Doses Of Dalteparin Research Articles

Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high-risk abdominal surgery

The aim of this study was to assess whether the synthetic factor Xa inhibitor fondaparinux reduced the risk of venous thromboembolism more efficiently than the low molecular weight heparin dalteparin in patients undergoing major abdominal surgery. In a double-blind double-dummy randomized study, patients scheduled for major abdominal surgery under general anaesthesia received once-daily subcutaneous injections of fondaparinux 2.5 mg or dalteparin 5000 units for 5-9 days. Fondaparinux was started 6 h after surgery. The first two doses of dalteparin, 2500 units each, were given 2 h before surgery and 12 h after the preoperative administration. The primary outcome measure was a composite of deep vein thrombosis detected by bilateral venography and symptomatic, confirmed deep vein thrombosis or pulmonary embolism up until day 10. The main safety outcome measure was major bleeding during treatment. Among 2048 patients evaluable for efficacy, the rate of venous thromboembolism was 4.6 per cent (47 of 1027) with fondaparinux compared with 6.1 per cent (62 of 1021) with dalteparin, a relative risk reduction of 24.6 (95 per cent confidence interval -9.0 to 47.9) per cent (P = 0.144), which met the predetermined criterion for non-inferiority of fondaparinux. Major bleeding was observed in 49 (3.4 per cent) of 1433 patients given fondaparinux and 34 (2.4 per cent) of 1425 given dalteparin (P = 0.122). Postoperative fondaparinux was at least as effective as perioperative dalteparin in patients undergoing high-risk abdominal surgery.

The effect of oral anticoagulation on clotting during hemodialysis

Between 5% and 10% of hemodialysis patients are treated with oral anticoagulants. It is currently unknown whether additional anticoagulation with heparin or low-molecular-weight heparin (LMWH) is needed to prevent clotting during hemodialysis. In this prospective, randomized, cross-over study 10 patients treated with oral anticoagulants (phenprocoumon) received either no additional anticoagulation or low dose dalteparin (bolus of 40 IU/kg body weight) before dialysis. Efficacy of hemodialysis was measured by normalized weekly Kt/V and urea reduction rate (URR). Thrombus formation was evaluated by measurement of D-dimer and inspection of air traps and dialyser. The median international normalized ratio (INR) did not differ between both observation periods (phenprocoumon 2.2(2 to 3) vs. dalteparin 2.1(2 to 2.9). The anti-Xa level in dalteparin patients was 0.33 (0.27 to 0.38) IU/mL after 2 hours and 0.16 (0.03 to 0.23) IU/mL after 4 hours of hemodialysis. The median increase of D-dimer was significantly higher in patients without additional dalteparin therapy during hemodialysis (DeltaD-dimer 0.23 microg/mL vs. 0.03 mug/mL) (P= 0.0004). Complete thrombosis of the dialyser membrane occurred in one patient in the phenprocoumon group but in none with combined treatment. The extent of thrombosis in the arterial and venous air trap and dialyser was significantly less in patients with additional dalteparin therapy (P= 0.0014, P= 0.0002, and P= 0.0005, respectively). Weekly Kt/V and URR was similar in both groups. Standard oral anticoagulation with an INR between 2 and 3 is insufficient to prevent clotting during hemodialysis. Additional low dose anticoagulation with a LMWH or heparin is necessary to facilitate treatment.

Peak Antifactor Xa Activity Produced by Dalteparin Treatment in Patients with Renal Impairment Compared with Controls

To evaluate the relationship between impaired renal function and antifactor Xa activity in patients receiving dalteparin. Open-label prospective study. Inpatient and outpatient units of a large teaching hospital. Eleven patients with renal impairment and 11 control subjects with normal renal function. Subjects were administered dalteparin at a dosage of approximately 100 U/kg subcutaneously every 12 hours. Peak steady-state antifactor Xa levels were compared between the groups. Mean +/- SD levels were similar for patients with and without renal impairment: 0.47 +/- 0.25 and 0.55 +/- 0.20 U/ml, respectively. A test of equivalency showed statistical significance (p=0.0001). No meaningful difference in peak antifactor Xa activity was found between patients with renal impairment and control subjects. To the extent that peak antifactor Xa levels can be used as markers for adjusting doses of dalteparin, these data suggest that such adjustments are not necessary for patients with renal impairment who are not receiving dialysis.

