It was the aim of the review to determine the risks and benefits of primary thromboprophylaxis with anticoagulants in cancer patients with central venous devices. Medline, Central and Google Scholar databases were searched for randomized controlled trials (RCTs) in June 2006. Two reviewers extracted data and appraised the quality of RCTs. Results were expressed as relative risk (RR) with 95% confidence intervals (CI) using random effects model for the outcomes of catheter-related thrombosis, bleeding and thrombocytopenia. Eight RCTs (1,428 patients) were included. There was no statistically significant difference in the risk of catheter-related thrombosis for the use of warfarin versus placebo (3 trials, 425 patients, RR 0.75, 95% CI 0.24-2.35, p = 0.63), heparin versus placebo (4 trials, 886 patients, RR 0.46 95% CI 0.18-1.20, p = 0.06) or warfarin, unfractionated heparin or low-molecular-weight heparin versus placebo (7 trials, 1,311 patients, RR 0.59, 95% CI 0.31-1.13, p = 0.11). Substantial statistical heterogeneity was noted among these trials (I(2)>> 50%). The use of anticoagulants showed no statistically significant difference in the risk of overall bleeding (5 trials, 1,193 patients, RR 1.24, 95% CI 0.84-1.82, p = 0.28), and thrombocytopenia for heparin versus placebo (4 trials, 958 patients, RR 0.85, 95% CI 0.49, 1.46, p = 0.55) without any statistical heterogeneity (I(2) = 0%). In cancer patients with central venous devices, thromboprophylaxis has no significant effect on the risk of catheter related thrombosis or bleeding. The use of primary thromboprophylaxis in cancer patients with central venous catheters while not causing any harm provides no benefit.

Renal vein thrombosis is a complication that occurs in neonates with various underlying risk factors. It carries a grave prognosis for affected kidneys. Anticoagulant and fibrinolytic therapies have been promoted in the past with anecdotal success in some circumstances. However, prospective controlled trials are still lacking, and to date there have been no evidence-based guidelines available for the treatment of neonates with renal vein thrombosis. We retrospectively reviewed all the available medical literature pertaining to renal vein thrombosis published in English during the past 15 years. A total of 271 patients from 13 case series were identified by using the terms "renal vein thrombosis" and "neonates" via PubMed and Cochrane Library searches. Data then were extracted from each of the studies for analysis. During the past 15 years, a male predominance (67.2%) in neonatal renal vein thrombosis has been reported. More than 70% of patients had unilateral renal vein thrombosis, which was more prevalent on the left side (63.6%). The thrombus involved the inferior vena cava and was associated with adrenal hemorrhage in 43.7% and 14.8% of neonates, respectively. Forty percent of the patients were treated conservatively with supportive care alone. Among those patients who received anticoagulation therapy, unfractionated heparin and low molecular weight heparin were used alone in 21.6% and 20.7% of the patients, respectively. Fibrinolytic treatment alone was used in 11.2% of the patients. Only a minority of patients were treated with antithrombin (1.7%), warfarin alone, (0.9%) or underwent surgical intervention (0.3%). The majority (70.6%) of the involved kidneys became atrophic. A total of 9 neonates died with non-renal vein thrombosis-related conditions during the study period. Evidence-based recommendations on treatment cannot be made at the present time. Cooperative prospective studies that involve multiple centers are needed to elucidate the optimal treatment for neonatal renal vein thrombosis.

OBJECTIVE

To determine the safety and efficacy of a pharmaco-invasive reperfusion strategy utilizing half-dose fibrinolysis combined with transfer for immediate percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction (STEMI) patients presenting to remote rural hospitals. Primary PCI is preferred for STEMI if performed in a timely manner. However, <20% of STEMI patients transferred for PCI in the USA have door-to-balloon times <2 h.

RESULTS

Prospective data from the Level 1 MI programme were analysed. All STEMI patients presenting to the Minneapolis Heart Institute or 31 referral hospitals received aspirin, clopidogrel, and unfractionated heparin (UFH) at the presenting hospital and those presenting to hospitals ≥60 miles away also received half-dose fibrinolytic with transfer for immediate PCI. From April 2003 through December 2009, we enrolled 2634 consecutive STEMI patients in the Level 1 MI database including 660 transferred from remote hospitals utilizing pharmaco-invasive therapy and 600 patients who presented directly to the PCI centre. There were no significant differences in 30-day mortality (5.5 vs. 5.6%; P= 0.94), stroke (1.1 vs. 1.3%; P= 0.66) or major bleeding (1.5 vs. 1.8%; P= 0.65), or re-infarction/ischaemia (1.2 vs. 2.5%; P= 0.088) in patients receiving a pharmaco-invasive strategy compared with patients presenting directly to the PCI centre, despite a significantly longer door-to-balloon time.

CONCLUSIONS

Within a regional STEMI system of care, half-dose fibrinolysis combined with immediate transfer for PCI may be a safe and effective option for STEMI patients with expected delays due to long-distance transfer.

OBJECTIVE

Bleeding frequently complicates critical illness and may have serious consequences. Our objectives are to describe the predictors of major bleeding and the association between bleeding and mortality in medical-surgical critically ill patients receiving heparin thromboprophylaxis.

