BACKGROUND

Pulmonary embolism is a common complication of deep vein thrombosis. It has been established that low molecular weight heparin may be used to treat deep vein thrombosis or pulmonary embolism and randomized studies have established that outpatient management of deep vein thrombosis with low molecular weight heparin is at least as effective as in-hospital management with unfractionated heparin.

METHODS

This was a prospective cohort study of eligible patients with pulmonary embolism managed as outpatients using dalteparin (200 U/kg s/c daily) for a minimum of five days and warfarin for 3 months. Outpatients included those managed exclusively out of hospital and those managed initially for 1-3 days as inpatients who then completed therapy out of hospital. Reasons for admission included hemodynamic instability; hypoxia requiring oxygen therapy; admission for another medical reason; severe pain requiring parenteral analgesia or high risk of major bleeding. Patients were followed for three months for clinically apparent recurrent venous thromboembolism and bleeding.

RESULTS

Between three teaching hospitals, a total of 158 patients with pulmonary embolism were identified. Fifty patients were managed as inpatients and 108 as outpatients. Of the outpatients, 27 were managed for an average of 2.5 days as inpatients and then completed dalteparin therapy as outpatients. The remaining 81 patients were managed exclusively as outpatients with dalteparin. For all outpatients the overall symptomatic recurrence rate of venous thromboembolism was 5.6% (6/108) with only 1.9% (2/108) major bleeds. There were a total of four deaths with none due to pulmonary embolism or major bleed.

CONCLUSIONS

This prospective study suggests that outpatient management of pulmonary embolism is feasible and safe for the majority of patients.

Traditional anticoagulant drugs, including unfractionated heparin and warfarin, have several limitations. A new strategy for the design of new antithrombotic drugs is based on selective inhibition of a specific coagulation factor. These include direct thrombin inhibitors and factor Xa inhibitors. Two parenteral direct thrombin inhibitors, lepirudin and argatroban, have FDA approval for the management of heparin-induced thrombocytopenia. Ximelagatran, an oral prodrug of the direct thrombin inhibitor melagatran, has shown efficacy in the prevention and treatment of venous thromboembolism as well as stroke prevention in patients with atrial fibrillation. Fondaparinux is a synthetic pentasaccharide, which binds to antithrombin, thereby indirectly selectively inhibiting factor Xa. Fondaparinux has demonstrated its efficacy compared to low-molecular-weight heparin in randomized clinical trials and is FDA approved for the prevention and treatment of venous thromboembolism. A number of oral direct factor Xa inhibitors as well as other oral direct thrombin inhibitors are in clinical development for the prevention and treatment of thrombosis.

OBJECTIVE

We sought to determine whether the observed benefits of enoxaparin were maintained beyond the early phase; a one-year follow-up survey was undertaken for patients enrolled in the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q wave Coronary Events (ESSENCE) study.

BACKGROUND

We have previously reported a significant benefit of low molecular weight as compared with unfractionated heparin (UFH) in the 14- and 30-day incidence of a composite end point of death, myocardial infarction (MI) or recurrent angina in patients with unstable angina or non-Qwave MI.

METHODS

The study recruited 3,171 patients with recent-onset rest angina and underlying ischemic heart disease. All patients received oral aspirin daily and were randomized to receive enoxaparin subcutaneously every 12 h or UFH (intravenous bolus followed by continuous infusion) in a double-blind, double-dummy fashion for a median of 2.6 days.

RESULTS

The incidence of the composite triple end point at one year was lower among patients receiving enoxaparin as compared with those receiving UFH (32.0% vs. 35.7%, p = 0.022), with a trend toward a lower incidence of the secondary composite end point of death or MI (11.5% vs. 13.5%, p = 0.082). At one year, the need for diagnostic catheterization and coronary revascularization was lower in the enoxaparin group (55.8% vs. 59.4%, p = 0.036 and 35.9% vs. 41.2%, p = 0.002, respectively).

CONCLUSIONS

In patients with unstable angina or non-Qwave MI, enoxaparin therapy significantly reduced the rates of recurrent ischemic events and invasive diagnostic and therapeutic procedures in the short term with sustained benefit at one year.

