OBJECTIVE

We sought to evaluate whether enoxaparin (ENOX) is superior to unfractionated heparin (UFH) as adjunctive therapy for patients with ST-segment elevation myocardial infarction (STEMI) who receive fibrinolytic therapy and subsequently undergo percutaneous coronary intervention (PCI) by analyzing data from the ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis In Myocardial Infarction 25) trial.

BACKGROUND

Limited data are available on the use of ENOX compared with UFH as adjunctive therapy in STEMI patients treated with fibrinolytic therapy and subsequent PCI.

METHODS

A total of 20,479 STEMI patients who received fibrinolytic therapy were randomized to a strategy of ENOX throughout index hospitalization or UFH for at least 48 h, with blinded study drug to continue if PCI was performed. The primary end point of death or recurrent MI through 30 days was compared for ENOX versus UFH among the patients who underwent subsequent PCI (n = 4,676).

RESULTS

After initial fibrinolysis, fewer patients underwent PCI through 30 days in the ENOX versus the UFH group (22.8% vs. 24.2%; p = 0.027). Among patients who underwent PCI by 30 days, the primary end point occurred in 10.7% of ENOX and 13.8% of UFH patients (0.77 relative risk; p < 0.001). There were no differences in major bleeding for ENOX versus UFH (1.4% vs. 1.6%; p = NS). Results were similar when PCI was carried out in patients receiving blinded study drug during PCI (n = 2,178).

CONCLUSIONS

Among patients treated with fibrinolytic therapy for STEMI who underwent subsequent PCI, ENOX administration was associated with a reduced risk of death or recurrent MI without difference in the risk of major bleeding. The strategy of ENOX support for fibrinolytic therapy followed by PCI is superior to UFH and provides a seamless transition from the medical management to the interventional management phase of STEMI without the need for introducing a second anticoagulant in the cardiac catheterization laboratory.

Upper extremity deep-vein thrombosis has recently been recognized as being a more common and less benign disease than previously reported. It arises generally in the presence of recognizable risk factors, such as central venous catheters and cancer. However, as many as 20% of patients present with apparently spontaneous episodes. The prevalence of inherited coagulation defects in patients with this disease ranges from 10% to 26%. The clinical picture of upper extremity DVT is characterized by pain, edema, and functional impairment, although it may be completely asymptomatic. Because the prevalence of this thrombotic disease is less than 50% among symptomatic subjects, objective diagnosis is mandatory prior to instituting an anticoagulant treatment. When available, compression ultrasonography (alone or associated with Doppler or color Doppler facilities) should be the preferred initial diagnostic test. However, contrast venography may be necessary before anticoagulants are withheld because of negative findings on compression ultrasonography. Pulmonary embolism complicates upper extremity deep-vein thrombosis in up to 36% of patients and may even be the presenting manifestation of this disorder. Its long-term clinical course is complicated by recurrent thromboembolism and post-thrombotic sequelae. Among the therapeutic options advocated for the therapy of upper extremity deep-vein thrombosis, unfractionated or low molecular weight heparin followed by at least 3 months of oral anticoagulants should be regarded as the treatment of choice. Thrombolysis and surgical procedures may be indicated in selected cases. The prevention of this disease requires the institution of appropriate pharmacologic measures (i.e., low-dose unfractionated or low molecular weight heparin or low-dose warfarin) whenever an indwelling central venous catheter is indicated. This review suggests that upper extremity deep-vein thrombosis is at least as serious a disease entity as deep-vein thrombosis of the lower extremities.

In the initial treatment of venous thromboembolism (VTE) fondaparinux, a pentasaccharide, is a good alternative to heparin. Whether this is also true for cancer patients is unknown. We performed two post-hoc analyses of two randomized studies to compare efficacy, safety and overall survival of fondaparinux to standard initial (low-molecular-weight) heparin (LMWH) treatment in cancer patients with venous thromboembolism. Two hundred thirty-seven cancer patients with deep venous thrombosis (DVT) were initially treated with fondaparinux or enoxaparin. Two hundred forty cancer patients with pulmonary embolism (PE) received fondaparinux or unfractionated heparin. The initial treatment was followed by vitamin K antagonists. In DVT patients, the three-month recurrence rate was 5.4% in the enoxaparin recipients compared to 12.7% in those treated with fondaparinux [absolute difference 7.3%, 95% CI 0.1, 14.5]. A recurrence was observed in 8.9% of the PE patients treated with fondaparinux compared to 17.2% in the unfractionated heparin recipients [absolute difference -8.3, 95% CI -16.7, 0.1]. In both studies no difference in bleeding and overall survival was observed. Regarding overall survival and bleeding fondaparinux is comparable to enoxaparin and unfractionated heparin in cancer patients. No significant differences in recurrent VTE were observed when comparing fondaparinux with unfractionated or LMWH. Because of study limitations these results should be considered hypothesis-generating.

OBJECTIVE

This study was designed to determine the impact of bivalirudin on 1-year outcomes in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI).

BACKGROUND

The ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial demonstrated that in moderate- and high-risk ACS patients undergoing PCI, bivalirudin alone compared to unfractionated heparin (UFH) or enoxaparin plus a glycoprotein (GP) IIb/IIIa inhibitor resulted in less major bleeding and similar ischemic outcomes at 30 days. The impact of bivalirudin on 1-year outcomes in ACS patients undergoing PCI is unknown.

METHODS

In the ACUITY trial, 13,819 patients were enrolled, and 7,789 (56.4%) patients had PCI. Composite ischemia (death, myocardial infarction, or unplanned revascularization) and mortality at 1 year were assessed.