METHODS

We prospectively studied patients from 67 intensive care units and six countries enrolled in a thromboprophylaxis trial (NCT00182143) comparing dalteparin with unfractionated heparin. Patients with trauma, orthopedic surgery or neurosurgery were excluded. Trained research coordinators used a validated tool to document bleeding, which underwent duplicate independent blinded adjudication. Major bleeding was defined as hypovolemic shock, bleeding into critical sites, requiring an invasive intervention or transfusion of at least two units of red blood cells, or associated with hypotension or tachycardia in the absence of other causes. Adjusted Cox proportional hazard regression analysis was used to identify major bleeding predictors and the association between bleeding and mortality.

RESULTS

Among 3,746 patients, bleeding occurred in 208 [5.6 %, 95 % confidence interval (CI) 4.9-6.3 %]. Time-dependent predictors were prolonged activated partial thromboplastin time [hazard ratio (HR) 1.10, 1.05-1.14 per 10 s increase], lower platelet count (HR 1.16, 1.09-1.24 per 50 × 10(9)/L decrease), therapeutic heparin (HR 3.26, 1.72-6.17), antiplatelet agents (HR 1.38, 1.02-1.88), renal replacement therapy (HR 1.75, 1.20-2.56), and recent surgery (HR 1.64, 1.01-2.65). Type of pharmacologic thromboprophylaxis was not associated with bleeding. Patients with bleeding had a higher risk of in-hospital death (HR 2.09, 1.69-2.57).

CONCLUSIONS

As major bleeding has modifiable risk factors and is associated with in-hospital mortality, strategies to mitigate these factors should be evaluated in critically ill patients.

Due to several limitations of heparin, a widely used antithrombotic drug, there is large interest to develop alternatives. The aim of the presented study was to produce fully synthetic highly branched heparin mimetics. For this purpose, a new type of 'treelike' polysulfated polymers based on dendritic polyglycerol was synthesized. An efficient synthetic approach has been chosen to prepare several polyglycerol sulfates with different molecular weights as well as a polyglycerol carboxylate analogue and to evaluate them for their anticoagulant and anticomplementary activities. In contrast to the nonderivatized and the carboxylated polyglycerols, the polyglycerol sulfates prolong the activated partial thromboplastin time (APTT) and thrombin time (TT) and inhibit both the classical (CCA) and alternative complement activation (ACA). Whereas their anticoagulant activity in the APTT and in the TT amounts to 5.7-8.1% and 15.7-33.6%, respectively, of that of unfractionated heparin (UFH), their CCA and ACA inhibitory activity is 13.4-23.9 and 2.7-3.7 times, respectively, higher. In contrast to sulfated polysaccharides, the activities are not clearly dependent on the molecular weight, which might be due to the globular 3D-structure of the dendritic molecules. Due to the coherence between coagulation, complement activation and inflammation in the pathophysiology of numerous diseases, polyglycerol sulfates with both anticoagulant and anticomplementary activities represent promising candidates for the development of potential drugs.

The human hyaluronic acid (HA) receptor for endocytosis (HARE/stabilin-2) is the primary clearance receptor for systemic HA, chondroitin sulfates, and heparin, but not for heparan sulfate or keratan sulfate (Harris EN, Weigel JA, Weigel PH. J Biol Chem 283: 17341-17350, 2008). HARE is expressed in the sinusoidal endothelial cells (SECs) of liver and lymph nodes where it acts as a scavenger for uptake and degradation of glycosaminoglycans, both as free chains and proteoglycan fragments. Unfractionated heparin (UFH; approximately 14 kDa) and low-molecular-weight heparin (LMWH; approximately 4 kDa) are commonly used in treatments for thrombosis and cancer and in surgical and dialysis procedures. The reported half-lives of UFH and LMWH in the blood are approximately 1 h and 2-6 h, respectively. In this study, we demonstrate that anti-HARE antibodies specifically block the uptake of LMWH and UFH by isolated rat liver SECs and by human 293 cells expressing recombinant human HARE (hHARE). hHARE has a significant affinity (K(d) = 10 microM) for LMWH, and higher affinity (K(d) = 0.06 microM) for the larger UFH. Rat liver SECs or cells expressing the recombinant 190-kDa HARE isoform internalized both UFH and LMWH, and both heparins cross-compete with each other, suggesting that they share the same binding sites. These cellular results were confirmed in ELISA-like assays using purified soluble 190-hHARE ectodomain. We conclude that both UFH and LMWH are cleared by HARE/Stab2 and that the differences in the affinities of HARE binding to LMWH and UFH likely explain the longer in vivo circulating half-life of LMWH compared with UFH.

OBJECTIVE

Heparin binds to human platelets and can cause activation and aggregation, although the mechanisms are unknown. To determine how heparin alters platelet function, we identified platelet-binding sites for heparin and measured heparin's influence on the function of platelet integrin alpha(IIb)beta(3) (glycoprotein IIb/IIIa).

METHODS

Photoaffinity cross-linking and affinity chromatography experiments were performed to identify platelet membrane proteins that bind heparin. Heparin's effect on fibrinogen binding to platelets was measured with a radioligand-binding assay. The translocation to the cytoskeleton of Rap2, a guanosine triphosphate-binding protein, was measured from platelets aggregating in response to heparin and other agonists.

