Advances in neuroimaging have modified our knowledge on cerebral vein thrombosis (CVT). This disease is now diagnosed more frequently, and increasing evidence as to what are the most common risk factors and on the natural history of the disease is becoming available. Most patients with CVT have a benign prognosis: only a minority of patients die during the acute phase or in the following months. Most patients surviving CVT recover completely, or have only mild functional or cognitive deficits. Unfractionated or low-molecular weight heparin is widely used as a first-line therapy of CVT, despite the absence of conclusive evidence about the safety and efficacy in this setting. Vitamin K antagonists are usually prescribed for secondary prevention, but the optimal duration of treatment remains unknown. Because most patients with CVT have partial or complete recanalization of the vessels within the first few months after the index event, and because recurrences of CVT after a first episode appear to be uncommon, routine use of long-term therapy or event life-long secondary prevention seem to be unnecessary.

The relationship between the inhibition of venous thrombosis and antifactor Xa (AXa) plasma levels, measured as ex vivo AXa activity at the moment of experimental thrombosis induction, was evaluated in rats treated by different administration routes with different doses of heparins of various molecular masses: unfractionated heparin (UH, 13 kDa), low-molecular-mass heparin (LMM-H, 5kD) and oligo-heparin (OL-H, 2 kD). The AXa activity levels of plasma samples were measured by an amidolytic method and expressed in AXa U/ml. The antithrombotic effect was determined by a vena cava ligature model and expressed as the percent inhibition of thrombus weight. A correlation between the two parameters was determined, regardless of the administration route used. Every heparin requires different AXa plasma levels to develop the same antithrombotic activity: the plasma concentration inducing a 50% protection was 0.09, 0.12 and 0.15 AXa U/ml, for UH, LMM-H and OL-H, respectively. Oligo-H has a significant antithrombotic activity when delivered by the intraileal route and the time course pharmacodynamics showed two phases for the parameters considered: in the second phase, a dissociation between AXa plasma level and antithrombotic effect was observed.

OBJECTIVE

Superior mesenteric vein thrombosis (SMVT) is generally difficult to diagnose and can be fatal. Mesenteric and portal vein thrombosis is rare and can be presented as more serious conditions than that of SMVT. We report patients with combined SMVT and portal vein thrombosis (PVT) who were treated successfully with early initiation of anticoagulation.

METHODS

The medical records of six patients (five male, one female) who presented with combined SMVT and PVT in our institute between January 1994 and September 2003 were reviewed retrospectively. All of the patients were treated with early initiation of anticoagulation using unfractionated heparin or low molecular weight heparin.

RESULTS

The mean hospital stay was 31 days and the mean follow-up period was 32 months. Three patients had an antithrombin III deficiency. The most common symptom was diffuse abdominal pain and signs included abdominal distension and tenderness. During the follow-up period, there were two patients who developed stricture of the small bowel necessitating resection and anastomosis of the small bowel. There was no case of peritonitis due to bowel necrosis or mortality.

CONCLUSIONS

The early initiation of anticoagulation in patients of SMVT combined with PVT could minimise the serious complication such as peritonitis due to bowel necrosis required immediate exploratory laparotomy.

OBJECTIVE

To review systematically the published literature on the treatment of deep venous thromboembolism after spinal cord injury (SCI).

METHODS

MEDLINE/PubMed, CINAHL, EMBASE, and PsycINFO databases were searched for articles addressing the treatment of deep venous thromboembolism post-SCI. Randomized controlled trials (RCTs) were assessed for methodologic quality using the Physiotherapy Evidence Database Scale, while non-RCTs were assessed using the Downs and Black evaluation tool.

METHODS

Studies included RCTs, non-RCTS, cohort, case-control, case series, pre-post, and postinterventional studies. Case studies were included only when no other studies were available.

METHODS

Data extracted included demographics, the nature of the study intervention, and study results.

RESULTS

Levels of evidence were assigned to the interventions using a modified Sackett scale.

CONCLUSIONS

Twenty-three studies met inclusion criteria. Thirteen studies examined various pharmacologic interventions for the treatment or prevention of deep venous thrombosis in patients with SCI. There was strong evidence to support the use of low-molecular-weight heparin in reducing venous thrombosis events, and a higher adjusted dose of unfractionated heparin was found to be more effective than 5000 units administered every 12 hours, although bleeding complications were more common. Nonpharmacologic treatments were also reviewed, but again limited evidence was found to support these treatments.

