use or other anticoagulant use in hospitalized patients with AF.

METHODS

Retrospective observational study using claims data from the Wolters Kluwer Pharma Solutions Hospital Patient Level Database, evaluating characteristics of patients hospitalized in the US between 1 November 2003 and 31 October 2004.

METHODS

Hospital care.

METHODS

The study included 44,193 patients aged>>or=40 years who were hospitalized between 1 November 2003 and 31 October 2004 and had a diagnosis of AF during hospitalization (AF did not need to be the cause of hospitalization).

METHODS

Use of warfarin or other anticoagulants (unfractionated heparin [UFH] or low-molecular-weight heparin [LMWH]) was evaluated.

METHODS

A logistic regression model was used to identify factors associated with warfarin use, international normalized ratio (INR) monitoring, or the use of anticoagulants (UFH or LMWH).

RESULTS

In this analysis of hospitalized patients with AF in the real-world setting, about 56% of patients received anticoagulation therapy with warfarin. Elderly patients aged>>or=75 years were less likely to be treated with warfarin than younger patients, but patients between the ages of 60 and 74 years were more likely to use warfarin than their younger counterparts. Except for patients with congestive heart failure or vascular malformation, patients with other bleeding risk factors (hepatic disease, renal disease, aspirin use, and fractures) were significantly less likely to receive warfarin than those without these risk factors. CHADS(2) scores for stroke risk of 2 and 3 were associated with a significantly higher likelihood of warfarin treatment than scores of 0 or 1. Patients admitted through a routine admission (an outpatient department) were significantly more likely to be prescribed warfarin than patients admitted through an emergency room. Patients aged>>or=75 years and aspirin users were more likely to have their INR monitored during hospitalization. With respect to other anticoagulant use, females and older patients >>or=65 years) were less likely to use UFH or LMWH, and patients with renal disease or vascular malformation and those receiving aspirin were more likely to use UFH or LMWH than patients without these conditions/not receiving aspirin. Patients admitted through the emergency room were more likely to receive an anticoagulant than patients admitted through an outpatient department, an inpatient transfer, or any other source.

CONCLUSIONS

Older age, female sex, and certain risk factors for bleeding, including hepatic disease, renal disease, aspirin use, and fractures, were associated with a lower likelihood of warfarin treatment, while a higher stroke risk (as indicated by CHADS(2) scores) was associated with a higher likelihood of warfarin treatment, in hospitalized patients with a diagnosis of AF. The likelihood of INR being monitored increased for patients aged>>or=75 years and for aspirin users. Older patients and female patients were less likely to be prescribed other anticoagulants (UFH or LMWH) also.

Transcatheter aortic valve implantation (TAVI) has emerged as a therapeutic alternative for patients with symptomatic aortic stenosis at high or prohibitive surgical risk. However, patients undergoing TAVI are also at high risk for both bleeding and stroke complications, and specific mechanical aspects of the procedure itself can increase the risk of these complications. The mechanisms of periprocedural bleeding complications seem to relate mainly to vascular/access site complications (related to the use of large catheters in a very old and frail elderly population), whereas the pathophysiology of cerebrovascular events remains largely unknown. Further, although mechanical complications, especially the interaction between the valve prosthesis and the native aortic valve, may play a major role in events that occur during TAVI, post-procedural events might also be related to a prothrombotic environment or state generated by the implanted valve, the occurrence of atrial arrhythmias, and associated comorbidities. Antithrombotic therapy in the setting of TAVI has been empirically determined, and unfractionated heparin during the procedure followed by dual antiplatelet therapy with aspirin (indefinitely) and clopidogrel (1 to 6 months) is the most commonly recommended treatment. However, bleeding and cerebrovascular events are common; these may be modifiable with optimization of periprocedural and post-procedural pharmacology. Further, as the field of antiplatelet and anticoagulant therapy evolves, potential drug combinations will multiply, introducing variability in treatment. Randomized trials are the best path forward to determine the balance between the efficacy and risks of antithrombotic treatment in this high risk-population.

BACKGROUND

Indications for long-term anticoagulation are expanding. Osteoporosis is a complication which can develop after prolonged treatment with unfractionated heparin and is probably multifactorial. Data on osteoporosis associated with low-molecular-weight heparins (LMWH) are contradictory. Vitamin K participates in bone metabolism and since oral anticoagulants antagonize vitamin K, their use may also increase the risk of osteoporosis.

OBJECTIVE

To assess and compare the effects of long-term secondary venous thromboembolic prophylaxis with LMWH or acenocoumarol on bone structure.

METHODS

We assessed bone mineral density (BMD) by densitometry in 86 patients receiving LMWH or acenocoumarol for 3-24 months. The initial BMD was compared to the final result expressed as the percentage difference. The Z-score was also assessed and defined for individual patients as the number of standard deviations of BMD from its ideal value calculated for age and sex groups.

