Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in hospitalized patients. Where appropriate, evidence-based methods of prophylaxis are implemented and the burden of VTE can be reduced substantially. Obesity, including morbid obesity, is associated with a high risk of VTE and, unfortunately, fixed doses of US FDA-approved anticoagulant regimens, including unfractionated heparins, low-molecular-weight heparins and factor Xa inhibitors, may not provide optimal VTE prophylaxis in these patients. Although the data are still limited, a rapidly growing body of literature and cumulative evidence suggests that anticoagulant dose adjustments in morbidly obese patients may optimize pharmacodynamic activity and reduce VTE risk. With the prevalence of morbid obesity continuing to rise, more high-quality clinical data are needed to better understand the pathobiology of VTE in obesity and provide effective, yet safe, prevention strategies.

Laboratory monitoring is widely recommended to measure the anticoagulant effect of unfractionated heparin and to adjust the dose to maintain levels in the target therapeutic range. The most widely used laboratory assay for monitoring unfractionated heparin therapy is the activated partial thromboplastin time (aPTT). A fixed therapeutic range for the aPTT of 1.5 to 2.5 times the control value has become widely accepted, but the evidence supporting this range is weak and the clinical validity of using the aPTT for predicting thrombotic or bleeding events is questionable. The aPTT test is also affected by numerous preanalytic and analytic variables that are unrelated to the anticoagulant effect of unfractionated heparin, further eroding its potential value for monitoring unfractionated heparin treatment. Unfractionated heparin dose appears to be more important than the aPTT in predicting clinical efficacy. Despite serious limitations, the reliance on the aPTT is likely to continue because of its ready availability and familiarity of clinicians with the test. The focus of clinicians who manage unfractionated heparin therapy should be to ensure that an adequate starting dose of unfractionated heparin is used and that the aPTT method is standardized. Future research efforts should be directed towards developing methods to improve standardization of the aPTT assay for monitoring unfractionated heparin. Direct measures of the concentration of unfractionated heparin in the blood are attractive because these assays are not affected by many of the biologic variables that interfere with the aPTT and may be suitable for automation. However, currently available unfractionated heparin assays are much more expensive than the aPTT, are not widely available, and their validity has not been adequately assessed in clinical outcome studies.

Heparin and HS (heparan sulfate) exert their wide range of biological activities by interacting with extracellular protein ligands. Among these important protein ligands are various angiogenic growth factors and cytokines. HS binding to VEGF (vascular endothelial growth factor) regulates multiple aspects of vascular development and function through its specific interaction with HS. Many studies have focused on HS-derived or HS-mimicking structures for the characterization of VEGF165 interaction with HS. Using a heparinase 1-prepared small library of heparin-derived oligosaccharides ranging from hexasaccharide to octadecasaccharide, we systematically investigated the heparin-specific structural features required for VEGF binding. We report the apparent affinities for the association between the heparin-derived oligosaccharides with both VEGF165 and VEGF55, a peptide construct encompassing exclusively the heparin-binding domain of VEGF165. An octasaccharide was the minimum size of oligosaccharide within the library to efficiently bind to both forms of VEGF and a tetradecasaccharide displayed an effective binding affinity to VEGF165 comparable to unfractionated heparin. The range of relative apparent binding affinities among VEGF and the panel of heparin-derived oligosaccharides demonstrate that the VEGF binding affinity likely depends on the specific structural features of these oligosaccharides, including their degree of sulfation, sugar-ring stereochemistry and conformation. Notably, the unique 3-O-sulfo group found within the specific antithrombin binding site of heparin is not required for VEGF165 binding. These findings afford new insight into the inherent kinetics and affinities for VEGF association with heparin and heparin-derived oligosaccharides with key residue-specific modifications and may potentially benefit the future design of oligosaccharide-based anti-angiogenesis drugs.

Venous thromboembolism (VTE) often complicates the clinical course of cancer. The risk is further increased by chemotherapy, but the trade-off between safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain. This is the second update of a review first published in February 2012.

To assess the efficacy and safety of primary thromboprophylaxis for VTE in ambulatory cancer patients receiving chemotherapy compared with placebo or no thromboprophylaxis.

For this update the Cochrane Vascular Information Specialist searched the Cochrane Vascular Group Specialised Register (June 2016). In addition, the Information Specialist searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 5). Clinical trials registries were searched up to June 2016.

Randomised controlled trials comparing any oral or parenteral anticoagulant or mechanical intervention to no thromboprophylaxis or placebo, or comparing two different anticoagulants.

We extracted data on methodological quality, participant characteristics, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively.

