Rat skin heparin proteoglycan labelled biosynthetically with 35S was fractionated on a column of antithrombin-Sepharose into fractions with varying degrees of affinity for antithrombin. These were treated with NaOH to release heparin chains (Mr 60,000-100,000), by beta-elimination or incubated with serum to produce fragments of the same order of size as commercial heparin (Mr 5000-30,000), by endoglycosidase cleavage. Chains and fragments were then fractionated on antithrombin-Sepharose. The various fractions were deaminated with HNO2 at pH 1.5 followed by reduction with NaB3H4. Approx 90% of the incorporated 3H was associated with disaccharides. These were fractionated by high-performance ion-exchange chromatography. A unique minor component corresponding to the sequence glucuronosyl-N-sulphoglucosaminyl (3,6-di-O-sulphate) in the polysaccharide was found only in fractions with high affinity for antithrombin. The glucosamine residue linked to C-4 of this glucuronosyl unit was predominantly (or exclusively) N-sulphated rather than N-acetylated, pointing to a structural difference between the antithrombin-binding region of rat heparin and that of pig mucosal heparin. Calculations based on the distribution of the glucosaminyl 3-O-sulphate group showed that approximately two-thirds of the total antithrombin-binding regions present in the unfractionated material were accommodated by only 20% of the proteoglycan molecules, and by 10% of the polysaccharide chains. While most of the proteoglycan molecules thus lacked such regions (and hence affinity for antithrombin) a minor proportion of the polysaccharide chains contained on the average three binding regions per molecule. These findings support by direct chemical analysis an earlier proposal, based on anticoagulant activities of similar rat skin heparin fractions, that the distribution of antithrombin-binding sites in intact heparin proteoglycans is markedly non-random.

Bivalirudin, a direct thrombin inhibitor, is as effective as unfractionated heparin (UFH), with decreased bleeding in patients with acute coronary syndromes who undergo percutaneous coronary intervention (PCI). The aim of this study was to evaluate the effectiveness of bivalirudin versus UFH in selected PCI patients at high bleeding risk. Four hundred one consecutive patients who underwent PCI fulfilling ≥ 1 enrollment criterion (age >75 years, chronic renal failure, and diabetes mellitus) were randomized to bivalirudin (bolus 0.75 mg/kg followed by infusion during the procedure; n = 198) or UFH (75 IU/kg; n = 203). In the overall population, 39% were aged >75 years, 22% had renal failure, 63% had diabetes, and 29% had acute coronary syndromes. The primary efficacy end point was the 30-day incidence of major adverse cardiac events (cardiac death, myocardial infarction, stent thrombosis, or target vessel revascularization). The primary safety end point was the occurrence of any bleeding or entry-site complications after PCI. All patients were preloaded with clopidogrel 600 mg. Glycoprotein IIb/IIIa inhibitors were used at the operators' discretion. Thirty-day major adverse cardiac event rates were 11.1% in the bivalirudin group and 8.9% in the UFH group (p = 0.56); the primary efficacy end point was reached mainly because of periprocedural myocardial infarction; 1 patient in the bivalirudin group had stent thrombosis. Occurrence of the primary safety end point was 1.5% in the bivalirudin group and 9.9% in the UFH group (p = 0.0001); this benefit was essentially driven by the prevention of entry-site hematomas >10 cm (0.5% vs 6.9%, p = 0.002). In conclusion, Anti-Thrombotic Strategy for Reduction of Myocardial Damage During Angioplasty-Bivalirudin vs Heparin (ARMYDA-7 BIVALVE) indicates that bivalirudin, compared with UFH, causes significantly lower bleeding and has a similar incidence of major adverse cardiac events in patients with older age, diabetes mellitus, or chronic renal failure who undergo PCI.

Early coronary intervention in patients with non-ST segment elevation acute coronary syndromes (ACS) may be facilitated by adjunctive pharmacotherapies. Concomitant therapies such as low-molecular-weight heparins and platelet glycoprotein (GP) IIb/IIIa receptor blockade offer advantages in safety and efficacy during coronary intervention. Data from randomized clinical trials support the administration of both enoxaparin and platelet GP IIb/IIIa blockade to patients who present with non-ST segment elevation ACS. Enoxaparin, with its proven efficacy, predictability of action, and ease of administration, has been shown to be superior to unfractionated heparin in preventing major coronary events. Abciximab administration during percutaneous coronary intervention (PCI) reduces the incidence of ischemic adverse outcomes and appears to improve survival in long-term follow-up. The preliminary experience with combining these two therapies during PCI in the NICE 4 trial demonstrates a low incidence of minor/major bleeding and transfusion, and infrequent major cardiac events to 30 days follow-up. Algorithms for the use of these newer adjunctive pharmacotherapies in the care of patients presenting to the cardiac catheterization laboratory are presented.