RESULTS

Excessive decrease in BMD was evidenced, which seemed to relate to the duration as well as type of treatment. At 1 and 2 years of follow-up, the mean decrease in BMD of the femur was 1.8% and 2.6% in patients on acenocoumarol and 3.1 and 4.8% in patients on enoxaparin, respectively.

CONCLUSIONS

Long-term exposure to treatment and prophylaxis of venous thromboembolism cause a modest but progressive decrease in BMD, more evident in patients on LMWH than on acenocoumarol. It might be advisable to perform densitometry before starting long-term anticoagulation and to repeat it every 12 months, especially in patients with concomitant risk factors for osteoporosis in order to identify patients in need of its prophylaxis.

Anticoagulant therapy is indicated during pregnancy for the prevention and treatment of VTE, for the prevention and treatment of systemic embolism in patients with mechanical heart valves, and, in combination with aspirin, for the prevention of pregnancy loss in women with APLA and previous pregnancy losses. Several questions concerning anticoagulant therapy remain unanswered. Oral anticoagulants are fetopathic, but the true risks of the warfarin embryopathy and CNS abnormalities are unknown. There is some evidence that warfarin embryopathy occurs only when oral anticoagulants are administered between the 6th and the 12th weeks of gestation and that oral anticoagulants may not be fetopathic when administered in the first 6 weeks of gestation. Oral anticoagulant therapy should be avoided in the weeks before delivery because of the risk of serious perinatal bleeding caused by the trauma of delivery to the anticoagulated fetus. The safety of aspirin during the first trimester of pregnancy is still a subject of debate. There is a concern about the efficacy of unfractionated heparin in the prevention of arterial embolism in pregnant women with mechanical heart valves. Finally, the role of LMWH and heparinoids and appropriate dosing have still to be determined. Because it is safe for the fetus, heparin is the anticoagulant of choice during pregnancy for situations in which its efficacy is established. The evidence for the efficacy of heparin for the prevention and treatment of VTE disorders during pregnancy is based on level IV studies. There is some doubt that heparin is effective for the prevention of systemic embolism in patients with mechanical heart valves. Low doses of heparin or poorly controlled heparin therapy are not effective in preventing systemic embolism in patients with mechanical heart valves.

OBJECTIVE

We investigated the safety and pharmacodynamics of escalating doses of recombinant nematode anticoagulant protein c2 (rNAPc2) in patients undergoing elective coronary angioplasty.

BACKGROUND

Recombinant NAPc2 is a potent inhibitor of the tissue factor/factor VIIa complex, which has the potential to reduce the risk of thrombotic complications in coronary artery disease.

METHODS

In a randomized, double-blinded, dose-escalation, multicenter trial, 154 patients received placebo or rNAPc2 at doses of 3.5, 5.0, 7.5, and 10.0 microg/kg body weight as a single subcutaneous administration 2 to 6 h before angioplasty. All patients received aspirin, unfractionated heparin during angioplasty, and clopidogrel in case of stent implantation.

RESULTS

Minor bleeding rates for the doses 3.5 to 7.5 microg/kg were comparable to that with placebo (6.7%), whereas an incidence of 26.9% was observed at the 10.0 microg/kg dose level (p < 0.01). Major bleedings occurred in the 5.0 microg/kg (n = 3) and 7.5 microg/kg (n = 1) dose groups. The three patients in the 5.0 microg/kg dose group also received a glycoprotein IIb/IIIa receptor inhibitor at the moment of major bleeding. Systemic thrombin generation, as measured by prothrombin fragment 1+2 (F(1+2)), was suppressed in all rNAPc2 dose groups to levels below pretreatment values for at least 36 h. In the placebo group, a distinct increase of F(1+2) levels was observed following cessation of heparin.

CONCLUSIONS

Inhibition of the tissue factor/factor VIIa complex with rNAPc2, at doses up to 7.5 microg/kg, in combination with aspirin, clopidogrel, and unfractionated heparin appears to be a safe and effective strategy to prevent thrombin generation during coronary angioplasty.

OBJECTIVE

There have been no health-care cost evaluations comparing the use of low-molecular-weight heparin (LMWH) to unfractionated heparin (UH) as "bridge therapy" in the perioperative period in patients receiving long-term oral anticoagulant (OAC) therapy who need interruption of therapy to undergo an elective surgical procedure. We performed a retrospective analysis of the medical and administrative records of health plan members in a managed care organization who underwent bridge therapy perioperatively with either i.v. UH, administered in a hospital setting, or LMWH, administered primarily in the outpatient setting using disease management guidelines.

METHODS

A retrospective analysis of medical and administrative records of treated health plan members meeting inclusion/exclusion criteria during the two study periods (ie, from 1994 to 1996 and from 1998 to 2000).

METHODS

Staff-model health maintenance organization serving New Mexico.