The efficacy of low-molecular-weight heparin as a prophylactic agent was assessed in 150 consecutive patients over the age of 40 undergoing major abdominal surgery. Fifty of these patients received 1250 activated partial thromboplastin time (APTT) units of low-molecular-weight heparin every 12 hours: three developed isotopic deep vein thrombosis, which was confirmed by phlebography in two cases. The other 100 patients received a single injection of 1850 APTT units of low-molecular-weight heparin. Three of them developed isotopic deep vein thrombosis; phlebography failed to confirm the presence of thrombi in each case. None of the 150 patients studied died from fatal or contributory pulmonary emboli. Low-molecular-weight heparin was not associated with any increase in preoperative or postoperative bleeding. The effect of equal amounts of postoperative bleeding. The effect of equal amounts of low-molecular-weight heparin and unfractionated heparin on the coagulation mechanism during surgery was investigated in another 30 patients. The clotting assays and results of in-vivo platelet function tests indicated that both preparations produced similar effect. Intragroup comparisons, however, showed significant differences in the anti-factor Xa activity, lipoprotein lipase release, and plasma prekallikrein concentrations. A single injection of low-molecular-weight heparin daily is a convenient way of preventing deep vein thrombosis in high-risk patients undergoing major abdominal surgery.

Venous thromboembolism (VTE) is an increasingly frequent complication of anticancer therapy. The underlying mechanisms are not completely understood, but are related in part to oncogene activation and tissue factor (TF) expression. Several risk factors have been identified including site and stage of cancer, patient comorbidities, and specific therapeutic agents. Candidate biomarkers such as blood counts, TF, and P-selectin have recently been identified. A risk model predictive of chemotherapy-associated VTE has been validated. Thromboprophylaxis with low molecular weight heparin (LMWH), unfractionated heparin (UFH), or fondaparinux is recommended for hospitalized medical and surgical cancer patients. Long-term anticoagulation with LMWH is safe and effective in reducing recurrent VTE in cancer. The role of thromboprophylaxis in ambulatory cancer patients receiving chemotherapy is an area of active investigation.

Protamine is unable to completely reverse the anticoagulant effect of the low-molecular-weight heparins (LMWH), a fact of clinical importance given the rapid increase in use of LMWH in clinical practice. This investigation sought to determine the mechanism by which LMWH were able to resist protamine-mediated inactivation. Affinity fractionation of LMWH by passage through a protamine column, with subsequent determination of molecular mass and sulphate charge density, demonstrated that the protamine-resistant fraction in LMWH is an ultra-low-molecular-weight fraction with low sulphate charge density. This group of molecules was not found in unfractionated heparin, even when species of similar molecular mass were compared. We then determined that different commercially available LMWH varied in their ability to be neutralized by protamine, and that this variability correlated with the total sulphate content of the LMWH. We conclude that reduced sulphate charge, not molecular mass, is the principle reason that protamine is unable to fully inactivate LMWH. Furthermore, different LMWH vary in their ability to be neutralized by protamine, suggesting that product-specific recommendations for neutralization might be developed.

BACKGROUND

Pulmonary embolism (PE) occurs in 50% or more of patients with proximal deep-vein thrombosis. Low-molecular-weight heparin treatment is effective and safe in patients with deep vein thrombosis and may also be so in patients with PE. Recent rigorous clinical trials have established objective criteria for determining a high probability of PE by perfusion lung scanning.

OBJECTIVE

To compare low-molecular-weight heparin with intravenous heparin for the treatment of patients with objectively documented PE and underlying proximal deep vein thrombosis.

METHODS

In a multicenter, double-blind, randomized trial, we compared fixed-dose subcutaneous low-molecular-weight heparin (tinzaparin sodium) given once daily with dose-adjusted intravenous heparin given by continuous infusion using objective documentation of clinical outcomes. Pulmonary embolism at study entry was documented by the presence of high-probability lung scan findings.

