Markers of hemostatic system activation during treatment of deep vein thrombosis with subcutaneous unfractionated or low-molecular weight heparin. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. An objective study of alternative methods of heparin administration. Subcutaneous administration of heparin. A randomised comparison with intravenous administration of heparin to patients with deep-vein thrombosis. Subcutaneous adjusted-dose unfractionated heparin vs fixed-dose low-molecular-weight heparin in the initial treatment of venous thromboembolism. Subcutaneous low molecular weight heparin versus subcutaneous unfractionated heparin in the treatment of deep vein thrombosis: a Polish multicenter trial. [Subcutaneous injections and intravenous infusion of sodium salt of heparin in the treatment of thrombosis of deep veins of the lower extremities]. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. Subcutaneous heparin treatment of deep venous thrombosis: a comparison of unfractionated and low molecular weight heparin. [Heparin treatment. Comparison between intravenous and subcutaneous administration]. Adjusted subcutaneous heparin or continuous intravenous heparin in patients with acute deep vein thrombosis. A randomized trial. [Efficacy of a very low molecular weight heparin fragment (CY 222) compared to standard heparin in patients with deep venous thrombosis. A randomized study]. Subcutaneous calcium heparin versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legs: a multicentre prospective randomised trial. Subcutaneous vs intravenous heparin in the treatment of deep venous thrombosis--a randomized clinical trial. Comparison of low-molecular-weight heparin, administered primarily at home, with unfractionated heparin, administered in hospital, and subcutaneous heparin, administered at home for deep-vein thrombosis.
Prothrombin fragments (F1+2), thrombin-antithrombin complexes (TAT) and D-dimers, markers of hemostatic system activation, were measured in 59 consecutive patients with deep vein thrombosis (DVT). Patients were randomly treated either with subcutaneous unfractionated heparin (UH) administered in two to three subcutaneous doses adjusted to activated partial thromboplastin time (APTT) or with low-molecular weight heparin (LMWH) (dalteparin) administered in a fixed dose of 200 IU/kg body weight in one subcutaneous injection daily. Before treatment, F1+2, TAT and D-dimer were above the cut-off level in 27/59 (46%), 34/59 (58%) and all (100%) patients, respectively. Significant associations were observed between F1+2 and TAT (r=.66, P<.001), TAT and D-dimer (r=.36, P<.005) and F1+2 and D-dimer (r=.30, P<.050). On the third day of treatment, F1+2 and TAT significantly decreased to reference values in almost all patients (in 64/66 determinations of both F1+2 and TAT) and remained low on the seventh day of treatment. Compared to pretreatment values, a nonsignificant decrease of D-dimer was noted in both groups, but all values remained above the cut-off value. When markers of hemostatic system activation in the UH and LMWH groups were compared, no significant differences were observed. It was concluded that subcutaneous UH in an APTT-adjusted dose and subcutaneous LMWH in a once-daily weight-adjusted dose controlled these markers of hemostatic system activation in a similar manner. We performed a randomized double-blind trial comparing continuous intravenous heparin with intermittent subcutaneous heparin in the initial treatment of 115 patients with acute proximal deep-vein thrombosis. Intermittent subcutaneous heparin as administered in this trial was inferior to continuous intravenous heparin in preventing recurrent venous thromboembolism. The subcutaneous heparin regimen induced an initial anticoagulant response below the target therapeutic range in the majority of patients and resulted in a high frequency of recurrent venous thromboembolism (11 of 57 patients, 19.3 percent), which was virtually confined to patients with a subtherapeutic anticoagulant response. In contrast, continuous intravenous heparin induced a therapeutic anticoagulant response in the majority of patients and a low frequency of recurrent events (3 of 58 patients, 5.2 percent; P = 0.024); the recurrences were limited to patients with an initial subtherapeutic anticoagulant response. The results of this trial establish the efficacy of intravenous heparin in the treatment of proximal venous thrombosis and suggest a relation between the effectiveness of heparin and the levels of anticoagulation achieved; such a relation could explain the observed failure of the subcutaneous regimen. nan One-hundred and forty-one patients with clinical signs of acute deep venous thrombosis (DVT) in the legs were randomly allocated to receive heparin either as two daily subcutaneous injections (s.c.) or as continuous intravenous infusion (i.v.). The thrombi extended into the popliteal or femoral veins in 83% of the patients. Verification of diagnosis and evaluation of therapy was performed by phlebography, plethysmography and thermography. The results showed that heparin administered s.c. twice daily was as efficient as continuous i.v. infusion in preventing extension of the thrombus. In two patients the s.c. administration was stopped due to local haematomas at the injection sites. Retroperitoneal or intramuscular bleedings occurred in four patients, two in each group. Two major, non-fatal pulmonary emboli occurred, one in each group. Few reports have addressed the value of unfractionated heparin (UFH) or low-molecular-weight heparin in treating the full spectrum of patients with venous thromboembolism (VTE), including recurrent VTE and pulmonary embolism.