Anti-Xa effect of a low molecular weight heparin (dalteparin) does not accumulate in extended duration therapy for venous thromboembolism in cancer patients

Many patients with venous thromboembolism are being treated with low molecular weight heparin for extended periods of time. It is not certain if it is necessary to assess anti-Xa levels for extended treatment periods. This study is a prospective assessment of anti-Xa levels in patients on long-term therapy for acute venous thromboembolism who have active cancer. Consecutive consenting patients from one center in a multicenter trial that compared 6 months of low molecular weight heparin with oral anticoagulant therapy were treated with therapeutic doses of dalteparin (200 IU per kilogram) subcutaneously daily. Anti-Xa levels were assessed at the end of weeks 1 and 4,4-6 hours after injection of dalteparin. Patients were followed for bleeding and recurrent venous thromboembolism. There were 24 patients who had anti-Xa levels measured at weeks 1 and 4. Two other patients had week 1 measurements performed but died before the week 4 sample was collected due to their underlying cancer. The mean anti-Xa levels at weeks 1 and 4 were 1.11 and 1.03 anti-Xa units/ml respectively (P=0.13). These results suggest that for patients with active cancer receiving extended duration therapy with low molecular weight heparin (dalteparin) there is no accumulation of anti-Xa effect over the first month of therapy. Monitoring of anti-Xa levels in this situation is usually not required.

Safety and Efficacy of Venous Thromboembolism Prophylaxis with Low Molecular Weight Heparin in Hospitalised Patients with Acute Medical Illness and Renal Failure.

Objectives: To study the incidence of bleeding complications during thromboprophylaxis with dalteparin in patients with acute medical illness and renal failure.Design: Prospective, cohort study.Setting: Community Hospital.Main outcome: The primary safety outcome was the incidence of major and minor bleeding, while the primary efficacy outcomes were objectively verified symptomatic DVT, pulmonary embolism, and objectively verified asymptomatic DVT detected on routine compression ultrasonography. Secondary outcomes included anti-Xa heparin levels.Patients: 56 consecutives patients (29 males, age 77.86±10.27 y, 27 females, age 84.60±6,78 y) admitted with acute medical illness were considered for the study. Eligible patients were 18 years or older and had none of the following: hepatic failure (prothrombin time <50%), platelet count <100.000/ml, chronic use of warfarin, or an ongoing requirement for anticoagulation. Two doses of dalteparin were prescribed as dictated by a venous thromboembolism risk score. 44 patients judged to be at high risk (age >75 y, 44 of 56, 78%, active cancer, 5 of 56, 8.9%, previous venous thromboembolism, 1 of 56, 1.8%) received a dose of 5.000 IU daily; the other 12 received 2.500 IU daily. Dalteparin was given at 8 am for 6 days. The timing of anti-Xa activity determination and of compression ultrasound examination of leg veins is shown in table 1.MethodsResults: there was 1 case (1 of 56, 1.8%) of nose bleeding at the third day of treatment in a patient with moderate renal failure. The bled was easily stopped. None of the following variables: dose of dalteparin, age, sex, creatinine clearance, and anti-Xa activity when entered in a regression model were able to predict the hemorrhagic complication. There were no cases of venous thromboembolism. Though, peak anti-Xa activity was higher in patients with marked renal impairment, it never reached therapeutic levels (>0.5 IU/mL).anti-Xa activity at day 6Conclusions: The modest (and not significant) increase in anti-Xa activity in patients with reduced creatinine clearance was not associated with a clinically apparent risk of bleeding. Thromboprophylaxis with dalteparin appears safe even in acutely ill medical patients with renal failure.day 0Creatinine Clearanceanti-Xa activity before DalteparinCUSday 6Creatinine Clearanceanti-Xa activity 4 h after DalteparinCUSCrCl >90 ml/minCrCl >89–60 ml/minCrCl >59–30 ml/minCrCl <29 ml/minPatients5122613anti-Xa activity IU/mL0.012±0.020.016±0.0540.066±0.120.20±0.66p=0.45

Chemotherapy-Induced Activation of Hemostasis: Dalteparin Suppresses Both Thrombin and Interleukin-6 Expression in Breast Cancer Patients Receiving Adjuvant Chemotherapy.