RESULTS

Of 200 patients with high-probability lung scan findings at study entry, none of the 97 who received low-molecular-weight heparin had new episodes of venous thromboembolism compared with 7 (6.8%) of 103 patients who received intravenous heparin (95% confidence interval for the difference, 1.9%-11.7%; P = .01). Major bleeding associated with initial therapy occurred in 1 patient (1.0%) who was given low-molecular-weight heparin and in 2 patients (1.9%) given intravenous heparin (95% confidence interval for the difference, -2.4% to 4.3%).

CONCLUSIONS

Low-molecular-weight heparin administered once daily subcutaneously was no less effective and probably more effective than use of dose-adjusted intravenous unfractionated heparin for preventing recurrent venous thromboembolism in patients with PE and associated proximal deep vein thrombosis. Our findings extend the use of low-molecular-weight heparin without anticoagulant monitoring to patients with submassive PE.

BACKGROUND

Venous thromboembolism (VTE) prophylaxis in medically ill patients has received a level 1A recommendation in previously published clinical guidelines. Pharmacologic prophylaxis for VTE includes unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and fondaparinux. Few direct comparisons between anticoagulants exist in medically ill patients.

OBJECTIVE

This meta-analysis was conducted to assess UFH and LMWH (including the selective factor Xa inhibitor fondaparinux) in the reduction of in-hospital VTE in unselected medically ill patients.

METHODS

We searched MEDLINE, EMBASE, and the Cochrane Controlled Trials Registry databases from January 1981 through September 2007 (English language) for randomized controlled trials using the following terms: dalteparin, enoxaparin, fondaparinux, nadroparin, and heparin. References of included articles and key review papers for additional studies were also searched. Data from studies were included in the analysis if the studies included medically ill patients with risk factors for VTE who had been followed up for 7 to 21 days.

RESULTS

A total of 12,391 patients (of whom 8357 were in placebo-controlled trials) from 9 studies were included. Mean age for the entire cohort was 72.8 years; mean (SD) body mass index, 25.6 kg/m2; and mean (SD) actual body weight, 68.2 kg. Deep vein thrombosis (DVT) was significantly reduced with the addition of an LMWH compared with placebo (odds ratio [OR], 0.60; 95% CI, 0.47-0.75; P < or = 0.001), but rates of DVT were similar when comparing LMWH with UFH (OR, 0.92; 95% CI, 0.56-1.52). No significant differences in pulmonary embolism (PE) or death were found among the UFH, LMWH, and placebo groups. LMWH was associated with a significant increased risk for minor bleeding compared with placebo (OR, 1.64; 95% CI, 1.18-2.29; P = 0.003). However, no significant difference was found between LMWH and UFH (OR, 0.68; 95% CI, 0.27-1.70). Major bleeding events were similar among all groups: LMWH/fondaparinux versus placebo, OR, 1.65 (95% CI, 0.8-3.4); LMWH/fondaparinux versus UFH, OR, 0.69 (95% CI, 0.29-1.68); LMWH/fondaparinux versus UFH or placebo, OR, 1.16 (95% CI, 0.66-2.04).

CONCLUSIONS

This analysis suggests that VTE prophylaxis with an LMWH (including fondaparinux) or UFH is effective in reducing the rate of DVT, but this benefit did not extend to enhanced protection against PE. Additionally, LMWH and UFH had similar bleeding outcomes.

As a result of numerous clinical trials and meta-analyses supporting the superior efficacy and relative safety of low-molecular-weight heparins (LMWHs) compared with unfractionated heparin (UFH), LMWHs are emerging as the antithrombotic agents of choice for the prevention and treatment of deep vein thrombosis and pulmonary embolism. In addition, data indicate that enoxaparin given with low-dosage aspirin is more effective than UFH in treating acute coronary syndromes. Anti-Xa activity can be used as a biologic marker of LMWH activity. Because of the more predictable anticoagulant response to subcutaneous administration of LMWHs compared with UFH, routine monitoring of anti-Xa activity in clinically stable adults with uncomplicated disease is not recommended. Because the optimal dosage of LMWHs has not been established for patients with renal insufficiency or extremes of body weight, during pregnancy, or for children, anti-Xa activity monitoring may be warranted in these subsets.

