BACKGROUND

Two phase III trials of enoxaparin for unstable angina/non-Q-wave myocardial infarction have shown it to be superior to unfractionated heparin for preventing a composite of death and cardiac ischemic events. A prospectively planned meta-analysis was performed to provide a more precise estimate of the effects of enoxaparin on multiple end points.

RESULTS

Event rates for death, the composite end points of death/nonfatal myocardial infarction and death/nonfatal myocardial infarction/urgent revascularization, and major hemorrhage were extracted from the TIMI 11B and ESSENCE databases. Treatment effects at days 2, 8, 14, and 43 were expressed as the OR (and 95% CI) for enoxaparin versus unfractionated heparin. All heterogeneity tests for efficacy end points were negative, which suggests comparability of the findings in TIMI 11B and ESSENCE. Enoxaparin was associated with a 20% reduction in death and serious cardiac ischemic events that appeared within the first few days of treatment, and this benefit was sustained through 43 days. Enoxaparin's treatment benefit was not associated with an increase in major hemorrhage during the acute phase of therapy, but there was an increase in the rate of minor hemorrhage.

CONCLUSIONS

The accumulated evidence, coupled with the simplicity of subcutaneous administration and elimination of the need for anticoagulation monitoring, indicates that enoxaparin should be considered as a replacement for unfractionated heparin as the antithrombin for the acute phase of management of patients with high-risk unstable angina/non-Q-wave myocardial infarction.

New oral anticoagulants (OACs) that directly inhibit Factor Xa (FXa) or thrombin have been developed for the long-term prevention of thromboembolic disorders. These novel agents provide numerous benefits over older vitamin K antagonists (VKAs) due to major pharmacological differences. VKAs are economical and very well characterized, but have important limitations that can outweigh these advantages, such as slow onset of action, narrow therapeutic window and unpredictable anticoagulant effect. VKA-associated dietary precautions, monitoring and dosing adjustments to maintain international normalized ratio (INR) within therapeutic range, and bridging therapy, are inconvenient for patients, expensive, and may result in inappropriate use of VKA therapy. This may lead to increased bleeding risk or reduced anticoagulation and increased risk of thrombotic events. The new OACs have rapid onset of action, low potential for food and drug interactions, and predictable anticoagulant effect that removes the need for routine monitoring. FXa inhibitors, e.g. rivaroxaban and apixaban, are potent, oral direct inhibitors of prothrombinase-bound, clot-associated or free FXa. Both agents have a rapid onset of action, a wide therapeutic window, little or no interaction with food and other drugs, minimal inter-patient variability, and display similar pharmacokinetics in different patient populations. Since both are substrates, co-administration of rivaroxaban and apixaban with strong cytochrome P450 (CYP) 3A4 and permeability glycoprotein (P-gp) inhibitors and inducers can result in substantial changes in plasma concentrations due to altered clearance rates; consequently, their concomitant use is contraindicated and caution is required when used concomitantly with strong CYP3A4 and P-gp inducers. Although parenteral oral direct thrombin inhibitors (DTIs), such as argatroban and bivalirudin, have been on the market for years, DTIs such as dabigatran are novel synthetic thrombin antagonists. Dabigatran etexilate is a low-molecular-weight non-active pro-drug that is administered orally and converted rapidly to its active form, dabigatran--a potent, competitive and reversible DTI. Dabigatran has an advantage over the indirect thrombin inhibitors, unfractionated heparin and low-molecular-weight heparin, in that it inhibits free and fibrin-bound thrombin. The reversible binding of dabigatran may provide safer and more predictable anticoagulant treatment than seen with irreversible, non-covalent thrombin inhibitors, e.g. hirudin. Dabigatran shows a very low potential for drug-drug interactions. However, co-administration of dabigatran etexilate with other anticoagulants and antiplatelet agents can increase the bleeding risk. Although the new agents are pharmacologically better than VKAs--particularly in terms of fixed dosing, rapid onset of action, no INR monitoring and lower risk of drug interactions--there are some differences between them: the bioavailability of dabigatran is lower than rivaroxaban and apixaban, and so the dabigatran dosage required is higher; lower protein binding of dabigatran reduces the variability related to albuminaemia. The risk of metabolic drug-drug interactions also appears to differ between OACs: VKAs>> rivaroxaban>> apixaban>> dabigatran. The convenience of the new OACs has translated into improvements in efficacy and safety as shown in phase III randomized trials. The new anticoagulants so far offer the greatest promise and opportunity for the replacement of VKAs.

Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating IgG antibodies that recognize platelet factor 4 (PF4) bound to heparin. Immunogenicity of heparins differs in that unfractionated heparin (UFH) induces more anti-PF4/heparin antibodies than low-molecular-weight heparin (LMWH) and UFH also causes more HIT. Fondaparinux, a synthetic anticoagulant modeled after the antithrombin-binding pentasaccharide, is believed to be nonimmunogenic. We tested 2726 patients for anti-PF4/heparin antibodies after they were randomized to receive antithrombotic prophylaxis with fondaparinux or LMWH (enoxaparin) following hip or knee surgery. We also evaluated in vitro cross-reactivity of the IgG antibodies generated against PF4 in the presence of UFH, LMWH, danaparoid, or fondaparinux. We found that anti-PF4/heparin antibodies were generated at similar frequencies in patients treated with fondaparinux or enoxaparin. Although antibodies reacted equally well in vitro against PF4/UFH and PF4/LMWH, and sometimes weakly against PF4/danaparoid, none reacted against PF4/fondaparinux, including even those sera obtained from patients who formed antibodies during fondaparinux treatment. At high concentrations, however, fondaparinux inhibited binding of HIT antibodies to PF4/polysaccharide, indicating that PF4/fondaparinux interactions occur. No patient developed HIT. We conclude that despite similar immunogenicity of fondaparinux and LMWH, PF4/fondaparinux, but not PF4/LMWH, is recognized poorly by the antibodies generated, suggesting that the risk of HIT with fondaparinux likely is very low.