BACKGROUND

Venous thromboembolic disease (VTE) is a major cause of morbidity and mortality in hospitalized patients. Most hospitalized patients with a fatal pulmonary embolism are medical patients who do not have a history of recent surgery [BMJ 302 (1991) 709; J. R. Soc. Med. 82 (1989) 198]. There is evidence suggesting that VTE prophylaxis is indicated in many high risk medical patients [Chest 119 (2001) 132S; NEJM 341 (1999) 793]. However, previous studies have shown that only about one third of high risk medical patients receive VTE prophylaxis [Ann. Intern. Med. 115 (1991) 591; Chest 106 (1994) 13; Chest 107 (1995) 296]. The objective of this study was to determine the frequency of use of VTE prophylaxis in medical inpatients at two teaching hospitals in Hamilton, Ontario.

METHODS

A retrospective chart review of consecutive patients admitted to medical wards at two acute care sites of McMaster University affiliated teaching hospitals between October 10, 2001 and December 11, 2001 was performed. For each patient, demographic data, risk factors for VTE, method of VTE prophylaxis and contraindications to VTE prophylaxis were recorded.

RESULTS

756 patient charts were reviewed and 310 (41%) were excluded because the primary diagnosis required anticoagulation, the patients were being treated with anticoagulation (warfarin or heparin) before admission or the patient was admitted to the intensive care unit. Of the remaining 446 patients, 146 (33%) received some form of VTE prophylaxis. Of the patients receiving prophylaxis, 4% had early ambulation, 9% wore anti-embolic stockings (AES), 1% used intermittent pneumatic compression, 23% used unfractionated heparin and 3% used low molecular weight heparin. Two hundred five (46%) patients had one identifiable VTE risk factor and 63 (14%) had two or more risk factors. Patients with more VTE risk factors were more likely to receive prophylaxis.

CONCLUSIONS

One third of medical inpatients at two teaching hospitals in Hamilton received some form of VTE prophylaxis.

OBJECTIVE

The aim of this study was to compare outcomes in patients receiving consistent unfractionated heparin (UFH)/enoxaparin (ENOX) therapy and in those switched at randomization to bivalirudin monotherapy.

BACKGROUND

Crossover between UFH and ENOX has been associated with increased adverse outcomes in patients with acute coronary syndromes. The ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial demonstrated superior net clinical outcomes with similar rates of ischemia and significantly less major bleeding with bivalirudin monotherapy compared with UFH/ENOX plus a glycoprotein (GP) IIb/IIIa inhibitor. It is unknown if these results would be preserved in patients switched from UFH/ENOX to bivalirudin monotherapy.

METHODS

We compared composite ischemia, major bleeding, and net clinical outcomes at 30 days in patients receiving consistent UFH/ENOX therapy and in those switched at randomization from pre-treatment with UFH/ENOX to bivalirudin monotherapy. We also compared outcomes in patients naive to antithrombin therapy who were randomized to UFH/ENOX or bivalirudin monotherapy.

RESULTS

Two thousand one hundred thirty-seven patients received consistent UFH/ENOX (UFH n = 1,294, ENOX n = 843), and 2,078 patients pre-treated with UFH/ENOX were switched to bivalirudin. Patients switching to bivalirudin had similar rates of ischemia (6.9% vs. 7.4%, p = 0.52), less major bleeding (2.8% vs. 5.8%, p < 0.01), and improved net clinical outcomes (9.2% vs. 11.9%, p < 0.01) than those on consistent UFH/ENOX plus a GP IIb/IIIa inhibitor. Patients naive to antithrombin therapy who were administered bivalirudin (n = 1,427) had similar rates of ischemia (6.2% vs. 5.5%, p = 0.47), less major bleeding (2.5% vs. 4.9%, p < 0.001), and similar net clinical outcomes (8.0% vs. 9.4%, p = 0.17) compared with naive patients administered UFH/ENOX plus a GP IIb/IIIa inhibitor (n = 1,462).

