Clinical trials have demonstrated the usefulness of antiplatelet agents, percutaneous coronary intervention, and glycoprotein (GP) IIb/IIIa inhibitors in patients with acute coronary syndrome (ACS) based on risk stratification. Studies like RITA 3 and FRISC II have shown that an early invasive strategy in high-risk patients was associated with lower mortality over the long term compared with conservative treatment. High-risk patients with unstable angina/non-ST-elevation myocardial infarction derive particular benefit from GP IIb/IIIa inhibitors and an early invasive strategy. The TIMI risk score for patients with unstable angina/non-ST-elevation myocardial infarction provides an easily implemented tool for therapeutic decision-making. Simultaneous assessment of troponin, C-reactive protein, and brain natriuretic peptide at the time of presentation of ACS provides incremental prognostic information. Recent evidence supports the fact that thrombosis and inflammation are interrelated (platelets are involved in inflammation and, similarly, leukocytes are involved in hemostasis). The platelet, which was once viewed as a bystander in hemostasis, is now recognized as a key mediator of thrombosis as well as inflammation. Antithrombotic drugs block platelet aggregation and activation at various points in the thrombotic cascade and include aspirin, the thienopyridine clopidogrel, and its predecessor ticlopidine, intravenous GP IIb/IIIa inhibitors, which block the final common pathway of platelet activation and aggregation, unfractionated heparin and low-molecular-weight heparin, notably enoxaparin, and direct thrombin inhibitors (eg, bivalirudin). Bivalirudin has proven noninferior to heparin in patients undergoing percutaneous coronary intervention. Enoxaparin is emerging as a safer and better alternative to unfractionated heparin in invasively managed patients. Declining renal function is a major cause of excess dosing of antithrombotic agents and frequently increases the risk of bleeding in elderly patients. Class I American College of Cardiology/American Heart Association recommendations for acute (<24 hours) management of patients with high-risk non-ST-elevation ACS include the use of aspirin, beta-blockers, unfractionated heparin or low-molecular-weight heparin, or GP IIb/IIIa inhibitors for patients undergoing catheterization and revascularization and clopidogrel for patients undergoing percutaneous coronary intervention. Medical therapy should be coupled with an early invasive strategy of catheterization and revascularization within 48 hours. Predischarge initiation of secondary prevention therapies for risk factor modification may have substantial advantages for improving the long-term prognosis of patients. A large proportion of patients with ACS undergo interventional treatment, which underscores the importance of upstream initiation of antithrombotic agents. Data from CRUSADE suggests that the majority of patients are likely to benefit from aggressive upstream antithrombotic therapy. Patients with ACS who have diabetes have a higher risk for recurrent events than their nondiabetic counterparts but stand to benefit more from early aggressive therapy. Combining GP IIb/IIIa inhibition with drug-eluting stents offers the potential to optimize outcomes after revascularization in patients with diabetes. Whereas the use of drug-eluting stents has greatly reduced the risk of restenosis, patients with diabetes who have ACS and who undergo stenting remain at high risk for restenosis and are more likely to require revascularization. Increasing adherence to American College of Cardiology/American Heart Association guidelines is key to improving outcomes. The optimal management of patients with ACS continues to change as new therapies and strategies of care are developed and proven effective. The clinical challenge remains to increase physician adherence to evidence-based cardiac care for all patients.

BACKGROUND

Compared to patients without cancer, patients with cancer who receive anticoagulant treatment for venous thromboembolism are more likely to develop recurrent venous thromboembolism (VTE).

OBJECTIVE

To compare the efficacy and safety of three types of parenteral anticoagulants for the initial treatment of VTE in patients with cancer.

METHODS

A comprehensive search for studies of anticoagulation in cancer patients including a February 2010 electronic search of: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ISI Web of Science.

METHODS

Randomized clinical trials (RCTs) comparing low molecular weight heparin (LMWH), unfractionated heparin (UFH), and fondaparinux in patients with cancer and objectively confirmed VTE.

METHODS

Using a standardized data form, data was extracted in duplicate on methodological quality, participants, interventions, and outcomes of interest that included mortality, recurrent VTE, major bleeding, minor bleeding, postphlebitic syndrome, quality of life, and thrombocytopenia.

RESULTS

Of 3986 identified citations, 16 RCTs were eligible: 13 compared LMWH to UFH, two compared fondaparinux to heparin, and one compared dalteparin to tinzaparin. Meta-analysis of 11 studies showed a statistically significant reduction in mortality at three months of follow up with LMWH compared with UFH (relative risk (RR) 0.71; 95% confidence interval (CI) 0.52 to 0.98). There was little change in the effect estimate after excluding studies of lower methodological quality (RR 0.72; 95% CI 0.52 to 1.00). A meta-analysis of three studies comparing LMWH with UFH showed no statistically significant reduction in VTE recurrence (RR 0.78; 95% CI 0.29 to 2.08). The overall quality of evidence was low for LMWH versus UFH due to imprecision and likely publication bias. There were no statistically significant differences between heparin and fondaparinux for the outcomes of death (RR 1.27; 95% CI 0.88 to 1.84), recurrent VTE (RR 0.95; 95% CI 0.57 to 1.60), major bleeding (RR 0.79; 95% CI 0.39 to1.63) or minor bleeding (RR 1.50; 95% CI 0.87 to 2.59). The one study comparing dalteparin to tinzaparin did not find a statistically significant difference in mortality (RR 0.86; 95% CI 0.43 to 1.73).