We identified five additional randomised controlled trials (2491 participants) in the updated search, considering in this update 26 trials with a total of 12,352 participants, all evaluating pharmacological interventions and performed mainly in people with locally advanced or metastatic cancer. The quality of the evidence ranged from high to very low across the different outcomes and comparisons. The main limiting factors were imprecision and risk of bias. One large trial of 3212 participants found a 64% (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.22 to 0.60) reduction of symptomatic VTE with the ultra-low molecular weight heparin (uLMWH) semuloparin relative to placebo, with no apparent difference in major bleeding (RR 1.05, 95% CI 0.55 to 2.00). When compared with no thromboprophylaxis, LMWH significantly reduced the incidence of symptomatic VTE (RR 0.54, 95% CI 0.38 to 0.75; no heterogeneity, Tau2 = 0.00%) with a non-statistically significant 44% higher risk of major bleeding events (RR 1.44, 95% CI 0.98 to 2.11). In participants with multiple myeloma, LMWH was associated with a significant reduction in symptomatic VTE compared with the vitamin K antagonist warfarin (RR 0.33, 95% CI 0.14 to 0.83), while the difference between LMWH and aspirin was not statistically significant (RR 0.51, 95% CI 0.22 to 1.17). Major bleeding was observed in none of the participants treated with LMWH or warfarin and in less than 1% of those treated with aspirin. Only one study evaluated unfractionated heparin against no thromboprophylaxis but did not report on VTE or major bleeding. When compared with placebo, warfarin was associated with a non-statistically significant reduction of symptomatic VTE (RR 0.15, 95% CI 0.02 to 1.20). Antithrombin, evaluated in one study involving paediatric patients, had no significant effect on VTE or on major bleeding when compared with no antithrombin. The direct oral factor Xa inhibitor apixaban was evaluated in a phase II dose-finding study that suggested a low rate of major bleeding (2.1% versus 3.4%) and symptomatic VTE (1.1% versus 13.8%) in comparison with placebo.

In this second update, we confirmed that primary thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic VTE in ambulatory cancer patients treated with chemotherapy. In addition, the uLMWH semuloparin, which is not commercially available, significantly reduced the incidence of symptomatic VTE. The risk of major bleeding associated with LMWH, while not reaching statistical significance, suggest caution and mandate additional studies to determine the risk-to-benefit ratio of LMWH in this setting. Despite the encouraging results of this review, routine prophylaxis in ambulatory cancer patients cannot be recommended before safety issues are adequately addressed. We need additional studies investigating targeted primary prophylaxis in people with specific types or stages of cancer associated with a higher risk of VTE.

The activation of the clotting cascade leading to deep venous thrombosis begins during total hip arthroplasty, but few studies have assessed changes in coagulation during surgery. A better understanding of thrombogenesis during total hip arthroplasty may provide a more rational basis for treatment. In 3 separate studies, the following observations were made. Circulating indices of thrombosis and fibrinolysis: prothrombin F1.2, thrombin-antithrombin complexes, fibrinopeptide A, and D-dimer, did not increase during osteotomy of the neck of the femur or during insertion of the acetabular component, but rose significantly during insertion of the femoral component. Thrombin-antithrombin complexes, fibrinopeptide A, and D-dimer were higher after insertion of a cemented component than insertion of a noncemented femoral component. A significant decline in central venous oxygen tension was observed after relocation of the hip joint and after insertions of cemented and noncemented femoral components, providing evidence of femoral venous occlusion during insertion of the femoral component. In patients receiving a cemented femoral component, mean pulmonary artery pressure increased after relocation of the hip joint, indicating intraoperative pulmonary embolism. No changes in mean pulmonary artery pressure were noted with noncemented total hip arthroplasty. Administration of 1000 units of unfractionated heparin before insertion of a cemented femoral component blunted the rise of fibrinopeptide A. The results of these studies suggest that (1) the greatest risk of activation of the clotting cascade during total hip arthroplasty occurs during insertion of the femoral component; (2) femoral venous occlusion and use of cemented components are factors in thrombogenesis during total hip arthroplasty; and (3) measures to prevent deep venous thrombosis during total hip arthroplasty (such as intraoperative anticoagulation) should begin during surgery rather than during the postoperative period and be applied during insertion of the femoral component.

OBJECTIVE

We aimed to identify correlates of Thrombolysis In Mycocardial Infarction (TIMI) major/minor bleeding among eptifibatide-treated patients undergoing percutaneous coronary intervention (PCI).

BACKGROUND

Evaluation of bleeding predictors among patients treated with glycoprotein IIb/IIIa receptor inhibition might aid in the identification of targets to reduce bleeding risk.

METHODS

Data were analyzed from 567 moderate- to high-risk PCI patients with non-ST-segment elevation acute coronary syndrome (NSTEACS) treated with eptifibatide/reduced-dose unfractionated heparin or eptifibatide/reduced-dose enoxaparin enrolled in the Randomized Trial to Evaluate the Relative Protection Against Post-PCI Microvascular Dysfunction and Post-PCI Ischemia Among Anti-Platelet and Anti-Thrombotic Agents-Thrombolysis In Myocardial Infarction-30 (PROTECT-TIMI-30).