RESULTS

Cross-linking and affinity chromatographic experiments positively identified the integrin alpha(IIb)beta(3) as a heparin-binding site. Heparin aggregation was calcium dependent. Low concentrations of unfractionated porcine mucosal heparin (2-5 U/mL) significantly increased fibrinogen I 125 binding to activated platelets, whereas higher doses did not. Heparin-mediated platelet aggregation was completely blocked by GRGDS peptide (5 mmol/L), a competitive inhibitor of fibrinogen binding, and was blocked by EDTA (2 mmol/L), which dissociates the functional integrin complex. Aggregation was associated with Rap2 translocation to the cytoskeleton, a sign of outside-in signaling.

CONCLUSIONS

Heparin binds to the alpha(IIb)beta(3) integrin in vitro and ex vivo, and heparin increases fibrinogen binding to the integrin. Heparin-mediated aggregation requires an intact integrin and ligand and leads to Rap2 translocation to the cytoskeleton-an outside-in signal of ligand engagement. Heparin may directly modulate platelet integrin function, most likely through direct binding and modulation of integrin function.

The Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox (MATRIX) programme was designed to assess the comparative safety and effectiveness of radial versus femoral access and of bivalirudin versus unfractionated heparin with optional glycoprotein IIb/IIIa inhibitors in patients with the whole spectrum of acute coronary syndrome undergoing invasive management. Here we describe the prespecified final 1-year outcomes of the entire programme.

MATRIX was a programme of three nested, randomised, multicentre, open-label, superiority trials in patients with acute coronary syndrome in 78 hospitals in Italy, the Netherlands, Spain, and Sweden. Patients with ST-elevation myocardial infarction were simultaneously randomly assigned (1:1) before coronary angiography to radial or femoral access and to bivalirudin, with or without post-percutaneous coronary intervention infusion or unfractionated heparin (one-step inclusion). Patients with non-ST-elevation acute coronary syndrome were randomly assigned (1:1) before coronary angiography to radial or femoral access and, only if deemed eligible to percutaneous coronary intervention after angiography (two-step inclusion), entered the antithrombin type and treatment duration programmes. Randomisation sequences were computer generated, blocked, and stratified by intended new or current use of P2Y12 inhibitor (clopidogrel vs ticagrelor or prasugrel), and acute coronary syndrome type (ST-elevation myocardial infarction, troponin-positive, or troponin-negative non-ST-elevation acute coronary syndrome). Bivalirudin was given as a bolus of 0·75 mg/kg, followed immediately by an infusion of 1·75 mg/kg per h until completion of percutaneous coronary intervention. Heparin was given at 70-100 units per kg in patients not receiving glycoprotein IIb/IIIa inhibitors, and at 50-70 units per kg in patients receiving glycoprotein IIb/IIIa inhibitors. Clinical follow-up was done at 30 days and 1 year. Co-primary outcomes for MATRIX access and MATRIX antithrombin type were major adverse cardiovascular events, defined as the composite of all-cause mortality, myocardial infarction, or stroke up to 30 days; and net adverse clinical events, defined as the composite of non-coronary artery bypass graft-related major bleeding, or major adverse cardiovascular events up to 30 days. The primary outcome for MATRIX treatment duration was the composite of urgent target vessel revascularisation, definite stent thrombosis, or net adverse clinical events up to 30 days. Analyses were done according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01433627.

Between Oct 11, 2011, and Nov 7, 2014, we randomly assigned 8404 patients to receive radial (4197 patients) or femoral (4207 patients) access. Of these 8404 patients, 7213 were included in the MATRIX antithrombin type study and were randomly assigned to bivalirudin (3610 patients) or heparin (3603 patients). Patients assigned to bivalirudin were included in the MATRIX treatment duration study, and were randomly assigned to post-procedure infusion (1799 patients) or no post-procedure infusion (1811 patients). At 1 year, major adverse cardiovascular events did not differ between patients assigned to radial access compared with those assigned to femoral access (14·2% vs 15·7%; rate ratio 0·89, 95% CI 0·80-1·00; p=0·0526), but net adverse clinical events were fewer with radial than with femoral access (15·2% vs 17·2%; 0·87, 0·78-0·97; p=0·0128). Compared with heparin, bivalirudin was not associated with fewer major adverse cardiovascular (15·8% vs 16·8%; 0·94, 0·83-1·05; p=0·28) or net adverse clinical events (17·0% vs 18·4%; 0·91, 0·81-1·02; p=0·10). The composite of urgent target vessel revascularisation, stent thrombosis, or net adverse clinical events did not differ with or without post-procedure bivalirudin infusion (17·4% vs 17·4%; 0·99, 0·84-1·16; p=0·90).

In patients with acute coronary syndrome, radial access was associated with lower rates of net adverse clinical events compared with femoral access, but not major adverse cardiovascular events at 1 year. Bivalirudin with or without post-procedure infusion was not associated with lower rates of major adverse cardiovascular events or net adverse clinical events. Radial access should become the default approach in acute coronary syndrome patients undergoing invasive management.