Thrombotic events are well documented in patients with cancer and have frequently been described in the setting of systemic chemotherapy. We have previously reported (Thromb Haemost2002; 88:213–220) that patients treated for breast and lung cancer demonstrate significant hemostatic activation, as documented by increases in thrombin-antithrombin (TAT) complexes and D-dimers, within 1 hour of receiving chemotherapy. The hemostatic effects appear to be cumulative with baseline pretreatment levels of TAT increasing with progressive cycles of chemotherapy. In the same study, we demonstrated that a single injection of dalteparin, a LMW heparin, administered prior to therapy could suppress hemostatic activation. We proposed that the progressive increases in basal thrombin generation resulted from chemotherapy-induced increases in inflammatory cytokines. We measured plasma levels of Il-6 in the 10 women with early stage breast cancer from this study who were receiving cyclophosphamide-doxorubicin adjuvant chemotherapy. Patients had plasma samples drawn prior to each cycle of chemotherapy, and at 1 hour, 24 and 48 hours after treatment. Prior to 2nd cycle of chemotherapy the patients received 2500 U dalteparin, prior to the 4th cycle of treatment, the patients received 5000 U dalteparin. No LMW heparin was given with the 1st and 3rd cycles. There were statistically significant increases in plasma TAT and D-dimers after chemotherapy in cycles 1 and 3. There was a significant increase in basal thrombin generation as measured over the four cycles of treatment unrelated to the presence of active cancer. Both pretreatment doses of dalteparin effectively prevented increases in markers of hemostatic activation after receiving chemotherapy. With each cyle of chemotherapy the 1 hour Il-6 levels were slightly lower than the pretreatment levels, but this was not statistically significant and could reflect a direct effect of the chemotherapeutic regimen on cytokine production. However, in cycle 1 and 3 the Il-6 levels increased to greater than pretreatment levels by 48 hours. There was a statistically significant increase in plasma Il-6 levels measured prior to the 4th cycle of chemotherapy when compared to the plasma Il-6 measured prior to the 1st cycle (4.976pg/ml± 1.620 vs 3.30 pg/ml±1.005 ; P&lt;0.05). There was a trend for the pretreatment Il-6 levels measured prior to the 3rd cycle and 21 days after receiving 2500 U dalteparin to be lower than the levels measured prior to cycle 2, although not statistically significant (4.032±2.415 vs. 6.203±3.862; p=0.072). A 21 day sample was not obtained following the fourth cycle in which 5000U dalteparin was given and therefore the effect of this dose on basal thrombin generation and Il-6 expression could not be determined. We conclude; 1) the progressively increasing basal generation of thrombin associated with systemic chemotherapy in patients with breast cancer is associated with increases in the inflammatory cytokine, Il-6. 2) The increased expression of Il-6 and possibly other cytokines may be responsible for the progressive increases in hemostatic activation with repeated cycles of chemotherapy. In our study, there is a suggestion that a LMW heparin, dalteparin, not only prevented chemotherapy-induced hemostatic activation, but may also suppress chemotherapy-related cytokine expression. However, the optimal dose of dalteparin necessary for suppression of chemotherapy-induced cytokine expression is unknown and may vary with different malignancies and chemotherapy agents.

The Safety of Co-Administered Low-Molecular-Weight Heparin and Continuous Epidural Analgesia after Major Orthopedic Surgery: Assessment of a Standardized Management Protocol.

Background: In patients who have had major orthopedic surgery, low-molecular-weight heparin (LMWH) has established efficacy in preventing venous thromboembolism (VTE) after surgery, and continuous epidural analgesia (CEA) provides better pain control than parenteral analgesia and may reduce the risk of cardiorespiratory complications. However, there is concern about the co-administration of LMWH and CEA after surgery because of an increased risk of epidural hematoma. No study, to our knowledge, has investigated the safety of a standardized treatment regimen that allows co-administered LMWH and CEA after surgery.Patients and Methods: We assessed the safety of a standardized management protocol in 970 patients who were scheduled to undergo knee or hip replacement surgery and who received post-operative thromboprophylaxis with LMWH and pain control with CEA. All patients received intra-operative spinal (regional) anesthesia, with an indwelling epidural catheter left in place after surgery to administer epidural analgesia with an infusion of fentanyl and bupivacaine. Subcutaneous LMWH (enoxaparin 30 mg twice-daily or dalteparin 5000 IU daily) was started on the morning after surgery and continued for at least 5 days. CEA was administered for 2–3 days after surgery, with the epidural catheter removal occurring during the trough anticoagulant effect of the LMWH, 10 hours and 22 hours after the preceding dose of enoxaparin and dalteparin, respectively. In patients who were to receive warfarin, this treatment was initiated, with a 2.5 mg dose, on the evening prior to the scheduled removal of the epidural catheter. Drugs that are known to affect hemostasis were avoided during CEA, and patients at increased risk for bleeding were not given LMWH. During the period of hospitalization, we calculated the incidence and associated 95% confidence interval (CI) for the following outcomes: epidural hematoma; other bleeding (major and minor); VTE, myocardial infarction, stroke, death.Results: 970 patients (mean age: 68.2 years; mean weight: 81.4 kg; 63% female) who underwent knee replacement (527 patients) or hip replacement (443 patients) received co-administered LMWH and CEA. The mean duration of LWMH therapy was 7.2±5.3 days. The mean duration (±standard deviation) of CEA was 1.9±0.80 days, respectively. Warfarin was initiated in 758 (78%) patients. There were no episodes of symptomatic epidural hematoma (0%; 95% CI: 0–0.38). During the in-hospital follow-up period, there were 13 episodes of VTE (1.3%; 95% CI: 0.71–2.3), 47 bleeds (4.7%; 95% CI: 3.5–6.3); 4 myocardial infarcts (0.41%; 95% CI: 0.12–1.1), and 4 deaths (0.41%; 95% CI: 0.12–1.1).Conclusion: Co-administered LMWH and CEA appears safe after major orthopedic surgery when using a standardized management protocol.