A total of 1290 patients were enrolled in a randomized multicentre double blind study in order to investigate the use of two doses of a new low molecular weight heparin, Logiparin, in the prevention of deep vein thrombosis (DVT) in general surgery. Patients who were included had no contraindication to heparin therapy and had at least one of the recognized risk factors for DVT. Patients were randomized to receive unfractionated heparin (UH) 5000 units b.d., Logiparin 2500 units daily or Logiparin 3500 units daily. Each treatment was given subcutaneously 2 h before surgery and continued for 7-10 days. Daily 125I-labelled fibrinogen uptake tests (FUTs) were performed from day 2 to day 7 to detect DVT, and phleboangiography was used to confirm the diagnosis. The wound was examined on a daily basis to check for haematoma formation, and all patients were followed up for 1 month after operation. All three treatment arms were well matched for age, sex, weight, diagnosis and type of operation performed. The three major inclusion criteria in the trial were malignancy, age over 60 years and a history of varicose veins. Positive FUTs (UH = 4.2 per cent, Logiparin 2500 units daily = 7.9 per cent, Logiparin 3500 units daily = 3.7 per cent) and positive angiograms (UH = 3.0 per cent, Logiparin 2500 units daily = 5.6 per cent, Logiparin 3500 units daily = 2.3 per cent) were significantly more common in the Logiparin 2500 units daily group than in the UH and Logiparin 3500 units daily groups. The rates of major complications (severe haemorrhage, death, pulmonary embolism, reintervention) were similar in the three groups.

OBJECTIVE

The purpose of this study was to determine the mechanistic basis for thrombin generation and increased prothrombotic potential after the abrupt cessation of intravenous (i.v.) unfractionated heparin among patients with acute coronary syndromes.

BACKGROUND

A "rebound" increase in prothrombotic potential has been observed biochemically and clinically after the abrupt cessation of unfractionated heparin (UFH) among patients with acute coronary syndromes. Although the mechanism is unknown, tissue factor and the extrinsic coagulation cascade, both operative in atherosclerotic vascular disease and arterial thrombosis, are thought to be centrally involved.

METHODS

In a single-center, pilot study, 30 patients with either unstable angina or non-ST segment elevation myocardial infarction who had received a continuous i.v. infusion of UFH for 48 h were randomly assigned to: 1) abrupt cessation, 2) i.v. weaning over 12 h or 3) subcutaneous weaning over 12 h.

RESULTS

Thrombin generation (prothrombin fragment 1.2) was evident within 1 h of UFH cessation, increased progressively (by nearly two-fold) at 24 h (p = 0.002) and correlated inversely with tissue factor pathway inhibitor concentration (r = -0.61). Thrombin generation was greatest among patients randomized to abrupt cessation (1.6-fold increase at 24 h) and least in those with i.v. weaning.

CONCLUSIONS

Thrombin generation after the abrupt cessation of UFH may represent a drug-induced impairment of physiologic vascular thromboresistance in response to locally generated tissue factor. A dosing strategy of abbreviated i.v. weaning attenuates but does not prevent heparin rebound among patients with acute coronary syndromes.

OBJECTIVE

To estimate the cost-effectiveness of low-molecular-weight heparin (LMWH) in the treatment of proximal lower extremity deep venous thrombosis.

METHODS

Cost-effectiveness analysis that includes the treatment of the index case and simulated 3-month follow-up.

METHODS

Acute care facility.

METHODS

Hypothetical cohorts of 1,000 patients who present with proximal deep venous thrombosis.

METHODS

Intravenous unfractionated heparin (UH), LMWH (40% at home, 60% in hospital), or selective UH/LMWH (UH for hospitalized patients and LMWH for patients treated at home).

RESULTS

The outcomes were recurrent thrombosis, mortality, direct medical costs, and marginal cost-effectiveness ratios from the payer's perspective. At the base-case and under most assumptions in the sensitivity analysis, the LMWH and the selective UH/LMWH strategies dominate the UH strategy i.e., they result in fewer cases of recurrent thrombosis and fewer deaths, and they save resources. The savings occur primarily by decreasing the length of stay. The LMWH strategy resulted in lower costs as compared with the UH strategy when the proportion of patients treated at home was more than 14%. Treating 1, 000 patients with the LMWH strategy as compared with the UH/LMWH strategy would result in 10 fewer cases of recurrent thrombosis, 1.2 fewer deaths, at an additional cost of $96,822; the cost-effectiveness ratio was $9,667 and $80,685 per recurrent thrombosis or death prevented, respectively.