CONCLUSIONS

Switching from UFH/ENOX to bivalirudin monotherapy results in comparable ischemic outcomes and an approximately 50% reduction in major bleeding compared with consistent UFH/ENOX plus a GP IIb/IIIa inhibitor. Patients naive to antithrombin therapy administered bivalirudin monotherapy had a significant reduction in bleeding and similar rates of ischemia compared with naive patients initiated with UFH or ENOX plus a GP IIb/IIIa inhibitor.

Two clinical trials in patients with acute deep venous thrombosis have indicated that the outpatient management with fixed-dose, subcutaneous low-molecular-weight heparin is at least as effective and safe as inpatient treatment with unfractionated intravenous heparin with respect to recurrent venous thromboembolism and major bleeding. We performed an economic evaluation alongside one of these trials to assess the cost consequences of the outpatient management strategy. Data were collected through case record forms, complemented by a prospective questionnaire in 78 consecutive patients, interviews with health care providers, and hospital data bases. Our study demonstrated that seventy-five percent of patients allocated to low-molecular-weight heparin received treatment either entirely at home or after a brief hospital stay. Fifteen percent of these patients required professional domiciliary care. Within-centre comparisons of resource utilisation in terms of natural units showed that outpatient management with low-molecular-weight heparin reduced the average number of hospital days in the initial treatment period in nine centres by 59 percent (95% CI: 43 to 71 percent) accompanied by a limited increase in outpatient and professional domiciliary care. The average reduction in hospital days at the end of follow up was 40 percent (95% CI: 25 to 54 percent). A cost-minimisation analysis, focusing on resource utilisation directly related to the treatment of deep venous thrombosis and associated costs in one centre demonstrated a cost reduction of 64 percent (95% CI: 56 to 72 percent) with the outpatient management with low-molecular-weight heparin. These data suggest that outpatient management of patients with proximal venous thrombosis using low-molecular-weight heparin reduces resource utilisation and total treatment cost. Implementation should be preceded by a cautious evaluation of a potential cost shifting and organisational prerequisites.

OBJECTIVE

We sought to determine the most efficient perioperative prophylactic strategy for deep venous thrombosis (DVT) in craniotomy patients by use of a decision analysis model.

METHODS

We conducted a structured review of the relevant literature and compiled the reported incidences of DVT, pulmonary embolism, and postoperative intracranial hemorrhage (ICH) in craniotomy patients. We also obtained from the literature estimates of the likelihood and the impact of various outcomes of these complications. Data from 810 craniotomies performed at our own institution were also examined. The decision analytic model was then used to compare the effectiveness of pneumatic compression boots with pneumatic compression boots combined with either unfractionated or low-molecular-weight heparin. The model dealt with variability by using both sensitivity analysis and Monte Carlo simulation.

RESULTS

As expected, the addition of heparin lowered the incidence of both DVT and pulmonary embolism, but at the cost of increasing ICH. Because the deleterious effects of ICH were so much greater than the benefits from heparinization, overall outcomes were best with mechanical prophylaxis alone. This was especially true for low-molecular-weight heparin, which is associated with a relatively high risk of ICH. Our own institutional data support the findings in the literature. Although the differences are modest, they reach statistical significance in the case of low-molecular-weight heparin.

CONCLUSIONS

Using decision analytic modeling, we have shown that mechanical prophylaxis yields outcomes in craniotomy patients superior to those of either unfractionated or low-molecular-weight heparin.

BACKGROUND

Medical intensive care unit (ICU) patients are at moderate risk of venous thromboembolism (VTE) and prophylaxis against VTE is recommended.

OBJECTIVE

To observe the range and frequency of VTE prophylaxis administered to medical ICU patients and to determine factors associated with different strategies in French and Canadian ICUs.

METHODS

Prospective cross-sectional observational study.