Heparin inhibits blood coagulation by binding to the protease inhibitor antithrombin, thus promoting inactivation of the protease "factors" of the coagulation cascade mechanism. The article provides an overview of the studies, by different research groups, that led to the structural elucidation of the antithrombin-binding region of heparin. These studies were triggered by the finding that only a fraction of heparin molecules were capable of binding with high affinity to antithrombin, and further that this fraction essentially accounted for the anticoagulant activity of the unfractionated material. Oligosaccharides obtained by selective, partial depolymerization of heparin were fractionated on immobilized antithrombin, and the smallest high-affinity molecules recovered were subjected to structural analysis, in conjunction with various modification steps. The results were interpreted in terms of a binding site for antithrombin constituted by a pentasaccharide sequence with an internal unique 3-O-sulfated glucosamine unit, in addition to sugar residues and sulfate groups present elsewhere also in the polysaccharide. The structure/function relations deduced were verified by chemical synthesis of several pentasaccharide variants with the predicted bioactivities.

BACKGROUND

Low-molecular-weight heparins are effective for treating venous thrombosis, but their cost-effectiveness has not been rigorously assessed.

OBJECTIVE

To evaluate the cost-effectiveness of low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis.

METHODS

Decision model.

METHODS

Probabilities for clinical outcomes were obtained from a meta-analysis of randomized trials. Cost estimates were derived from Medicare reimbursement and other sources.

METHODS

Two hypothetical cohorts of 60-year-old men with acute deep venous thrombosis.

METHODS

Patient lifetime.

CONCLUSIONS

Societal.

METHODS

Fixed-dose low-molecular-weight heparin or adjusted-dose unfractionated heparin.

METHODS

Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. An in-patient hospital setting was used for the base-case analysis. Secondary analyses examined outpatient treatment with low-molecular-weight heparin.

RESULTS

Total costs for inpatient treatment were $26,516 for low-molecular-weight heparin and $26,361 for unfractionated heparin. The cost of initial care was higher in patients who received low-molecular-weight heparin, but this was partly offset by reduced costs for early complications. Low-molecular-weight heparin treatment increased quality-adjusted life expectancy by approximately 0.02 years. The incremental cost-effectiveness of inpatient low-molecular-weight heparin treatment was $7820 per QALY gained. Treatment with low-molecular-weight heparin was cost saving when as few as 8% of patients were treated at home.

RESULTS

When late complications were assumed to occur 25% less frequently in patients who received unfractionated heparin, the incremental cost-effectiveness ratio increased to almost $75,000 per QALY gained. When late complications were assumed to occur 25% less frequently in patients who received low-molecular-weight heparin, this treatment resulted in a net cost savings. Inpatient low-molecular-weight heparin treatment became cost saving when its pharmacy cost was reduced by 31% or more, when it reduced the yearly incidence of late complications by at least 7%, when as few as 8% of patients were treated entirely as outpatients, or when at least 13% of patients were eligible for early discharge.

CONCLUSIONS

Low-molecular-weight heparins are highly cost-effective for inpatient management of venous thrombosis. This treatment reduces costs when small numbers of patients are eligible for outpatient management.

BACKGROUND

Women who present with acute coronary syndromes (ACSs) have different characteristics than men. Reports have conflicted about whether different outcomes exist for women with use of a routine invasive management strategy. However, these studies were performed prior to the widespread use of platelet glycoprotein IIb/IIIa inhibitors and intracoronary stents.

OBJECTIVE

To determine sex differences in baseline characteristics and outcomes in ACS and whether women benefit from a contemporary early invasive management strategy.

METHODS

Prospective analysis of women and men enrolled in the TACTICS-TIMI 18 randomized trial, conducted December 1997 to December 1999 in 169 centers in 9 countries in North America and Europe, with follow-up at 1 and 6 months.

METHODS

A total of 2220 patients (757 women and 1463 men) with ACS.

METHODS

All patients received aspirin, 325 mg/d; intravenous unfractionated heparin; and tirofiban for 48 hours or until revascularization, with tirofiban administered for at least 12 hours after percutaneous coronary revascularization. Patients assigned to the early invasive strategy (n = 1114) underwent coronary angiography 4 to 48 hours after randomization and revascularization when appropriate. Patients assigned to the early conservative strategy (n = 1106) were treated medically and underwent coronary angiography and appropriate revascularization only if they met specified criteria.

METHODS

Baseline characteristics and the primary composite end point of death, myocardial infarction, or rehospitalization for ACS at 6 months in women and men assigned to early invasive vs conservative management.

RESULTS

Women were older and more frequently had hypertension (P<.001 for both). Women less frequently had previous myocardial infarction, coronary artery bypass grafting, and elevations in cardiac markers (P<.001 for all), but there was no difference in distribution of TIMI risk scores (P =.76). Angiography and intervention rates were similar, but women had less severe coronary artery disease, including no critical lesions in 17% of women vs 9% of men (P<.001). Women had a 28% odds reduction in the primary end point with an early invasive strategy (adjusted odds ratio [OR], 0.72; 95% confidence interval [CI], 0.47-1.11), similar to the benefit in men (adjusted OR, 0.64; 95% CI, 0.47-0.88; P =.60 for sex interaction). When adjusted for baseline characteristics, the benefit of invasive therapy in women with elevated troponin T levels was further enhanced (adjusted OR, 0.47; 95% CI, 0.26-0.83).

CONCLUSIONS

Despite differences between women and men in baseline characteristics, the benefit of an early invasive strategy incorporating tirofiban and intracoronary stents was similar in women and men and was enhanced in women presenting with markers of increased risk.