CONCLUSIONS

Treatment with LMWH leads to savings and better outcomes as compared with UH in patients with lower extremity deep venous thrombosis. The selective UH/LMWH strategy is an alternative option.

1. We have investigated the effect of an unfractionated heparin preparation, a low-molecular weight heparinoid (Org 10172) and the polyanionic molecule polyglutamic acid against PAF-induced airway hyperresponsiveness and pulmonary cell infiltration in neonatally immunized rabbits in vivo. 2. Exposure of neonatally immunized rabbits to aerosolized platelet activating factor (PAF) (80 micrograms ml-1 for 60 min) elicited an increase in airway responsiveness to inhaled histamine 24 h and 72 h following challenge which was associated with an infiltration of inflammatory cells into the airways, as assessed by bronchoalveolar lavage (BAL). 3. A significant increase in the total numbers of cells recovered from BAL fluid was associated with significantly increased cell numbers of neutrophils, eosinophils and mononuclear cells 24 h following PAF exposure. The numbers of eosinophils and neutrophils in the airways remained elevated 72 h after challenge. 4. The intravenous administration of an unfractionated preparation of heparin (100 units kg-1) or Org 10172 (100 micrograms kg-1) 30 min prior to PAF exposure significantly inhibited the airway hyperresponsiveness induced by PAF, 24 h and 72 h following challenge. PAF-induced hyperresponsiveness was not significantly affected by prior intravenous administration of polyglutamic acid (100 micrograms kg-1). 5. The intravenous administration of unfractionated heparin (100 units kg-1), Org 10172 (100 micrograms kg-1) or polyglutamic acid (100 micrograms kg-1) 30 min prior to PAF exposure significantly inhibited the expected increase in total cell infiltration. 6. This study shows that unfractionated heparin and a low-molecular weight heparinoid, Org 10172, are capable of inhibiting both the airway hyperresponsiveness and pulmonary cell infiltration induced by PAF in the rabbit.

BACKGROUND

In several open and 1 controlled trial, unfractionated heparin was effective in the treatment of active ulcerative colitis (UC). Low molecular weight heparin (LMWH) had a similar effect in several open studies.

METHODS

We studied the efficacy, safety, and tolerability of LMWH in mild to moderately active UC in a randomized, double-blind, placebo-controlled trial. In all, 29 patients with a mild or moderate recurrence of UC during salicylate treatment were randomized to receive either reviparin 3,436 IU (n = 15) subcutaneously twice daily or placebo (n = 14). The study period was 8 weeks. Treatment was discontinued if there was no improvement at 4 weeks or at any disease progression. Primary outcome measure was clinical improvement at 8 weeks measured by the Colitis Activity Index (CAI) and the Clinical Symptoms Grading (CSG, based on the CAI). Endoscopic and histologic grading and quality of life as measured by the Inflammatory Bowel Disease Questionnaire (IBDQ) were secondary outcome measures. Patients were closely monitored for adverse events.

RESULTS

Twenty of 29 patients finished the 8-week treatment period (reviparin versus placebo: 11 versus 9; P = 0.70). There was no difference in CSG, CAI, endoscopic and histologic grading, or IBDQ. Treatment was well tolerated and no serious adverse events occurred.

CONCLUSIONS

In this study, treatment with LMWH showed no significant clinical advantage compared to placebo in mild to moderately active UC.

Mucus obstruction of the airway in patients with cystic fibrosis (CF) reduces lung function, invites infection, and limits delivery of inhaled drugs including gene therapy vectors to target cells. Not all patients respond to presently available mucolytics, and new approaches are needed. Our objectives were to investigate the in vitro effects of unfractionated heparin (UFH) on the morphology and rheology of sputum and the effect of UFH on diffusion of 200-nm nanospheres through sputum from adult CF patients. Confocal laser scanning microscopy was used to image fluorescently stained actin and DNA components of CF sputum, and atomic force microscopy was used to image isolated DNA networks. The viscoelasticity of CF sputum was measured using dynamic oscillatory rheometry. Nanosphere diffusion was measured through CF sputum using a Boyden chamber-based assay. Actin-DNA bundles in CF sputum were disaggregated by UFH at concentrations of 0.1-10 mg/ml, and UFH enhanced the endonuclease activity in sputum from patients on dornase alfa therapy. UFH significantly reduced the elasticity and yield stress, but not the viscosity, of CF sputum from patients not receiving dornase alfa therapy. Heparin dose-dependently significantly increased the diffusion of nanospheres through CF sputum from patients not on dornase alfa therapy from 10.5 +/- 2.5% at baseline to 36.9 +/- 4.4% at 10 mg/ml but was more potent, with maximal effect at 0.1 mg/ml, in patients who were on dornase alfa therapy. Thus the mucoactive properties of UFH indicate its potential as a new therapeutic approach in patients with cystic fibrosis.