A prospective trial that demonstrates that dalteparin requirements increase in pregnancy to maintain therapeutic levels of anticoagulation

Objective The purpose of this study was to determine whether standard therapeutic doses of dalteparin maintain peak therapeutic levels of anticoagulation during pregnancy. Study design This was a prospective trial in which 13 pregnancies that required therapeutic anticoagulation were treated with dalteparin 100 U/kg every 12 hours; peak and trough (predose) low molecular weight heparin (anti-Xa activity) levels were monitored every 2 weeks. Dosage adjustments were made to maintain peak anti-Xa activity between 0.5 and 1.0 IU/ml. Bone density and bone turnover markers were measured. Results A total of 250 peak and trough low-molecular-weight heparin (LMWH) levels were obtained. Eighty-five percent of pregnancies (11/13) required an upward dosage adjustment. Trough levels were in the therapeutic range only 9% of the time, despite the maintenance of therapeutic peak levels. Bone resorption markers and density were unchanged in singleton pregnancies. Conclusion Dalteparin dosing, based on weight alone, every 12 hours is inadequate to maintain most pregnant women in the therapeutic range throughout pregnancy as measured by anti-Xa activity. Trough levels are rarely in the therapeutic range, despite maintenance of therapeutic peak levels. These notable changes in low molecular weight heparin peak may explain reported failures in pregnancy.

The effect of anticoagulant drugs on cancer

The effect of anticoagulant drugs on cancer

Prophylaxis of port system-associated thromboses in advanced oncology patients using heparin flushing.

Thromboses occur in connection with the use of venous port systems. Valid data on the instillation of heparin-based solutions in the lumen of the port system are lacking. One hundred and seventy-three patients with malignancy from 19 centres who had participated in an observation study of subcutaneous thromboprophylaxis with dalteparin-Na (Fragmin P/-Forte) were analysed with a view to flushing the port systems and investigating any related influence on the occurrence of catheter-associated thromboses. All catheter-associated thromboses were seen in centres which used either no UFH, or UFH concentrations of up to 250 IU/ml (8/108; 7.4%). The rate of thrombosis rose to 10% (6/60) if no high-risk dose of dalteparin was applied subcutaneously. On the other hand, the rate of catheter-associated thromboses under the high-risk dose of dalteparin and/or a more highly concentrated instillation fluid, at 0.9% (1/113), was much lower. One haemorrhage from gastric ulcer occurred under the highest UFH concentration in the instillation fluid (2,500 IU UFH/ml). The results indicate that a concentration between 500 IU UFH/ml and 1,000 IU UFH/ml in the instillation solution, at the same time as high-risk prophylaxis with subcutaneous dalteparin for prevention of catheter-associated thromboses, is effective in patients with manifest tumour disease. The instillation of LMWH-based solutions at a concentration of approx 500 anti-Xa units/ml should be discussed as a pending issue.