                In an open, multicenter clinical trial, 720 consecutive patients with acute symptomatic VTE, including 119 noncritically ill patients (16.5%) with pulmonary embolism and 102 (14.2%) with recurrent VTE, were randomly assigned to treatment with subcutaneous UFH with dose adjusted by activated partial thromboplastin time by means of a weight-based algorithm (preceded by an intravenous loading dose), or fixed-dose (adjusted only to body weight) subcutaneous nadroparin calcium. Oral anticoagulant therapy was started concomitantly and continued for at least 3 months. We recorded the incidence of major bleeding during the initial heparin treatment and that of recurrent VTE and death during 3 months of follow-up.
                Fifteen (4.2%) of the 360 patients assigned to UFH had recurrent thromboembolic events, as compared with 14 (3.9%) of the 360 patients assigned to nadroparin (absolute difference between rates, 0.3%; 95% confidence interval, -2.5% to 3.1%). Four patients assigned to UFH (1.1%) and 3 patients assigned to nadroparin (0.8%) had episodes of major bleeding (absolute difference between rates, 0.3%; 95% confidence interval, -1.2% to 1.7%). Overall mortality was 3.3% in each group.
                Subcutaneous UFH with dose adjusted by activated partial thromboplastin time by means of a weight-based algorithm is as effective and safe as fixed-dose nadroparin for the initial treatment of patients with VTE, including those with pulmonary embolism and recurrent VTE. In a prospective multicenter trial, 149 consecutive patients with phlebographically proven proximal and/or distal deep vein thrombosis of the leg were randomly allocated to receive subcutaneously for 10 days either low molecular weight heparin CY 216 (Fraxiparine) in a fixed dose or unfractionated heparin (UFH) in doses adjusted according to the activated partial thromboplastin time. Pre- and post-treatment phlebograms were assessed blindly using the Arnesen's score system in 134 patients available for analysis of the treatment efficacy. The mean phlebographic score after 10 days of treatment was significantly decreased in both groups (p less than 0.001) in comparison with the baseline score but the difference in score changes between the two groups was not statistically significant. There was an improvement in 45/68 patients (66%) in the Fraxiparine group and in 32/66 patients (48%) in the UFH group, and an increase in the thrombus size in 10/68 (15%) and 12/66 (18%), respectively. One symptomatic non-fatal pulmonary embolism and one major bleeding episode were observed in the UFH group. During a follow-up period of 3 months, two rethromboses had occurred in the UFH group and none in the Fraxiparine group. It is concluded that subcutaneous fixed dose Fraxiparine is safe and at least as effective as subcutaneous adjusted UFH in the treatment of deep vein thrombosis. Ninety-four patients with deep vein thrombosis of inferior limbs were randomly allocated to receive sodium heparin either by subcutaneous injections or by continuous intravenous infusion for six days. No significant difference was observed in the therapeutic efficiency as judged by phlebographic examinations and in rate of symptomatic pulmonary embolism between the two groups. There was one instance of major bleeding in the subcutaneous group. Minor bleedings occurred in 10 of the 48 patients treated with subcutaneous heparin and in 13 of the 46 patients receiving intravenous heparin. The results showed that subcutaneous injections of sodium heparin are as effective and safe as continuous intravenous infusion of this drug in the treatment of deep vein thrombosis. When unfractionated heparin is used to treat acute venous thromboembolism, it is usually administered by intravenous infusion with coagulation monitoring, which requires hospitalization. However, subcutaneous administration of fixed-dose, weight-adjusted, unfractionated heparin may be suitable for inpatient and outpatient treatment of venous thromboembolism.
                To determine if fixed-dose, weight-adjusted, subcutaneous unfractionated heparin is as effective and safe as low-molecular-weight heparin for treatment of venous thromboembolism.
                Randomized, open-label, adjudicator-blinded, noninferiority trial of 708 patients aged 18 years or older with acute venous thromboembolism from 6 university-affiliated clinical centers in Canada and New Zealand conducted from September 1998 through February 2004. Of the randomized patients, 11 were subsequently excluded from the analysis of efficacy and 8 from the analysis of safety.
                Unfractionated heparin was administered subcutaneously as an initial dose of 333 U/kg, followed by a fixed dose of 250 U/kg every 12 hours (n = 345). Low-molecular-weight heparin (dalteparin or enoxaparin) was administered subcutaneously at a dose of 100 IU/kg every 12 hours (n = 352). Both treatments could be administered out of hospital and both were overlapped with 3 months of warfarin therapy.
                Recurrent venous thromboembolism within 3 months and major bleeding within 10 days of randomization.
                Recurrent venous thromboembolism occurred in 13 patients in the unfractionated heparin group (3.8%) compared with 12 patients in the low-molecular-weight heparin group (3.4%; absolute difference, 0.4%; 95% confidence interval, -2.6% to 3.3%). Major bleeding during the first 10 days of treatment occurred in 4 patients in the unfractionated heparin group (1.1%) compared with 5 patients in the low-molecular-weight heparin group (1.4%; absolute difference, -0.3%; 95% confidence interval, -2.3% to 1.7%). Treatment was administered entirely out of hospital in 72% of the unfractionated heparin group and 68% of the low-molecular-weight heparin group.