The purpose of this article is to review and critically appraise the cost-effectiveness analyses that have compared various modalities for the prevention and treatment of deep vein thrombosis (DVT) and pulmonary embolism. Studies were identified by MEDLINE search and review of bibliographies of retrieved articles. Original economic analyses for the prevention or treatment of venous thromboembolism published in the English language literature were included in the analysis. In addition to collecting clinical and economic data, the methodological quality of the studies was evaluated using predefined criteria. Separate analyses were performed for studies of the prevention, and of the treatment, of venous thromboembolism following general surgery and following total hip arthroplasty. Fourteen cost-effectiveness analyses involving thromboembolic prophylaxis following total hip arthroplasty and 7 following general surgery met the eligibility criteria for this analysis. Each of the total hip arthroplasty studies containing a 'no intervention arm' determined that effective forms of prophylaxis not only reduced the rates of venous thromboembolic complications, but were less costly than a strategy of not providing venous thromboembolic prophylaxis. Six of 7 studies found low-molecular-weight (LMW) heparin to be more effective, and 4 of 7 found it to be less costly, than either unfractionated heparin or warfarin for the prevention of venous thrombosis following total hip arthroplasty. Following general surgical procedures, 6 of 7 studies found prophylaxis to be both more effective and less costly than no prophylaxis. Two studies also concluded that LMW heparin was more effective and less costly than unfractionated heparin for the prevention of DVT after general surgery. In general, the studies included in this overview were of high methodological quality with 11 of 15 studies fulfilling 4 or more of the 6 criteria for sound cost-effectiveness analyses. Effective venous thromboembolic prophylaxis results in fewer complications and is less costly than no prophylaxis following general surgery and total hip arthroplasty. LMW heparin was reported to be more efficacious and cost effective than unfractionated heparin following general surgery, and unfractionated heparin and warfarin following total hip arthroplasty. However, these findings must be regarded with caution in view of recent clinical trials and a meta-analysis reporting that the efficacy of LMW heparin and unfractionated heparin are similar following general surgery, and the efficacy of LMW heparin and warfarin are similar following total hip arthroplasty. Conclusions about the most cost-effective treatment for DVT await the publication of cost analyses from clinical trials comparing outpatient subcutaneous LMW heparin with inpatient therapy with intravenous unfractionated heparin.

Hospitalization for surgery has a high risk of developing venous thromboembolism, a condition that encompasses both deep-vein thrombosis and its potentially fatal complication, pulmonary embolism. Colorectal surgery implies a specific high risk for postoperative thromboembolic complications relative to other general surgery. This may be a result of pelvic dissection, the perioperative positioning of these patients, or the presence of additional risk factors common to this patient group, such as cancer, advanced age, or inflammatory bowel disease. The potential impact of venous thromboembolism and the need for effective thromboprophylaxis often are underestimated in these patients. Recommendations for thromboprophylaxis in colorectal surgery patients are based on the American College of Chest Physicians guidelines for thrombosis prevention in general surgery patients, with treatment stratified according to the type of surgery and additional venous thromboembolism risk factors present. Prophylaxis with low-molecular-weight heparin or unfractionated heparin is recommended for colorectal surgery patients classified as moderate to high risk. The small number of studies focusing specifically on colorectal patients, or on cancer or abdominal surgery patients with a colorectal subgroup, has shown that both low-molecular-weight heparin and unfractionated heparin can effectively reduce the incidence of venous thromboembolism. Low-molecular-weight heparin has the practical advantage of once-daily administration and shows a lower risk of heparin-induced thrombocytopenia. This review will assess the risk of venous thromboembolism in colorectal surgery patients and discuss current evidence-based guidelines and recommendations for prevention of venous thromboembolism.

The objective of the present study was to compare the efficacy and safety of low-dose unfractionated heparin (UFH) and a low-molecular-weight heparin (LMWH) as prophylaxis against venous thromboembolism in critically ill surgical patients undergoing major surgery. This was a randomized prospective study in which critically ill patients scheduled to undergo major elective surgery were allocated to receive subcutaneously either LMWH once daily and a placebo injection containing sterile 0.9% normal saline or 5000 IU UFH twice daily subcutaneously. Each patient was evaluated postoperatively clinically and confirmed by Doppler study for development of deep vein thrombosis (DVT). One hundred and fifty-six patients completed the protocol. There was similar efficacy of UFH as compared with LMWH in the prophylaxis of DVT. There was also no statistically significant difference in the incidence of major complications in the heparin group as compared with the LMWH group. However, minor hemorrhagic complications such as wound hematoma and surgical site bleeding were significantly more in the heparin group as compared with the LMWH group. Both UFH 5000 units subcutaneously twice daily and LMWH 40 mg once daily provide highly effective and well tolerated prophylaxis for critically ill surgical patients. Considering the advantage of once-daily dosing, a wider adoption of prophylaxis with LMWH may be justified on the basis of patient acceptability and saving of nursing time.