RESULTS

The incidence of significant bleeding was 3.2% with a median time to event of 7.0 h after the first eptifibatide bolus. Increased age was the only independent correlate of bleeding events. Among patients with reduced creatinine clearance (CrCl), lack of adjustment of the maintenance infusion for CrCl < or =50 ml/min occurred frequently (15 of 33 patients, or 45%) and was associated with a high rate of bleeding (20%). The association of CrCl with bleeding appeared to be largely mediated by the incorporation of age in the estimation of CrCl. Patient gender, Cr, weight, and the peak activated clotting time were not associated with bleeding.

CONCLUSIONS

Among NSTEACS PCI patients treated with eptifibatide, increased age was a significant correlate of bleeding events and appeared to explain the association between low CrCl and bleeding. The more widespread use of CrCl or other estimates of renal function over Cr may lead to more appropriate dose adjustments of eptifibatide.

Direct oral anticoagulants (DOAs)--inhibitors of thrombin or factor-Xa--are expected to replace vitamin K antagonists in most of their indications. Patients receiving long-term treatment with DOAs are likely to be exposed to elective or emergency surgery or invasive procedures. Owing to the present lack of experience in such conditions, we cannot make recommendations, but only propose perioperative management for optimal safety regarding the risk of bleeding and thrombosis. DOAs may increase surgical bleeding, they have no validated antagonists, they cannot be monitored by simple standardized laboratory assays and their pharmacokinetics vary significantly between patients. Although DOAs differ in many respects, the proposals in the perioperative setting need not be specific to each. For procedures with low haemorrhagic risk, a therapeutic window of 48 hours (last administration 24 hours before surgery, restart 24 hours after) is proposed. For procedures with medium or high haemorrhagic risk, we suggest stopping DOAs 5 days before surgery to ensure complete elimination in all patients. Treatment should be resumed only when the risk of bleeding has been controlled. In patients at high thrombotic risk (e.g. those in atrial fibrillation with a history of stroke), bridging with heparin (low molecular-weight heparin, or unfractionated heparin, if the former is contraindicated) is proposed. In an emergency, the procedure should be postponed for as long as possible (minimum 1-2 half-lives) and non-specific antihaemorrhagic agents, such as recombinant human activated factor VIIa or prothrombin complex concentrates should not be given for prophylactic reversal due to their uncertain benefit-risk.

OBJECTIVE

Dabigatran is effective for both the prevention of stroke and bleeding in patients with atrial fibrillation (AF). However, the safety and efficacy of the use of dabigatran in the peri-procedural period for radiofrequency catheter ablation (RFCA) of AF is unknown. Therefore, the purpose of this study was to evaluate the safety and efficacy of dabigatran in the peri-procedural period for RFCA of AF and the duration of hospital stay.

METHODS

Consecutive patients (n = 227) who underwent RFCA for AF were prospectively analyzed. Peri-procedural anticoagulant therapy with dabigatran (n = 101, D group) was compared with warfarin and heparin bridging (n = 126, W group). Dabigatran was discontinued 12-24 h before and restarted 3 h after the procedure. Warfarin was stopped 3 days before the procedure and unfractionated heparin was administered.

RESULTS

Ischemic stroke occurred in one patient of the D group (0.8 %). There was no significant difference between the two groups in the incidence of major bleeding (three cases of cardiac tamponade in each group and one case of intracranial bleeding in the W group, p = 0.93) or minor bleeding (five cases in the D group vs. five in the W group, p = 0.54). The duration of hospital stay was significantly shorter in the D group than in the W group (7.2 vs. 10.3 days, p = 0.0001).

CONCLUSIONS

Peri-procedural anticoagulation therapy with dabigatran for RFCA of AF was equally safe and effective compared with warfarin and heparin bridging. The use of dabigatran for RFCA of AF shortened the duration of hospital stay.

OBJECTIVE

To assess the treatment of venous thromboembolism (VTE) in hospitalized patients enrolled in a national, multicenter database.

METHODS

This was a retrospective, cohort study that randomly selected VTE patients from 38 academic/teaching, community, and Veterans Administration (VA) hospitals. The study included a physician survey component. The patients selected were those treated between January 2002 and June 2003 who had an ICD-9-CM code for pulmonary embolus (PE), deep vein thrombosis (DVT), or pregnancy-related PE or DVT.

RESULTS

The study included 939 patients: 52.7% with DVT, 28.4% with PE, and 18.8% with PE and DVT. Mean age was 59.5 years. Risk factors included obesity (body mass index>> 30) in 30.1%, history of VTE in 28.0%, malignancy in 27.4%, surgery in 21.1%, and immobility in 18.5%. Only 56.1% of patients were treated with low-molecular-weight heparin (LMWH). Bridging from LMWH or unfractionated heparin (UFH) to warfarin was completed during hospitalization in 486 (68.6%), but only 246 (50.6%) had an international normalized ratio (INR)>> or = 2 for 48 hours before discontinuation of the injectable anticoagulant. Length of stay in patients discharged on bridge therapy was 4.0 +/- 3.7 days vs 8.1 +/- 5.8 days for patients discharged on warfarin therapy (P < .001). Ninety-two (10.1%) patients were discharged with neither oral nor injectable anticoagulation and had a mean duration of treatment of only 10.6 +/- 16.2 days. Of 245 physicians surveyed from participating hospitals, 84% and 53%, respectively, indicated that LMWH was their preferred agent for treatment of DVT and treatment of PE. With regard to warfarin, 30% did not believe it was necessary to have a therapeutic INR for>> or = 2 days before discontinuing LMWH or UFH, and 27% responded that it was necessary to keep DVT patients in the hospital until they were therapeutic.