RESULTS

Among patients undergoing PCI, 2,561, 2,609, and 2,619 were randomized to UFH or enoxaparin plus a GP IIb/IIIa inhibitor, bivalirudin plus a GP IIb/IIIa inhibitor, and bivalirudin monotherapy, respectively. At 1 year, there were no differences in composite ischemia (17.8% vs. 19.4% vs. 19.2%, p = NS) or mortality (3.2% vs. 3.3% vs. 3.1%, p = NS) among the 3 groups, respectively.

CONCLUSIONS

Bivalirudin compared with UFH or enoxaparin plus a GP IIb/IIIa inhibitor results in similar rates of composite ischemia and mortality at 1 year in moderate- and high-risk ACS patients undergoing PCI.

BACKGROUND

ORG31540/SR90107A, a synthetic pentasaccharide, is a selective inhibitor of factor-Xa. It was hypothesized that prolonged factor-Xa inhibition with pentasaccharide may be an effective and safe antithrombotic co-therapy in acute myocardial infarction.

RESULTS

Patients (n=333) with evolving ST-segment elevation acute myocardial infarction were treated with aspirin and alteplase and randomized to unfractionated heparin, given intravenously during 48 to 72 h, or to a low, medium or high dose of pentasaccharide, administered daily for 5 to 7 days, intravenously on the first day, then subcutaneously. Coronary angiography was performed at 90 min and on days 5 to 7. Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 rates at 90 min were similar in the four treatment groups. Among patients with TIMI 3 flow at 90 min and who did not undergo a coronary intervention (n=155), a trend towards less reocclusion of the infarct-related vessel on days 5 to 7 was observed with pentasaccharide: 0.9% vs 7.0% with unfractionated heparin (P=0.065). Also, fewer revascularizations during the 30-day follow-up period were performed in patients given pentasaccharide (39% vs 51% for unfractionated heparin;P=0.054). The primary safety end-point, the combined incidence of intracranial haemorrhage and need for blood transfusion, was identical with pentasaccharide and unfractionated heparin (7.1%). One non-fatal intracranial haemorrhage occurred in the 241 patients given pentasaccharide (0.4%).

CONCLUSIONS

In this study, pentasaccharide given together with alteplase was safe and as effective as unfractionated heparin in restoring coronary artery patency. Prolonged administration of pentasaccharide was associated with a trend towards less reocclusion and fewer revascularizations. Selective factor-Xa-inhibition seems to be an attractive therapeutic concept in patients presenting with ST-segment elevation acute myocardial infarction.

BACKGROUND

In comparison with treatment with unfractionated heparin (UFH) and aspirin (ASA), both tirofiban administered with UFH and ASA, and enoxaparin plus ASA have shown superiority in reducing cardiac ischemic events in patients with unstable angina and non-ST-segment elevation myocardial infarction. Replacing UFH with enoxaparin when tirofiban is administered to patients may offer further therapeutic benefit, but could also increase bleeding.

OBJECTIVE

Our objective was to provide estimates of the frequency of bleeding complications, as defined by means of the Thrombolysis In Myocardial Infarction(TIMI) group, and collect data on clinical efficacy of the combination of tirofiban with enoxaparin plus ASA.

METHODS

Five hundred twenty-five patients with UA/NSTEMI were treated with tirofiban coadministered with ASA and randomized to receive either UFH (n = 210) or enoxaparin (n = 315). Therapy was administered for 24 to 96 hours. Bleeding incidences were assessed until 24 hours after trial therapy was discontinued; other clinical outcomes were assessed for as long as 30 days.

RESULTS

The total bleeding rate (TIMI major + minor + loss-no-site) for the UFH group versus the enoxaparin group was 4.8% vs 3.5% (odds ratio [OR] 1.4, CI 0.6-3.4). The TIMI major and minor bleeding rates for the UFH versus the enoxaparin groups were 1.0% versus 0.3% (OR 3.0, CI 0.3-33.8) and 4.3% versus 2.5% (OR 1.7, CI 0.7-4.6). There was an increase in nuisance cutaneous and oral bleeds (<50 mL of blood loss) in the enoxaparin group. Death or myocardial infarction occurred with similar frequency in the 2 groups (9.0% vs 9.2%). However, refractory ischemia requiring urgent revascularization and rehospitalization because of unstable angina occurred more frequently in the UFH group (4.3% vs 0.6% and 7.1% vs 1.6%, respectively).

CONCLUSIONS

Combination therapy with tirofiban plus enoxaparin appears safe, relative to therapy with tirofiban plus UFH.

OBJECTIVE

There is no randomized trial comparing low-molecular weight heparin (LMWH) and unfractionated heparin (UFH) for thromboprophylaxis in medical-surgical ICU patients. The primary objective of this randomized pilot study on LMWH vs UFH was to assess the feasibility of conducting a large randomized trial with respect to timely enrollment and blinded study drug administration, practicality of twice-weekly lower limb ultrasounds to screen for deep venous thrombosis, LMWH bioaccumulation and dose adjustment in renal insufficiency, and recruitment rates for a future trial in medical-surgical intensive care unit (ICU) patients. Its additional goals were to evaluate the suitability of the exclusion criteria and to document the range of research activities that precede accrual of patients into a trial to plan multisite management.