A 65-year-old woman with a complete atrioventricular block was diagnosed as having cardiac sarcoidosis. (18)F-FDG PET/CT imaging without unfractionated heparin loading revealed systemic abnormal uptake indicating sarcoidosis. However, the cardiac lesions were vague because of the physiological FDG uptake. One month later, (18)F-FDG PET/CT using heparin loading was performed to evaluate the lesion activity prior to the start of steroid administration. (18)F-FDG PET/CT imaging with heparin loading showed the cardiac lesions more clearly and suppressed the FDG uptake in normal myocardium. Heparin loading during FDG PET/CT may be useful for detecting cardiac involvement in patients with cardiac sarcoidosis.

Patients receiving chronic anticoagulation therapy pose a clinical challenge when therapy needs to be interrupted for surgical or invasive procedures. Maintaining anticoagulation places them at risk for serious bleeding complications, whereas discontinuing anticoagulation puts them at risk of thromboembolic complications. Most patients can undergo dental procedures, cataract surgery, and diagnostic endoscopy without discontinuing anticoagulation. The main patient groups that may require a periprocedural alternative to oral anticoagulation (periprocedural thromboprophylaxis or bridging) include patients with prosthetic heart valves, atrial fibrillation, and hypercoagulable states and patients with chronic venous thrombosis who are undergoing surgery. Currently, there is little consensus on the appropriate perioperative treatment of patients on long-term warfarin therapy. There are an increasing number of studies that evaluate the benefits of periprocedural bridging with low-molecular-weight heparin (LMWH) in place of unfractionated heparin (UFH). An advantage of LMWH over UFH is that perioperative conversion from warfarin therapy with LMWH can be carried out in the outpatient setting, which is more convenient for patients and is cost effective. As with the use of UFH, there are reports of maternal thromboembolic complications with LMWHs in pregnant women with mechanical heart valves. This review brings together the available data on periprocedural bridging to assess the available options for patients on long-term warfarin therapy who are undergoing surgical procedures. It provides a rationale for using LMWHs while individualizing the risks versus benefits in a given patient population.

Despite the wide contemporary availability of pharmacological and mechanical means of reperfusion, a very significant proportion of ST-segment elevation myocardial infarction (STEMI) patients are still not offered any reperfusion therapy, and some of them are considered "ineligible for reperfusion." Spontaneous reperfusion and contraindications to the use of fibrinolytics and/or mechanical reperfusion methods account only for a small part of these clinical situations. The boundary between "timely" and "late" presentation in STEMI, the appropriateness of percutaneous intervention in patients presenting late after onset of symptoms, and the impact of sex and age on the eligibility and/or choice of reperfusion therapy continue to be challenged by the most recent published data. In the current invasive-driven reperfusion era, if scientific evidence and clinical guidelines are applied diligently, the vast majority of eligible STEMI patients should receive reperfusion therapy. Pharmacological nonlytic therapy of patients with STEMI, regardless of the choice of reperfusion strategy or the absence of it, is clearly defined by the current practice guidelines. Available data suggest that for patients who do not receive any form of reperfusion, anticoagulation therapy with low molecular weight heparin provides a clear additional mortality benefit versus placebo. Fondaparinux as compared with usual care (unfractionated heparin infusion or placebo) significantly reduces the composite of death or myocardial reinfarction without increasing severe bleeding or number of strokes. In the treatment of late-presenting patients with STEMI (beyond the first 12 h after onset of symptoms), clinical evaluation and risk stratification represent the crucial elements helping in decision making between therapeutic interventions.

The Seventh American College of Chest Physicians (ACCP) Conference on Antithrombotic and Thrombolytic Therapy provides guidelines for outpatient management of anticoagulation therapy. The ACCP guidelines recommend short-term warfarin therapy, with the goal of maintaining an International Normalized Ratio (INR) of 2.5 +/- 0.5, after major orthopedic surgery. Therapy for venous thromboembolism includes an INR of 2.5 +/- 0.5, with the length of therapy determined by associated conditions. For patients with atrial fibrillation, the INR is maintained at 2.5 +/- 0.5 indefinitely; for most patients with mechanical valves, the recommended INR is 3.0 +/- 0.5 indefinitely. Use of outpatient low-molecular-weight heparin (LMWH) is as safe and effective as inpatient unfractionated heparin for treatment of venous thromboembolism. The ACCP recommends starting warfarin with unfractionated heparin or LMWH for at least five days and continuing until a therapeutic INR is achieved. Because patients with venous thromboembolism and cancer who have been treated with LMWH have a survival advantage that extends beyond their venous thromboembolism treatment, the ACCP recommends beginning their therapy with three to six months of LMWH. When invasive procedures require the interruption of oral anticoagulation therapy, recommendations for bridge therapy are determined by balancing the risk of bleeding against the risk of thromboembolism. Patients at higher risk of thromboembolization should stop warfarin therapy four to five days before surgery and start LMWH or unfractionated heparin two to three days before surgery.