Italian Society of Invasive Cardiology, The Medicines Company, Terumo, amd Canada Research Chairs Programme.

BACKGROUND

Annually, 2 million people in the United States develop deep venous thrombosis (DVT), and nearly 100,000 sustain fatal pulmonary emboli. Prophylaxis against DVT/pulmonary embolism (PE) is a critical issue, and options include elastic stockings, intermittent pneumatic compression stockings, low-dose unfractionated heparin (5000 U every 8-12 hours), and low molecular-weight heparin (ie, enoxaparin and dalteparin). The risks and benefits associated with different prophylaxis regimens used in the prevention of DVT and PE in neurosurgical procedures were analyzed.

METHODS

Neurosurgical studies focusing on different methods of prophylaxis used for the prevention of DVT and PE were reviewed. The efficacy, risks, and benefits of varied treatment options were evaluated, with particular emphasis on minor and major hemorrhages occurring where heparin-based protocols were used.

RESULTS

In Flinn et al series (Arch Surg. 1996;131(5):472-80), the incidence of DVT was greater for cranial (7.7%) than spinal procedures (1.5%). Although intermittent pneumatic compression devices provided adequate reduction of DVT/PE in some cranial and combined cranial/spinal series, low-dose subcutaneous unfractionated heparin or low molecular-weight heparins further reduced the incidence, not always of DVT, but of PE (Br J Neurosurg 1995;9(2):159-63; J Intensive Care Med 2003;18(2):59-79). Nevertheless, low-dose heparin-based prophylaxis in cranial and spinal series risks minor and major postoperative hemorrhages: 2% to 4% in a cranial series, 3.4% minor and 3.4% major hemorrhages in a combined cranial/spinal series, and a 0.7% incidence of major/minor hemorrhages in a spinal series (J Neurosurg 2003;99(4):680-4; Neurosurgery 1986;18(4):440-5; Eur Spine J 2004;13(1):1-8; J Intensive Care Med 2003;18(2):59-79).

CONCLUSIONS

Although mechanical prophylaxis provided effective prophylaxis against DVT/PE in many series, the added efficacy of low-dose heparin regimens has to be weighed against risks of major postoperative hemorrhages and their neurological sequelae.

OBJECTIVE

To obtain a realistic overview of management and clinical outcomes of patients with venous thromboembolism (VTE) in Spain on the basis of data from a national multicenter registry.

METHODS

A prospective registry was initiated in Spain in March 2001. Data were collected from patients with objectively confirmed deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and entered into the online registry by physicians who were responsible for the management of these patients.

RESULTS

As of August 2002, 4011 patients with confirmed VTE were included in the registry: 60% with DVT, 23% with PE, and 17% with both DVT and PE. Diagnostic methods for VTE included compression ultrasonography (86%), venography (10%), V/Q lung scans (42%), computed tomography scan (28%), and pulmonary angiography (0.9%). D-dimer testing was performed in 61% of cases and was positive in 92% of patients with confirmed VTE. The majority of DVT (95%) were located in the lower extremities (82% proximal and 4% bilateral), while 4.8% were located in the upper extremities or neck veins. Most patients (90.5%) were admitted to hospital. In the acute phase, treatment consisted of low molecular weight heparin (LMWH) in 88%, unfractionated heparin (UFH) in 11%, and fibrinolysis in 0.8%. Cava filters were inserted in 2% of patients, mainly because of active bleeding (13%), increased hemorrhagic risk (38%), or recurrent VTE (29%). Absolute bed rest was recommended to 63% of patients. Secondary prevention of VTE included oral anticoagulants (75%) and LMWH (24.5%). Therapeutic compression stockings were prescribed to 53% of patients at the time of hospital discharge. Regarding the main clinical outcomes during an average (+/-SD) follow-up period of 156 +/- 95 days, 19% had adverse events: 12.5% of patients died, 5.5% had clinically confirmed VTE recurrence, and 9.8% suffered bleeding complications (44% with major bleeding).

CONCLUSIONS

This prospective observational multicenter registry provides a large database reflecting the actual day-to-day clinical practice regarding VTE management in a European country. The most important findings were the increasing use of spiral computed tomography for PE diagnosis, the unexpectedly high proportion of patients admitted to hospital despite the use of LMWH in almost 90% of cases in the acute phase, and the utilization of LMWH for secondary prevention in almost 25% of cases. On the other hand, this large-scale prospective registry permits on-line consultation of high-risk situations to assess how difficult cases were treated and what their outcomes were. This will provide a most useful tool for the practicing physician responsible for the management of VTE patients.

OBJECTIVE

We compared the efficacy and safety of percutaneous endovenous intervention (PEVI) plus anticoagulation with anticoagulation alone in the reduction of venous thromboembolism (VTE) and post-thrombotic syndrome (PTS) in acute proximal deep venous thrombosis (DVT).

BACKGROUND

Recurrent VTE and PTS are common complications of DVT. There are no randomized trials investigating the efficacy of PEVI in the reduction of the above complications.

METHODS

Patients with symptomatic proximal DVT were randomized to receive PEVI plus anticoagulation or anticoagulation alone. Anticoagulation consisted of intravenous unfractionated heparin or subcutaneous low-molecular weight heparin plus warfarin. PEVI consisted of one or more of a combination of thrombectomy, balloon venoplasty, stenting, or local low-dose thrombolytic therapy.