RESULTS

113/251 (45.0%) French and 29/30 (96.6%) Canadian ICUs agreed to participate. Of 1,222 critically ill medical patients, most were mechanically ventilated (62.5%). Overall, heparin VTE prophylaxis was administered to 63.9% patients, similarly between the 2 countries. Excluding patients with contraindications to heparin and those receiving therapeutic anticoagulation, 91.7% of medical ICU patients appropriately received either low dose unfractionated heparin (UFH) or low molecular weight heparin (LMWH) prophylaxis. Independent predictors of heparin prophylaxis were invasive mechanical ventilation (odds ratio [OR]; 95%CI, 2.4 (1.4-4.3) and obesity (OR 3.1; 1.1-8.8). LMWH was less likely to be prescribed for patients with renal failure (OR 0.1; 0.0009-0.9), or receiving antiembolic stockings (OR 0.4, 0.1-0.9), and much more likely to be prescribed in French ICUs (OR 9.2; 5.0-16.9); however, among patients receiving LMWH, high doses were more likely to be prescribed in Canadian ICUs (OR 8.7; 2.0-37.6). Patients who were pregnant or postpartum (OR 7.7, 1.3-44.3), had neurologic failure (OR 2.1, 1.3-3.4), or were Canadian (OR 3.0, 2.1-4.4) were most likely to receive mechanical VTE prophylaxis (with antiembolic stockings or pneumatic compression devices), whereas those who were already receiving heparin were less likely to receive mechanical prophylaxis (OR 0.5, 0.3-0.7).

CONCLUSIONS

In this binational cross-sectional observational study of medical ICU patients, we found that 92% of eligible patients received either UFH or LWMH for VTE prophylaxis. Differences in prescribing between countries include significantly greater use of LMWH in France, but use of lower doses than in Canada, and greater use of mechanical VTE prophylaxis in Canada. More randomized trials of VTE prophylaxis in critically ill medical patients would better inform practice.

OBJECTIVE

The purpose of this study was to evaluate the impact of arterial access site on bleeding and ischaemic outcomes, overall and by treatment strategy, in patients with acute coronary syndromes (ACS).

RESULTS

In the ACUITY trial, 13,819 patients with moderate and high-risk ACS were randomised to either heparin (unfractionated or enoxaparin) plus a glycoprotein IIb/IIIa inhibitor (GPI), bivalirudin plus a GPI, or bivalirudin alone. Per operator choice, femoral access was utilised in 11,989 patients (93.8%) and radial access in 798 patients (6.2%). There was no significant difference in composite ischaemia between the radial and femoral approaches at 30 days (8.1% vs 7.5%, p=0.18) or 1 year (14.7% vs 15.5%, p=0.77), although fewer major bleeding complications occurred with the use of radial access (3.0%vs4.8%, p=0.03). Use of bivalirudin monotherapy was associated with significantly less 30-day major bleeding than heparin plus GPI after femoral access (3.0% vs 5.8%, p<0.0001), but not with radial access (4.2% vs 2.2%, P=0.19). Major or minor organ bleeding was reduced with bivalirudin monotherapy compared to heparin plus GPI to a similar extent with both femoral (4.1% vs 7.4%, P<0.0001) and radial (4.9% vs 7.2%, P=0.26) access.

CONCLUSIONS

Transradial compared to femoral arterial access is associated with similar rates of composite ischaemia and with fewer major bleeding complications in patients with ACS managed invasively. Bivalirudin monotherapy compared to heparin plus GPIs significantly reduces access site related major bleeding complications with femoral but not radial artery access, though non-access site related bleeding is reduced by bivalirudin monotherapy in all patients.

Deep vein thrombosis (DVT) is a common complication in patients undergoing elective hip surgery. Because of the associated risk of pulmonary embolism, prophylaxis with standard (unfractionated) heparin is becoming increasingly important. Recent clinical trials have shown a low molecular weight form of heparin, enoxaparin, to be more effective than standard heparin in preventing DVT, but the new drug is also more expensive. Data on clinical effectiveness and cost were combined in an economic evaluation of the two regimens. It was found that prophylaxis with enoxaparin would be expected to lead to a net saving of 20 pounds per patient. The economic results are sensitive to the costs of enoxaparin, the costs of drug administration and the probability of false clinical diagnosis of DVT or pulmonary embolism.

Recent meta-analyses indicate that low molecular weight heparins (LMWH) are more effective than unfractionated heparin (UH) in preventing and treating deep vein thrombosis. This article presents the arguments for and against the need for laboratory monitoring. At the present time, the only tests currently available for monitoring LMWH therapy are those which measure the anti Xa activity in the plasma. Due to lower binding to plasma proteins and to cell surfaces, the plasma anti Xa activity generated by a given dose of LMWH is more predictable than for UH. Some clinical trials suggest that LMWH delivered at the recommended dose expose the patient to less bleeding risk than UH. Several meta-analyses indicate comparable risk while any overdose unacceptably increases the haemorrhagic risk. The lowest dose of LMWH still effective in treating established DVT is presently unknown; some reports indicate that inadequate doses of LMWH are associated with a lack of efficacy for prevention. An overview of the published clinical trials indicates that the LMWH dose has never been monitored for prevention of DVT. In the treatment of established DVT, several trials have been performed without any monitoring, while in others the dose was adapted to target a given anti Xa activity. These considerations suggest that in prevention of DVT, monitoring the dose is not required.(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE

To comprehensively review and critically assess the available gynecologic surgery venous thromboembolism prophylaxis literature and provide clinical practice guidelines.