METHODS

By computerized telephone randomization, we allocated 129 medical-surgical ICU patients to treatment with dalteparin 5,000 IU QD SC or that with UFH 5,000 IU BID SC. Within each clinical center, only the study pharmacist was not blinded. We performed bilateral lower limb compression ultrasounds within 48 hours of ICU admission, twice weekly, on suspicion of deep venous thrombosis, and 7 days after ICU discharge. Research coordinators and investigators at 7 centers reported the time they engaged in all research activities before the first patient was randomized.

RESULTS

Timely complete study drug administration occurred after enrollment. More than 99% of scheduled doses were administered in a blinded fashion. Scheduled ultrasounds were performed without exception. No bioaccumulation of dalteparin was observed when creatinine clearance decreased to lower than 30 mL/min. Average recruitment was 2 patients/center per month before the study exclusion criteria were modified. Study startup activities required, on average, 65.5 hours of combined investigator and research coordinator time at each center. Careful examination of the accrual in the pilot study led to a reexamination of the Prophylaxis of Thromboembolism in Critical Care Trial (PROTECT) study exclusion criteria.

CONCLUSIONS

This pilot study suggests that a multicenter randomized clinical trial comparing LMWH with UFH in critically ill medical-surgical patients is feasible. Pilot studies can improve the design of larger trials and may enhance successful timely completion.

OBJECTIVE

To compare the cost effectiveness of prophylaxis with a low-molecular-weight heparin with that of prophylaxis with unfractionated heparin for the prevention of venous thromboembolism in acutely ill medical inpatients.

METHODS

Cost-effectiveness analysis based on decision-tree model.

METHODS

A hypothetical cohort of 10 000 patients was assumed to receive either (1) prophylaxis with enoxaparin, a low-molecular-weight heparin, 40 mg daily; (2) prophylaxis with unfractionated heparin, 5000 IU twice daily; or (3) no prophylaxis. We developed a decision-analytic model with parameter estimates derived from published clinical trials and other secondary sources. Then, for each strategy, we estimated the risks of venous thromboembolism, complications of prophylaxis and treatment (heparin-induced thrombocytopenia and bleeding), mortality, and costs of prophylaxis and treatment within a 30-day period.

RESULTS

In a hypothetical cohort of 10 000 inpatients, expected numbers of deaths attributable to venous thromboembolism or drug complications related to both prophylaxis for and treatment of VTE over a 30-day period were 37 with enoxaparin prophylaxis, 53 with unfractionated heparin prophylaxis, and 81 with no prophylaxis. In 2001, corresponding expected costs of prevention, diagnosis, and management of VTE were $3 502 000 for enoxaparin, $3 772 000 for unfractionated heparin, and $3 105 000 for no prophylaxis. The incremental cost per death averted with enoxaparin prophylaxis versus no prophylaxis was $9100. Enoxaparin dominated unfractionated heparin by being both more effective and less costly in the base-case analysis, as well as in sensitivity analyses in which equal efficacy and equal risks of bleeding were assumed.

CONCLUSIONS

Thromboprophylaxis with this low-molecular-weight heparin represents a cost-effective use of healthcare resources in acutely ill medical inpatients and dominates thromboprophylaxis with unfractionated heparin.

Thrombocytopenia is a relatively frequent and usually benign clinical complication of heparin therapy. However, some patients receiving heparin and heparin-based products experience an immune-mediated reaction due to the development of heparin-induced antibodies. This reaction leads to a highly specific and paradoxical form of thrombocytopenia, known as type II heparin-induced thrombocytopenia (HIT). Unlike other types of drug-induced thrombocytopenia, HIT promotes thrombosis rather than bleeding; therefore HIT should be suspected in patients who experience thrombotic events despite adequate anticoagulation therapy. Early identification and treatment of HIT can prevent more serious complications associated with this disorder (e.g., exacerbation of venous thromboembolism, limb gangrene, and skin necrosis). Both arterial and venous thrombosis can arise from a single episode of HIT. Routine assessment of platelet counts is necessary with heparin therapy, as a decreased platelet level is usually the only indication of HIT. Although compared with unfractionated heparin, low-molecular-weight heparin therapy is less likely to result in HIT, the use of these agents is contraindicated in HIT patients. Concomitant warfarin therapy is not contraindicated in such patients but must be carefully monitored. Treatment with a direct thrombin inhibitor, such as lepirudin or argatroban, is an effective strategy in reversing the thrombocytopenia associated with HIT and reducing its complications. This article discusses the clinical syndrome of HIT, including pathophysiology, diagnostic criteria, clinical presentations, and current available management strategies in the context of 2 case studies.

BACKGROUND

Low-molecular-weight heparins (LMWH) have been shown to be safer, more effective and more convenient than unfractionated heparin (UFH) in many clinical situations. However, their use is limited in patients with renal insufficiency (RI) due to bioaccumulation.

METHODS

The literature is critically reviewed and known pharmacokinetic properties are summarised. An approach to using LMWH in patients with RI is proposed on the basis of currently available evidence.

CONCLUSIONS

Pharmacokinetic data of commonly used LMWH and of UFH are summarised in respect of RI. Most data are known on enoxaparin. A dose reduction is recommended in patients with severe RI. Limited data on dalteparin and tinzaparin suggest that there is less bioaccumulation. However, further studies are needed, in respect of long-term use and clinical end-points in particular.There are no data on certoparin and only very limited data on nadroparin. A detailed approach is suggested for the use of LMWH in patients with severe RI. Briefly: (1) before using LMWH, evaluate the patient's renal function, ist expected course, imminent interventions, and general bleeding risk; (2) prefer LMWH to UFH in view of better efficacy and lower bleeding risk in general; (3) however, prefer i.v. UFH to s.c. LMWH if a patient is unstable, is awaiting emergency interventions, or has a high bleeding risk, since UFH can be stopped more quickly due to i.v. administration, has a shorter half-life time, and can be effectively antagonised; (4) prefer a well documented LMWH; use established dosing schemes; (5) monitor LMWH with peak anti-Xa levels in patients with severe RI regularly, and adjust dose to be in target range; (6) do not use LMWH in patients with severe RI if there is no possibility of measuring anti-Xa levels.