Coagulation, inflammation and myocardial dysfunction in unstable coronary artery disease and the influence of glycoprotein IIb/IIIa inhibition and low molecular weight heparin

Patients with unstable coronary artery disease (CAD) have an increased risk of subsequent myocardial infarction and death. This study evaluated the safety and efficacy of treatment with glycoprotein IIb/IIIa inhibition in addition to aspirin, low molecular- weight heparin and its influence on coagulation and inflammation. Also, early and differentiated risk assessment utilising markers of inflammation, myocardial damage and dysfunction were evaluated.The Global Utilisation of Strategies To open Occluded arteries-IV (GUSTO-IV) trial randomised 7800 patients with unstable CAD to 24 or 48 hours infusion of abciximab or placebo in addition to routine treatment with aspirin and heparin or dalteparin. Baseline levels of creatinine, C-reactive protein (CRP), troponin T (TnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) were analysed. At selected sites, all patients received subcutaneous dalteparin (n=974), in stead of heparin infusion (n=6826). In a sub-population of dalteparin treated patients (n=404), serial measurements of markers of coagulation, fibrinolysis and inflammation were also performed. Addition of abciximab to dalteparin as the primary treatment of unstable CAD was not associated with any significant reduction in cardiac events but a doubled risk of bleedings. The combination of abciximab with dalteparin seemed as safe when used with heparin. Despite full dose dalteparin and aspirin there was a simultaneous activation of the inflammation, coagulation and fibrinolysis systems without any influence of the abciximab treatment. Elevated levels of CRP, TnT, and NT-proBNP and reduced creatinine clearance were independently related to short and long-term mortality. The best prediction of high and low risk was provided by a combination of NT-proBNP and creatinine clearance. Any detectable elevation of TnT and reduced creatinine clearance, but neither elevation of CRP nor NT-proBNP, were also independently associated to a raised risk of subsequent myocardial infarction.Abbreviations: Acute coronary syndrome (ACS), Brain natriuretic peptide (BNP), Coefficient of variance(CV), Coronary artery disease (CAD), Coronary artery bypass grafting (CABG), Creatine kinase-MB (CK-MB), C-reactive protein (CRP), Electrocardiogram (ECG), Glycoprotein IIb/IIIa (GPIIb/IIIa), Global Utilisation of Strategies To Open Occluded Arteries IV (GUSTO-IV), Interleukin-6(Il-6), Low-molecular weight heparin (LMWH), N-terminal pro-Brain natriuretic peptide (NT-proBNP),Myocardial infarction (MI), Percutaneous coronary intervention (PCI), Plasminogen activator(tPA), Plasminogen activator inhibitor (PAI-1), Soluble fibrin (SF), Thrombin-antithrombin complex(TAT), Troponin T (TnT), Unfractionated heparin (UFH).

Low molecular weight heparin (dalteparin) for the treatment of venous thromboembolism in pregnancy

To evaluate the effect and dose of dalteparin given to pregnant women with acute venous thromboembolism. An observational study of pregnant women in Norway. Delivery and haematological departments in Norway. Twenty women, aged 22-41 years, with acute venous thromboembolism verified by objective means. Patients were treated with dalteparin from diagnosis until delivery. Treatment was monitored with anti-activated factor Xa (anti-Xa) activity, and the dose was adjusted to achieve target 0.5-1.0 U/mL 2-3 hours post-injection. Anti-Xa activity and side effects. None of the patients suffered recurrent venous thromboembolism or major bleeding complications. In 9 of 13 women starting with conventional dose of dalteparin (100 iu/kg bd), dose escalation was necessary to reach target anti-Xa activity. None of the six women who started with 105-118 iu/kg bd required dose escalation. One woman who started with 133 iu/kg bd required dose reduction. Bioaccumulation of dalteparin was not observed. Our study suggests that dalteparin may be used for the treatment of acute venous thromboembolism in pregnancy. Approximately 10-20% higher doses of dalteparin may be needed as compared with non-pregnant individuals.

Low molecular weight heparin (dalteparin) for the treatment of venous thromboembolism in pregnancy

Objective To evaluate the effect and dose of dalteparin given to pregnant women with acute venous thromboembolism. Design An observational study of pregnant women in Norway. Setting Delivery and haematological departments in Norway. Population Twenty women, aged 22–41 years, with acute venous thromboembolism verified by objective means. Methods Patients were treated with dalteparin from diagnosis until delivery. Treatment was monitored with anti-activated factor Xa (anti-Xa) activity, and the dose was adjusted to achieve target 0.5–1.0 U/mL 2–3 hours post-injection. Main outcome measure Anti-Xa activity and side effects. Result None of the patients suffered recurrent venous thromboembolism or major bleeding complications. In 9 of 13 women starting with conventional dose of dalteparin (100 iu/kg bd), dose escalation was necessary to reach target anti-Xa activity. None of the six women who started with 105–118 iu/kg bd required dose escalation. One woman who started with 133 iu/kg bd required dose reduction. Bioaccumulation of dalteparin was not observed. Conclusion Our study suggests that dalteparin may be used for the treatment of acute venous thromboembolism in pregnancy. Approximately 10–20% higher doses of dalteparin may be needed as compared with non-pregnant individuals.