CONCLUSIONS

LMWH is possibly superior to UFH in the initial treatment of VTE in patients with cancer. Additional trials focusing on patient important outcomes will further inform the questions addressed in this review.

The risk of procedure-related bleeding while taking anticoagulants needs to be weighed against the risk of thromboembolism from discontinuing these drugs. It is not necessary to adjust anticoagulation for low-risk procedures, such as upper endoscopy with biopsy, colonoscopy with biopsy or endoscopic retrograde cholangiopancreatography with stent insertion (but without sphincterotomy). Procedures that incur a high risk of bleeding include polypectomy, endoscopic sphincterotomy, laser therapy, mucosal ablation and treatment of varices. For these procedures, warfarin should be discontinued four to five days beforehand. Depending on the risk of thromboembolism, that is based on the nature of the underlying condition, the patient may require vitamin K and/or fresh frozen plasma (to ensure that coagulation parameters are within the normal range) or heparin infusions (to ensure that some degree of anticoagulation is maintained). Low molecular weight heparin is an alternative to unfractionated heparin for select cases with a high risk of thromboembolism. Warfarin therapy may generally be resumed on the night of the procedure and may be supplemented by heparin in patients with a high risk of thromboembolism. It is not necessary to discontinue acetylsalicylic acid or nonsteroidal anti-inflammatory drugs, when used in standard doses, for endoscopic procedures. There are insufficient data to make recommendations regarding newer antiplatelet drugs, such as ticlopidine or clopidogrel, but it is prudent to discontinue these medications seven to 10 days before a high-risk procedure.

Perioperative management of chronically anticoagulated patients and/or patients treated with antiplatelet therapy is a complex medical problem. This review considers the pharmacokinetic and pharmacodynamic properties of commonly used antiplatelet and anticoagulant drugs with special emphasis on loss of effects after discontinuation and possible counteracting (or antidote) strategies. These drugs are aspirin (acetylsalicylic acid), ticlopidine/clopidogrel, abciximab, tirofiban and eptifibatide, heparin (unfractionated and low-molecular-weight), warfarin and direct thrombin inhibitors. Since the pharmacological mechanisms of some of these drugs are based on irreversible or slowly reversible effects, their pharmacokinetic profiles are not necessarily predictive for their pharmacodynamic profiles. A close and direct relationship between plasma concentrations and effects is seen only for the glycoprotein (GP) IIb/IIIa inhibitors tirofiban and eptifibatide with a fast off-rate for dissociation from the GPIIb/IIIa receptor, and for direct thrombin inhibitors (hirudin and argatroban). For other compounds, drug concentrations in plasma and pharmacodynamic effects are not closely correlated because of, for example, irreversible binding to their target (aspirin, clopidogrel and abciximab), inhibition of the generation of a subset of clotting factors with differing regeneration and degradation rates (coumarins) or sustained binding to the vascular wall (heparins). Surgery in patients on anticoagulant and/or antiplatelet therapy may be categorised as: (i) elective versus urgent; and (ii) cardiopulmonary bypass (CPB) versus non-CPB. Monotherapy with clopidogrel or aspirin need not be discontinued in elective non-CPB surgery, and temporary discontinuation of warfarin should be accompanied by preoperative intravenous heparin only in selected high-risk patients. Vitamin K as an antidote for warfarin should only be used subcutaneously and solely in urgent/emergency surgery. In elective surgery requiring CPB (coronary artery bypass grafting), it is recommended to discontinue aspirin 7 days preoperatively in patients with a low risk profile. Patients requiring urgent CPB surgery (e.g. after failure of a percutaneous coronary angioplasty with or without coronary stent deployment) are usually pretreated with several antiplatelet agents (e.g. aspirin and clopidogrel, together with a GPIIb/IIIa inhibitor) together with unfractionated or low-molecular-weight heparin. With judicious planning, urgent/emergency cardiac surgery can be safely performed on these patients. Delaying surgery (e.g. for 12 hours in patients treated with abciximab) should be considered if possible. Standard heparin doses should be given to achieve optimal anticoagulation for CPB. Prophylactic use of aprotinin (intra- and/or postoperatively), aminocaproic acid or tranexamic acid should be considered. Early (in the operating theatre prior to chest closure) and judicious use of replacement blood products (platelets) should be commenced when clinically indicated.