METHODS

MEDLINE and Cochrane databases from inception to July 2010. We included randomized controlled trials in gynecologic surgery populations. Interventions and comparators included graduated compression stockings, intermittent pneumatic compression, unfractionated heparin, and low molecular weight heparin; placebo and routine postoperative care were allowed as comparators.

METHODS

One thousand two hundred sixty-six articles were screened, and 14 randomized controlled trials (five benign gynecologic, nine gynecologic oncology) met eligibility criteria. In addition, nine prospective or retrospective studies with at least 150 women were identified and provided data on venous thromboembolism risk stratification, gynecologic laparoscopy, and urogynecologic populations.

RESULTS

Two reviewers independently screened articles with discrepancies adjudicated by a third. Eligible randomized controlled trials were extracted for these characteristics: study, participant, surgery, intervention, comparator, and outcomes data, including venous thromboembolism incidence and bleeding complications. Studies were individually and collectively assessed for methodologic quality and strength of evidence. Overall incidence of clinical venous thromboembolism was 0-2% in the benign gynecologic population. With use of intermittent pneumatic compression for benign major procedures, venous thromboembolism incidence was less than 1%. No venous thromboembolisms were identified in prospective studies of benign laparoscopic procedures. Overall quality of evidence in the benign gynecologic literature was poor. Gynecologic-oncology randomized controlled trials reported venous thromboembolism incidence (including "silent" venous thromboembolisms) of 0-14.8% with prophylaxis and up to 34.6% without prophylaxis. Fair quality of evidence supports that unfractionated heparin and intermittent pneumatic compression are both superior to placebo or no intervention but insufficient to determine whether heparins are superior to intermittent pneumatic compression for venous thromboembolism prevention. Combining two of three risks (aged 60 years or older, cancer, or personal venous thromboembolism history) substantially elevated the risk of venous thromboembolism.

CONCLUSIONS

Intermittent pneumatic compression provides sufficient prophylaxis for the majority of gynecology patients undergoing benign surgery. Additional risk factors warrant the use of combined mechanical and pharmacologic prophylaxis.

OBJECTIVE

To demonstrate a novel method that utilizes retrospective data to develop statistically optimal dosing strategies for medications with sensitive therapeutic windows. We illustrate our approach on intravenous unfractionated heparin, a medication which typically considers only patient weight and is frequently misdosed.

METHODS

We identified available clinical features which impact patient response to heparin and extracted 1,511 patients from the multi-parameter intelligent monitoring in intensive care II database which met our inclusion criteria. These were used to develop two multivariate logistic regressions, modeling sub- and supra-therapeutic activated partial thromboplastin time (aPTT) as a function of clinical features. We combined information from these models to estimate an initial heparin dose that would, on a per-patient basis, maximize the probability of a therapeutic aPTT within 4-8 h of the initial infusion. We tested our model's ability to classifying therapeutic outcomes on a withheld dataset and compared performance to a weight-alone alternative using volume under surface (VUS) (a multiclass version of AUC).

RESULTS

We observed statistically significant associations between sub- and supra-therapeutic aPTT, race, ICU type, gender, heparin dose, age and Sequential Organ Failure Assessment scores with mean validation AUC of 0.78 and 0.79 respectively. Our final model improved outcome classification over the weight-alone alternative, with VUS values of 0.48 vs. 0.42.

CONCLUSIONS

This work represents an important step in the secondary use of health data in developing models to optimize drug dosing. The next step would be evaluating whether this approach indeed achieves target aPTT more reliably than the current weight-based heparin dosing in a randomized controlled trial.

BACKGROUND

The relative benefits and harms of low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) are required for judgments regarding the appropriate perioperative thromboprophylaxis in patients with cancer. We systematically reviewed the literature to quantify these effects.