BACKGROUND

Haemodialysis catheters used for vascular access are frequently complicated by infection and catheter-related thrombosis. Improvement of interdialytic locking solutions could reduce these problems. Trisodium citrate (TSC) has been advocated in recent years because it might have antimicrobial qualities.

METHODS

Antimicrobial efficacy of four concentrations of TSC (2.2, 7.5, 15 and 30%) was compared with three equi-osmolal sodium chloride (NaCl) concentrations, unfractionated heparin 5000 IU/ml and a solution of gentamicin 1 mg/ml in TSC 7.5%. We analysed antimicrobial properties by two classical in vitro susceptibility tests. All tests were performed in triplicate by incubation of test fluids with Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa and Candida albicans.

RESULTS

Increasing TSC concentrations effectively killed the staphylococcal strains in both assays. For E.coli and P.aeruginosa complete killing was achieved only with TSC 30%. TSC 30% was also the only solution that significantly inhibited growth of C.albicans. Heparin manifested no antimicrobial effect of any significance. Adding gentamicin to TSC provided superior bacterial growth inhibition but had no effect on yeast growth. TSC solutions manifested superior antimicrobial activity compared with iso-osmolal NaCl solutions in both assays.

CONCLUSIONS

This in vitro study demonstrates superior antimicrobial activity of TSC, especially in higher concentrations, in contrast to heparin. The mechanism seems to differ from hyperosmolality. Ca(2+) and Mg(2+) chelating effects are probably more important. Adding gentamicin provided the most potent antimicrobial solution. However, for reasons concerning development of bacterial resistance and sensitization of the patient, continuous exposition to aminoglycosides seems not advisable.

Venous thromboembolism (VTE) is a serious complication during and after hospitalization, yet is a preventable cause of in-hospital death.Without VTE prophylaxis, the overall VTE incidence in medical and general surgery hospitalized patients is in the range of 10% to 40%, while it ranges up to 40% to 60% in major orthopaedic surgery. With routine VTE prophylaxis, fatal pulmonary embolism is uncommon in orthopaedic patients and the rates of symptomatic VTE within three months are in the range of 1.3% to 10%.VTE prophylaxis methods are divided into mechanical and pharmacological. The former include mobilization, graduated compression stockings, intermittent pneumatic compression device and venous foot pumps; the latter include aspirin, unfractionated heparin, low molecular weight heparin (LMWH), adjusted dose vitamin K antagonists, synthetic pentasaccharid factor Xa inhibitor (fondaparinux) and newer oral anticoagulants. LMWH seems to be more efficient overall compared with the other available agents. We remain sceptical about the use of aspirin as a sole method of prophylaxis in total hip and knee replacement and hip fracture surgery, while controversy still exists regarding the use of VTE prophylaxis in knee arthroscopy, lower leg injuries and upper extremity surgery. Cite this article: EFORT Open Rev 2018;3:136-148. DOI: 10.1302/2058-5241.3.170018.

Elderly people represent a patient population at high thromboembolic risk, but also at high hemorrhagic risk. There is a general tendency among physicians to underuse anticoagulants in the elderly, probably both because of underestimation of thromboembolic risk and overestimation of bleeding risk. The main indications for anticoagulation are venous thromboembolism (VTE) prophylaxis in medical and surgical settings, VTE treatment, atrial fibrillation (AF) and valvular heart disease. Available anticoagulants for VTE prophylaxis and initial treatment of VTE are low molecular weight heparins (LMWH), unfractionated heparin (UFH) or synthetic anti-factor Xa pentasaccharide fondaparinux. For long-term anticoagulation vitamin K antagonists (VKA) are the first choice and only available oral anticoagulants nowadays. Assessing the benefit-risk ratio of anticoagulation is one of the most challenging issues in the individual elderly patient, patients at highest hemorrhagic risk often being those who would have the greatest benefit from anticoagulants. Some specific considerations are of utmost importance when using anticoagulants in the elderly to maximize safety of these treatments, including decreased renal function, co-morbidities and risk of falls, altered pharmacodynamics of anticoagulants especially VKAs, association with antiplatelet agents, patient education. Newer anticoagulants that are currently under study could simplify the management and increase the safety of anticoagulation in the future.