Hepatic veno-occlusive disease (VOD), a common complication of bone marrow transplantation (BMT), is a result of intensive conditioning by chemo-radiotherapy. Endometrial injury causes fibrin deposition in the affected hepatic venules, leading to abnormal laboratory parameters followed by lethal full-blown disease. Previous studies have shown that unfractionated heparin can prevent VOD in BMT patients. Since low molecular weight heparin (LMWH) preserves the antithrombotic, but not the anticoagulant, activity of unfractionated heparin, we initiated a pilot study to determine the safety of LMWH for the prevention of VOD. Sixty-one patients undergoing BMT (allogeneic, n=24; autologous, n=37) were randomized to receive subcutaneous injection of enoxaparin (40 mg/day x 1) or a placebo prior to BMT conditioning and until day 40 after transplantation or discharge from the hospital. LMWH administration did not influence marrow engraftment, nor was it associated with bleeding tendency. Hemorrhagic events occurred significantly less frequently (P=0.025) were shorter duration (P=0.006) in the LMWH group than in the placebo group. Time to platelet recovery was significantly shorter (16.5 vs 29.6 days, (P=0.0075), and platelet transfusion requirements were lower (p=0.05) in the LMWH patients. VOD parameters occurred less frequently in the experimental group, including duration of elevated bilirubin levels (P=0.01) and incidence of hepatomegaly (P=0.04). LMWH, which seems to enhance platelet recovery, may be safely administrated to BMT patients in an attempt to prevent VOD of the liver.

This article will review the results of recent clinical trials evaluating low molecular weight heparins (LMWHs) in the management of patients with acute coronary syndromes of unstable angina and non-ST segment elevation MI. Low molecular weight heparins are a new class of anticoagulants that have a number of advantages over unfractionated heparin (UFH) leading to their increasing use for thrombotic vascular disorders. There is convincing evidence that LMWH is more effective than placebo and at least as effective as UFH in reducing the hard end points of death and recurrent myocardial infarction. Convincing evidence for a superior efficacy is mostly limited to the least robust but most prevalent end point of recurrent angina, and benefits appear to be confined predominantly to high-risk patients. The benefits are sustained long-term, but there appears to be no incremental benefit with prolonged treatment. The risk for major bleeding is approximately equivalent to UFH, but minor hemorrhage is clearly increased, especially with vascular instrumentation. The increased bleeding risk together with its long half-life and absence of specific antidote warrants exercising caution when using LMWH with coronary intervention. Low molecular weight heparins have the potential of being cost-neutral or even cost-saving by reducing resource utilization, especially in the setting of aggressive interventional practice pattern. Last, the issue of whether one LMWH preparation is more effective and cost-effective than others remains an open question that can be answered only by direct head-to-head comparison of different LMWH preparations in randomized trials. In conclusion, subcutaneous weight-adjusted LMWH is as effective and safe as intravenous UFH in the management of patients with acute coronary syndromes. The logistic ease of administration without the need for monitoring anticoagulation appears to be the major advantage over UFH.

Antiphospholipid antibodies, that is, lupus anticoagulants and anticardiolipin antibodies, are associated with thrombosis and obstetric complications in the antiphospholipid syndrome. Venous thrombosis occurs mostly in the lower limbs, with or without pulmonary embolism, and cerebral ischemia and transient ischemic attacks are the most common arterial events. Overall, the prevalence of thrombosis is about 30%, the rate of first event approximates 1%/year, and that of recurrence of patients not receiving anticoagulation is about 10-29%/year. The presence of lupus anticoagulants carries an odds ratio for thrombosis ranging from 5 to 16, and that of anticardiolipin antibodies from nonsignificant to 18. The detection of anti-beta2-glycoprotein I, but not antiprothrombin, antibodies might also help to identify antiphospholipid-positive patients at risk of thrombosis. Unfractionated or low-molecular-weight heparin followed by oral anticoagulation represents the current treatment of both arterial and venous thrombosis. However, uncertainty still exists about the optimal duration and intensity of oral anticoagulation following the first event. Several therapeutic clinical trials are currently being conducted, which soon clarify these issues. The prevalence of obstetric complications is about 15-20%. The presence of lupus anticoagulants carries an odds ratio for recurrent miscarriages and fetal death ranging from 3.0 to 4.8, whereas that of anticardiolipin antibodies goes from 0.86 to 20. Unfractionated or low-molecular-weight heparin in combination with low-dose aspirin represents the current standard of treatment of pregnant antiphospholipid-positive women to prevent recurrent obstetric complications. Upon treatment, the live birth rate increases from 0-40% to 70-80%.

BACKGROUND

The optimal antithrombotic therapy to accompany tenecteplase in cases of acute ST-segment elevation myocardial infarction (STEMI) remains unclear. We undertook a prespecified pooled analysis of data from the ASSENT-3 and ASSENT-3 PLUS trials.

METHODS

We created a combined database of the 2040 and 818 patients who received enoxaparin in ASSENT-3 and ASSENT-3 PLUS, respectively, and compared them with the 2038 and 821 patients who received unfractionated heparin.