Combination of low molecular weight heparins with antiplatelet agents in non-ST elevation acute coronary syndromes: an update.

This article reviews the use of low molecular weight heparin (LMWH) and antiplatelet agents in the treatment of unstable angina and non-ST segment elevation myocardial infarction (NSTEMI), which together account for 1 million hospitalisations annually in the US alone. Mortality and recurrent myocardial infarction (MI) in these conditions is currently approximately 8 to 16% at 1 month, and there is a need to optimise treatment further. Since their introduction, LMWHs have been shown to be successful and well tolerated in the treatment of unstable angina and NSTEMI, but differences have been seen in their efficacy compared with the parent compound, unfractionated heparin (UFH). A meta-analysis of all LMWHs, grouped, versus UFH showed equivalent efficacy and safety. The LMWHs dalteparin sodium and nadroparin calcium have independently been shown to be as effective as UFH. However, enoxaparin sodium has been shown to have greater clinical efficacy than UFH in patients with unstable angina (UA)/NSTEMI. One area of new research is patients with UA/NSTEMI who later undergo percutaneous coronary interventions (PCI), and early data suggest enoxaparin can be safely used as an anticoagulant instead of UFH in these patients. There is a wealth of data for glycoprotein (GP) IIb/IIIa receptor antagonists (abciximab, eptifibatide, lamifiban, and tirofiban), although some are conflicting. Recent meta-analyses suggest that some benefit is conferred by using these compounds, particularly in patients who undergo PCI. Recent trials have focussed on combining GP IIb/IIIa antagonists with LMWH, and although data is still scant, the ACUTE (Anti-thrombotic Combination Using Tirofiban and Enoxaparin) and ACUTE II studies indicate the safety and potential clinical benefit of combining enoxaparin with tirofiban in patients with UA/NSTEMI not undergoing PCI, compared with UFH and tirofiban. The NICE (National Investigators Collaborating on Enoxaparin) 4 study collected data on the combination of enoxaparin and abciximab in patients undergoing PCI, and both safety and efficacy data compared well with historical data collected on the use of UFH with abciximab. The more recent NICE 3 study extended this finding to the combination of enoxaparin with abciximab, tirofiban or eptifibatide. The safety of two doses of dalteparin and abciximab had also been investigated, with the higher dose the efficacious, and also with safety, in patients undergoing PCI. In addition, a GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes) IV substudy found that dalteparin had equivalent safety to UFH when co-administered with abciximab in patients not undergoing PCI. The NICE 3 and 4 trials were not randomised comparisons, and as such there results must be interpreted with caution. Recently, the CRUISE (Coronary Revascularisation Utilizing Integrelin [eptifibatide] and Single-bolus Enoxaparin) and INTERACT (Integrelin and Enoxaparin randomised assessment of Acute Coronary Syndromes Treatment) studies have provided evidence for both the safety and efficacy of enoxaparin combined with eptifibatide in non-ST elevation patients with acute coronary syndromes. A further study (SYNERGY [Superior Yield of the New strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa inhibitors]) will investigate the efficacy of the combination of enoxaparin with abciximab versus that of UFH and abciximab in a large cohort of 8000 patients. The use of GP IIb/IIIa agents and LMWH in patients with UA/STEMI has led to their use in those with ST-elevation MI, and studies indicate LMWH is efficacious and can be used safely as an adjunct to thrombolysis. New studies will investigate the use of these agents in patients with STEMI not undergoing thrombolysis and we await the results of these studies.

Chemotherapy-Induced Activation of Hemostasis: Effect of a Low Molecular Weight Heparin (Dalteparin Sodium) on Plasma Markers of Hemostatic Activation