RESULTS

At 6 months follow-up, recurrent VTE developed in 2 of 88 patients of the PEVI plus anticoagulation group versus 12 of 81of the anticoagulation-alone group (2.3% vs. 14.8%, P = 0.003). PTS developed in 3 of 88 patients of the PEVI plus anticoagulation Group and 22 of 81 of the anticoagulation-alone group (3.4% vs. 27.2%, P < 0.001).

CONCLUSIONS

In patients with symptomatic proximal DVT, PEVI plus anticoagulation may be superior to anticoagulation-alone in the reduction of VTE and PTS at 6 months.

Hepatic veno-occlusive disease (VOD) is a common and serious regimen-related toxicity after hematopoietic stem cell transplantation (HSCT). There is no safe and proven therapy for established VOD, and focus has been on its prevention. Previous studies have shown that a continuous infusion of unfractionated heparin or ursodiol may reduce the incidence of VOD. In order to compare the efficacy of heparin plus ursodiol with that of heparin alone, we conducted a prospective, randomized study involving 165 consecutive patients who underwent HSCT for a variety of disorders. Eighty-two patients were assigned to receive heparin plus ursodiol, and 83 were assigned to receive heparin alone. Thirteen and 16 patients were diagnosed as having VOD in the heparin plus ursodiol group and the heparin alone group, respectively (15.9% vs 19.3%; P = 0.348). Eighty-nine percent of the heparin plus ursodiol group and 89.2% of the heparin alone group were surviving at day 100 post-HSCT (P = 0.298). The only independent variable associated with an increased risk of VOD was an allogeneic type of HSCT (P = 0.018). In conclusion, this study shows that there is no difference in efficacy between heparin plus ursodiol and heparin alone for the prevention of hepatic VOD.

The incidence of antibodies to heparin-PF4 complexes (H-PF4) has been evaluated in patients who were under heparin therapy for more than 7 days: 109 patients treated with unfractionated heparin (UH) and 100 patients with low-molecular-weight heparin (LMWH). The presence of antibodies was identified in 17% of the former group and 8% of the latter. In both the UH and the LMWH groups, IgM antibodies were found in all but four patients who showed IgA antibodies. IgG isotypes were only detected in five patients and were consistently associated to either IgM or IgA antibodies. The follow-up of H-PF4 antibodies in 76 patients treated with UH from 1 to>> or = 12 days showed a relationship between the incidence of antibodies and the duration of therapy. Despite the presence of anti-H-PF4 antibodies there was no thrombocytopenia (<150 10(9)/L) in the patients. A significant drop of platelets requiring the discontinuation of heparin was observed, however, in three patients, but their platelet count consistently remained >150 10(9)/L. Our study demonstrates that the induction of antibodies to H-PF4 is a frequent phenomenon in patients treated with UH or with LMWH. The absence of thrombocytopenia and of clinical complications in these patients demonstrates that other conditions must be associated with H-PF4 antibodies for inducing type II HIT: optimal concentrations of heparin and PF4 in the blood circulation to allow the formation of macromolecular H-PF4 complexes, presence of activated platelets that present an increased binding of H-PF4 complexes, increased expression of FcgammaRIIA receptors, or presence of their H 131 phenotype. We conclude that the measurement of antibodies to H-PF4 complexes allows the detection of heparin-treated patients at risk of developing type II HIT.

BACKGROUND

The cost-effectiveness of the optimal use of hospital-based acute myocardial infarction (AMI) treatments and their potential impact on coronary heart disease (CHD) mortality in China is not well known.

RESULTS

The effectiveness and costs of optimal use of hospital-based AMI treatments were estimated by the CHD Policy Model-China, a Markov-style computer simulation model. Changes in simulated AMI, CHD mortality, quality-adjusted life years, and total healthcare costs were the outcomes. The incremental cost-effectiveness ratio was used to assess projected cost-effectiveness. Optimal use of 4 oral drugs (aspirin, β-blockers, statins, and angiotensin-converting enzyme inhibitors) in all eligible patients with AMI or unfractionated heparin in non-ST-segment-elevation myocardial infarction was a highly cost-effective strategy (incremental cost-effectiveness ratios approximately US $3100 or less). Optimal use of reperfusion therapies in eligible patients with ST-segment-elevation myocardial infarction was moderately cost effective (incremental cost-effectiveness ratio ≤$10,700). Optimal use of clopidogrel for all eligible patients with AMI or primary percutaneous coronary intervention among high-risk patients with non-ST-segment-elevation myocardial infarction in tertiary hospitals alone was less cost effective. Use of all the selected hospital-based AMI treatment strategies together would be cost-effective and reduce the total CHD mortality rate in China by ≈9.6%.

CONCLUSIONS

Optimal use of most standard hospital-based AMI treatment strategies, especially combined strategies, would be cost effective in China. However, because so many AMI deaths occur outside of the hospital in China, the overall impact on preventing CHD deaths was projected to be modest.