CONCLUSIONS

LMWH may be considered for patients with severe RI. However, experience, judicious choice and careful monitoring of patients with severe RI treated with LMWH are necessary.

Unfractionated heparin (UFH) is the anticoagulant of choice for most maintenance hemodialysis units in the United States. Low molecular weight heparin (LMWH) is the norm in Western Europe, but is not approved for this indication in the United States. UFH is likely to remain the agent of choice in the United States because of its relative ease of use, safety, and low cost. Coating tubing and dialyzers with heparin is now possible, but systemic anticoagulation with heparin is usually still required. The additional cost of this innovation does not yet justify its use. Side effects of both UFH and LMWH include heparin-induced thrombocytopenia, hypertriglyceridemia, and hyperkalemia. It is uncertain whether osteoporosis is an important side effect, as vitamin D deficiency, secondary hyperparathyroidism, age, and debility are confounding factors. When UFH poses a risk or its use is contraindicated, e.g., after development of heparin-induced thrombocytopenia, the use of direct thrombin inhibitors, regional citrate anticoagulation, citrate dialysate, and heparin-free dialysis may be appropriate.

Ample evidence suggests that many of the in vivo anti-metastatic effects by heparins reflect their actions on P-selectin-mediated binding. We hypothesized that the ability of widely used heparins and derivatives to interfere with P-selectin-dependent tumour cell interactions under flow in vitro could be used to identify anticoagulants with advanced inhibitory functions on experimental blood-borne metastasis in vivo. To test this assumption, the impact of unfractionated heparin, the low-molecular-weight heparins (LMWH) nadroparin and enoxaparin, and the synthetic pentasaccharide fondaparinux on P-selectin-dependent tumour interactions in vitro and metastasis formation in vivo were evaluated. Our data revealed that these commonly used anticoagulants widely differ in their potential to interfere with P-selectinmediated cell binding. Importantly, the superior inhibitory capacity on P-selectin function of unfractionated heparin and LMWH nadroparin as opposed to LMWH enoxaparin and synthetic heparin pentasaccharide fondaparinux strongly correlated to the inhibitory potency of each in inhibiting experimental lung metastasis in vivo. Hence, P-selectin inhibition may constitute a valuable feature to identify anticoagulants that are suitable for anticancer therapy.

Recent studies have demonstrated a strong association between type II (immunologically mediated) <em>heparin</em>-induced thrombocytopenia/thrombosis (HITP) and antibodies reactive with complexes consisting of <em>heparin</em> and platelet factor 4 (PF4), a <em>heparin</em>-binding protein normally found in platelet-alpha granules. However, the frequency with which such antibodies develop in patients given treatment with <em>heparin</em> has not yet been defined. We studied the development of <em>heparin</em>:PF4-specific antibodies in 51 patients who received a single dose of <em>unfractionated</em> <em>heparin</em> (UFH) during cardiac catheterization and were then given UFH or low-molecular-weight <em>heparin</em> (LMWH) again during and after open heart surgery. Eleven of the 51 patients (22%) had antibodies reactive with <em>heparin</em>:PF4 when they were admitted for cardiac surgery; these antibodies were mainly of the immunoglobulin M (IgM) class and were apparently stimulated by exposure to UFH at cardiac catheterization. Seventeen of 34 patients (50%) without preexisting antibody who were given UFH during and for 1 to 3 days after surgery formed immunoglobulin G antibodies or IgM antibodies (or both) by the sixth postoperative day. Overall, 27 of 44 patients (61%) who were given UFH at surgery had antibodies by the time of hospital discharge. None of 6 patients without preexisting antibody who were given LMWH at surgery formed antibodies (p < 0.03). However, LMWH was given as a single injection only on the day of surgery. The titer of the antibodies formed by patients receiving UFH ranged from 1:10 to 1:200, significantly lower than those in patients with a clinical diagnosis of HITP. Moderate thrombocytopenia was common after open heart surgery, but platelet levels in patients who had preexisting antibodies or formed new antibodies did not differ significantly from those in patients without antibody. Clinically significant thrombosis did not develop in any patient and HITP was not diagnosed in any patient. Antibodies reactive with <em>heparin</em>:PF4 formed in only 3 of 66 patients (4.5%) undergoing other types of surgery. One of these patients had been given UFH 3 months previously; the other 2 may have been exposed to <em>heparin</em> used to flush intravenous lines postoperatively. No antibodies reactive with <em>heparin</em>:PF4 were found in any of 108 normal subjects. We conclude that UFH is more immunogenic than has been thought and that patients exposed to this anticoagulant during open heart surgery are at high risk to form low titer (</= 1:200) antibodies reactive with <em>heparin</em>:PF4. Further studies are needed to determine whether such antibodies are clinically significant--that is, whether sensitized patients are at risk to develop HITP if <em>heparin</em> treatment is continued for more than 1 to 3 days or is reinstituted at a later date.