BACKGROUND

Low-molecular-weight heparins administered subcutaneously once or twice daily have been reported to be as safe and efficacious as intravenous unfractionated heparin in the treatment of acute venous thromboembolic disease.

OBJECTIVE

To determine whether subcutaneous enoxaparin administered once or twice daily is as effective as continuously infused unfractionated heparin in acute symptomatic venous thromboembolic disease.

METHODS

Randomized, controlled, partially blinded equivalence trial.

METHODS

74 hospitals in 16 countries.

METHODS

900 patients with symptomatic lower-extremity deep venous thrombosis, including 287 (32%) with confirmed pulmonary embolism.

METHODS

Initial therapy with dose-adjusted intravenous unfractionated heparin compared with subcutaneous enoxaparin at fixed dosages of 1.0 mg/kg of body weight twice daily or 1.5 mg/kg once daily. Long-term oral anticoagulation was started in all patients within 72 hours of randomization.

METHODS

Clinical end points assessed during a 3-month follow-up period.

RESULTS

Equivalent efficacy was seen in the heparin group and both enoxaparin groups. Symptomatic venous thromboembolism recurred in 12 of 290 patients receiving unfractionated heparin (4.1%), 13 of 298 patients receiving once-daily enoxaparin (4.4%), and 9 of 312 patients receiving twice-daily enoxaparin (2.9%). Compared with unfractionated heparin, the treatment difference was 0.2% (95% CI, -3.04% to 3.49%) for once-daily enoxaparin and -1.2% (CI, -4.2% to 1.7%) for twice-daily enoxaparin. Incidence of major hemorrhage did not differ among the three treatment groups. Major hemorrhage occurred in 6 of 290 patients (2.1%) in the unfractionated heparin group, 5 of 298 patients (1.7%) in the once-daily enoxaparin group, and 4 of 312 patients (1.3%) in the twice-daily enoxaparin group.

CONCLUSIONS

Subcutaneous enoxaparin once or twice daily is as effective and safe as dose-adjusted, continuously infused unfractionated heparin in the prevention of recurrent symptomatic venous thromboembolic disease.

BACKGROUND

Despite its limitations, unfractionated heparin has been the standard anticoagulant used during percutaneous coronary intervention (PCI). Several small studies have suggested that intravenous enoxaparin may be a safe and effective alternative. Our primary aim was to assess the safety of enoxaparin as compared with that of unfractionated heparin in elective PCI.

METHODS

In this prospective, open-label, multicenter, randomized trial, we randomly assigned 3528 patients with PCI to receive enoxaparin (0.5 or 0.75 mg per kilogram of body weight) or unfractionated heparin adjusted for activated clotting time, stratified according to the use or nonuse of glycoprotein IIb/IIIa inhibitors. The primary end point was the incidence of major or minor bleeding that was not related to coronary-artery bypass grafting. The main secondary end point was the percentage of patients in whom the target anticoagulation levels were reached.

RESULTS

Enoxaparin at a dose of 0.5 mg per kilogram was associated with a significant reduction in the rate of non-CABG-related bleeding in the first 48 hours, as compared with unfractionated heparin (5.9% vs. 8.5%; absolute difference, -2.6; 95% confidence interval [CI], -4.7 to -0.6; P=0.01), but the higher enoxaparin dose was not (6.5% vs. 8.5%; absolute difference, -2.0; 95% CI, -4.0 to 0.0; P=0.051). The incidence of major bleeding was significantly reduced in both enoxaparin groups, as compared with the unfractionated heparin group. Target anticoagulation levels were reached in significantly more patients who received enoxaparin (0.5-mg-per-kilogram dose, 79%; 0.75-mg-per-kilogram dose, 92%) than who received unfractionated heparin (20%, P<0.001).

CONCLUSIONS

In elective PCI, a single intravenous bolus of 0.5 mg of enoxaparin per kilogram is associated with reduced rates of bleeding, and a dose of 0.75 mg per kilogram yields rates similar to those for unfractionated heparin, with more predictable anticoagulation levels. The trial was not large enough to provide a definitive comparison of efficacy in the prevention of ischemic events. (ClinicalTrials.gov number, NCT00077844 [ClinicalTrials.gov].).

OBJECTIVE

The role of anticoagulant treatment for acute cardioembolic stroke is uncertain. We performed an updated meta-analysis of all randomized trials to obtain the best estimates of the efficacy and safety of anticoagulants for the initial treatment of acute cardioembolic stroke.

METHODS

Using electronic and manual searches of the literature, we identified randomized trials comparing anticoagulants (unfractionated heparin or low-molecular-weight heparin or heparinoids), started within 48 hours, with other treatments (aspirin or placebo) in patients with acute ischemic cardioembolic stroke. Two reviewers independently selected studies and extracted data on study design, quality, and clinical outcomes, including death or disability, all strokes, recurrent ischemic stroke, and cerebral symptomatic bleeding. Odds ratios for individual outcomes were calculated for each trial and data from all the trials were pooled using the Mantel-Haenszel method.

RESULTS

Seven trials, involving 4624 patients with acute cardioembolic stroke, met the criteria for inclusion. Compared with other treatments, anticoagulants were associated with a nonsignificant reduction in recurrent ischemic stroke within 7 to 14 days (3.0% versus 4.9%, odds ratio 0.68, 95% CI: 0.44 to 1.06, P=0.09, number needed to treat=53), a significant increase in symptomatic intracranial bleeding (2.5% versus 0.7%, odds ratio 2.89; 95% CI: 1.19 to 7.01, P=0.02, number needed to harm=55), and a similar rate of death or disability at final follow up (73.5% versus 73.8%, odds ratio 1.01; 95% CI: 0.82 to 1.24, P=0.9).