Heparin has been the mainstay of treatment and prevention of venous and arterial thromboembolism for many years. Its use, however, is associated with a serious and potentially fatal immunological drug reaction termed heparin-induced thrombocytopenia (HIT). Current treatment consists of discontinuing heparin therapy and the administration of an alternate anticoagulant (e.g. danaparoid, lepirudin, bivalirudin or argatroban). Fondaparinux is a novel synthetic heparin pentasaccharide capable of inhibiting factor Xa via the action of antithrombin (AT) but devoid of anti-factor IIa (thrombin) activity. Although the drug is identical in structure to the pentasaccharide domain found on unfractionated heparin (UH), it is too small to be recognized by the majority of heparin-reactive antibodies. It is theoretically an excellent candidate agent for the treatment of HIT. Currently, fondaparinux is licensed for orthopaedic venous thromboprophylaxis but not for the treatment of HIT. Successes in the use of fondaparinux in the treatment of HIT, as demonstrated in recent published case reports, warrant further study in larger controlled trials for this indication.

Disseminated intravascular coagulation (DIC) is the most common complication of solid tumours. In this study, the effectiveness of three polysaccharide anticoagulants (PSAs), at therapeutic doses, at inhibiting solid tumour growth was investigated. Mice with tumour xenografts were subcutaneously injected with either unfractionated heparin (UFH; 200 units kg(-1) day(-1)), dalteparin (75 units kg(-1) day(-1)) or danaparoid (50 units kg(-1) day(-1)). At these concentrations, these PSAs are equieffective at inhibiting blood coagulation activated factor X. In mice with Lewis lung carcinoma (LLC) tumours dalteparin and, to a lesser extent, UFH inhibited both tumour growth and angiogenesis, whereas danaparoid did not. In contrast, in mice with KLN205 tumours, all the PSAs inhibited tumour growth and angiogenesis. All the PSAs significantly inhibited proliferation, migration of endothelial cells and vessel formation in matrigel plugs containing vascular endothelial growth factor (VEGF) and there were no significant differences between these effects of the PSAs. The PSAs had no effect on endothelial cell tubular formation in vitro. Although all the PSAs inhibited VEGF production in KLN205 tumours in vivo and cells in vitro, in LLC tumours and cells only UFH and dalteparin inhibited VEGF production, whereas danaparoid did not. In both LLC and KLN205 tumours in vivo, heparanase activity was inhibited by UFH and dalteparin, but not by danaparoid. Hence, UFH and dalteparin may be more effective than danaparoid at inhibiting cancer progression in DIC patients with solid tumours, due at least in part to their ability to suppress VEGF and heparanase in tumours.

The use of low-molecular-weight heparin offers multiple advantages over unfractionated heparins in pediatric patients with acute ischemic stroke. The safety and efficacy of low-molecular-weight heparin have been demonstrated in adults, but less is known about their use in children. This study reviews retrospectively the use of low-molecular-weight heparin in children with acute, ischemic, nonhemorrhagic strokes. A database search was used to locate all children who experienced an ischemic stroke between July 1991 and January 2001 and who were subsequently treated with low-molecular-weight heparin. Eight children were identified (aged 37 months to 17 years; median age, 133 months) who were treated with the low-molecular-weight heparin enoxaparin. Enoxaparin was used in one case as the sole treatment, in six cases as a bridge to oral anticoagulant therapy with warfarin, and in one case as a replacement treatment after several days of warfarin therapy. The median duration of treatment with enoxaparin was 4 days. During this period, no major bleeding complications were observed, and no new thrombi or extensions of thrombi occurred. One patient did experience mild oozing at an intravenous site, and another experienced an episode of epistaxis. Enoxaparin was discontinued in one patient because of discomfort associated with the subcutaneous injections. Although the number of patients was limited, it appears that enoxaparin is a safe and efficacious alternative to the use of unfractionated heparin in children with acute, nonhemorrhagic ischemic stroke.

BACKGROUND

In patients receiving chronic oral anticoagulation with vitamin K antagonists (VKAs) it may be necessary to temporarily discontinue VKA therapy to allow surgery or other invasive procedures to be performed, as maintaining treatment may increase the risk of bleeding during the procedure. This, however, creates a clinical dilemma, since discontinuing VKAs may place the patient at risk of thromboembolism.

METHODS

We undertook a systematic narrative review of patients on chronic oral anticoagulation, requiring a periprocedural bridging therapy with heparin during invasive procedures.

RESULTS

For patients requiring temporary discontinuation of VKA, current guidelines recommend the use of 'bridging' therapy with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) in patients considered to be at intermediate-to-high risk of thromboembolism, such as those with prosthetic heart valves or atrial fibrillation. Recent studies show that LMWHs are associated with low rates of thromboembolism and, when compared with UFH, are as effective and safe as UFH when used as periprocedural bridging therapy in such patients. LMWHs also offer advantages such as ease of administration and predictable anticoagulant effects. Moreover, outpatient-based periprocedural bridging therapy with LMWH has been shown to result in significant cost savings compared with in-hospital UFH.