Heparanase is an endoglycosidase which cleaves heparan sulfate (HS) and hence participates in degradation and remodeling of the extracellular matrix (ECM). The enzyme also releases angiogenic factors from the ECM and thereby induces an angiogenic response in vivo. Heparanase is preferentially expressed in human tumors and its over-expression in tumor cells confers an accelerated growth and invasive phenotype in experimental animals. In contrast, heparanase gene silencing is associated with a marked inhibition of tumor progression. Heparanase upregulation correlates with increased tumor vascularity and poor postoperative survival of cancer patients. Studies on relationships between structure and the heparanase-inhibiting activity of nonanticogulant heparins systematically differing in their O-sulfation patterns, degrees of N-acetylation, and glycol-splitting of nonsulfated uronic acid residues, have permitted to select effective inhibitors of the enzymatic activity of heparanase. N-acetylated, glycol-split heparins emerged as highly effective and specific inhibitors of heparanase and tumor growth and metastasis. Several observations support the involvement of heparanase in haemostasis. A marked induction of tissue factor (TF) was noted in response to heparanase over-expression in tumor-derived cell lines and heparanase over-expressing transgenic mice. A direct correlation was also found between heparanase and TF expression levels in leukemia patients. TF induction was even more pronounced upon exogenous addition of heparanase to primary endothelial cells that do not normally express TF, and this induction was associated with enhanced coagulation. These and other results indicate that pro-heparanase is rapidly tethered on cell surfaces, partially depending on cell surface heparan sulfate, generating a local procoagulant effect. In addition, pro-heparanase can reverse the anti-coagulant effect of unfractionated heparin and the Factor Xa inhibitory activity of low molecular weight heparin (LMWH). These effects were also demonstrated in plasma derived from patients treated with LMWH. The pro-coagulant effects of pro-heparanase were also exerted by a peptide corresponding to its major functional heparin-binding domain. Heparanase pro-coagulant activities suggest its possible role as a natural regulator of heparinoid anti-coagulant activities, and point to a possible use of this molecule or its heparin binding domain as antidote for heparinoid therapies.

1. The effects of an unfractionated heparin preparation (Multiparin), a low molecular weight heparin preparation (Fragmin) and a selectively O-desulphated derivative of heparin lacking anticoagulant activity, have been investigated for their effects on the adhesion of human polymorphonuclear leucocytes (PMNs) to cultured human umbilical vein endothelial cells (HUVECs) in vitro. The effect of poly-L-glutamic acid, a large, polyanionic molecule was also studied. 2. Unfractionated heparin (50-1000 U ml-1), the O-desulphated derivative (0.3-6 mg ml-1) and the low molecular weight heparin (50 U-1000 U ml-1) all inhibited significantly the adhesion of 51Cr labelled PMNs to HUVECs stimulated with interleukin-1 beta (IL-1 beta; 10 U ml-1), bacterial lipopolysaccharide (LPS; 2.5 micrograms ml-1) or tumour necrosis factor-alpha (TNF-alpha; 125 U ml-1) for 6 h, whereas poly-L-glutamic acid had no effect. In addition, the three heparin preparations in the same concentration range inhibited significantly the adhesion of f-met-leu-phe-stimulated PMNs to resting HUVECs. 3. The effects of unfractionated heparin upon the expression of adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and E-selection were also investigated, as were the effects of unfractionated heparin upon adhesion of human PMNs to previously stimulated HUVECs. Heparin had little effect upon levels of expression of these adhesion molecules on stimulated HUVECs. However, a profound effect upon PMN adhesion to previously stimulated HUVECs was demonstrated using the same preparation, suggesting that inhibition of adhesion molecule expression is not a major component of the described inhibitory effects of heparin. 4. Pre-incubation of PMNs with heparin followed by washing inhibited their adhesion to HUVECs, under different conditions of cellular activation, implying that heparin can bind to these cells and exert its anti-adhesive effects even when not directly present in the system. 5. These observations would suggest that both heparin and a low molecular weight heparin are capable of inhibiting adhesion of human PMNs to endothelial cells, an effect not dependent solely upon the polyanionic nature of these molecules, nor dependent upon their ability to act as anticoagulants.

OBJECTIVE

The purpose of this study was to evaluate the efficacy and safety of the low molecular weight heparin enoxaparin as anticoagulant in continuous veno-venous hemofiltration (CVVH) compared with unfractionated heparin.

METHODS

Prospective randomized controlled crossover study.

METHODS

Medical and Surgical Intensive Care Unit of a University Hospital.

METHODS

Forty consecutive adult medical and surgical ICU patients with normal anticoagulation parameters requiring CVVH.

METHODS

CVVH was performed with pre-filter fluid replacement at 2500 ml/h and blood flow rates of 180 ml/min. Heparin-treated patients received an initial pre-filter bolus of 30 IU/kg and a maintenance infusion at 7 units/kg h(-1), titrated to achieve a systemic activated partial thromboplastin time (aPTT) of 40-45 s. Enoxaparin-treated patients received an initial pre-filter bolus of 0.15 mg/kg and a maintenance infusion starting at 0.05 mg/kg h(-1), which was subsequently adjusted to maintain systemic anti-factor Xa activity (anti-Xa) at 0.25-0.30 IU/ml. Each patient received both regimens in a crossover design. Maximum treatment duration for each set was 72 h.

RESULTS

Patients included had a mean APACHE II score of 22 (10-35). Thirty-seven patients completed both study arms. Mean filter life span was 21.7 h (+/- 16.9 h) for heparin and 30.6 h (+/- 25.3) for enoxaparin (p = 0.017, ANOVA for repeated measures). One major bleeding episode occurred during heparin as well as during enoxaparin treatment. Cost analysis showed average daily costs of 270 and 240 euro for heparin and enoxaparin, respectively.