In a double-blind study, patients with phlebographically proven deep venous thrombosis (DVT) were treated with subcutaneous injections twice a day of either unfractionated heparin (UH; n = 27) or low molecular weight heparin (LH; n = 29) for 7 days, and the dose was adjusted until therapeutic range was reached, according to a chromogenic substrate anti-Xa assay. Forty-eight percent of the LH group did not need dose adjustment as compared to 24% of the UH group. During the course of heparin administration, deviation from initial heparin activity was frequent in both groups, but mean activity did not indicate a cumulative effect in either group. There was 1 incidence of pulmonary embolism (LH) and only 1 minor bleeding episode (UH). Half of the patients in both groups were phlebographically improved. We conclude that subcutaneous heparin treatment with UH or LH appears safe and convenient.

This chapter about fibrinolytic, antiplatelet, and antithrombin treatment for acute ST-segment elevation (STE) myocardial infarction (MI) is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patient values may lead to different choices (for a full understanding of the grading see the chapter by Guyatt et al, CHEST 2008; 133[suppl]:123S-131S). Among the key recommendations in this chapter are the following: for patients with ischemic symptoms characteristic of acute MI of < or = 12 h in duration and persistent STE, we recommend that all undergo rapid evaluation for reperfusion (primary percutaneous coronary intervention [PCI] or fibrinolytic) therapy and have a reperfusion strategy implemented promptly after contact with the health-care system (Grade 1A). For patients with ischemic symptoms characteristic of acute MI of < or = 12 h in duration and persistent STE, we recommend administration of streptokinase, anistreplase, alteplase, reteplase, or tenecteplase over no fibrinolytic therapy (all Grade 1A). For patients with symptom duration < or = 6 h, we recommend the administration of alteplase or tenecteplase over streptokinase (both Grade 1A). We recommend aspirin over no aspirin therapy followed by indefinite therapy (Grade 1A); we also recommend clopidogrel in addition to aspirin for up to 28 days (Grade 1A). In addition to aspirin and other antiplatelet therapies, we recommend the use of antithrombin therapy (eg, unfractionated heparin (UFH), enoxaparin, or fondaparinux) over no antithrombin therapy (Grade 1A), including for those patients receiving fibrinolysis (and regardless of which lytic agent is administered), primary PCI, or patients not receiving reperfusion therapy.

While parenteral anticoagulants such as unfractionated and low molecular weight heparins and the oral vitamin K antagonists are effective for the prevention and treatment of thrombosis, they have a number of limitations. Up until recently, vitamin K antagonists (e.g. warfarin) have been the only available oral anticoagulants. These drugs have a delayed onset of action, food and drug interactions, and variable pharmacokinetics/pharmacodynamics such that regular laboratory monitoring and dose adjustments are required to maintain the International Normalized Ratio (INR) in the therapeutic range. New oral anticoagulants that selectively inhibit either thrombin (dabigatran etexilate) or factor Xa (rivaroxaban, apixaban) have now gained approval in many countries for some clinical indications. Unlike warfarin, these drugs have a rapid onset of action and a relatively wide therapeutic range such that coagulation monitoring is not required. These agents are more convenient for patients and health care providers, but also have potential for improving clinical outcomes and being more cost-effective than existing agents. This will result in major changes in the way that thrombosis is managed, both with respect to prevention and treatment. The new oral inhibitors of thrombin and factor Xa, however, have limitations and the absence of a need for regular laboratory monitoring makes medication compliance extremely important for maintaining efficacy given their relatively short half-lives. Furthermore there will be challenges in managing patients on these agents who develop recurrent thrombosis or major bleeding until methods to monitor and assess the levels of the new agents are readily available and specific antidotes are developed.