METHODS

The UH group included persons receiving long-term warfarin therapy from 1994 to 1996 (26 patients), and the LMWH group included persons receiving long-term warfarin therapy from 1998 to 2000 (40 patients) with perioperative use of heparin (either UH or LMWH) as bridge therapy for an elective surgical procedure.

METHODS

Costs were calculated for the period from 10 days before the procedure through 30 days after the procedure. The rates of adverse events (ie, valvular or mural thrombus, intracranial event, transient ischemic attack, peripheral arterial event, venous thromboembolic event, major and minor bleeding, thrombocytopenia, and death) occurring 1 to 30 days postprocedure were determined.

RESULTS

The groups were similar in age, sex, Charlson score, indication for long-term warfarin therapy (ie, arterial/cardiac vs venous), mean international normalized ratio prior to procedure, procedure duration, use of intraprocedural anticoagulant agents or thrombolytic agents, and use of general anesthesia during the procedure (all p>> 0.05). A total of 34.6% of UH patients and 40.0% of LMWH patients experienced one or more clinical adverse events within 30 days of the postoperative period, a difference that was not statistically significant (p = 0.67). The mean total health-care costs were 31,625 dollars in the UH group and 18,511 dollars in the LMWH group (p < 0.01). The mean inpatient costs were 28,515 dollars in the UH group and 14,330 dollars in the LMWH group (p < 0.01). Outpatient surgery costs (1,159 dollars vs 53 dollars, respectively; p = 0.01) and pharmacy costs (639 dollars vs 133 dollars, respectively; p < 0.01) were higher in the LMWH group.

CONCLUSIONS

The mean total health-care costs in the perioperative period were significantly lower (by 13,114 dollars) in patients receiving long-term OAC therapy using LMWH compared to those receiving it using UH for an elective surgical procedure. The cost savings associated with LMWH use were accomplished through the avoidance or minimization of inpatient stays and no increase in the overall rate of clinical adverse events in the postoperative period.

Patients with mechanical prosthetic heart valves require long-term oral anticoagulant therapy (OAT). During the temporary interruption of OAT, bridging anticoagulant therapy with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) is recommended. This prespecified subgroup analysis from REGIMEN-a large, prospective, multicenter registry-compared UFH (n = 73) and LMWH (n = 172) as bridging anticoagulation in patients with mechanical heart valves on long-term OAT. Patient demographics and co-morbidities were generally similar between groups. There were more bileaflet valves in the LMWH group (67.4% vs 43.8%, p = 0.0005), but no differences in valve positions between groups. The LMWH group was less likely to undergo major surgery (33.7% vs 58.9%, p = 0.0002) and cardiothoracic surgery (7.6% vs 19.2%, p = 0.008), and to receive intraprocedural anticoagulants or thrombolytics (4.1% vs 13.7%, p = 0.007). Major adverse event rates (5.5% vs 10.3%, p = 0.23) and major bleeds (4.2% vs 8.8%, p = 0.17) were similar in the LMWH and UFH groups, respectively; 1 arterial thromboembolic event occurred in each group. More LMWH-bridged patients were treated as outpatients or discharged from the hospital in <24 hours (68.6% vs 6.8%, p <0.0001). Multivariate logistic analysis found no significant differences in major bleeds and major composite adverse events when adjusting for cardiothoracic or major surgery between groups. In conclusion, for patients with mechanical prosthetic heart valves on long-term OAT, mostly outpatient-based LMWH bridging therapy appears to be feasible for selected procedures, is as safe as UFH, and is associated with a low arterial thromboembolic rate.

OBJECTIVE

Detailed data on patients admitted for acute myocardial infarction (AMI) on a European-wide basis are lacking. The Euro Heart Survey 2009 Snapshot was designed to assess characteristics, management, and hospital outcomes of AMI patients throughout European Society of Cardiology (ESC) member countries in a contemporary 'real-world' setting, using a methodology designed to improve the representativeness of the survey.

METHODS

Member countries of the ESC were invited to participate in a 1-week survey of all patients admitted for documented AMI in December 2009. Data on baseline characteristics, type of AMI, management, and complications were recorded using a dedicated electronic form. In addition, we used data collected during the same time period in national registries in Sweden, England, and Wales. Data were centralized at the European Heart House.

RESULTS

Overall, 4236 patients (mean age 66±13 years; 31% women) were included in the study in 47 countries. Sixty per cent of patients had ST-segment elevation myocardial infarction, with 50% having primary percutaneous coronary intervention and 21% fibrinolysis. Aspirin and thienopyridines were used in >90%. Unfractionated and low-molecular-weight heparins were the most commonly used anticoagulants. Statins, beta-blockers, and angiotensin-converting enzyme inhibitors were used in >80% of the patients. In-hospital mortality was 6.2%. Regional differences were observed, both in terms of population characteristics, management, and outcomes.

CONCLUSIONS

In-hospital mortality of patients admitted for AMI in Europe is low. Although regional variations exist in their presentation and management, differences are limited and have only moderate impact on early outcomes.