CONCLUSIONS

Our findings indicate that in patients with acute cardioembolic stroke, early anticoagulation is associated with a nonsignificant reduction in recurrence of ischemic stroke, no substantial reduction in death and disability, and an increased intracranial bleeding.

BACKGROUND

Recent studies have shown that symptomatic venous thromboembolism after total hip arthroplasty most commonly develops after the patient is discharged from the hospital. Risk factors associated with these symptomatic thromboembolic events are not well defined.

METHODS

Using administrative data from the California Medicare records for 1993 through 1996, we identified 297 patients 65 years of age or older who were rehospitalized for thromboembolism within three months after total hip arthroplasty. We compared demographic, surgical, and medical variables potentially associated with the development of thromboembolism in these patients and 592 unmatched controls.

RESULTS

A total of 89.6 percent of patients with thromboembolism and 93.8 percent of control patients were treated with pneumatic compression, warfarin, enoxaparin, or unfractionated heparin, alone or in combination. In addition, 22.2 percent and 29.7 percent, respectively, received warfarin after discharge. A body-mass index (the weight in kilograms divided by the square of the height in meters) of 25 or greater was associated with rehospitalization for thromboembolism, with an odds ratio of 2.5 (95 percent confidence interval, 1.8 to 3.4). In a multivariate model, the only prophylactic regimens associated with a reduced risk of thromboembolism were pneumatic compression in patients with body-mass indexes of less than 25 (odds ratio, 0.3; 95 percent confidence interval, 0.2 to 0.6) and warfarin treatment after discharge (odds ratio, 0.6; 95 percent confidence interval, 0.4 to 1.0).

CONCLUSIONS

In patients who underwent total hip arthroplasty, a body-mass index of 25 or greater was associated with subsequent hospitalization for thromboembolism. Pneumatic compression in patients with a body-mass index of less than 25 and prophylaxis with warfarin after discharge were independently protective against thromboembolism.

BACKGROUND

Obesity is considered a highly prevalent risk factor for venous thromboembolism (VTE) in hospitalized patients. However, recommendations for VTE prophylaxis in obese patients are not clear.

METHODS

To evaluate obesity as a risk factor for VTE in medical and bariatric patients and the efficacy of VTE prophylaxis, we performed a systematic review in MEDLINE, Cochrane Database of Systematic Reviews and LILACS from 1976 to 2006. Evidence was evaluated independently by 2 authors and presented descriptively.

RESULTS

Of the 124 studies found, 87 were excluded based on predefined criteria. There is no consensus among studies, but prospective cohorts show that obesity is associated with a higher risk of VTE in medical patients. There is evidence that the risk of VTE exceeds that attributable to the surgical procedure alone in bariatric surgery. Only 6 studies evaluated prophylactic methods (unfractionated heparin, low molecular weight heparin and sequential compression devices) in obese patients. Although these studies have some methodological flaws, they suggest efficacy of VTE prophylaxis in medical and surgical obese patients.

CONCLUSIONS

Obesity is a risk factor for VTE in obese medical patients and patients undergoing bariatric surgery. Obesity appears to play an adjuvant role for the development of VTE in hospitalized patients with other risk factors. The small number of prospective trials in this population prevents a definite conclusion about the most effective and safe VTE prophylactic method for obese patients. Thus, randomized clinical trials to compare VTE prophylactic methods in obese patients are still highly warranted.

OBJECTIVE

To summarize new information on frequency of heparin-induced thrombocytopenia (HIT) in patients treated in intensive care units (ICU), developments in the interpretation of assays for detecting anti-PF4/heparin antibodies, and treatment of HIT patients.

METHODS

All data on the frequency of laboratory-confirmed HIT in ICU patients were included; for laboratory testing of HIT and treatment of patients, this review focuses on recent data that became available in 2005 and 2006.

METHODS

HIT is a potentially life-threatening adverse effect of heparin treatment caused by platelet-activating antibodies of immunoglobulin G class usually recognizing complexes of platelet factor 4 and heparin. HIT is more often caused by unfractionated heparin than low-molecular-weight heparin and is more common in postsurgical than in medical patients. In the ICU setting, HIT is uncommon (0.3-0.5%), whereas thrombocytopenia from other causes is very common (30-50%). For laboratory diagnosis of HIT antibodies, both antigen assays and functional (platelet activation) assays are available. Both tests are very sensitive (high negative predictive value) but specificity is problematic, especially for the antigen assays, which also detect nonpathogenic immunoglobulin M and immunoglobulin A class antibodies. Detection of immunoglobulin M or immunoglobulin A antibodies could potentially lead to adverse events such as bleeding if a false diagnosis of HIT prompts replacement of heparin by an alternative anticoagulant. For treatment of HIT, three alternative anticoagulants are approved: the direct thrombin inhibitors, lepirudin and argatroban, and the heparinoid, danaparoid (not approved in the United States). Recent data indicate that the approved dosing regimens of the direct thrombin inhibitors are too high, especially in ICU patients.

CONCLUSIONS

HIT affects <1% of ICU patients even though 30-50% develop thrombocytopenia. The choice of the optimal alternative anticoagulant depends on patient characteristics. Many ICU patients require lower doses of alternative anticoagulant than those recommended by the manufacturer.

BACKGROUND

Patients with severe sepsis frequently receive prophylactic heparin during drotrecogin alfa (activated) (DrotAA) treatment due to risk of venous thromboembolic events (VTEs). Biological plausibility exists for heparin to reduce DrotAA efficacy and/or increase bleeding.

OBJECTIVE

Primary: demonstrate in adult patients with severe sepsis receiving DrotAA treatment that 28-day mortality was equivalent for patients treated with concomitant prophylactic heparin compared with placebo; secondary: safety and VTE incidence.