RESULTS

The efficacy end point (a composite of 30-day mortality, reinfarction or refractory ischemia) was 12.2% with enoxaparin versus 16.0% with unfractionated heparin (p < 0.001); the combined end point of efficacy plus safety (a composite of 30-day mortality, reinfarction, refractory ischemia, intracranial hemorrhage [ICH] or major systemic bleeding) was 15.0% versus 18.0%, respectively (p = 0.003) [corrected] The 1049 patients urgently revascularized had greater benefit from enoxaparin (15.4% v. 10.1%, p = 0.013), yet the excess in major systemic bleeding evident with enoxaparin (3.3% v. 2.4%, p = 0.01) was largely confined to the 3492 patients without or before revascularization. Although ICH rates in the groups were similar (1.3% v. 0.9%, p = 0.26), an excess of ICH occurred among those administered enoxaparin during the ASSENT-3 PLUS trial (6.7% v. 0.8%, p = 0.013), especially among women over 75 years of age.

CONCLUSIONS

These data demonstrated the benefit of enoxaparin used in conjunction with tenecteplase, but raised caution about its prehospital use to treat STEMI in elderly women.

We evaluated 40 patients undergoing high-dose chemo/radiotherapy (HDCT) and hematopoietic stem cell transplantation (HSCT) (allogeneic (22), autologous (18)) to determine the safety and feasibility of administering low molecular weight heparin (LMWH) as hepatic veno-occlusive disease (VOD) prophylaxis. Patients received a once daily subcutaneous injection of dalteparin 2500 anti-Xa i.u. commencing the day prior to starting HDCT, and continuing until day +30 post HSCT or hospital discharge, whichever came first. Dosage adjustments were made for patients developing renal failure. All bleeding episodes were recorded and graded and VOD was diagnosed and graded according to Seattle criteria. At 100 days of follow-up, the overall survival and probability of regimen-related mortality were 85 and 15%, respectively. Nine patients developed VOD. The probability of developing VOD post allogeneic and autologous HSCT was 28% (95% CI, 6-45) and 17% (95% CI, 0-32), respectively. VOD was graded as moderate (n=8) and severe (n=1). VOD resolved in all cases except for one patient who died secondary to severe VOD and multiorgan failure. Clinically significant bleeding episodes occurred in three patients; 24 patients developed minor bleeding not requiring specific therapy. All bleeding episodes resolved. These results suggest that LMWH for VOD prophylaxis is safe with a low incidence of serious bleeding events. Whether it is superior to unfractionated heparin, however, is unknown and should be addressed within the context of a randomized controlled trial.

BACKGROUND

Therapy with intravenous unfractionated heparin improves clinical outcome in patients with active thromboembolic disease, but achieving and maintaining a therapeutic level of anticoagulation remains a major challenge for clinicians.

METHODS

A total of 113 patients requiring heparin for at least 48 hours were randomly assigned at 7 medical centers to either weight-adjusted or non-weight-adjusted dose titration. They were separately assigned to either laboratory-based or point-of-care (bedside) coagulation monitoring.

RESULTS

Weight-adjusted heparin dosing yielded a higher mean activated partial thromboplastin time (aPTT) value 6 hours after treatment initiation than non-weight-adjusted dosing (99.9 vs 78.8 seconds; P =.002) and reduced the time required to exceed a minimum threshold (aPTT >45 seconds) of anticoagulation (10.5 vs 8.6 hours; P =.002). Point-of-care coagulation monitoring significantly reduced the time from blood sample acquisition to a heparin infusion adjustment (0.4 vs 1.6 hours; P <.0001) and to reach the therapeutic aPTT range (51 to 80 seconds) (16.1 vs 19.4 hours; P =.24) compared with laboratory monitoring. Although a majority of patients participating in the study surpassed the minimum threshold of anticoagulation within the first 12 hours and reached the target aPTT within 24 hours, maintaining the aPTT within the therapeutic range was relatively uncommon (on average 30% of the overall study period) and did not differ between treatment or monitoring strategies.

CONCLUSIONS

Weight-adjusted heparin dosing according to a standardized titration nomogram combined with point-of-care coagulation monitoring using the BMC Coaguchek Plus System represents an effective and widely generalizable strategy for managing patients with thromboembolic disease that fosters the rapid achievement of a desired range of anticoagulation. Additional work is needed, however, to improve on existing patient-specific strategies that can more effectively sustain a therapeutic state of anticoagulation.

A review and meta analysis of randomized prophylaxis studies in total hip arthroplasty (THA) surgery with the low molecular weight heparin (LMWH) compounds presently marketed in Europe. Thromboprophylaxis with recommended dosages of LMWH was significantly more effective than both placebo (no prophylaxis), dextran 70 and low-dose unfractionated heparin (UH) (5,000 IU thrice daily) in terms of protection against objectively diagnosed deep vein thrombosis (DVT), which is the main source of postoperative pulmonary embolism. The efficacy of LMWH was similar to that of adjusted-dose UH but only 2 studies have been conducted with this regimen so far. When combined with 0.5 mg dihydroergotamine (DHE), UH was as effective as LMWH, but DHE bears a definite risk of circulatory disturbances in the lower limbs. In all studies LMWH prophylaxis was safe under the clinical conditions. A cost-effectiveness analysis based on the reported efficacy and safety of LMWH in the European studies showed that, compared with no prophylaxis, dextran 70, and low-dose UH, LMWH prophylaxis used routinely in patients undergoing THA is more profitable for the health care system due to fewer expenses used on treatment of postoperative thromboembolic complications. LMWH therefore leads to better utilization of the economic resources.