The purpose of this study was to purify and characterize the agent responsible for the antimetastatic activity of an extract of the salivary glands (SGE) of the Mexican leech Haementeria officinalis. When administered intravenously in mice on the same day as the intravenous inoculation of T241 sarcoma cells, SGE markedly reduces the number and size of lung tumor colonies. In designing a purification protocol for the antimetastatic agent, we postulated that the antimetastatic agent would also display anticoagulant activity. Thus, we discovered that heparin affinity chromatography followed by anion-exchange chromatography results in a fraction highly enriched in both potent anticoagulant activity and potent antimetastatic activity. Approximately, 200-300 micrograms of purified protein is isolated from 150 mg of SGE. As little as 15 micrograms of this material inhibits tumor cell metastasis to the same extent as 1.0 mg of the unfractionated SGE. When analyzed on sodium dodecyl sulfate gels the active fraction consists mainly of one polypeptide band having an apparent molecular weight of approximately 17,000 under either reducing or nonreducing conditions. The protein has a pI of approximately 9.5 and a molecular weight of approximately 17,000 under nondenaturing conditions. A specific antiserum prepared against the 17,000-dalton protein indicated that this protein is the major anticoagulant and antimetastatic agent of leech salivary gland extract. We have termed this anticoagulant, antimetastatic agent "antistasin." We hypothesize that antistatin inhibits coagulation via factor Xa, and not thrombin, since factor Xa, but not thrombin, is rapidly inactivated upon addition of antistasin. The mechanism of antistasin's antimetastatic activity is currently under investigation.

BACKGROUND

Thrombosis is not uncommon in children with serious medical conditions. Unfractionated heparin, the most commonly used anticoagulant in the acute management of thrombosis, has significant pharmacologic limitations, especially in infants. Newer anticoagulants have improved properties relative to heparin, and this may enhance the outcome in children.

OBJECTIVE

To determine dosing, and to assess the safety and efficacy of bivairudin for infants with thrombosis.

METHODS

Infants <6 months old were chosen for this pilot study as they may most benefit from a direct thrombin inhibitor because of their physiologically low antithrombin levels. This was an open label, dose-finding and safety study. Patients received one of three bolus doses and one of two initial infusion doses with subsequent dosing adjusted utilizing the activated partial thromboplastin time. Safety was assessed by specific bleeding endpoints. Efficacy was determined by reassessing the initial imaging study at 48-72 h and by measurement of molecular markers of thrombin generation.

RESULTS

Sixteen patients completed the study. All three bolus doses resulted in therapeutic anticoagulation, as did both initial infusion doses. A dose-response effect was noted for the continuous infusion but not the bolus dosing. Two patients met the study criteria for major bleeding, both with gross hematuria, which resolved with a reduction in the bivalirudin infusion rate. In terms of efficacy, 37.5% of patients had complete or partial resolution of their thrombosis by 48-72 h. There was a significant decrease in all three molecular markers of thrombin generation.

CONCLUSIONS

This study demonstrates the potential utility of bivalirudin in the pediatric population.

OBJECTIVE

The specific objective of the REDUCE trial was to evaluate the effect of low molecular weight heparin on the incidence and occurrence of restenosis in patients undergoing percutaneous transluminal coronary angioplasty (PTCA).

BACKGROUND

Unfractionated heparin and its low molecular weight fragments possess antiproliferative effects and have been shown to reduce neointimal smooth muscle cell migration and proliferation in response to vascular injury in experimental studies.

METHODS

The REDUCE trial is an international prospective, randomized, double-blind, multicenter study. Twenty-six centers in Europe and Canada enrolled 625 patients with single-lesion coronary artery obstructions suitable for PTCA. Three hundred six patients received reviparin as a 7,000-U bolus before PTCA, followed by 10,500 U as an infusion over 24 h and then twice-daily 3,500-U subcutaneous application for 28 days. The 306 patients in the control group received a bolus of 10,000 U of unfractionated heparin followed by an infusion of 24,000 U over 24 h. These patients then underwent 28 days of subcutaneous placebo injections. The primary end points were efficacy (defined as a reduction in the incidence of major adverse events [i.e., death, myocardial infarction, need for reintervention or bypass surgery]), absolute loss of minimal lumen diameter and incidence of restenosis during the observation period of 30 weeks after PTCA.