To evaluate the effect of standard chemotherapeutic regimens on the hemostatic profile of patients with breast and lung carcinoma; and to evaluate the effect of a single dose of a low molecular weight (LMW) heparin, dalteparin sodium, administered prior to the chemotherapy on markers of hemostatic activation. 11 patients with breast cancer and 10 patients with lung cancer receiving systemic chemotherapy were studied. 10 breast cancer patients and 9 lung cancer patients completed at least 1 cycle of treatment and had all hemostatic studies. Patients had a complete hemostatic and prothrombotic profile performed at study initiation. Markers of hemostatic activation consisting of immunoassays for thrombin-antithrombin (TAT) complex and D-dimer were measured in plasma samples obtained prior to chemotherapy and at 1, 24 and 48 h after treatment. A 2500 U dose of dalteparin was given prior to the 2nd cycle of chemotherapy; 5000 U of dalteparin was given prior to the 4th treatment cycle. Chemotherapy resulted in statistically significant increases in TAT and D-dimer for the 1, 24 and 48 h plasma samples in both the breast and lung cancer patients for all cycles of chemotherapy given without LMW heparin. There were statistically significant increases in basal thrombin generation over the 4 cycles of treatment which was unrelated to active cancer. Both pretreatment doses of dalteparin effectively prevented increases in the markers of hemostatic activation. However, in the lung cancer patients, who had significantly increased basal thrombin generation, the 5000 U dose dalteparin was more effective. Chemotherapy results in significant hemostatic activation in patients with breast and lung cancer. The effect of treatment appears to be cumulative. A single dose of LMW heparin administered prior to therapy can suppress hemostatic activation.

A critical review of clinical trials for low-molecular-weight heparin therapy in unstable coronary artery disease.

Unstable angina and non-ST-segment elevation myocardial infarction (MI) are collectively referred to as unstable coronary artery disease (UCAD). They are conditions that share a common pathophysiology and represent frequently encountered, potentially life-threatening clinical manifestations of advanced atherosclerosis. Therefore, treatment of UCAD is a major focus for practicing clinicians, and although pharmacologic agents have been developed that impact on patient outcome, recent data suggest that a further reduction in ischemic complications is possible. Acute-phase treatment with aspirin is associated with a significant reduction in death and nonfatal MI in patients with UCAD. This benefit is enhanced by the addition of unfractionated heparin (UFH) to the treatment strategy; however, UFH requires careful monitoring and titration. In contrast, low-molecular-weight heparins (LMWHs), produced by chemical or enzymatic depolymerization of UFH, yield a predictable and consistent pharmacokinetic profile and anticoagulant response, making them an attractive treatment alternative to UFH in patients with UCAD. The optimal duration of treatment with LMWH is an important question influenced by the observation that reactivation of coagulation occurs following the early and abrupt discontinuation of heparin treatment. Early trials, such as FRISC and FRIC, demonstrated the benefit of acute therapy with dalteparin sodium; however, the results of extended treatment with dalteparin were inconclusive. The extended phase of these studies included relatively low-risk patients, and a once-daily, relatively low-dose strategy was employed. The findings derived from the FRISC II trial, which used a twice-daily dose of dalteparin, suggest a benefit for at least 60 days with extended treatment in high-risk patients with UCAD. Although an early-invasive treatment strategy is particularly beneficial, patients in whom early revascularization is not possible should be considered for extended treatment with dalteparin for up to 45 days, especially those awaiting percutaneous coronary intervention. Extended treatment with dalteparin therefore provides a protective "bridge" to enhance the outcome of patients with UCAD awaiting revascularization.

P-Selectin Antagonism Causes Dose-dependent Venous Thrombosis Inhibition

Inhibition of P-selectin by antibody or selectin antagonist decreases inflammation and thrombosis. This study evaluates the dose-response relationship using a selectin receptor antagonist. Eight male baboons (Papio anubis) underwent inferior vena caval thrombosis using a 6 h balloon occlusion model. Three animals received 500 microg/kg P-selectin antagonist (rPSGL-Ig) and five 1 mg/kg rPSGL-Ig with or without a non-anticoagulant dose of Dalteparin. These animals were compared to our published results in this model with 4 saline controls and 8 animals that received 4 mg/kg rPSGL-Ig. A statistically significant dose-response relationship existed between rPSGL-Ig dose and thrombosis (p < 0.01), and between rPSGL-Ig dose and spontaneous recanalization (p<0.05). Inflammatory assessment revealed decreased gadolinium enhancement in all rPSGL-Ig groups compared to previously reported control, despite no significant differences in inflammatory cell extravasation. No dose of rPSGL-Ig caused anticoagulation. Selectin antagonism results in a dose-dependent decrease in thrombosis and increase in spontaneous recanalization.