We have conducted a prospective randomized controlled trial to evaluate the role of low-dose unfractionated heparin prophylaxis in preventing central venous line-related thrombosis in patients with haemato-oncological disease. Patients were randomly assigned to receive either prophylactic intravenous unfractionated heparin (continuous infusion of 100 IU/kg/daily) or 50 ml/daily of normal saline solution as a continuous infusion. CVLs were externalized, non tunneled, double lumen catheters. All CVLs were placed percutaneously by the same physician in the subclavian vein. Upper limb veins were systematically examined by ultrasonography just before, or <24 hours after, catheter removal, and in case of clinical signs of thrombosis. One hundred and twenty-eight CVLs were inserted. Catheter-related thrombosis occurred in 1.5% of the catheters inserted in patients of the heparin group, and in 12.6% in the control group (p = 0.03). No other risk factors were found for the development of catheter-related thrombosis. Two and three patients experienced severe bleeding in the heparin group, and in the control group, respectively (p = 0.18). There were no other side-effects clearly ascribable to the use of unfractionated heparin. This is the first prospective, randomized study, which shows that low-dose of unfractionated heparin is safe and effective to prevent catheter-related thrombosis in patients with haemato-oncological disease.

OBJECTIVE

Neonatal renal venous thrombosis is a rare disorder that can result in severe renal damage. To evaluate the experience over 10 years and review the effectiveness of fibrinolytic and/or heparin therapy, chart reviews were performed for newborns with renal venous thrombosis. PATIENTS, INTERVENTIONS, AND OUTCOME MEASURES: Twenty-eight newborns with renal venous thrombosis were treated at Children's Hospitals and Clinics of Minnesota and Fairview University Medical Center from 1991 to 2001.

RESULTS

Unilateral involvement was noted in 25 neonates (89%) and bilateral involvement in 3 (11%). Unilateral renal venous thrombosis affected mostly term infants, whereas 2 of 3 infants with bilateral renal venous thrombosis were <32 weeks' gestational age (birth weight: 745-1505 g). One mother had antiphospholipid syndrome. Of 11 neonates evaluated for congenital thrombophilia, 1 had the factor V Leiden mutation. Ten neonates received either unfractionated or low molecular weight heparin for 3 days to 7 months. Three infants with unilateral renal venous thrombosis treated with heparin alone did not seem to benefit from such therapy. Seven neonates were treated with fibrinolytics and unfractionated heparin (4 neonates with unilateral renal venous thrombosis and 3 with bilateral renal venous thrombosis). Treatment with fibrinolytics did not result in restoration of renal function in the 4 neonates with unilateral renal venous thrombosis but was associated with return of almost normal function in the 2 neonates with bilateral renal venous thrombosis who received fibrinolytics immediately after renal venous thrombosis diagnosis. Two neonates treated with fibrinolytics suffered bleeding complications at the area of adrenal hemorrhage. Two neonates (not treated for renal venous thrombosis) died as a result of underlying disease.

CONCLUSIONS

Most neonatal renal venous thrombosis is unilateral and does not respond to fibrinolytic therapy and heparin. The use of fibrinolytics may prevent chronic renal failure in neonates with bilateral renal venous thrombosis if begun within 24 hours of diagnosis. Fibrinolytic therapy, however, is associated with a risk of bleeding, specifically if there is an associated adrenal hemorrhage.

The development of a non-invasive drug delivery system for unfractionated heparin (UFH) and low molecular weight heparins (LMWHs) has been the elusive goal of several research groups since the initial discovery of this glycosaminogylcan by McLean in 1916. After a brief update on current parenteral formulations of UFH and LMWHs, this review revisits past and current strategies intended to identify alternative routes of administration (e.g. oral, sublingual, rectal, nasal, pulmonary and transdermal). The following strategies have been used to improve the bioavailability of this bioactive macromolecule by various routes: (i) enhancement in cell-membrane permeabilization, (ii) modification of the tight-junctions, (iii) increase in lipophilicity and (iv) protection against acidic pH of the stomach. Regardless of the route of administration, a simplified unifying principle for successful non-invasive macromolecular drug delivery may be: "to reversibly overcome the biological, biophysical and biochemical barriers and to safely and efficiently improve the in vivo spatial and temporal control of the drug in order to achieve a clinically acceptable therapeutic advantage". Future macromolecular drug delivery research should embrace a more systemic approach taking into account recent advances in genomics/proteomics and nanotechnology.