OBJECTIVE

The purpose of this study was to compare the effect of receiving pretreatment with antithrombin before randomization as well as overall efficacy and safety of enoxaparin versus unfractionated heparin (UFH) in the SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors) trial.

BACKGROUND

The SYNERGY trial results demonstrated noninferiority in outcomes with enoxaparin compared with UFH. Randomized treatment was independent of prerandomization treatment.

METHODS

Analyses were first performed on the 4 prerandomization subgroups: patients who received no antithrombin therapy and those who were treated with enoxaparin or UFH or both. Then, we focused on the subgroup of patients who received no pretreatment or were pretreated with and randomized to the same drug. Of the 9,978 patients, 2,440 did not receive prerandomization therapy and 6,138 received consistent therapy through randomization. The primary end point was the composite of death and nonfatal myocardial infarction (MI) at 30 days.

RESULTS

After adjustment for differences among the subgroups, no significant difference in the association between the 4 pretreatment groups and death or MI remained (p = 0.171). The randomized treatment effect on 30-day death or MI tended to vary with pretreatment (p = 0.055 for interaction test after adjustment). Patients who received consistent therapy with enoxaparin had significantly less death or MI than patients randomized to UFH (adjusted p = 0.041) with a trend toward increased bleeding.

CONCLUSIONS

Treatment with antithrombin therapy before randomization had potential impact on comparison of study drug effects. After adjustment for differences in baseline characteristics between subgroups, consistent therapy with enoxaparin might be superior to UFH in reducing death or nonfatal MI, with a modest excess in bleeding.

OBJECTIVE

To determine predictive factors, clinical and demographics characteristics of patients with pulmonary embolism (PE) in ICU, and to identify factors associated with poor outcome in the hospital and in the ICU.

METHODS

During a four-year prospective study, a medical committee of six ICU physicians prospectively examined all available data for each patient in order to classify patients according to the level of clinical suspicion of pulmonary thromboembolism. During the study periods, all patients admitted to our ICU were classified into four groups. The first group includes all patients with confirmed PE; the second group includes some patients without clinical manifestations of PE; the third group includes patients with suspected and not confirmed PE and the fourth group includes all patients with only deep vein thromboses (DVTs) without suspicion of PE. The diagnosis of PE was confirmed either by a high-probability ventilation/perfusion (V/Q) scan or by a spiral computed tomography (CT) scan showing one or more filling defects in the pulmonary artery or in its branches. The diagnosis was also confirmed by echocardiography when a thrombus in the pulmonary artery was observed.

RESULTS

During the study periods, 4408 patients were admitted in our ICU. The diagnosis of PE was confirmed in 87 patients (1.9%). The mean delay of development of PE was 7.8 +/- 9.5 days. On the day of PE diagnosis, clinical examination showed that 50 patients (57.5%) were hypotensive, 63 (72.4%) have SIRS, 15 (17.2%) have clinical manifestations of DVT and 71 (81.6%) have respiratory distress requiring mechanical ventilation. In our study, intravenous unfractionated heparin was used in 81 cases (93.1%) and low molecular weight heparins were used in 4 cases (4.6%). The mean ICU stay was 20.2 +/- 25.3 days and the mean hospital stay was 25.5 +/- 25 days. The mortality rate in ICU was 47.1% and the in-hospital mortality rate was 52.9%. Multivariate analysis showed that factors associated with a poor prognosis in ICU are the use of norepinephrine and epinephrine. Furthermore, factors associated with in-hospital poor outcome in multivariate analysis were a number of organ failure associated with PE>>/= 3. MOREOVER, COMPARISON BETWEEN PATIENTS WITH AND WITHOUT PE SHOWED THAT PREDICTIVE FACTORS OF PE ARE: acute medical illness, the presence of meningeal hemorrhage, the presence of spine fracture, hypoxemia with PaO(2)/FiO(2) ratio <300 and the absence of pharmacological prevention of venous thromboembolism.