METHODS

The comprehensive searches included (1) an electronic search of MEDLINE, EMBASE, ISI the Web of Science, and CENTRAL (The Cochrane Central Register of Controlled Trials); (2) a hand search of relevant conference proceedings; (3) a reference check of included trials; and (4) use of the PubMed "Related Articles" feature. Outcomes of interest included mortality, deep venous thrombosis, pulmonary embolism, bleeding complications, and thrombocytopenia.

RESULTS

Of 3986 identified citations, we included 14 randomized clinical trials in the meta-analysis (all using preoperative prophylactic anticoagulation). The overall methodological quality was moderate. The meta-analysis showed no differences in mortality in patients receiving LMWH compared with UFH (relative risk [RR], 0.89; 95% confidence interval [CI], 0.61-1.28) or in clinically suspected deep venous thrombosis (RR, 0.73; 95% CI, 0.23-2.28). In a post hoc analysis including all studies assessing deep venous thrombosis, irrespective of the diagnostic strategy used, LMWH was superior to UFH (RR, 0.72; 95% CI, 0.55-0.94). There were no differences in rates of pulmonary embolism (RR, 0.60; 95% CI, 0.22-1.64), minor bleeding (RR, 0.88; 95% CI, 0.47-1.66), or major bleeding (RR, 0.95; 95% CI, 0.51-1.77).

CONCLUSIONS

We found no differences in mortality in patients with cancer receiving perioperative thromboprophylaxis with LMWH vs UFH. Further trials are needed to more carefully evaluate the benefits and harms of different heparin thromboprophylaxis strategies in this population.

The low-molecular-weight heparins (LMWHs) enoxaparin and dalteparin have shown superior and equivalent efficacy, respectively, over unfractionated heparin (UFH) in patients with unstable angina pectoris (UAP) or non-ST-segment elevation myocardial infarction (NSTEMI). This study aimed to identify markers of blood cell activation that are independent predictors of outcomes at 1 month and to compare the effects of enoxaparin, dalteparin, and UFH on any such markers. In this multicenter, prospective, open-label study, 141 patients with UAP or NSTEMI were randomized to treatment for 48 to 120 hours with enoxaparin (n = 46), dalteparin (n = 48), or UFH (n = 47). Blood samples were taken at the time of randomization and after>> or =48 hours of treatment but before catheterization. Multivariate analysis identified increased plasma levels of von Willebrand factor (vWF) and decreased platelet levels of glycoprotein Ib/IX complexes as independent predictors of 1-month adverse outcome (a composite of death, myocardial infarction, and recurrent ischemia). vWF release was strongly related to and may have been released by inflammation as measured by C-reactive protein. Both LMWHs reduced the release of vWF in plasma (as well as C-reactive protein) compared with UFH. Enoxaparin had a more favorable effect on glycoprotein Ib/IX complexes than either dalteparin or UFH. The incidence of the composite clinical efficacy end point was: 13% (enoxaparin), 19% (dalteparin), and 28% (UFH). vWF and its receptor glycoprotein Ib/IX play a key role in acute coronary syndromes. vWF is linked to inflammation and, like glycoprotein Ib/IX, is affected more favorably by the LWMHs than by UFH.

OBJECTIVE

The goal of this study was to evaluate combinations of eptifibatide with reduced-dose tenecteplase (TNK) in ST-elevation myocardial infarction (STEMI).

BACKGROUND

Glycoprotein IIb/IIIa inhibitors enhance thrombolysis. The role of combination therapy in clinical practice remains to be established.

METHODS

Patients (n = 438) with STEMI <6 h were enrolled. In dose-finding, 189 patients were randomized to different combinations of double-bolus eptifibatide and reduced-dose TNK. In dose-confirmation, 249 patients were randomized 1:1 to eptifibatide 180 microg/kg bolus, 2 microg/kg/min infusion, and 180 microg/kg bolus 10 min later (180/2/180) plus half-dose TNK (0.27 mg/kg) or standard-dose (0.53 mg/kg) TNK monotherapy. All patients received aspirin and unfractionated heparin (60 U/kg bolus; infusion 7 U/kg/h [combination], 12 U/kg/h [monotherapy]). The primary end point was Thrombolysis In Myocardial Infarction (TIMI) grade 3 epicardial flow at 60 min.