CONCLUSIONS

In this cross-section of United States hospitals, lower than anticipated use of LMWH, insufficient bridging from UFH or LMWH to warfarin, and continuation of anticoagulation after hospitalization were all problems discovered with the treatment of VTE. Physician knowledge, attitudes, and beliefs are partially responsible for the gap between actual practice and international guidelines. These results suggest that hospitals should evaluate their adherence to international VTE treatment guidelines and develop strategies to optimize antithrombotic therapy.

Neutralization of a low molecular weight (LMW) heparin fraction by protamine sulfate was evaluated in vitro and in vivo. Anti-Xa and anti-IIa activities were measured by amidolytic and coagulation methods (activated partial thromboplastin time, APTT). Fifteen patients (4 males and 11 females) underwent surgery with extracorporeal circulation. In vitro, anti-Xa and anti-IIa activities and APTT of unfractionated heparin were neutralized with a protamine/heparin (P/H) gravimetric ratio of 1.6, 1.33 and about 2, respectively. Anti-IIa activity and APTT induced by PK 10169 were completely corrected at a P/H ratio of 1 and 2, respectively, while anti-Xa activity was incompletely neutralized at a ratio of 5. In vivo, in 9 patients who did not receive intravenous protamine sulfate, a good correlation was found between doses of PK 10169 infused, anti-IIa plasma level and blood loss. In 3 patients who were treated prophylactically with protamine, bleeding was normal or only slightly increased. In 3 patients who received protamine because of hemorrhage, mean anti-Xa and anti-IIa were 2.3 and 0.54 U before and 1.32-0.06 U after neutralization. Bleeding was stopped by a second dose of protamine in 1 patient, but blood loss was abnormal in the other patients. However, a correlation between bleeding and anti-Xa or anti-IIa activities was not clearly evident.

OBJECTIVE

In ISAR-REACT 3, 30-day outcomes in 4570 biomarker negative patients undergoing percutaneous coronary intervention (PCI)>> or =2 h after pre-treatment with 600 mg of clopidogrel revealed less bleeding with bivalirudin compared with unfractionated heparin, but no difference in 30-day net clinical benefit. The objective of the present analysis was to assess the impact of bivalirudin vs. heparin on 1-year outcomes in ISAR-REACT 3.

RESULTS

The primary outcome for this analysis was the composite of death, myocardial infarction, or target vessel revascularization 1 year after randomization. The composite of death or myocardial infarction was a secondary outcome. At 1 year, the primary outcome occurred in 17.1% of patients assigned to bivalirudin vs. 17.5% assigned to heparin [hazard ratio (HR), 0.98; 95% confidence interval (CI), 0.86-1.13; P = 0.816]. The combined incidence of death or myocardial infarction was 7.7% in the bivalirudin group vs. 6.7% in the heparin group (HR, 1.15; 95% CI, 0.93-1.43; P = 0.200). The mortality rate was 1.9% in the bivalirudin group and 1.7% in the heparin group (HR, 1.10; 95% CI, 0.71-1.70; P = 0.667). At 1 year, no significant differences in the primary outcome were observed with bivalirudin and heparin in any of the subgroups analysed.

CONCLUSIONS

Bivalirudin and unfractionated heparin during PCI provide comparable outcomes at 1 year in biomarker negative patients undergoing PCI after pre-treatment with 600 mg of clopidogrel.

BACKGROUND

URL www.clinicaltrials.gov; Unique identifier NCT00262054.

Combination antithrombotic therapy with heparin plus aspirin decreases the risk of recurrent ischemic events in patients with acute coronary syndromes without persistent ST-segment elevation. Compared with standard unfractionated heparin, low-molecular-weight heparin (LMWH) has a more predictable antithrombotic effect, is easier to administer, and does not require coagulation monitoring. At 176 hospitals in 3 continents, 3,171 patients with rest unstable angina or non-wave myocardial infarction were randomly assigned to either enoxaparin (a LMWH), 1 mg/kg twice daily subcutaneously, or to continuous intravenous unfractionated heparin, for a minimum of 48 hours to a maximum of 8 days. Trial medication was administered in a double-blind, placebo-controlled fashion. At 14 days, the primary endpoint, the composite risk of death, myocardial infarction, or recurrent angina with electrocardiographic changes or prompting intervention, was significantly lower in patients assigned to enoxaparin compared with heparin (16.6% vs 19.8%; odds ratio [OR] 1.24; 95% confidence interval [CI] 1.04-1.49; p = 0.019). At 30 days, the composite risk of death, myocardial infarction, or recurrent angina remained significantly lower in the enoxaparin group compared with the unfractionated heparin group (19.8% vs 23.3%, OR 1.23; 95% CI 1.0-1.46, p = 0.016). The rate of revascularization procedures at 30 days was also significantly lower in patients assigned to enoxaparin (27.1% vs 32.2%, p = 0.001). The 30-day incidence of major bleeding complication was 6.5% versus 7.0% (p = not significant), but the incidence of minor bleeding was significantly higher in the enoxaparin group (13.8% vs 8.8%, p <0.001) due primarily to injection-site ecchymosis. Thus, combination antithrombotic therapy with enoxaparin plus aspirin is more effective than unfractionated heparin plus aspirin in decreasing ischemic outcomes in patients with unstable angina or non-Q-wave myocardial infarction in the early (30 days) phase. The lower recurrent ischemic event rate seen with the LMWH, enoxaparin, is achieved without an increase in major bleeding, but with an increase in minor bleeding complications due mainly to injection-site ecchymosis.