Unfractionated heparin (UFH) has been in clinical use for over 50 years and extensive clinical trials have demonstrated its effectiveness in the prevention and treatment of thrombotic disease. In the last 2 decades, low molecular weight heparins (LMWHs) have been developed and subjected to extensive laboratory and clinical studies. In clinical comparison with UFH in the treatment of venous thromboembolism, LMWHs appear to offer a superior benefit-risk profile. In addition, the ease of drug administration and lack of drug monitoring associated with LMWHs are attractive clinical features. We calculated the overall costs of UFH and LMWH therapy using recently published clinical data and local cost information. Although the acquisition costs of LMWHs are higher than for UFH, LMWHs are more cost effective in surgical prophylaxis of deep venous thrombosis (DVT) if the costs of failed prophylaxis are considered. The costs of using subcutaneous (SC) LMWH as therapy for established DVT are lower than those of UFH administered by intravenous infusion. The financial benefit of using LMWH treatment becomes more pronounced when the rates of antithrombotic failure and bleeding complications are incorporated. If UFH is given by SC injection, however, the cost differential favouring LMWH for the treatment of DVT is not so great. If current trials demonstrate that LMWH treatment can be given on an ambulatory outpatient basis, the economic advantages of LMWH will be considerable. However, the extent of this will vary from place to place depending on local funding arrangements.

Bivalirudin demonstrated similar efficacy but resulted in a lower rate of bleeding compared to unfractionated heparin (UFH) plus platelet glycoprotein IIb/IIIa inhibitors in patients undergoing percutaneous coronary intervention. It has not been clearly evaluated whether this can also be applied to patients with diabetes mellitus. A total of 335 consecutive patients with diabetes mellitus referred for elective percutaneous coronary intervention were randomized in the Novel Approaches for Preventing or Limiting EventS (NAPLES) trial to receive bivalirudin monotherapy or UFH plus routine tirofiban. The primary composite end point (30-day composite incidence of death, urgent repeat revascularization, myocardial infarction, and all bleeding) was lower in the bivalirudin group than in the UFH plus tirofiban group (18.0% vs 31.5%, odds ratio 0.47, 95% confidence interval 0.28 to 0.79, p = 0.004). No death, urgent revascularization, or Q-wave myocardial infarction occurred. The rate of non-Q-wave myocardial infarction was similar in the 2 groups (10.2% in the bivalirudin group vs 12.5% in the UFH plus tirofiban group, p = 0.606). In contrast, fewer patients in the bivalirudin group experienced bleeding (8.4% vs 20.8%, odds ratio 0.34, 95% confidence interval 0.18 to 0.67, p = 0.002). This difference was mainly ascribed to the lower rate of minor bleeding (7.8% in the bivalirudin group vs 18.5% in the UFH plus tirofiban group, odds ratio 0.37, 95% confidence interval 0.19 to 0.74, p = 0.005), although the rate of major bleeding in the 2 groups was comparable (0.6% vs 2.4%, respectively; p = 0.371). In conclusion, in patients with diabetes mellitus undergoing elective percutaneous coronary intervention, the strategy of bivalirudin monotherapy compared to UFH plus routine tirofiban is safe and feasible and associated with a significant reduction of in-hospital bleeding.

BACKGROUND

People with venous thromboembolism are generally treated for five days with intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin followed by three months of vitamin K antagonists treatment. Treatment with vitamin K antagonists requires regular laboratory measurements and some patients have contraindications for treatment.

OBJECTIVE

To evaluate the efficacy and safety of long-term treatment of venous thromboembolism with low-molecular-weight heparins compared to vitamin K antagonists.

METHODS

Searches of MEDLINE, EMBASE and ISI Web of Science, the Specialised Trials Register of the Cochrane Peripheral Vascular Disease Group and the Cochrane Controlled Trials Register were made and relevant journals were hand-searched. Additional trials were sought through communication with colleagues and pharmaceutical companies.

METHODS

Two reviewers evaluated studies independently for methodological quality.

METHODS

Two reviewers extracted data independently. Primary analysis concerned all trial participants during the period of randomized treatment. Separate analyses were performed for category I and category II studies; i.e. studies using similar treatments initially in both study arms, and those that did not; and the different periods of follow-up.

RESULTS

All seven studies fulfilling our criteria combined, a statistically non-significant reduction in the risk of recurrent venous thromboembolism favoring low-molecular-weight heparin treatment (OR 0.70; 95% CI [0.42, 1.16]) was found. Analysis of pooled data for category I studies showed a non-significant reduction in the risk of recurrent venous thromboembolism favoring low-molecular-weight heparin treatment (OR 0.75; 95% CI [0.40, 1.39]). Omitting a potentially-confounded study, a statistically non-significant reduction in the risk of recurrent venous thromboembolism favoring vitamin K antagonist treatment remained (OR 1.95; 95% CI [0.74, 5.19]). All studies combined, the difference in bleeding significantly favored treatment with low-molecular-weight heparin (OR 0.38; 95% CI [0.15, 0.94]), however, considering only category I studies a non-significant trend favoring low-molecular-weight heparin remained (OR 0.80; 95% CI [0.21, 3.00]). No difference was observed in mortality (OR 1.13; 95% CI [0.47, 2.69]).