METHODS

International, randomized, double-blind, phase 4, equivalence-design trial (n = 1994). Patients were eligible if indicated for and receiving DrotAA treatment under the country's approved label. Study drug (low molecular weight/unfractionated heparin) or placebo (saline) was administered every 12 hours during DrotAA infusion (24 ug/kg/hr for 96 hr). In patients on baseline heparin and randomized to placebo, heparin was stopped.

RESULTS

Twenty-eight-day mortality was not equivalent between treatment groups. Heparin mortality was numerically lower (28.3 vs. 31.9%; p = 0.08). In the prospectively defined subgroup of patients exposed to heparin at baseline, patients receiving placebo experienced higher mortality (35.6 vs. 26.9%; p = 0.005). For safety, significant differences were observed during Days 0-6 for any bleeding event (placebo, n = 78; heparin, n = 105; p = 0.049) and ischemic stroke during Days 0-6 (placebo, n = 12; heparin, n = 3; p = 0.02) and Days 0-28 (placebo, n = 17; heparin, n = 5; p = 0.009). The VTE rate was low, with no statistical difference between groups (0-6 d, p = 0.60; 0-28 d, p = 0.26).

CONCLUSIONS

Compared with placebo, concomitant prophylactic heparin was not equivalent, did not increase 28-day mortality, and had an acceptable safety profile in patients with severe sepsis receiving DrotAA. Heparin discontinuation should be carefully weighed in patients considered for DrotAA treatment. XPRESS clinical trial registered with www.clinicaltrials.gov (NCT 00049777). The study ID numbers are 6743; F1K-MC-EVBR.

BACKGROUND

The combination of fibrinolytic therapy and heparin for acute myocardial infarction fails to achieve reperfusion in 40-70% of patients, and early reocclusion occurs in a substantial number. We did a randomised, open-label trial to compare the thrombin-specific anticoagulant, bivalirudin, with heparin in patients undergoing fibrinolysis with streptokinase for acute myocardial infarction.

METHODS

17073 patients with acute ST-elevation myocardial infarction were randomly assigned an intravenous bolus and 48-h infusion of either bivalirudin (n=8516) or heparin (n=8557), together with a standard 1.5 million unit dose of streptokinase given directly after the antithrombotic bolus. The primary endpoint was 30-day mortality. Secondary endpoints included reinfarction within 96 h and bleeding. Strokes and reinfarctions were adjudicated by independent committees who were unaware of treatment allocation. Analysis was by intention to treat.

RESULTS

By 30 days, 919 patients (10.8%) in the bivalirudin group and 931 (10.9%) in the heparin group had died (odds ratio 0.99 [95% CI 0.90-1.09], p=0.85). The mortality rates adjusted for baseline risk factors were 10.5% for bivalirudin and 10.9% for heparin (0.96 [0.86-1.07], p=0.46). There were significantly fewer reinfarctions within 96 h in the bivalirudin group than in the heparin group (0.70 [0.56-0.87], p=0.001). Severe bleeding occurred in 58 patients (0.7%) in the bivalirudin group versus 40 patients (0.5%) in the heparin group (p=0.07), and intracerebral bleeding occurred in 47 (0.6%) versus 32 (0.4%), respectively (p=0.09). The rates of moderate and mild bleeding were significantly higher in the bivalirudin group than the heparin group (1.32 [1.00-1.74], p=0.05; and 1.47 [1.34-1.62], p<0.0001; respectively). Transfusions were given to 118 patients (1.4%) in the bivalirudin group versus 95 patients (1.1%) in the heparin group (1.25 [0.95-1.64], p=0.11).

CONCLUSIONS

Bivalirudin did not reduce mortality compared with unfractionated heparin, but did reduce the rate of adjudicated reinfarction within 96 h by 30%. Small absolute increases were seen in mild and moderate bleeding in patients given bivalirudin. Bivalirudin is a new anticoagulant treatment option in patients with acute myocardial infarction treated with streptokinase.

BACKGROUND

Low molecular weight heparins (LMWH) have been shown to be effective and safe in preventing venous thromboembolism (VTE), and may also be effective for the initial treatment of VTE.

OBJECTIVE

To determine the effect of LMWH compared with unfractionated heparin (UFH) for the initial treatment of VTE.

METHODS

Trials were identified from the Cochrane Peripheral Vascular Diseases Group's Specialised Register, CENTRAL and LILACS. Colleagues and pharmaceutical companies were contacted for additional information.

METHODS

Randomised controlled trials comparing fixed dose subcutaneous LMWH with adjusted dose intravenous or subcutaneous UFH in people with VTE.

METHODS

At least two reviewers assessed trials for inclusion and quality, and extracted data independently.

RESULTS

Twenty-two studies were included (n = 8867). Thrombotic complications occurred in 151/4181 (3.6%) participants treated with LMWH, compared with 211/3941 (5.4%) participants treated with UFH (odds ratio (OR) 0.68; 95% confidence intervals (CI) 0.55 to 0.84, 18 trials). Thrombus size was reduced in 53% of participants treated with LMWH and 45% treated with UFH (OR 0.69; 95% CI 0.59 to 0.81, 12 trials). Major haemorrhages occurred in 41/3500 (1.2%) participants treated with LMWH, compared with 73/3624 (2.0%) participants treated with UFH (OR 0.57; 95% CI 0.39 to 0.83, 19 trials). In eighteen trials, 187/4193 (4.5%) participants treated with LMWH died, compared with 233/3861 (6.0%) participants treated with UFH (OR 0.76; 95% CI 0.62 to 0.92). Nine studies (n = 4451) examined proximal thrombosis; 2192 participants treated with LMWH and 2259 with UFH. Subgroup analysis showed statistically significant reductions favouring LMWH in thrombotic complications and major haemorrhage. By the end of follow up, 80 (3.6%) participants treated with LMWH had thrombotic complications, compared with 143 (6.3%) treated with UFH (OR 0.57; 95% CI 0.44 to 0.75). Major haemorrhage occurred in 18 (1.0%) participants treated with LMWH, compared with 37 (2.1%) treated with UFH (OR 0.50; 95% CI 0.29 to 0.85). Nine studies (n = 4157) showed a statistically significant reduction favouring LMWH with respect to mortality. By the end of follow up, 3.3% (70/2094) of participants treated with LMWH had died, compared with 5.3% (110/2063) of participants treated with UFH (OR 0.62; 95% CI 0.46 to 0.84).