BACKGROUND

Pulmonary embolism (PE) is a cardiovascular emergency with high morbidity and mortality.

METHODS

Review of relevant literature retrieved by a selective Medline search, including current guidelines.

RESULTS

Hemodynamically unstable patients are considered to have high-risk PE, whereas hemodynamically stable patients are considered to have non-high-risk PE. After classification into one of these two risk groups, patients undergo further diagnostic evaluation for PE according to the appropriate risk-adapted algorithm. Patients who are in cardiogenic shock or have persistent arterial hypotension (high-risk PE) should undergo multidetector computed tomography (MDCT) or echocardiography at once, so that a PE, if present, can be treated immediately by thrombolysis. For hemodynamically stable patients with non-high-risk PE the proper diagnostic strategy is determined by the clinical probability of PE, which can be calculated with the aid of validated scoring systems and is based on both MDCT and D-dimer levels. For further risk stratification in hemodynamically stable patients, tests are performed to detect right ventricular dysfunction or myocardial injury, either of which indicates intermediate-risk PE. In addition to specific therapy, patients with high-risk PE, patients at high risk for hemorrhage and these with severe renal insufficiency should be anticoagulated with unfractionated heparin. All other patients should be treated with low-molecular-weight heparin or fondaparinux. Thereafter, long-term oral anticoagulation with vitamin K antagonists is recommended.

CONCLUSIONS

Modern algorithms have considerably simplified the diagnosis and treatment of acute PE. It would be desirable for these algorithms to be rapidly implemented in routine practice, because speedy diagnosis and immediate treatment can lower the morbidity and mortality associated with PE.

BACKGROUND

Patients with traumatic brain injury (TBI) are at high risk for venous thromboembolism (VTE), but physicians are cautious with chemical prophylaxis in these patients because of concern about exacerbating intracranial hemorrhage. We hypothesized that early use of chemical thromboprophylaxis would reduce VTE incidence without increasing intracranial hemorrhage.

METHODS

Records of all patients admitted with a TBI to a Level I trauma center from 2006 to 2008 were reviewed. TBI was defined as intracranial hemorrhage, hematoma, contusion, or diffuse axonal injury with a head Abbreviated Injury Scale score >2. Patients were excluded if they were discharged or died within 72 hours of admission. Chemical prophylaxis was defined as subcutaneous or intravenous unfractionated heparin or low molecular weight heparin before any VTE diagnosis. Progression of TBI was defined by worsening CT findings. VTE was defined as deep venous thrombosis or pulmonary embolus confirmed by radiology reports. Primary outcomes were progression of hemorrhage and VTE events.

RESULTS

Eight hundred and twelve of the 1,258 patients admitted to the trauma center with a TBI met study criteria. Chemical thromboprophylaxis was given to 49.5% (n = 402). Mean head Abbreviated Injury Scale score was 3.4 in both groups. One hundred and sixty-nine patients started prophylaxis within 48 hours and 242 patients began within 72 hours. Patients receiving chemical prophylaxis had a lower incidence of VTE (1% versus 3%; p = 0.019). Although not statistically significant, they also had a lower rate of injury progression, 3% versus 6% (p = 0.055).

CONCLUSIONS

Use of chemical thromboprophylaxis in TBI patients with a stable or improved head CT after 24 hours substantially reduces the incidence of VTE and does not increase the risk of progression of intracranial hemorrhage.

In a prospective multicenter trial, 149 consecutive patients with phlebographically proven proximal and/or distal deep vein thrombosis of the leg were randomly allocated to receive subcutaneously for 10 days either low molecular weight heparin CY 216 (Fraxiparine) in a fixed dose or unfractionated heparin (UFH) in doses adjusted according to the activated partial thromboplastin time. Pre- and post-treatment phlebograms were assessed blindly using the Arnesen's score system in 134 patients available for analysis of the treatment efficacy. The mean phlebographic score after 10 days of treatment was significantly decreased in both groups (p less than 0.001) in comparison with the baseline score but the difference in score changes between the two groups was not statistically significant. There was an improvement in 45/68 patients (66%) in the Fraxiparine group and in 32/66 patients (48%) in the UFH group, and an increase in the thrombus size in 10/68 (15%) and 12/66 (18%), respectively. One symptomatic non-fatal pulmonary embolism and one major bleeding episode were observed in the UFH group. During a follow-up period of 3 months, two rethromboses had occurred in the UFH group and none in the Fraxiparine group. It is concluded that subcutaneous fixed dose Fraxiparine is safe and at least as effective as subcutaneous adjusted UFH in the treatment of deep vein thrombosis.