RESULTS

Using the intention to treat analysis for all patients, 102 (33.3%) in the reviparin group and 98 (32%) in the control group have reached a primary clinical end point (relative risk [RR] 1.04, 95% confidence interval [CI] 0.83 to 1.31, p = 0.707). Likewise, no difference in late loss of minimal lumen diameter was evident for both groups. Acute events within 24 h occurred in 12 patients (3.9%) in the reviparin group and 25 (8.2%) in the control group (RR 0.49, 95% CI 0.26 to 0.92, p = 0.027) during or immediately after the initial procedure. In the control group, eight major bleeding complications occurred, and in the reviparin group, seven were observed within 35 days after PTCA.

CONCLUSIONS

Reviparin use during and after coronary angioplasty did not reduce the occurrence of major clinical events or the incidence of angiographic restenosis over 30 weeks.

Cancer patients undergoing surgery are at a high risk of venous thromboembolism, but few studies have described the rate of autopsy-confirmed fatal pulmonary embolism after heparin thromboprophylaxis. In a post hoc analysis of a randomized study (MC-4), which compared the efficacy and safety of certoparin (3000 anti-Xa IU, subcutaneously, once-daily) with unfractionated heparin (5000 IU, subcutaneously, three-times daily) in 23078 patients undergoing surgery lasting more than 30 min, the incidence of autopsy-confirmed fatal pulmonary embolism, death and bleeding in the cancer patients (n=6124) was compared with non-cancer patients (n=16954). Fatal pulmonary embolism was significantly more frequent in cancer patients (0.33% [20/6124]) than in non-cancer patients (0.09% [15/16954], relative risk (RR), 3.7 [95% confidence intervals (CI), 1.80, 7.77], p=0.0001) at 14 days post-prophylaxis. Perioperative mortality was also significantly higher in cancer patients than in noncancer patients (3.14% [192/6124] vs. 0.71% [120/16954], RR, 4.54 [95% CI, 3.59, 5.76], p=0.0001), as were blood loss (p<0.0001), and transfusion requirements (p<0.0001). Prevention of venous thromboembolism in cancer surgical patients remains a clinical challenge.

Clinical and experimental studies have suggested that unfractionated heparin (UFH) effects malignancy progression. We reviewed all published clinical reports concerning the effects of UFH, as compared to no treatment on survival of cancer patients. Studies were classified on methodological strength and subdivided as to whether therapeutic or prophylactic dosages of UFH were used. Mortality rates after 3 years were extracted or calculated. One randomized study that evaluated the use of UFH in therapeutic dosages in patients with small cell lung carcinoma reported on an improved survival (odds ratio (OR) 0.64; 95% confidence interval (CI): 0.25 to 1.62). A detrimental effect was observed in 2 randomized studies which investigated the effects of intraportal UFH treatment in a prophylactic dose after surgery for gastrointestinal cancer (OR 1.66; 95% CI: 1.02 to 2.71). In contrast, level 2 studies in which either therapeutic or prophylactic dosages of UFH on mortality of patients with gastrointestinal cancer were evaluated, showed OR of 0.58 (95% CI; 0.11-3.13) and 0.65 (95% CI 0.51 to 0.84), respectively. We conclude that there is no convincing evidence of either positively or negatively effects of UFH on survival of patients with malignancy.