CONCLUSIONS

Enoxaparin can be safely used for anticoagulation during CVVH resulting in higher filter lifespan compared with unfractionated heparin.

BACKGROUND

Since hypercoagulability might result in recurrent miscarriage, anticoagulant agents could potentially increase the live-birth rate in subsequent pregnancies in women with either inherited thrombophilia or unexplained recurrent miscarriage.

OBJECTIVE

To evaluate the efficacy and safety of anticoagulant agents, such as aspirin and heparin, in women with a history of at least two miscarriages without apparent causes other than inherited thrombophilia.

METHODS

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (April 2008), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2007, Issue 1), MEDLINE (January 1966 to March 2007), and EMBASE (1980 to March 2007). We scanned bibliographies of all located articles for any unidentified articles.

METHODS

Randomised and quasi-randomised controlled trials that assessed the effect of anticoagulant treatment on the live-birth rate in women with a history of at least two miscarriages (up to 20 weeks of amenorrhoea) without apparent causes other than inherited thrombophilia were eligible. Interventions included aspirin, unfractionated heparin, and low molecular weight heparin for the prevention of miscarriage. One treatment could be compared with another or with placebo.

METHODS

Two authors assessed the trials for inclusion in the review and extracted the data. We double checked the data.

RESULTS

Two studies (189 participants) were included in the review. In one study, 54 pregnant women with recurrent miscarriage (RM) but no detectable anticardiolipin antibodies were randomised to low-dose aspirin or placebo. RM was defined as three or more consecutive miscarriages (occurring before 22 weeks' gestational age (based on last menstrual period)). Similar live-birth rates were observed with aspirin and placebo, both 81% (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.78 to 1.29). In the other study, 107 women with consecutive recurrent miscarriage without any apparent cause and no hereditary thrombophilia were randomised between enoxaparin and aspirin. Here RM was stated as three or more consecutive first trimester miscarriages or at least two consecutive second trimester miscarriages. Similar live birth rates were observed with enoxaparin and aspirin, respectively 82% and 84% (RR 0.97, 95% CI 0.81 to 1.16).

CONCLUSIONS

There is a paucity in studies on the efficacy and safety of aspirin and heparin in women with a history of at least two miscarriages without apparent causes other than inherited thrombophilia. The two reviewed trials studied different treatments and only one study was placebo-controlled. Neither of the studies showed a benefit of one treatment over the other. Therefore, the use of anticoagulants in this setting is not recommended. However, large randomised placebo-controlled trials are still urgently needed.

Prevention of clotting in the extracorporeal circuit was one of the major hurdles that had to be overcome to enable the expansion of routine outpatient hemodialysis to free-standing satellite centers and the home. Unfractionated heparin, the anticoagulant of choice for many years, is now being replaced by low-molecular-weight heparins (LMWHs) in an expanding number of countries. This trend is attributable to the ease and convenience of the administration of LMWHs coupled with their reliability and predictability of dosing. However, the choice of which LMWH to use depends on the duration and frequency of the dialysis sessions. For patients who are allergic to heparin or have heparin-induced thrombocytopenia, alternative anticoagulants--the direct thrombin inhibitors and heparinoids--are now available. These agents either have short half-lives (and therefore need to be delivered by infusions), or prolonged half-lives, which allows simple bolus administration, but increases the risk of drug accumulation, overdosage and hemorrhage. In patients at risk of bleeding, regional anticoagulants enable anticoagulation to be limited to the extracorporeal circuit. Prostanoids and nafamostat mesilate are expensive regional anticoagulants, and citrate infusions add complexity to the procedure. A citrate-based dialyzate has now been introduced that might enable heparin-free dialysis or reduce systemic anticoagulant requirements.

BACKGROUND

Tissue factor (TF) and its specific inhibitor, tissue factor pathway inhibitor (TFPI), are important contributors to the initiation of the coagulation process.

OBJECTIVE

To compare plasma levels of soluble TF (sTF) and free-TFPI (f-TFPI) between patients with stable angina pectoris (SAP) and acute coronary syndrome (ACS) and to assess the impact of the two variables on long-term prognosis.

METHODS

Patients with SAPs (n = 1146) and acute coronary syndrome (n = 523) from the AtheroGene study were included and followed for 2.3 years. Because of the strong impact of unfractionated heparin (UFH) on f-TFPI levels, but not on sTF levels, patients having received UFH before blood drawing were excluded from the analyses on f-TFPI (n = 226).

RESULTS

On admission, no significant differences in sTF levels were observed between SAP and ACS patients. By comparison to patients with stable angina, f-TFPI levels significantly increased in patients with acute unstable angina and further increased in patients presenting with non-ST-elevation myocardial infarction and ST-elevation myocardial infarction (P < 10(-4)). Among the 1669 individuals with a coronary artery disease, 56 died from a cardiovascular cause. In prospective analyses, high sTF levels were independently associated with an increased risk of cardiovascular death in individuals with ACS (fully adjusted hazard ratio associated with one quartile increase = 2.06; 95% confidence interval 1.24-3.45; P = 0.006) but not in those with SAP (hazard ratio = 1.07; 95% confidence interval 0.78-1.46; P = 0.67). In SAP and ACS patients, high f-TFPI levels were not independently associated with an increased risk of cardiovascular death.

CONCLUSIONS

Plasma sTF levels were predictive of cardiovascular mortality in individuals with ACS, whereas f-TFPI levels were associated with the severity of myocardial damage on admission but were not independently related to outcome.