CONCLUSIONS

Low-molecular-weight heparins are possibly as effective as vitamin K antagonists in preventing symptomatic venous thromboembolism after an episode of symptomatic deep venous thrombosis, but are much more expensive. Treatment with low-molecular-weight heparin is significantly safer than treatment with vitamin K antagonists and is possibly a safe alternative in some patients; especially those in geographically inaccessible places, reluctant to visit the thrombosis service regularly, or with contraindications to vitamin K antagonists. However, treatment with vitamin K antagonists remains the treatment of choice for the majority of patients.

In a randomized controlled clinical trial, the efficacy and safety of two low molecular weight heparin ( LMWH ) fractions in the prophylaxis of deep vein thrombosis (DVT) were assessed. One hundred twenty-six patients undergoing major abdominal surgery received alternatively 2,500 APTT units b.i.d. of two LMWH fractions or 5,000 APTT units b.i.d. of an unfractionated sodium mucosal heparin ( UFH ). LMWH 2 differed from LMWH 1 by presenting a lower mean molecular weight and a higher anti-Xa/APTT ratio in vitro. Patients were randomly allocated to the three groups, and the development of DVT was studied with the 125I-fibrinogen uptake test ( RFUT ). The study was interrupted and the code broken prematurely because of otherwise unexplainable bleeding events. While no thrombosis and no severe bleeding were detected in the UFH group, three (7%) RFUT -positive DVT and two (5%) hemorrhagic complications occurred in the LMWH 1 group. No thrombosis and nine (22%) cases of severe bleeding were observed in the LMWH 2 group. Thus, the latter group differed significantly from the control group with regard to subjective and objective criteria for postoperative bleeding. Although these results do not allow general conclusions as to the value of LMWH fractions in the prevention of DVT, they indicate that these preparations just as ordinary heparin have a limited therapeutic range.

BACKGROUND

As suggested by observational and animal studies, heparin has antiinflammatory effects that could prevent acute post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. Low-molecular-weight heparin did not reduce the incidence of post-ERCP pancreatitis in a controlled study. The current study aimed to determine whether prophylactic administration of low-dose unfractionated heparin, which has potentially more antiinflammatory capability, can prevent acute post-ERCP pancreatitis.

METHODS

Patients scheduled for ERCP in the authors' department were randomized to receive unfractionated heparin (5,000 IU) or placebo (saline solution 0.5 ml) administered subcutaneously 20 to 30 min before the ERCP. Patients who had undergone endoscopic sphincterotomy in the past were excluded from the study. Post-ERCP pancreatitis was defined according to criteria established by Cotton: abdominal pain combined with a threefold elevation of blood amylase 24 h after the ERCP.

RESULTS

The study enrolled 106 patients. One patient was excluded from the analysis due to inaccessible papilla of Vater, leaving 51 patients in the heparin group and 54 in the placebo group, for a total of 105 patients (62 women and 43 men) with a mean age of 64.6 years. The rate of post-ERCP pancreatitis was not different between the groups (heparin, 4 patients, 7.8%; placebo, 4 patients, 7.4%). Two patients in each group experienced mild bleeding.

CONCLUSIONS

The study did not demonstrate a significant effect of low-dose unfractionated heparin in the prevention of post-ERCP pancreatitis. A multicenter trial with a larger number of patients is needed to demonstrate a benefit from this drug.

BACKGROUND

Thromboembolism in children is typically treated with unfractionated heparin (UH) or low molecular weight heparin (LMWH). Both rely on antithrombin (AT) for their action. In addition, heparin-induced thrombocytopenia (HIT) is a potentially serious complication of heparin use in children. Bivalirudin or other direct thrombin inhibitors may be a useful alternative to heparins in treating thrombosis in children.

METHODS

We report a retrospective review to assess the efficacy and safety of bivalirudin in pediatric patients with thrombosis.

RESULTS

Sixteen children received bivalirudin for thrombosis or prevention of thrombosis at the Children's Hospital of Illinois from January 2005 to January 2007. Patients received a bolus dose of 0.25 mg/kg followed by a continuous infusion (0.16 +/- 0.07 mg kg(-1) hr(-1)) titrated to 1.5-2.5 times the baseline activated partial thromboplastin time (aPTT). Positive correlation between the bivalirudin average infusion rate and aPTT was observed in twelve patients. Ultrasonographic evidence of thrombus regression was noted at 72 hr in 10 of 10 patients. One patient experienced hematuria after catheterization of the urethra.

CONCLUSIONS

Bivalirudin was effective and well-tolerated in these patients. Further studies should be conducted to better define safety and efficacy of bivalirudin in pediatric patients.