CONCLUSIONS

Despite the high frequency of DVT in critically ill patients, symptomatic PE remains not frequently observed, because systematic screening is not performed. Pulmonary embolism is associated with a high ICU and in-hospital mortality rate. Predictive factors of PE are acute medical illness, the presence of meningeal hemorrhage, the presence of spine fracture, hypoxemia with PaO(2)/FiO(2) < 300 and the absence of pharmacological prevention of venous thromboembolism.

In a prospective, double-blind investigation of the prophylaxis of deep vein thrombosis (DVT) in patients undergoing elective major abdominal surgery, 269 patients were randomized into two groups. One hundred and thirty-two patients received a fixed combination of heparin sodium 5000 units plus dihydroergotamine mesylate 0.5 mg (H/DHE) twice a day and 137 patients received a fixed combination of low molecular weight heparin 1500 units plus dihydroergotamine mesylate 0.5 mg (LMWH/DHE) once a day as well as one injection of placebo per day. Treatment was initiated 2 h pre-operatively in both groups and continued for 7-10 days. The frequency of DVT determined by the 125I-labelled fibrinogen uptake test and phlebography was 10.3 per cent in patients receiving H/DHE and 10.4 per cent in those receiving LMWH/DHE. DVT of the femoral vein was detected in four patients of the H/DHE group and in none of the LMWH/DHE group. Intra- and postoperative blood loss did not differ significantly between both groups. Also no difference in the development of wound haematoma and injection site haematoma was found. While intra-operative volume substitution was comparable in both groups, significantly more patients under H/DHE prophylaxis received volume substitution during the postoperative phase. These results show that once-daily prophylaxis with the combination of low molecular weight heparin and dihydroergotamine is equally as effective and as safe as the twice-daily regimen using a combination of unfractionated heparin and dihydroergotamine in patients undergoing elective, major abdominal surgery. The advantages of the once-daily regimen of LMWH/DHE include greater patient acceptance, less nursing time and greater cost effectiveness, provided the new combination can be sold at a cost which maintains this advantage.

BACKGROUND

Determination of plasma rivaroxaban concentration may be necessary in certain clinical situations. Rivaroxaban concentration can be accurately and rapidly determined using a chromogenic anti-activated factor X (factor Xa) assay with specific drug calibrator material. However, there are currently no Food and Drug Administration (FDA)-approved rivaroxaban calibrators available in the United States.

OBJECTIVE

To determine whether FDA-approved commercial kits for measuring heparin anti-factor Xa activity can be used to assess rivaroxaban concentrations when calibrated for unfractionated heparin or low-molecular-weight heparins.

METHODS

Trough and peak samples were taken from 30 patients taking rivaroxaban as part of their routine care for atrial fibrillation or venous thromboembolism. The samples were tested using 3 different FDA-approved commercial kits for measuring heparin anti-factor Xa activity.

RESULTS

There was acceptable correlation between rivaroxaban levels and heparin anti-factor Xa activity using Berichrom and COAMATIC heparin kits. The STA liquid heparin method was the most sensitive to presence of rivaroxaban.

CONCLUSIONS

This study demonstrates a strong correlation, but variability between kits, for assessing rivaroxaban concentrations using heparin anti-factor Xa assays. The extent of the heparin calibration curve significantly limits the measurable rivaroxaban range, and this application may be useful only for trough samples. The STA liquid heparin, being exquisitely sensitive to rivaroxaban, may be suitable for ruling out presence of the drug. The routine use of heparin-calibrated anti-factor Xa assays to quantify rivaroxaban is not advocated, and when applied, it must be used with caution and limitations clearly understood.

The management of pregnant women with mechanical heart valves is challenging. Recently, based on small numbers of patients and poor-quality data, correspondence from Aventis Pharmaceuticals Inc has described treatment "failures" and concerns about teratogenicity with the use of the low-molecular-weight heparin (LMWH) enoxaparin. The company issued a "Warning" that enoxaparin should not be used in patients with prosthetic heart valves and a "Precaution" about potential teratogenicity. This has created a huge problem for physicians managing pregnant women with prosthetic heart valves because the alternatives, unfractionated heparin and warfarin, are problematic. There have been case reports of failures (including death from thrombosed valves) with unfractionated heparin, whereas the package insert for warfarin states that the drug is contraindicated during pregnancy because of potential teratogenicity. Initially, LMWHs appeared suitable for pregnant patients with prosthetic heart valves. Unfortunately, the company correspondence, presumably supported by the Food and Drug Administration (FDA), raises medicolegal concerns with use of any LMWH. We believe that pharmaceutical companies and the FDA should not endorse scientifically unsupported claims that eliminate acceptable therapeutic options. This correspondence has created considerable confusion among patients and treating physicians and is likely to lead to frivolous lawsuits and preclude the performance of properly designed trials in pregnant women. We believe a consensus conference among experts in the field to identify key unresolved issues and a commitment by the FDA and industry to perform appropriate studies are now critical.