Outpatient Dalteparin Peri-Procedure Bridge Therapy In Patients Maintained On Long Term Warfarin

70 Background: Peri-operative anticoagulation management for patients maintained on chronic warfarin therapy in need for surgery or invasive procedures is controversial. Such data is lacking in patients with documented hypercoagulable states and history of ischemic stroke. Methods: This prospective cohort study evaluated the feasibility, efficacy, safety, and cost-effectiveness of peri-operative dalteparin bridge therapy in patients maintained on long-term warfarin undergoing surgical or invasive diagnostic procedures. Twenty one consecutive patients with documented hypercoagulable states (protein C defficiency, protein S defficiency, antiphospholipid antibody syndrome) and a history of ischemic stroke were included in the study. Warfarin was stopped 4 days prior to surgery and was restarted the night of surgery , once hemostasis was achieved, at the pre-operative dose. Dalteparin 100 IU/Kg given subcutaneously every 12 hours was initiated 3 days prior surgery and continued until a therapeutic international normalized ratio was reached after surgery. On the day of surgery, the morning dalteparin dose was held. Data was recorded at the completion of dalteparin therapy and at 3 months of follow-up on recurrent thromboembolic events, and major and minor bleeding events. An economic analysis compared outpatient dalteparin bridge therapy with inpatient intravenous unfractionated heparin therapy. Results: The 21 patients underwent 29 surgical procedures: dental surgery (15), colonoscopy (5), eye surgery (3), vascular surgery (4), surgical biopsies (2). No patients suffered an embolic event during the 3 month follow-up period. There were no major bleeding events, and there were 8 (38%) patients with a minor bleeding event (bruising at injection site). All patients self administered the injections. An average of 6.5 hospital days were avoided per patient. This resulted in cost savings of $3250.00 per patient treated with dalteparin. Conclusion: Dalteparin appears to be a feasible, safe, and cost-effective alternative to inpatient intravenous heparin for peri-procedure bridge anticoagulation therapy in stroke patients.

Outpatient Dalteparin Peri-Procedure Bridge Therapy In Patients Maintained On Long Term Warfarin

70 Background: Peri-operative anticoagulation management for patients maintained on chronic warfarin therapy in need for surgery or invasive procedures is controversial. Such data is lacking in patients with documented hypercoagulable states and history of ischemic stroke. Methods: This prospective cohort study evaluated the feasibility, efficacy, safety, and cost-effectiveness of peri-operative dalteparin bridge therapy in patients maintained on long-term warfarin undergoing surgical or invasive diagnostic procedures. Twenty one consecutive patients with documented hypercoagulable states (protein C defficiency, protein S defficiency, antiphospholipid antibody syndrome) and a history of ischemic stroke were included in the study. Warfarin was stopped 4 days prior to surgery and was restarted the night of surgery , once hemostasis was achieved, at the pre-operative dose. Dalteparin 100 IU/Kg given subcutaneously every 12 hours was initiated 3 days prior surgery and continued until a therapeutic international normalized ratio was reached after surgery. On the day of surgery, the morning dalteparin dose was held. Data was recorded at the completion of dalteparin therapy and at 3 months of follow-up on recurrent thromboembolic events, and major and minor bleeding events. An economic analysis compared outpatient dalteparin bridge therapy with inpatient intravenous unfractionated heparin therapy. Results: The 21 patients underwent 29 surgical procedures: dental surgery (15), colonoscopy (5), eye surgery (3), vascular surgery (4), surgical biopsies (2). No patients suffered an embolic event during the 3 month follow-up period. There were no major bleeding events, and there were 8 (38%) patients with a minor bleeding event (bruising at injection site). All patients self administered the injections. An average of 6.5 hospital days were avoided per patient. This resulted in cost savings of $3250.00 per patient treated with dalteparin. Conclusion: Dalteparin appears to be a feasible, safe, and cost-effective alternative to inpatient intravenous heparin for peri-procedure bridge anticoagulation therapy in stroke patients.

Prophylaxis and treatment of thromboembolic diseases during pregnancy with dalteparin

Objectives: To determine if a prophylactic dose of dalteparin, 5000 IU daily, and if the adjusted-weight dalteparin therapeutic dose of 100 IU/kg twice daily are appropriate in pregnancy. Method: Anti-Xa activity levels were used to assess prophylactic (33 women) and therapeutic (15 women) dalteparin dosage throughout pregnancy. Analysis of variance was used and P-values less than 0.05 were considered statistically significant. Results: In the prophylactic group, anti-Xa activity levels did not vary significantly throughout pregnancy ( P=0.15). The initial dalteparin dose was modified on the first anti-Xa activity measurement in eight women, whose weight was statistically different from those remaining on the initial dose ( P<0.001). The adjusted-weight therapeutic dalteparin dose induced adequate anti-Xa activity levels. Conclusions: Dalteparin, 5000 IU daily, is suitable for most pregnant women and does not need to be modified in the third trimester. A therapeutic dalteparin dose adjusted according to pregnancy weight is appropriate.