OBJECTIVE

Prophylaxis with unfractionated heparin (UFH) has been proven to reduce rates of venous thromboembolism (VTE) in hospitalized medical patients. While twice-daily (BID) and three-times-daily (TID) dosing regimens have been studied, the two have never been directly compared. We performed a metaanalysis to assess whether TID is superior to BID dosing in the prevention of VTE.

METHODS

Medline, EMBASE, and Cochrane Controlled Trials Register from 1966 through December 2004 were searched for randomized trials comparing subcutaneously dosed UHF (either BID or TID) with placebo or control for VTE prophylaxis in medical patient populations. Two reviewers independently rated study quality on the basis of predetermined criteria. Data were extracted on patient age, hospital setting, comorbidities, VTE rates, and bleeding complications.

RESULTS

Twelve studies were identified; 7,978 patients (1,664 patients in the TID arm, and 6,314 patients in the BID arm) were included. After adjustment for baseline risk, there was no difference in the overall rate (per 1,000 patient-days) of VTE (BID, 5.4; vs TID, 3.5; p = 0.87). TID heparin showed a trend toward a decrease in pulmonary embolism (PE) [BID, 1.5; vs TID, 0.5; p = 0.09] and in proximal DVT and PE (BID, 2.3; vs TID, 0.9; p = 0.05). The risk for major bleeding was significantly increased with TID heparin (BID, 0.35; vs TID, 0.96; p < 0.001).

CONCLUSIONS

BID heparin dosing causes fewer major bleeding episodes, while TID dosing appears to offer somewhat better efficacy in preventing clinically relevant VTE events. Practitioners should use underlying risk for VTE and bleeding to individualize pharmacologic prevention.

BACKGROUND

Data are sparse regarding comparative long-term mortality across the spectrum of patients presenting with acute coronary syndrome (ACS).

METHODS

We identified all patients hospitalized with suspected myocardial ischemia in an urban academic hospital from 1991 to 1992. We compared presenting characteristics, treatment, and long-term mortality between patients with unstable angina (UA), minor myocardial damage (MMD), definite non-ST-elevation myocardial infarction (NSTEMI), and STEMI.

RESULTS

Of 760 patients (mean age 68 years, 35% women), 22% had UA, 35% had MMD, 26% had NSTEMI, and 17% had STEMI. During a mean follow-up of 9.5 years, unadjusted mortality was highest in patients with MMD and NSTEMI (mortality for UA 43%, MMD 68%, NSTEMI 62%, STEMI 44%; P < .001). Patients with MMD and NSTEMI were older than patients with STEMI or UA, had more comorbid conditions (diabetes, prior myocardial infarction, congestive heart failure), and were less likely to receive aspirin, unfractionated heparin, or revascularization therapies during the index hospitalization. After multivariable adjustment for all significant covariates, mortality increased sequentially along the spectrum of ACS (hazards ratios for UA 1.0 [referent], MMD 1.12 [95% CI 0.84-1.49], NSTEMI 1.28 [0.95-1.72], and STEMI 1.52 [1.06-2.19]).

CONCLUSIONS

Patients presenting with MMD and definite NSTEMI had a worse unadjusted long-term prognosis up to 10 years after index hospitalization than patients with STEMI. This mortality excess for MMD/NSTEMI was associated with more comorbid conditions and decreased use of basic therapies for ACS. After controlling for baseline differences, STEMI patients had the highest mortality.

BACKGROUND

Advances in coronary angioplasty and adjunct pharmacology have improved patient outcomes after primary percutaneous coronary intervention (PCI) in acute myocardial infarction (AMI). However, several areas for improvement remain. Hemorrhagic complications, which are common in patients receiving intense anticoagulant and antiplatelet agents during primary PCI to suppress ischemia, have been strongly associated with early and late mortality. Moreover, restenosis after bare-metal stents (BMSs) frequently results in symptom recurrence and the need for repeat rehospitalization and revascularization procedures. Newer pharmacologic agents and drug-eluting stents may address both of these issues.

METHODS

In the HORIZONS-AMI trial, 3,602 patients with AMI undergoing primary PCI were prospectively randomized to unfractionated heparin plus routine use of glycoprotein (GP) IIb/IIIa inhibitors versus the direct thrombin inhibitor bivalirudin plus provisional use of GP IIb/IIIa inhibitors reserved for predefined thrombotic complications. In a second randomization, 3,011 eligible patients were randomly assigned to either a polymer-based paclitaxel-eluting stent or to an otherwise identical BMS. The study was powered for the assessment of sequential safety and efficacy end points for each specific randomization, with clinical end points assessed at 30 days, 1 year, and then annually for 5 years.

CONCLUSIONS

The ongoing HORIZONS-AMI trial will determine whether bivalirudin monotherapy reduces bleeding complications and improves overall event-free survival compared with unfractionated heparin plus the routine use of GP IIb/IIIa inhibitors in patients undergoing primary PCI for AMI. Furthermore, this study will determine whether paclitaxel-eluting stents safely reduce rates of ischemic target lesion revascularization compared with BMSs in the setting of primary PCI.