CONCLUSIONS

LMWH is more effective than UFH for the initial treatment of VTE. LMWH significantly reduces the occurrence of major haemorrhage during initial treatment and overall mortality at follow up.

BACKGROUND

Treatment of cerebral sinus thrombosis with anticoagulants has been controversial. Anticoagulants may prevent new venous infarcts, neurologic deterioration, and pulmonary embolism but may also promote haemorrhages.

OBJECTIVE

To review the available evidence regarding the effectiveness and safety of anticoagulant therapy in patients with confirmed cerebral sinus thrombosis.

METHODS

We searched the Cochrane Stroke Group Trials Register (last searched 18 March 2002). We also searched MEDLINE (1966-Oct 2001), EMBASE (1980-Feb 2002) and the Cochrane Controlled Trials Register (Cochrane Library, 2002 Issue 1) and contacted authors to identify additional published and unpublished studies.

METHODS

Unconfounded randomised controlled trials in which anticoagulant therapy was compared with placebo or open control in patients with cerebral sinus thrombosis (confirmed by intra-arterial contrast or magnetic resonance angiography).

METHODS

Two reviewers independently extracted outcomes for each of the two treatment groups (anticoagulant treatment and control). The outcome data for each patient are analysed in the treatment group to which the patient was originally allocated ('intention to treat' analysis). A weighted estimate of the treatment effects across trials (relative risk, absolute risk reduction) is calculated using the Cochrane statistical software.

RESULTS

Two small trials involving 79 patients fulfilled the inclusion criteria. One trial (20 patients) examined the efficacy of intravenous, adjusted dose unfractionated heparin. The other trial (59 patients) examined high dose, body weight adjusted, subcutaneous, low-molecular weight heparin (Nadroparin). Anticoagulant therapy was associated with a pooled relative risk of death of 0.33 (95 % CI 0.08 to 1.21) and of death or dependency of 0.46 (95 % CI 0.16 to 1.31). No new symptomatic intracerebral haemorrhages were observed. One major gastro-intestinal haemorrhage occurred after anticoagulant treatment. Two control patients (placebo) had a diagnosis of probable pulmonary embolism (one fatal).

CONCLUSIONS

Based upon the limited evidence available, anticoagulant treatment for cerebral sinus thrombosis appeared to be safe and was associated with a potentially important reduction in the risk of death or dependency which did not reach statistical significance.

The involvement of the vascular system in malignancy encompasses not only angiogenesis, but also systemic hypercoagulability and a pro-thrombotic state, and there is increasing evidence that pathways of blood coagulation and angiogenesis are reciprocally linked. In fact, cancer atients often display hypercoagulability resulting in markedly increased thromboembolism, which requires anti-coagulant treatment using heparins, for example. Clinical trials reveal that treatment with various low-molecular-weight heparins (LMWHs) improves the survival time in cancer patients receiving chemotherapy compared with those receiving unfractionated standard heparin (UFH) or no heparin treatment, as well as in cancer patients receiving LMWH as thrombosis prophylaxis during primary surgery. This anti-tumor effect of the heparins appears to be unrelated to their anti-coagulant activity, but the mechanisms involved are not fully understood. Tumor growth and spread are dependent on angiogenesis and it is noteworthy that the most potent endogenous pro- and anti-angiogenic factors are heparin-binding proteins that may be affected by systemic treatment with heparins. Heparin and other glycosaminoglycans play a role in vascular endothelial cell function, as they are able to modulate the activities of angiogenic growth factors by facilitating the interaction with their receptor and promoting receptor activation. To date, preclinical studies have demonstrated that only LMWH fragments produced by the heparinase digestion of UFH, i.e. tinzaparin, exert anti-angiogenic effects in any type of tissue in vivo. These effects are fragment-mass-specific and angiogenesis-type-specific. Data on the effect of various LMWHs and UFH on endothelial cell capillary tube formation and proliferation in vitro are also presented. We hope that this paper will stimulate and facilitate future research designed to elucidate whether the anti-angiogenic or anti-tumor effects of commercial LMWHs in their own right are agent specific and whether anti-angiogenic properties increase the anti-tumor properties of the LMWHs in the clinic.

OBJECTIVE

Unfractionated heparin reduces metastasis in many murine models. Multiple mechanisms are proposed, particularly anticoagulation and/or inhibition of P-selectin and L-selectin. However, the doses used are not clinically tolerable and other heparins are now commonly used. We studied metastasis inhibition by clinically relevant levels of various heparins and investigated the structural basis for selectin inhibition differences.

METHODS

Five clinically approved heparins were evaluated for inhibition of P-selectin and L-selectin binding to carcinoma cells. Pharmacokinetic studies determined optimal dosing for clinically relevant anticoagulant levels in mice. Experimental metastasis assays using carcinoma and melanoma cells investigated effects of a single injection of various heparins. Heparins were compared for structural relationships to selectin inhibition.

RESULTS

One (Tinzaparin) of three low molecular weight heparins showed increased selectin inhibitory activity, and the synthetic pentasaccharide, Fondaparinux, showed none when normalized to anticoagulant activity. Experimental metastasis models showed attenuation with unfractionated heparin and Tinzaparin, but not Fondaparinux, at clinically relevant anticoagulation levels. Tinzaparin has a small population of high molecular weight fragments not present in other low molecular weight heparins, enriched for selectin inhibitory activity.