In order to study whether a low molecular weight heparin (LMWH) of mw 4000 D is effective in the treatment of deep venous thrombosis (DVT), patients with DVT verified by phlebography were randomized to treatment by continuous intravenous infusion of either unfractionated heparin (UFH) or LMWH. The initial dose was 240 U (anti F Xa)/kg/12 h. This study (study I) was stopped because of major bleeding in 2 newly operated patients in the LMWH group after 27 patients had been treated. The heparin activity measured as F Xa inhibition assayed in retrospect, was found to be much higher in the LMWH group (mean 1.6-2.0 anti F Xa U/ml) than in the UFH group (mean 0.5-0.8 anti F Xa U/ml). A second study was therefore initiated in which the DVT patients were randomly given UFH (240 U/kg/12 h) or LMWH only 120 U (anti F Xa)/kg/12 h, as initial doses (study II). In this study 27 patients could be evaluated, the mean heparin activity still being higher in the LMWH group (0.9-1.2 anti F Xa U/ml) than in the UFH group (0.5-0.7 anti F Xa U/ml). A second phlebographic investigation showed progression of thrombus size in 3 (11%) of the UFH patients of studies I and II (n = 29) and improvement in 14 (48%). There was no progression in any LMWH patient, 6 (50%) had improved in study I and 10 (77%) in study II. The mean decrease of thrombus size score (according to Marder) during treatment did not differ between the 3 groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Novel anticoagulants to replace unfractionated heparins, low molecular weight heparins and vitamin K antagonists, are needed urgently. Coagulation factor Xa is an attractive target for drug development because of its position at the convergence of the intrinsic and extrinsic clotting pathways. There are two differing strategies of inhibiting factor Xa that are being pursued: indirect inhibition by compounds such as fondaparinux and idraparinux, requiring antithrombin as a cofactor; and direct inhibition by compounds such as rivaroxaban (BAY 597939), DX-9065a, otamixaban, LY517717 and YM150. Of these compounds, fondaparinux is approved for the prevention and treatment of venous thromboembolism, and idraparinux is in Phase III for venous thromboembolism treatment and stroke prevention in patients with atrial fibrillation. Rivaroxaban has undergone extensive Phase II studies for venous thromboembolism prevention after orthopaedic surgery, and Phase III studies have begun. In this review, we will discuss the pharmacological effects of factor Xa inhibitors and the latest clinical developments.

OBJECTIVE

To determine whether low-molecular-weight heparin (LMWH)+glycoprotein (GP) IIb/IIIa inhibitors provide greater benefit than unfractionated heparin (UFH)+GP IIb/IIIa inhibitors, irrespective of renal status.

RESULTS

Patients in the Global Registry of Acute Coronary Events (GRACE) were divided into three groups according to creatinine clearance (CrCl): normal renal function (CrCl >60 mL/min), moderate renal dysfunction (30<CrCl< or =60 mL/min), and severe (CrCl< or =30 mL/min) renal dysfunction. Data were analysed from 11 881 patients with acute coronary syndrome (ACS). Patients with moderate (n=3705) or severe (n=982) renal dysfunction were at higher risk of adverse outcomes than those with normal renal function. Decreasing CrCl was an independent predictor of mortality at 30 days and in-hospital major bleeding. LMWH+GP IIb/IIIa inhibitors were used significantly less frequently in patients with severe (2.0%) or moderate (3.1%) renal dysfunction than in those with normal function (3.9%, P=0.0056). LMWH alone was more beneficial than UFH alone, irrespective of renal status. LMWH alone was an independent predictor of 30 day survival [odds ratio (OR) 0.56; 95% confidence interval (CI) 0.43-0.73] and lower risk of in-hospital bleeding (OR 0.66; 95% CI 0.48-0.92). Bleeding rates were significantly lower with LMWH+GP IIb/IIIa inhibitors than those with UFH+GP IIb/IIIa inhibitors. Use of UFH+GP IIb/IIIa inhibitors was an independent predictor of bleeding (OR 2.02; 95% CI 1.42-2.90) compared with UFH alone.

CONCLUSIONS

In patients with renal dysfunction and non-ST-segment elevation ACS, bleeding complications are more frequent and outcomes appear worse in individuals treated with UFH compared with LMWH. Combination therapy with LMWH and GP IIb/IIIa inhibitors appears to be better tolerated than with UFH and GP IIb/IIIa inhibitors.