CONCLUSIONS

The decision to provide bridging therapy requires careful consideration of the relative risks of thromboembolism and bleeding in each patient. Based upon the studies reviewed we recommend a therapeutic dose of UFH or LMWH for patients at intermediate-to-high thromboembolic risk requiring interruption of VKA, especially for low bleeding risk procedures. We would like to propose upgrading the American College of Chest Physicians (ACCP) guideline recommendations from 2C to 1C. However, there is still a need for a randomized controlled trial on the efficacy and safety of the available bridging strategies, including heparin and placebo comparators, in preventing thromboembolism for specific patients and procedures.

Anticoagulation during pregnancy is complicated because of potential risks for mother and foetus. Unfractionated or low-molecular-weight heparin is used for most anticoagulant indications. Its efficacy, however, in pregnant women with prosthetic heart valves is questioned, therefore coumarins are preferred for this indication. We studied long-term effects of prenatal coumarin-exposure on growth and on neurological, behavioural and cognitive development in 274 school-age children in comparison with 231 age-matched non-exposed controls. No major abnormalities were found. The exposed children had an increased risk for minor neurological dysfunction and for a low intelligence quotient (IQ below 80). The risk for a combination of two or more (minor) abnormalities was higher for the exposed children, RR = 7.6. We conclude that prenatal exposure to coumarins is associated with an increased risk for disturbances in development in school-age children. However, for the vast majority of children there is no clinical significant effect on growth and long-term development.

Continuous intravenous (i.v.) heparin administered in the acute period after unstable coronary artery disease reduces the likelihood and severity of subsequent ischemic events. However, reactivation of the thrombotic process may occur when heparin therapy is withdrawn. Low-molecular-weight heparin provides more reliable anticoagulation and less need for patient monitoring and dosage adjustment than standard unfractionated heparin (UFH) and therefore is well suited for long-term anticoagulation on an outpatient basis. TIMI 11B is a randomized, double-blind, placebo-controlled clinical trial designed to compare the strategy of combined short-term and long-term administration of the low-molecular-weight heparin enoxaparin for unstable angina/non-Q-wave myocardial infarction versus the standard strategy of UFH administration only during the acute phase. Patients are randomized to receive either enoxaparin (30 mg i.v. bolus followed by subcutaneous (s.c.) injections of 1.0 mg/kg every 12 hours) or UFH (70 U/kg bolus followed by an infusion of 15 U/kg per hour, titrated to an activated partial thromboplastin time of 1.5 to 2.5 times control). Infusion of i.v. UFH or placebo continues for a minimum of 72 hours. S.c. weight-adjusted enoxaparin or placebo continues until hospital discharge or day 8, whichever comes first, at which time the long-term phase of the study begins. Patients randomized to receive enoxaparin in the acute phase receive fixed-dose s.c. enoxaparin (60 mg every 12 hours for patients>> or =65 kg, 40 mg every 12 hours for patients <65 kg). Patients randomized to receive UFH in the acute phase receive s.c. placebo injections during the chronic phase. The primary efficacy endpoint is the sum, through day 43, of the occurrence of death, nonfatal myocardial infarction not present at enrollment, or severe recurrent ischemia requiring urgent revascularization. The primary safety endpoint is the occurrence of either major bleeding or other serious adverse events.

OBJECTIVE

To determine the incidence of heparin-induced thrombocytopenia (HIT) in patients admitted to a medical service who were given unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) to prevent venous thromboembolism, the incremental cost of developing HIT, and the cost consequences of using LMWH to prevent venous thromboembolism in medical patients.

METHODS

Retrospective analysis with a nested case-control.

METHODS

University-affiliated tertiary-care hospital.

METHODS

A total of 10,121 adult medical patients admitted between August 1, 2000, and November 2, 2004, received UFH or LMWH to prevent venous thromboembolism during their admission. From these, patients with immune-mediated HIT were identified and served as case patients, and 3-5 matched control patients were identified for each case patient.

RESULTS

The development of HIT was determined for patients who received LMWH and for patients who received UFH. Costs were compared between the patients with HIT and the matched control patients. The cost of using LMWH to prevent venous thromboembolism was compared with the cost of using UFH. In patients receiving UFH and those receiving LMWH, the incidence of HIT was 0.51% (43/8420) and 0.084% (1/1189), respectively (p=0.037), with an overall incidence of 0.43% (44/10,121). Admissions that included development of HIT incurred an average cost of 56,364 dollars compared with 15,231 dollars (p<0.001) for admissions without HIT. Using LMWH to prevent venous thromboembolism in medical patients cost 13.88 dollars less per patient than using UFH.

CONCLUSIONS

For the prophylaxis of venous thromboembolism, LMWH was associated with a lower incidence of HIT than UFH in medical patients. An admission during which the patient develops HIT costs significantly more than an admission during which the patient does not develop HIT. Low-molecular-weight heparin is cost-effective for prevention of venous thromboembolism in medical patients.

BACKGROUND

The SYNERGY trial comparing enoxaparin and unfractionated heparin in high-risk patients with acute coronary syndromes (ACS) showed that enoxaparin was not inferior to unfractionated heparin in reducing death or nonfatal myocardial infarction (MI) at 30 days.

OBJECTIVE

To evaluate continued risk in this patient cohort through 6-month and 1-year follow-up.