The development of treatments for acute neurodegenerative diseases (stroke and brain trauma) has focused on (i) reestablishing blood flow to ischemic areas as quickly as possible (i.e. mainly antithrombotics or thrombolytics for stroke therapy) and (ii) on protecting neurons from cytotoxic events (i.e. neuroprotective therapies such as anti-excitotoxic or anti-inflammatory agents for stroke and neurotrauma therapies). This paper reviews the preclinical data for enoxaparin in in vivo models of ischemia and brain trauma in rats. Following a photothrombotic lesion in the rat, enoxaparin significantly reduced edema at 24 h after lesion when the treatment was started up to 18 h after insult. Enoxaparin was also tested after an ischemic insult using the transient middle cerebral artery occlusion (tMCAO) model in the rat. Enoxaparin, 2 x 1.5 mg/kg i.v., significantly reduced the lesion size and improved the neuroscore when the treatment was started up to 5 h after ischemia. Enoxaparin, administered at 5 h after insult, reduced cortical lesion size in a dose-dependent manner. In permanent MCAO, enoxaparin (5 and 24 h after insult) significantly reduced lesion size and improved neuroscore. A slight and reversible elevation of activated partial thromboplastin time (APTT) suggests that enoxaparin is neuroprotective at a non-hemorrhagic dose. Traumatic brain injury (TBI) is often accompanied by secondary ischemia due in part to edema-induced compression of blood vessels. When enoxaparin, at 0.5 mg/kg i.v. + 4 x 1 mg/kg s.c., was administered later than 30 h after TBI, it significantly reduced edema in hippocampus and parietal cortex. At one week after TBI the lesion size was significantly reduced and the neurological deficit significantly improved in enoxaparin treated animals. Finally, the cognitive impairment was significantly improved by enoxaparin at 48 h to 2 weeks after TBI. The anticoagulant properties of unfractionated heparin and specifically enoxaparin can explain their anti-ischemic effects in experimental models. Furthermore, unfractionated heparin and specifically enoxaparin, have, in addition to anticoagulant, many other pharmacological effects (i.e. reduction of intracellular Ca2+ release; antioxidant effect; anti-inflammatory or neurotrophic effects) that could act in synergy to explain the neuroprotective activity of enoxaparin in acute neurodegenerative diseases. Finally, we demonstrated, that in different in vivo models of acute neurodegenerative diseases, enoxaparin reduces brain edema and lesion size and improves motor and cognitive functional recovery with a large therapeutic window of opportunity (compatible with a clinical application). Taking into account these experimental data in models of ischemia and brain trauma, the clinical use of enoxaparin in acute neurodegenerative diseases warrants serious consideration.

BACKGROUND

Venous thromboembolism occurs commonly in patients with cancer. Direct oral anticoagulants are non-inferior to conventional anticoagulants for the treatment of venous thromboembolism. We hypothesised that edoxaban, a direct oral inhibitor of activated clotting factor Xa, might be more suitable than conventional anticoagulants in the management of cancer-associated venous thromboembolism. The aim of this study was to assess the efficacy and safety of edoxaban compared with warfarin in a subgroup of patients with cancer enrolled in the Hokusai-VTE trial.

METHODS

We did a prespecified subgroup analysis in August, 2013, and a post-hoc analysis of non-inferiority and safety in March, 2016, of the patients with cancer enrolled in the randomised, double-blind, double-dummy, multicentre, Hokusai-VTE trial done between Jan 28, 2010, and Oct 31, 2012. In this study, patients aged at least 18 years with acute symptomatic deep-vein thrombosis or acute symptomatic pulmonary embolism (with or without deep-vein thrombosis) were assigned to receive edoxaban 60 mg once per day (or 30 mg once per day for patients with a creatinine clearance of 30-50 mL/min, bodyweight <60 kg, or who were receiving concomitant treatment with the P-glycoprotein inhibitors quinidine or verapamil) or warfarin (dose adjusted to maintain the international normalised ratio between 2·0 and 3·0) or placebos for either group for at least 3 months up to 12 months. All patients received initial therapy with open-label enoxaparin or unfractionated heparin for at least 5 days. Edoxoban (or placebo) was started after discontinuation of initial heparin; warfarin (or placebo) started concurrently with the study regimen of heparin. In our analysis we examined data for a subgroup of these patients who had a history of cancer or who had been categorised as having active cancer by the study physician at the time of enrolment. Additionally, all patients with a history of cancer were reviewed post hoc and categorised according to the presence or absence of active cancer. The primary efficacy outcome was the proportion of these patients with symptomatic recurrent venous thromboembolism during the 12-month study period, analysed in the modified intention-to-treat population, with an upper limit of the CI for the hazard ratio (HR) of 1·5. The principal safety outcome was the proportion of patients who had clinically relevant bleeding in the population of patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT00986154.

RESULTS

Of 771 patients with cancer enrolled in the trial, 378 were assigned to edoxaban and 393 to warfarin. Recurrent venous thromboembolism occurred in 14 (4%) of 378 patients given edoxaban and in 28 (7%) of 393 patients given warfarin (hazard ratio [HR] 0·53, 95% CI 0·28-1·00; p=0·0007). The upper limit of this 95% CI did not exceed the non-inferiority margin of 1·5 that was prespecified for the trial. Clinically relevant bleeding (major or non-major) occurred in 47 (12%) of 378 patients who received edoxaban and in 74 (19%) of 393 patients who received warfarin; HR for clinically relevant bleeding 0·64, 95% CI 0·45-0·92; p=0·017. Major bleeding occurred in ten (3%) of 378 patients with a history of cancer who received edoxaban and in 13 (3%) of 393 who received warfarin (HR 0·80, 95% CI 0·35-1·83).

CONCLUSIONS

Edoxaban might be as effective as warfarin for the treatment of patients with cancer with venous thromboembolism, and with less clinically relevant bleeding. Additional clinical trials of edoxaban versus low-molecular-weight heparin for the treatment of venous thromboembolism in patients with cancer are warranted.

BACKGROUND

Daiichi Sankyo.