Adequate initial anticoagulant therapy of deep venous thrombosis (DVT) is required to prevent thrombus growth and pulmonary embolism (PE). Intravenous unfractionated heparin (UFH) is being replaced by low-molecular-weight heparin (LMWH) as the anticoagulant of choice for initial treatment of venous thromboembolism (VTE). Both agents are relatively safe and effective when used to treat VTE, with LMWH suitable for outpatient therapy because of improved bioavailability and more predictable anticoagulant response. Serious potential complications of heparin therapy, such as heparin-induced thrombocytopenia (HIT) and osteoporosis, seem less common with LMWH. The potential for fetal harm and changes in maternal physiology complicate the treatment of VTE during pregnancy. Although systemic thrombolysis is used in patients with massive PE and in some patients with proximal DVT, controversy persists with respect to appropriate patient selection for this intervention.

Heparin was discovered approximately 75 years ago and has been used extensively for the last 50 years to treat thromboembolic disorders. An endogenous glycosaminoglycan, heparin is found largely in the liver, lung and intestine. It is available for exogenous administration both as unfractionated and low molecular weight heparin. Unfractionated heparin is a heterogenous mixture of polysaccharide chains of varying length resulting in a range of molecular weights from 3000 to 30,000D while low molecular weight heparin ranges from 3000 to 6000D. Heparin produces its antithrombotic effect by binding to antithrombin III and this complex then binds to thrombin. In order to accomplish this a total of 18 to 22 monosaccharide units is necessary including a specific pentasaccharide binding site for antithrombin III. After either subcutaneous or intravenous injection heparin is distributed primarily within the intravascular space. A short distribution phase is seen which is thought to correspond to endothelial cell binding and internalisation. The disposition curve for unfractionated heparin has a unique concave-convex shape which is the result of combined saturable and nonsaturable elimination mechanisms. The nonsaturable elimination mechanism is renal and is the primary route of elimination for low molecular weight heparins. For this reason, the concave-convex pattern is not seen with low molecular weight preparations. Both forms of heparin are useful antithrombotic agents; however, the correlation between the antithrombotic effect and an in vitro laboratory test for either type still needs further clarification.

Low molecular weight (LMW) heparin has been compared to standard unfractionated (UF) heparin in hemodialysis/hemofiltration in a 12 month, randomized study. Seventy patients with end-stage chronic renal failure starting dialysis treatment were randomly assigned to one of two groups treated with either LMW or UF heparin. The LMW and UF heparin doses used produced similar plasma anti-FXa levels, and comparable antithrombotic effectiveness was observed in the two groups as reflected in similar incidences of thrombus formation in the extracorporeal circulation: 1.59% and 1.33% for LMW and UF heparin, respectively. No bleeding complications were seen with either heparin, but significantly (P less than 0.05) fewer erythrocyte concentrates were needed in the LMW heparin patients. Mean factor VIII activities had risen significantly (P less than 0.001) after 12 months in the UF heparin group, whereas they were unchanged in the LMW heparin group. A significant (P less than 0.05) increase in plasma triglycerides was observed in the UF heparin group which was attributable to six (18.8%) of the patients in this group. Triglyceride concentrations remained relatively constant in the LMW heparin group. Post-heparin lipolytic activity, and in particular hepatic lipase activity, was not stimulated to the same extent in the LMW heparin-treated patients as compared to the UF heparin group. We conclude that LMW heparin is a suitable alternative to standard UF heparin for anticoagulation in hemodialysis/hemofiltration therapy. It may offer potential advantages with regard to a lower requirement for erythrocyte concentrates and less derangement of certain metabolic parameters, such as factor VIII, triglycerides and plasma lipase activity.

OBJECTIVE

To compare the efficacy, safety, and cost of fixed-dose low-molecular-weight heparin (dalteparin) with adjusted-dose unfractionated heparin as anticoagulant for continuous hemofiltration.

METHODS

Prospective, randomized, controlled clinical trial.

METHODS

University-affiliated adult intensive care unit

METHODS

All patients requiring continuous hemofiltration for acute renal failure or systemic inflammatory response syndrome (SIRS) were eligible. Fifty-seven patients were enrolled. Eleven were excluded, seven because of major protocol violations and four died before hemofiltration.

METHODS

Patients received continuous venovenous hemodialysis with filtration with prefilter replacement at 500 mL/hr and countercurrent dialysate at 1000 mL/hr. Filters were primed with normal saline containing anticoagulant. Dalteparin-treated patients received a commencement bolus of 20 units/kg and a maintenance infusion at 10 units/kg/hr. Heparin-treated patients received a commencement bolus of 2000-5000 units and a maintenance infusion at 10 units/kg/hr, titrated to achieve an activated partial thromboplastin time in the patient of 70-80 secs.