In a multicenter, double-blind clinical trial in 1,968 inpatients 1 daily subcutaneous administration of LMW heparin plus 2 placebo injections or 3 x 5,000 IU unfractionated (UF) heparin was given for 10 (8-11) days. The primary end point was the incidence of proximal deep-vein thrombosis or pulmonary embolism. Patients were assessed during the study period for development of proximal deep-vein thrombosis by compression sonography at days 1 and 10 and for pulmonary embolism by scintigraphy in symptomatic patients. Aim of the study was to demonstrate the equivalence of both treatment regimens. A total of 1,968 patients were randomized to receive UF or LMW heparin. Of these, 378 patients were excluded during the study period, so that 780 patients on UF and 810 on LMW heparin were included in the efficacy analysis. Four primary end points were observed with UF and 6 with LMW heparin, demonstrating the equivalence of treatments (p = 0.012). Additionally, pulmonary embolism was suspected as the cause of death in 6 patients who died during the study (3 per treatment group). A higher frequency of death (n = 32) was observed in the LMW-heparin group (p = 0.02) particularly documented in a part of the centers. Safety analysis showed a higher frequency of local pruritus, local erythema and subcutaneous hematoma, a higher increase in plasma levels of triglycerides, total cholesterol, alanine aminotransferase and aspartate aminotransferase, and a decrease of antithrombin III in patients receiving UF heparin. A decrease in platelet count (values ranging between 40,000 and 80,000/microliter) was observed in 4 patients with UF and in none with LMW heparin. No severe thrombocytopenia was observed. Subcutaneous LMW heparin is as effective as UF heparin for prophylaxis of thromboembolism in bedridden, hospitalized medical patients.

OBJECTIVE

To evaluate the use of low-molecular-weight heparin (LMWH) in combination with low-dose aspirin (LDA) for the treatment of antiphospholipid antibody (APA)-associated recurrent pregnancy loss and to compare the results with the use of unfractionated heparin (UFH) plus LDA.

METHODS

Prospective, controlled, multicenter pilot study.

METHODS

Two academically based reproductive health centers.

METHODS

Patients with three or more pregnancy losses and positive APA.

METHODS

Patients were treated with LMWH and LDA (n = 25) or UFH and LDA (n = 25).

METHODS

Fetal outcome and maternal complications from treatments were compared between the two treatment groups.

RESULTS

Of the 25 patients in the LMWH group, 21 (84%) delivered a viable infant and 4 (16%) miscarried. Of the 25 patients in the UFH group, 20 (80%) delivered a viable infant and 5 (20%) miscarried. These differences were not statistically significant. No major bleeding episodes occurred during pregnancy or at the time of delivery. No cases of deep venous thrombosis, thrombocytopenia, pre-eclampsia, gestational diabetes, or bone fractures were noted in either of the two groups.

CONCLUSIONS

In this pilot study, the use of LDA in combination with LMWH during pregnancy for the prevention of recurrent pregnancy loss in women with antiphospholipid syndrome seems to be as safe as UFH plus LDA. Large, randomized trials will be required to determine differences in outcome with LMWH and LDA compared with treatment with UFH combined with LDA in this group of patients.

OBJECTIVE

Unfractionated heparin and its antidote, protamine sulfate, allow for rapid and reversible anticoagulation during cardiac surgery with cardiopulmonary bypass, yet limitations exist, including a variable dose-response, dependence on a cofactor for anticoagulant effect, and antigenic potential. This trial was performed to evaluate the safety and efficacy of bivalirudin as an alternative to heparin with protamine reversal in on-pump cardiac surgery.

METHODS

We conducted a randomized, open-label, multicenter trial comparing heparin with protamine reversal to bivalirudin in patients undergoing cardiac surgery with cardiopulmonary bypass. The primary objective was to demonstrate comparable rates of in-hospital procedural success defined as freedom from death, Q-wave myocardial infarction, stroke, or repeat revascularization. Twenty-one institutions enrolled 101 patients randomized to bivalirudin and 49 patients to heparin treatment.

RESULTS

The primary end point of procedural success was not significantly different between the bivalirudin arm and the heparin/protamine arms at 7 days, 30 days, or 12 weeks' follow-up. Adequate anticoagulation was achieved in all patients. Secondary end points including mortality, 24-hour blood loss, overall incidence of transfusions, and duration of surgery were similar between the two arms.

CONCLUSIONS

Bivalirudin is a safe and effective anticoagulant for patients undergoing a wide range of cardiac surgical procedures with cardiopulmonary bypass. Procedural success rates with bivalirudin were similar to rates in patients receiving heparin anticoagulation, with no difference in mortality. Avoidance of blood stasis and attention to the intraoperative medical management of patients is critical for successful use of bivalirudin during cardiopulmonary bypass.