CONCLUSIONS

Heparin can attenuate metastasis at clinically relevant doses, likely by inhibiting selectins. Equivalent anticoagulation alone with Fondaparinux is ineffective. Clinically approved heparins have differing abilities to inhibit selectins, likely explained by size distribution. It should be possible to size fractionate heparins and inhibit selectins at concentrations that do not have a large effect on coagulation. Caution is also raised about the current preference for smaller heparins. Despite equivalent anticoagulation, hitherto unsuspected benefits of selectin inhibition in various clinical circumstances may be unwittingly discarded.

Despite the discovery and application of many parenteral (unfractionated and low-molecular-weight heparins) and oral anticoagulant vitamin K antagonist (VKA) drugs, the prevention and treatment of venous and arterial thrombotic phenomena remain major medical challenges. Furthermore, VKAs are the only oral anticoagulants used during the past 60 years. The main objective of this study is to present recent data on non-vitamin K antagonist oral anticoagulants (NOACs) and to analyze their advantages and disadvantages compared with those of VKAs based on a large number of recent studies. NOACs are novel direct-acting medications that are selective for one specific coagulation factor, either thrombin (IIa) or activated factor X (Xa). Several NOACs, such as dabigatran (a direct inhibitor of FIIa) and rivaroxaban, apixaban and edoxaban (direct inhibitors of factor Xa), have been used for at least 5 years but possibly 10 years. Unlike traditional VKAs, which prevent the coagulation process by suppressing the synthesis of vitamin K-dependent factors, NOACs directly inhibit key proteases (factors IIa and Xa). The important indications of these drugs are the prevention and treatment of deep vein thrombosis and pulmonary embolisms, and the prevention of atherothrombotic events in the heart and brain of patients with acute coronary syndrome and atrial fibrillation. They are not fixed, and dose-various strengths are available. Most studies have reported that more advantages than disadvantages for NOACs when compared with VKAs, with the most important advantages of NOACs including safety issues (ie, a lower incidence of major bleeding), convenience of use, minor drug and food interactions, a wide therapeutic window, and no need for laboratory monitoring. Nonetheless, there are some conditions for which VKAs remain the drug of choice. Based on the available data, we can conclude that NOACs have greater advantages and fewer disadvantages compared with VKAs. New studies are required to further assess the efficacy of NOACs.

OBJECTIVE

This study reports a prospectively planned analysis of patients with acute coronary syndrome who underwent early percutaneous coronary intervention (PCI) in the OASIS-5 (Fifth Organization to Assess Strategies in Ischemic Syndromes) trial.

BACKGROUND

In the OASIS-5 trial, fondaparinux was similar to enoxaparin for short-term efficacy, but reduced major bleeding by one-half and 30-day mortality by 17%.

METHODS

The OASIS-5 trial was a double-blind, randomized comparison of fondaparinux and enoxaparin in 20,078 patients with acute coronary syndrome. A total of 12,715 patients underwent heart catheterization during the initial hospitalization, and 6,238 patients underwent PCI. In the fondaparinux group, intravenous fondaparinux was given for PCI. In the enoxaparin group, no additional anticoagulant was given if PCI was <6 h from last subcutaneous dose, and additional intravenous unfractionated heparin (UFH) was given if PCI was >6 h.

RESULTS

Fondaparinux compared with enoxaparin reduced major bleeding by more than one-half (2.4% vs. 5.1%, hazard ratio [HR] 0.46, p < 0.00001) at day 9, with similar rates of ischemic events, resulting in superior net clinical benefit (death, myocardial infarction, stroke, major bleeding: 8.2% vs. 10.4%, HR 0.78, p = 0.004). Fondaparinux reduced major bleeding 48 h after PCI irrespective of whether PCI was performed <6 h of the last enoxaparin dose (1.6% vs. 3.8%, HR 0.42, p < 0.0001) or >6 h when UFH was given (1.3% vs. 3.4%, HR 0.39, p < 0.0001). Catheter thrombus was more common in patients receiving fondaparinux (0.9%) than enoxaparin alone (0.4%), but was largely prevented by using UFH at the time of PCI, without any increase in bleeding.

CONCLUSIONS

Upstream therapy with fondaparinux compared with upstream enoxaparin substantially reduces major bleeding while maintaining efficacy, resulting in superior net clinical benefit. The use of standard UFH in place of fondaparinux at the time of PCI seems to prevent angiographic complications, including catheter thrombus, without compromising the benefits of upstream fondaparinux.

BACKGROUND

We compared the efficacy and safety of the low-molecular weight heparin enoxaparin with unfractionated heparin (UFH) for the prevention of venous thromboembolic disease in patients with heart failure or severe respiratory disease.

METHODS

This was a multicenter, controlled, randomized, open study in which patients received either enoxaparin (40 mg once daily) or UFH (5000 IU 3 times daily) for 10 +/- 2 days in 64 medical departments in Germany. Patients were stratified and enrolled according to their underlying disease: severe respiratory disease or heart failure. The primary efficacy parameter was a thromboembolic event up to 1 day after the treatment period.

RESULTS

Of the 665 patients enrolled, 451 patients were able to be evaluated in the primary efficacy analysis. The incidence of thromboembolic events was 8.4% with enoxaparin and 10.4% with UFH. Enoxaparin was at least as effective as UFH, with a 1-sided equivalence region of -4% (90% CI -2.5-6.5, P =.015). Enoxaparin was associated with fewer deaths, less bleeding, and significantly fewer adverse events (45.8% vs 53.8%, P =.044).