RESULTS

The primary outcome measure--time to failure of the hemofilter--was compared using survival analysis. Twenty-two patients (13 with acute renal failure and nine with SIRS; total, 41 filters) were randomized to heparin. Twenty-five patients (16 with acute renal failure and nine with SIRS; total, 41 filters) were randomized to dalteparin. Mean (SE) activated partial thromboplastin time in the heparin group was 79 (4.3) secs. Mean (SE) anti-factor-Xa activity in the six patients given dalteparin who were assayed was 0.49 (0.07). Mean (SE) prehemofiltration platelet count was 225 (35.5) x 10(9) for heparin and 178 (18.1) x 10(9) for dalteparin (p = .24, unpaired Student's t-test). Mean (SE) prehemofiltration hemoglobin was 11.4 (0.61) g/dL for heparin and 10.6 (0.38) g/dL for dalteparin (p = .31, unpaired Student's t-test).

METHODS

There was no significant difference in the time to failure between the two groups (p = .75, log rank test). For dalteparin, Kaplan-Meier (K-M) mean (SE) time to failure of the hemofilter was 46.8 (5.03) hrs. For heparin, K-M mean (SE) time to failure was 51.7 (7.51) hrs. The 95% CI for difference in mean time to failure was -13 to 23 hrs. The power of this study to detect a 50% change in filter life was >90%.

RESULTS

Mean (SE) reduction in platelet count during hemofiltration was 63 (25.8) x 10(9) for heparin and 41.8 (26.6) x 10(9) for dalteparin (p = .57, unpaired Student's t-test). Eight patients given dalteparin and four patients given heparin had screening for heparin-induced thrombocytopenia; three of the dalteparin patients and one of the heparin patients were positive (p = 1.0, Fisher's exact test). There were three episodes of trivial bleeding and two episodes of significant bleeding for dalteparin, and there were three episodes of trivial bleeding and four episodes of significant bleeding for heparin (p = .53, chi-square test). The mean (SE) decrease in hemoglobin concentration during hemofiltration was 0.51 (0.54) g/dL for heparin and 0.28 (0.49) g/dL for dalteparin (p = .75, unpaired Student's t-test). The mean (SE) packed-cell transfusion volume during hemofiltration was 309 (128) mL for heparin and 290 (87) mL for dalteparin (p = .90, unpaired Student's t-test). Daily costs, including coagulation assays, of hemofiltration were approximately 10% higher using dalteparin than with heparin.

CONCLUSIONS

Fixed-dose dalteparin provided identical filter life, comparable safety, but increased total daily cost compared with adjusted-dose heparin. Unfractionated heparin remains our anticoagulant of choice for continuous hemofiltration in intensive care.

OBJECTIVE

To review the state of the art as reflected in the medical literature and the consensus opinion of recognized experts in the field regarding the laboratory monitoring of unfractionated heparin therapy.

UNASSIGNED

The authors made an extensive review of the literature. The draft manuscript was circulated to every participant in the consensus conference prior to the convening of the conference. Extensive discussion concerning all of the issues addressed in the manuscript as well as the resulting recommendations occurred. This information was then used to revise the manuscript into its final form.

CONCLUSIONS

The resulting manuscript has 23 specific recommendations regarding preanalytic, analytic, and postanalytic phases of monitoring and testing for complications related to unfractionated heparin therapy. This report contains detailed discussion of these recommendations and includes literature citations that support them. A number of issues for which consensus could not be reached are also discussed. A method is provided to assist laboratories, particularly small laboratories, in providing clinicians with an appropriate therapeutic range for the activated partial thromboplastin time, the most commonly used test in monitoring heparin therapy.

BACKGROUND

Few reports have addressed the value of unfractionated heparin (UFH) or low-molecular-weight heparin in treating the full spectrum of patients with venous thromboembolism (VTE), including recurrent VTE and pulmonary embolism.

METHODS

In an open, multicenter clinical trial, 720 consecutive patients with acute symptomatic VTE, including 119 noncritically ill patients (16.5%) with pulmonary embolism and 102 (14.2%) with recurrent VTE, were randomly assigned to treatment with subcutaneous UFH with dose adjusted by activated partial thromboplastin time by means of a weight-based algorithm (preceded by an intravenous loading dose), or fixed-dose (adjusted only to body weight) subcutaneous nadroparin calcium. Oral anticoagulant therapy was started concomitantly and continued for at least 3 months. We recorded the incidence of major bleeding during the initial heparin treatment and that of recurrent VTE and death during 3 months of follow-up.

RESULTS

Fifteen (4.2%) of the 360 patients assigned to UFH had recurrent thromboembolic events, as compared with 14 (3.9%) of the 360 patients assigned to nadroparin (absolute difference between rates, 0.3%; 95% confidence interval, -2.5% to 3.1%). Four patients assigned to UFH (1.1%) and 3 patients assigned to nadroparin (0.8%) had episodes of major bleeding (absolute difference between rates, 0.3%; 95% confidence interval, -1.2% to 1.7%). Overall mortality was 3.3% in each group.

CONCLUSIONS

Subcutaneous UFH with dose adjusted by activated partial thromboplastin time by means of a weight-based algorithm is as effective and safe as fixed-dose nadroparin for the initial treatment of patients with VTE, including those with pulmonary embolism and recurrent VTE.