BACKGROUND

Tirofiban, an intravenous glycoprotein IIb/IIIa antagonist, and enoxaparin, a low molecular weight heparin, have each been shown to be effective at reducing cardiac ischemic events compared to unfractionated heparin alone in separate trials of patients with unstable angina and non-Q-wave myocardial infarction. The combination of these agents may offer further therapeutic benefit.

METHODS

Fifty-five patients with non-Q-wave myocardial infarction were randomized to receive double-blind treatment with tirofiban (0.1 microgram/kg/min i.v.) for 48-108 h coadministered with either enoxaparin (1 mg/kg sc q 12 h) (n=26) or unfractionated heparin (i.v. adjusted to activated partial-thromboplastin time) (n=27) to evaluate pharmacokinetics, pharmacodynamics, and safety. The primary objective of the study was to investigate the effect of unfractionated heparin versus enoxaparin on the plasma clearance of tirofiban.

RESULTS

Coadministration of tirofiban and enoxaparin was generally well tolerated. Plasma clearance of tirofiban was 176.7+/-59.8 and 187.5+/-81.8 ml/min, respectively, for enoxaparin and unfractionated heparin-treated patients (P=NS). The mean difference was well within the prespecified criterion for comparability. Administration of tirofiban with enoxaparin vs. unfractionated heparin resulted in lesser variability and a trend towards greater inhibition of platelet aggregation using 5 microM adenosine phosphate agonist. More patients achieved target inhibition of platelet aggregation >70% in the tirofiban and enoxaparin group (84% vs. 65%, P=0.19). Median bleeding time was 21 min for tirofiban and enoxaparin vs.>> or =30 min for tirofiban and unfractionated heparin (P=NS). For a given level of inhibition of platelet aggregation, bleeding time was less prolonged with tirofiban and enoxaparin than tirofiban and unfractionated heparin (adjusted mean bleeding time 19.6 vs. 24.9 min, P=0.02). Tirofiban plasma concentration and clearance were comparable whether coadministered with enoxaparin or unfractionated heparin. There were no major or minor bleeding events in either group by the TIMI criteria.

CONCLUSIONS

The more consistent inhibition of platelet aggregation and lower adjusted bleeding time of tirofiban and enoxaparin vs. tirofiban and unfractionated heparin support the therapeutic potential of combining these two agents. These data from the first clinical report of coadministration of a glycoprotein IIb/IIIa receptor antagonist and a low molecular weight heparin are consistent with prior data which show differential pharmacodynamic effects of enoxaparin and unfractionated heparin on platelet aggregation.

BACKGROUND

The lack of a specific counteragent to bivalirudin may complicate the management of patients with coronary artery (CA) perforation during percutaneous coronary intervention (PCI).

OBJECTIVE

Assess outcomes of patients with CA perforation from three PCI trials comparing intravenous bivalirudin with provisional glycoprotein (GP) IIb/IIIa inhibition versus unfractionated heparin (UFH) plus GP IIb/IIIa.

METHODS

A pooled analysis of patients treated with PCI in three randomized trials including REPLACE-2, ACUITY, and HORIZONS-AMI.

RESULTS

Among a total of 12,921 patients, CA perforation occurred in 35 patients (0.27%). By multivariable analysis, baseline creatinine clearance was the only independent predictor of CA perforation (per 10 mL/min decrease, odds ratio [95% confidence interval]= 1.28 [1.11, 1.47], P = 0.0007). At 30 days, patients with versus without CA perforation had significantly (all P values < or =0.001) higher rates of 30-day mortality (11.4% vs. 1.0%), myocardial infarction (MI) [Q wave: 22.9% vs. 5.7%; non-Q wave: 17.1% vs. 4.9%], target vessel revascularization (TVR) [20.1% vs. 1.8%], and composite end-point of death/MI/TVR (31.4% vs. 7.8%). Patients assigned to bivalirudin versus UFH plus a GP IIb/IIIa inhibitor had nonsignificantly lower rates of death (0% vs. 18.8%, P = 0.08), similar rates of MI (26.7% vs. 25.0%, P = 0.92), significantly lower rates of TVR (6.7% vs. 37.5%, P = 0.04), and similar rates of the composite end-point of death/MI/TVR (35.5% vs. 26.7%, P = 0.54).

CONCLUSIONS

In three PCI trials, treatment of patients experiencing CA perforation with adjunctive antithrombotic therapy of bivalirudin monotherapy was not associated with worse outcomes compared to treatment with UFH plus GP IIb/IIIa inhibitors.