Previous studies have compared bivalirudin and unfractionated heparin (UFH) plus the routine use of glycoprotein IIb/IIIa inhibitors. They have demonstrated that bivalirudin can decrease bleeding complications without a significant increase in ischemic complications, resulting in a better net clinical outcome, as defined by the efficacy (ischemic complications) or safety (bleeding complications) end point. The aim of the present study was to compare bivalirudin and UFH plus protamine in patients undergoing elective percutaneous coronary intervention and pretreated with clopidogrel and aspirin. We randomly assigned 850 patients with stable or unstable coronary artery disease to bivalirudin or UFH followed by protamine at the end of the percutaneous coronary intervention. The primary end point was in-hospital major bleeding. The main secondary end points were the 1-month composite of death, myocardial infarction, unplanned target vessel revascularization; and the 1-month net clinical outcome. The rate of major bleeding (primary end point) was 0.5% in patients randomized to bivalirudin and 2.1% in patients randomized to UFH (p = 0.033). At 30 days, the rate of major bleeding was 0.9% in the bivalirudin arm and 2.8% in the UFH arm (p = 0.043). The composite of death, myocardial infarction, and target vessel revascularization rate and the net clinical outcome rate was 2.8% and 6.4% (p = 0.014) and 3.3% and 7.8% (p = 0.004), respectively, in the bivalirudin and UFH arms. In conclusion, in percutaneous coronary intervention patients pretreated with clopidogrel and aspirin, bivalirudin was associated with less major bleeding and fewer ischemic complications and a better net clinical outcome than UFH.

The management of patients who require temporary interruption of vitamin K antagonists is a common clinical problem, affecting an estimated 400 000 patients per year in Europe and North America. Managing such patients is challenging because of the lack of randomized trials assessing different perioperative anticoagulation management strategies and inconsistent recommendations from consensus groups. Recent non-randomized trials have helped to estimate the risks for arterial thromboembolism and bleeding with bridging anticoagulation involving low-molecular-weight heparin. The objectives of this review are to describe bridging anticoagulation and how it may be used with a short-acting heparin, such as unfractionated heparin or low-molecular-weight heparin, to discuss preoperative patient management, focusing on risk stratification for thromboembolic events and interruption of vitamin K antagonist therapy, and to discuss postoperative patient management, focusing on surgery-related bleeding risk and the resumption of bridging anticoagulation and vitamin K antagonist therapy.

Thromboembolism is a major cause of morbidity and mortality in dogs with immune-mediated hemolytic anemia (IMHA). To the authors' knowledge, the role of platelets in thromboembolic events associated with IMHA has not been extensively investigated. In the study reported here, we evaluated cell membrane expression of P-selectin with flow cytometry to determine whether platelets circulate in an activated state in association with primary IMHA. Median P-selectin expression for 20 dogs with primary IMHA was 8.1-fold greater, compared with values for 20 healthy dogs. Fifteen of 20 dogs (75%) with IMHA had P-selectin median fluorescence intensity (MFI) values that exceeded the reference interval for healthy dogs. Additionally, P-selectin MFI after activation of platelets with phorbol myristate acetate was 2.1-fold greater for dogs with IMHA than for healthy control dogs. Despite treatment of all dogs with immunosuppressive therapy and 18 dogs with subcutaneously administered low-dose unfractionated heparin, 7 dogs developed clinical signs consistent with thromboembolism. These data provide support for the hypothesis that platelets circulate in an activated state in many dogs with IMHA.

The cytokine osteopontin (OPN) can be hydrolyzed by thrombin exposing a cryptic alpha(4)beta(1)/alpha(9)beta(1) integrin-binding motif (SVVYGLR), thereby acting as a potent cytokine for cells bearing these activated integrins. We show that purified milk OPN is a substrate for thrombin with a k(cat)/K(m) value of 1.14 x 10(5) m(-1) s(-1). Thrombin cleavage of OPN was inhibited by unsulfated hirugen (IC(50) = 1.2 +/- 0.2 microm), unfractionated heparin (IC(50) = 56.6 +/- 8.4 microg/ml) and low molecular weight (5 kDa) heparin (IC(50) = 31.0 +/- 7.9 microg/ml), indicating the involvement of both anion-binding exosite I (ABE-I) and anion-binding exosite II (ABE-II). Using a thrombin mutant library, we mapped residues important for recognition and cleavage of OPN within ABE-I and ABE-II. A peptide (OPN-(162-197)) was designed spanning the OPN thrombin cleavage site and a hirudin-like C-terminal tail domain. Thrombin cleaved OPN-(162-197) with a specificity constant of k(cat)/K(m) = 1.64 x 10(4) m(-1) s(-1). Representative ABE-I mutants (K65A, H66A, R68A, Y71A, and R73A) showed greatly impaired cleavage, whereas the ABE-II mutants were unaffected, suggesting that ABE-I interacts principally with the hirudin-like OPN domain C-terminal and contiguous to the thrombin cleavage site. Debye-Hückel slopes for milk OPN (-4.1 +/- 1.0) and OPN-(162-197) (-2.4 +/- 0.2) suggest that electrostatic interactions play an important role in thrombin recognition and cleavage of OPN. Thus, OPN is a bona fide substrate for thrombin, and generation of thrombin-cleaved OPN with enhanced pro-inflammatory properties provides another molecular link between coagulation and inflammation.