CONCLUSIONS

Enoxaparin is at least as effective as UFH in the prevention of thromboembolic events in patients with heart failure or severe respiratory disease. Its beneficial safety profile and once-daily administration is advantageous for inpatient and outpatient use.

OBJECTIVE

We sought to investigate the apparently high risk of early death after an ischemic stroke among patients with atrial fibrillation (AF), identify the main factors associated with early death, and assess the effect of treatment with different doses of subcutaneous unfractionated heparin (UFH) given within 48 hours.

METHODS

We studied the occurrence of major clinical events within 14 days among 18 451 patients from the International Stroke Trial, first for all treatment groups combined. Then, among patients with AF, we examined the effects of treatment with subcutaneous UFH started within 48 hours and continued until 14 days after stroke onset.

RESULTS

A total of 3169 patients (17%) had AF. Seven hundred eighty-four patients were allocated to UFH 12 500 IU SC BID, 773 to UFH 5000 IU SC BID, and 1612 to no heparin. Within each of these groups, half of the patients were randomly assigned to aspirin 300 mg once daily. Compared with patients without AF, patients with AF were more likely to be female (56% versus 45%), to be old (mean age, 78 versus 71 years), to have an infarct on prerandomization CT (57% versus 47%), and to have impaired consciousness (37% versus 20%). The initial ischemic stroke type was more often a large-artery infarct (36% versus 21%). A lacunar stroke syndrome was less common (13% versus 26%). Death within 14 days was more common in patients with AF (17% versus 8%) and more often attributed to neurological damage from the initial stroke (10% versus 4%). The frequency of recurrent ischemic or undefined stroke was not significantly different (3.9% versus 3.3%). The proportion of AF patients with further events within 14 days allocated to UFH 12 500 IU (n=784), UFH 5000 IU (n=773), and to no-heparin (n=1612) groups were as follows: ischemic stroke, 2.3%, 3.4%, 4.9% (P=0.001); hemorrhagic stroke, 2.8%, 1.3%, 0.4% (P<0.0001); and any stroke or death, 18.8%, 19.4% and 20.7% (P=0.3), respectively. No effect of heparin on the proportion of patients dead or dependent at 6 months was apparent.

CONCLUSIONS

Acute ischemic stroke patients with AF have a higher risk of early death, which can be explained by older age and larger infarcts but not by a higher risk of early recurrent ischemic stroke, although slightly more patients with AF died from a fatal recurrent stroke of ischemic or unknown type (1.3% versus 0.9%). In patients with AF the absolute risk of early recurrent stroke is low, and there is no net advantage to treatment with heparin. These data do not support the widespread use of intensive heparin regimens in the acute phase of ischemic stroke associated with AF.

Heparin-induced thrombocytopenia (HIT) is caused by antibodies against a "self" protein-platelet factor 4-bound to heparin. We observed an overrepresentation of the female gender in 290 patients who developed HIT after cardiac or orthopedic surgery compared with the representation found in national databases (study 1). Therefore, we investigated gender imbalance in HIT by logistic regression analysis of a randomized controlled trial of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) (study 2), and we analyzed individual patient data from 7 prospective studies comparing HIT frequency between UFH and LMWH, evaluating effects of gender, heparin (UFH vs LMWH), and patient type (surgical vs medical) (study 3). All 3 studies showed female overrepresentation, which for study 3 was a common odds ratio (OR) of 2.37 (95% confidence interval [95% CI], 1.37-4.09; P = .0015). Study 3 also showed an interaction between gender, heparin, and patient type. Although UFH was more likely than LMWH to cause HIT (P < .0001), this effect was predominantly seen in women compared with men (common OR, 9.22 vs 1.83; P = .020) and in surgical patients compared with medical patients (common OR, 13.93 vs 1.75; P = .005). We conclude that females are at greater risk for HIT and that using LMWH to prevent HIT may have greatest absolute benefit in females undergoing surgical thromboprophylaxis.

BACKGROUND

Current pharmacotherapeutic options for high-risk non-ST-segment elevation acute coronary syndrome patients include aspirin, clopidogrel, heparin, and platelet glycoprotein IIb/IIIa inhibition. A key issue of uncertainty is the safety and efficacy of combination glycoprotein IIb/IIIa inhibitor and low-molecular-weight heparin therapy.

RESULTS

We randomized 746 patients with rest ischemic discomfort within 24 hours after the onset of symptoms and ST-segment deviation and/or elevation of serum cardiac markers to receive open-label enoxaparin (1 mg/kg subcutaneously twice daily) or unfractionated heparin (70-U/kg bolus; 15 U x kg(-1) x h(-1) infusion, titrated to an activated partial thromboplastin time of 1.5 to 2 times control) for 48 hours. All patients received aspirin and eptifibatide (180- microg/kg bolus; 2 microg x kg(-1) x min(-1) infusion). Major non-coronary artery bypass surgery-related bleeding at 96 hours (primary safety outcome) was significantly lower among enoxaparin-treated patients than among heparin-treated patients (1.8% versus 4.6%, P=0.03). Minor bleeding was more frequent in the enoxaparin group (30.3% versus 20.8%, P=0.003). Patients in the enoxaparin group were less likely to experience ischemia as detected by continuous ECG evaluation (primary efficacy outcome) during the initial (14.3% versus 25.4%, P=0.0002) and subsequent (12.7% versus 25.9%, P<0.0001) 48-hour monitoring periods. Death or myocardial infarction at 30 days was significantly lower in the enoxaparin group (5% versus 9%, P=0.031).

CONCLUSIONS

When aspirin and eptifibatide are used in high-risk non-ST-segment elevation acute coronary syndrome patients, enoxaparin improves outcomes (determined on the basis of better safety and efficacy) compared with currently recommended unfractionated heparin therapy and provides a useful novel alternative therapeutic strategy.