RESULTS

In dose-finding, TIMI grade 3 flow rates were similar across groups (64% to 68%). Arterial patency was highest for eptifibatide 180/2/180 plus half-dose TNK (96%, p = 0.02 vs. eptifibatide 180/2/90 plus half-dose TNK). In dose-confirmation, this combination, compared with TNK monotherapy, tended to achieve more TIMI 3 flow (59% vs. 49%, p = 0.15), arterial patency (85% vs. 77%, p = 0.17), and ST-segment resolution (median 71% vs. 61%, p = 0.08) but was associated with more major hemorrhage (7.6% vs. 2.5%, p = 0.14) and transfusions (13.4% vs. 4.2%, p = 0.02). Intracranial hemorrhage occurred in 1.0%, 0.6%, and 1.7% of patients treated with any combination, eptifibatide 180/2/180 and half-dose TNK, and TNK monotherapy, respectively.

CONCLUSIONS

Double-bolus eptifibatide (180/2/180) plus half-dose TNK tended to improve angiographic flow and ST-segment resolution compared with TNK monotherapy but was associated with more transfusions and non-cerebral bleeding. Further study is needed before this combination can be recommended for general use.

OBJECTIVE

The aim of this study was to assess the impact of bivalirudin or unfractionated heparin (UFH) on platelet aggregation in patients, pretreated with a 600 mg loading dose clopidogrel, undergoing elective percutaneous coronary intervention (PCI).

RESULTS

Patients (n = 100) were recruited consecutively in the setting of a double-blind, randomized trial. Bivalirudin or UFH was administered during PCI. Blood was drawn immediately before PCI, following administration of bivalirudin or UFH directly after PCI, and 24 h after PCI. Adenosine diphosphate (ADP)-induced platelet aggregation was assessed with light transmission aggregometry (LTA) and multiple electrode aggregometry (MEA). Before PCI, ADP-induced platelet aggregation was similar in UFH and bivalirudin patients (P = 0.99 for LTA; P = 0.28 for MEA). Administration of bivalirudin during PCI resulted in significant additional suppression of platelet aggregation (P = 0.012 for LTA; P = 0.008 for MEA). Administration of UFH did not have a significant influence on platelet aggregation (P = 0.42 for LTA; P = 0.78 for MEA). Platelet aggregation was again similar in the two groups 24 h after PCI (P>> 0.05 for LTA and MEA).

CONCLUSIONS

Bivalirudin, given during PCI in patients pretreated with 600 mg of clopidogrel, is in contrast to UFH associated with further inhibition of platelet aggregation.

Thromboelastography (TEG) has been used increasingly as an intraoperative hemostasis monitoring device. Low-molecular-weight heparins are given increasingly to reduce the development of antibodies against the heparin-platelet factor 4 complex, and heparinoids are given to patients who have developed the antibody. We studied the effect of unfractionated heparin, a low-molecular-weight heparin (enoxaparin sodium [Lovenox]), and a heparinoid (danaparoid sodium [Orgaran]) on blood clotting assayed with TEG (TEG clotting) in vitro and the efficacy of protamine sulfate and heparinase for reversing the effect. Heparin, enoxaparin, and danaparoid all caused a dose-dependent inhibition of TEG clotting of normal blood. Concentrations of enoxaparin and danaparoid that totally inhibited TEG clotting only minimally prolonged the activated partial thromboplastin time. While inhibition of TEG clotting by heparin and enoxaparin was reversed by protamine sulfate and heparinase, inhibition by danaparoid was reversed only by heparinase. Abnormal TEG clotting was observed in patients receiving enoxaparin whose plasma level of the drug was more than 0.1 antiXa U/mL. However, the degree of TEG abnormality did not always coincide with plasma levels of the drug.