METHODS

Overall, 9978 patients were randomized from August 2001 through December 2003 in 487 hospitals in 12 countries. Patients were followed up for 6 months and for 1 year.

METHODS

Six-month outcomes were death, nonfatal MI, revascularization procedures, stroke, and site-investigator-reported need for rehospitalization; 1-year outcome was all-cause death.

RESULTS

Six-month and 1-year follow-up data were available for 9957 (99.8%) and 9608 (96.3%) of 9978 patients, respectively; 541 patients (5.4%) had died at 6 months and 739 (7.4%) at 1 year. Death or nonfatal MI at 6 months occurred in 872 patients receiving enoxaparin (17.6%) vs 884 receiving unfractionated heparin (17.8%) (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.89-1.07; P = .65). In the subgroup of patients receiving consistent therapy, ie, only enoxaparin or unfractionated heparin during the index hospitalization (n = 6138), a reduction in death or nonfatal MI with enoxaparin was maintained at 180 days (HR, 0.85; 95% CI, 0.75-0.95; P = .006). Rehospitalization within 180 days occurred in 858 patients receiving enoxaparin (17.9%) and 911 receiving unfractionated heparin (19.0%) (HR, 0.94; 95% CI, 0.85-1.03; P = .17). One-year all-cause death rates were similar in the 2 treatment groups (380/4974 [7.6%] for enoxaparin vs 359/4948 [7.3%] for unfractionated heparin; HR, 1.06; 95% CI, 0.92-1.22; P = .44). One-year death rates in patients receiving consistent therapy were also similar (251/3386 [7.4%] for enoxaparin vs 213/2720 [7.8%] for unfractionated heparin; HR, 0.95; 95% CI, 0.79-1.14; P = .55).

CONCLUSIONS

In the SYNERGY trial, patients continued to experience adverse cardiac events through long-term follow-up. The effect of enoxaparin on death or MI compared with that of unfractionated heparin at 6 months was similar to that observed at 30 days in the overall trial and in the consistent-therapy group. One-year death rates were also similar in both groups. High-risk patients with ACS remain susceptible to continued cardiac events despite aggressive therapies.ClinicalTrials.gov Identifier: NCT00043784.

BACKGROUND

Platelet-leukocyte aggregates have been implicated in atherogenesis. This study was designed to determine the influence in vivo of a direct thrombin inhibitor, bivalirudin, compared with unfractionated heparin (UFH) plus the GP IIb-IIIa inhibitor eptifibatide (E) on platelet reactivity, the formation of platelet-leukocyte aggregates, and leukocyte activation.

METHODS

Blood was taken before and after percutaneous coronary intervention (PCI) from 60 patients randomized to UFH+E (n=26) or bivalirudin (n=34). Platelet function and the formation in vivo of platelet-monocyte aggregates (PMA) and platelet-neutrophil aggregates (PNA) were assessed with the use of flow cytometry. Myeloperoxidase (MPO) elaborated during leukocyte activation was measured by ELISA.

RESULTS

Compared with those treated with bivalirudin, patients treated with UFH+E exhibited a 45% decrease in the capacity of platelets to bind fibrinogen (p=0.006) but a 2-fold increase in platelet surface expression of P-selectin (p=0.04) in samples taken from the coronary ostium before PCI. Platelet-leukocyte aggregation in vivo was greater (PMA=2-fold, p=0.04; PNA=3-fold, p=0.006) with UFH+E as was the concentration in blood of MPO (1.5-fold, p=0.007).

CONCLUSIONS

Increased platelet surface expression of P-selectin, augmented platelet-leukocyte aggregation in vivo, and consequent activation of leukocytes was seen before PCI in blood from patients treated with UFH+E compared with bivalirudin. Benefits associated with decreased platelet aggregation when PCI is performed with UFH plus GP IIb-IIIa inhibition may be partially offset by increased platelet-leukocyte aggregation.

The frequency of heparin-induced thrombocytopenia (HIT) varies between different clinical treatment settings and remains unknown for patients treated with unfractionated (UFH) or low-molecular-weight heparin (LMWH) because of deep vein thrombosis. In this multicentre, open-label study, 1137 patients with deep vein thrombosis were randomly assigned to UFH for 5-7 d, reviparin, a LMWH, for 5-7 d (short-treated group) or reviparin for 28 d (long-treated group). Heparin-platelet factor 4 antibodies (HPF4-A) were determined on d 5-7 and d 21. Heparin-induced thrombocytopenia was defined by clinical evaluation. Two patients in the UFH group (incidence: 0.53%, 95% confidence interval (CI): 0.06-1.91) and two patients in the long-treated LMWH group (incidence: 0.53%, 95% CI: 0.06-1.92) had HIT, while no HIT was observed in the short-treated LMWH group. Pulmonary embolism developed in one of the HIT-patients, who had HPF4-A and was treated with UFH. On d 5-7 the incidence of HPF4-A was 9.1% in the UFH group, 2.8% in the short-treated LMWH group and 3.7% in the long-treated LMWH group, with a significant increase to 20.7% in the UFH group and to 7.5% in the long-treated LMWH group on d 21. Therefore the incidence of HPF4-A and heparin-induced thrombocytopenia was lower in patients treated with LMWH compared with UFH for the same duration of treatment.