Superior bioavailability and simple weight-based dosing have made low-molecular-weight heparins (LMWH) the preferred agents for treatment and prevention of venous thromboembolism (VTE) for most indications. Despite improved pharmacokinetics, there remain populations where appropriate LMWH dose intensity and frequency are open to question. Obese patients have a lower proportion of lean body mass as a percentage of total body weight. As a result, LMWH dosing based on total body weight could cause supra-therapeutic anticoagulation. Elderly patients also have less lean body mass in addition to a higher incidence of age-related renal disease and increased risk of bleeding. Renal insufficiency presents a risk of LMWH accumulation as well as increased risk of bleeding. Among LMWH products, only dalteparin labeling recommends a maximum dose. Prospective data call into question the validity of this dose limitation. Additionally, because obese patients are already at higher risk of VTE recurrence, they may be particularly sensitive to subtherapeutic anticoagulation. Prospective data evaluating LMWH use in elderly patients have been limited to in-patient treatment. Few recommendations can be made in this population other than close monitoring. Renal insufficiency is a risk for bleeding during LMWH use. Available evidence supports the potential for enoxaparin accumulation, but not tinzaparin. Enoxaparin dose adjustment, either empiric or based on anti-Xa monitoring, has insufficient data to support widespread implementation. Unfractionated heparin is not reliant on renal elimination and is a sensible option for VTE treatment in patients with a creatinine clearance<30 ml/min.

Thrombosis is a common complication of malignancy. This is felt to be related to increased activity of the coagulation system as evidenced by markers of accelerated thrombin generation and increased platelet reactivity. Alterations in the hemostatic balance have been documented in patients with malignancy with increased tissue factor (TF) generation and the production of a cysteine protease. These can stimulate the coagulation mechanism via the extrinsic pathway and/or by activating factor X. The thrombotic presentations in malignancy are protean and may be venous or arterial. The underlying clinical pictures may be related to varying degrees of consumptive coagulopathy, microangiopathy, and nonbacterial endocarditis. Prophylaxis and management are, to a significant degree, dependent on the underlying malignancy and the prothrombotic mechanism. Specific agents and drugs must be selected from an expanding menu of options that includes unfractionated heparin, low-molecular-weight heparin (LMWH), warfarin, plasma apheresis, and the newer antithrombin agents.

Antithrombin and its cofactor, heparin, target both the product of prothrombin activation by prothrombinase, thrombin, as well as the enzyme responsible for the reaction, factor (F)Xa. These studies were carried out to quantify the effects of each of the prothrombinase components on the half-life of FXa in the presence of antithrombin and the low-molecular-weight heparins (enoxaparin, Aventis, Laval, Quebec, Canada) or the heparin pentasaccharide (fondaparinux, Organon Sanofi-Synthelabo, Cypress, TX, USA). Experiments were carried out using a recombinant form of prothrombin in which the active site serine has been mutated to cysteine and subsequently labeled with fluorescein. This mutant allowed calculation of the second order rate constant for inhibition of FXa by antithrombin in such a way that competition for antithrombin by thrombin is eliminated and competition for FXa by prothrombin is accounted for. Intrinsic rate constants for the inhibition of FXa by antithrombin-enoxaparin and antithrombin-fondaparinux, in the presence of the various prothrombinase components, were calculated. Addition of phospholipid had no significant effect on the second order rate constant for inhibition of FXa by antithrombin, while addition of FVa appeared to be mildly protective. Further addition of prothrombin however, caused profound protection of FXa, increasing its half-life from 1.1 to 353 s in the case of fondaparinux, and from 0.4 to 42 s in the case of enoxaparin. Similar results were reported for unfractionated heparin previously [1]. Therefore, in the presence of unfractionated heparin, fondaparinux, or enoxaparin, prothrombinase is profoundly protected from antithrombin.

The present investigation determined the molecular structure and the pharmacokinetic and pharmacodynamic profiles of oral unfractionated heparin containing oral absorption enhancer sodium N-[8-(2-hydroxybenzoyl) amino]caprylate, salcaprozate sodium (SNAC) and assessed the safety and tolerability of the orally dosed heparin solid dosage form versus other routes. Sixteen healthy men were included in this single-dose, 3-way crossover, randomized, open-label study. Disaccharide compositional analysis was performed using capillary high-performance liquid chromatography with electrospray ionization mass spectrometry detection. The pharmacodynamics of heparin were obtained from analysis of plasma anti-factor Xa, anti-factor IIa, activated partial thromboplastin time, and total tissue factor pathway inhibitor data. The molecular weight properties and the disaccharide composition of orally administered unfractionated heparin/SNAC and parenterally administered unfractionated heparin are identical and consistent with the starting pharmaceutical standard heparin. Furthermore, the anti-factor Xa/anti-factor IIa ratio achieved is of approximately 1:1. This is the first true pharmacokinetic study to measure the chemical compositions of heparin administered by different routes.