                Fixed-dose subcutaneous unfractionated heparin is as effective and safe as low-molecular-weight heparin in patients with acute venous thromboembolism and is suitable for outpatient treatment.
                clinicaltrials.gov Identifier: NCT00182403. In a double-blind study, patients with phlebographically proven deep venous thrombosis (DVT) were treated with subcutaneous injections twice a day of either unfractionated heparin (UH; n = 27) or low molecular weight heparin (LH; n = 29) for 7 days, and the dose was adjusted until therapeutic range was reached, according to a chromogenic substrate anti-Xa assay. Forty-eight percent of the LH group did not need dose adjustment as compared to 24% of the UH group. During the course of heparin administration, deviation from initial heparin activity was frequent in both groups, but mean activity did not indicate a cumulative effect in either group. There was 1 incidence of pulmonary embolism (LH) and only 1 minor bleeding episode (UH). Half of the patients in both groups were phlebographically improved. We conclude that subcutaneous heparin treatment with UH or LH appears safe and convenient. 48 patients with acute deep venous thrombosis of the lower limbs were treated with sodium heparin. In 23 patients heparin was injected subcutaneously (s.c.) twice a day and in 25 patients heparin was given by continuous intravenous perfusion (i.v.). Pain and edema disappeared after 8.7 days (s.c.) and 11.7 days (i.v.) respectively. One non fatal pulmonary embolism occurred in each group. A second venography was performed in 24 patients after 7 days of treatment and revealed no difference between the two groups. As judged by repeated thrombin time determination, anticoagulation was ineffective on at least one day in 39% of patients treated subcutaneously and in 60% of patients treated intravenously. The two pulmonary embolisms occurred in patients with ineffective anticoagulation. It is concluded that heparin may be used either intravenously or subcutaneously in the treatment of acute deep venous thrombosis. Thromboembolic complications occurred with both methods of treatment when anticoagulation was ineffective. Study Objective: To determine the efficacy and safety of adjusted subcutaneous calcium heparin compared with continuous intravenous calcium heparin as the initial treatment for acute deep vein thrombosis. Design: Randomized control trial. Setting: University-affiliated general hospital. Patients: Of 111 consecutive patients considered, 103 had acute proximal or calf vein thrombosis confirmed by ascending venography and met all other eligibility criteria. Interventions: Patients were randomly assigned to receive subcutaneous or intravenous heparin. The subcutaneous regimen consisted of an initial dose of 15,000 U, adjusted thereafter to prolong the activated partial thromboplastin time to 50 to 70 seconds. The continuous intravenous regimen was begun as a bolus injection of 5000 U, followed by an infusion of 1250 U/h, adjusted to maintain the activated partial thromboplastin time at 50 to 70 seconds. Measurements and Main Results: There was no significant difference in the rate of new pulmonary embolism between the two groups, as defined by new high-probability defect on repeat ventilation-perfusion scintigrams of the lung in 96 (93%) of the patients after 7 to 10 days of treatment. Five of forty-seven patients in the subcutaneous group and 5 of 49 in the intravenous group developed pulmonary embolism (95% confidence interval [CI] for the difference, -13.1% to 12.2%). Similarly, there was no significant difference in the frequency of hemorrhagic complications. Five of fifty-one patients in the subcutaneous group and 5 of 52 in the intravenous group had hemorrhagic complications (95% CI for the difference, -11.2% to 11.6%). Conclusion: Adjusted subcutaneous calcium heparin may be an effective and safe alternative to continuous intravenous calcium heparin in the initial treatment of acute proximal deep vein thrombosis. Low molecular weight heparin fractions have been demonstrated as efficient as low doses of standard heparin in preventing post-operative deep-vein thrombosis. Several clinical studies are, now, carrying out in patients with acute deep-vein thrombosis in order to assess efficacy and safety of low molecular weight heparin fractions as compared to standard heparin. In a randomised study including patients with deep-vein thrombosis treated either with low molecular weight heparin or with subcutaneously standard heparin, we demonstrated an effectiveness, in terms of thrombus reduction, of low molecular weight heparin as well as standard heparin. However, low molecular weight heparin seemed to be safer than standard heparin. One hundred patients with phlebographically proved acute deep vein thrombosis of the legs were prospectively randomised into two treatment groups to compare the safety and efficacy of subcutaneous calcium heparin versus intravenous sodium heparin administered by constant infusion pump. The dose of heparin was determined by daily measurement of the kaolin cephalin clotting time. Treatment was maintained for up to 14 days, after which phlebography was repeated. Of 49 patients who received subcutaneous calcium heparin, two showed an increase in thrombus size, while eight showed complete lysis. In the 47 patients who received intravenous sodium heparin thrombus increased in size in 13 while only one showed evidence of complete lysis. These differences were significant. There were no significant differences between the two groups in the incidence of serious complications, although almost half of those receiving intravenous heparin had some minor problem with the constant infusion pump and just over half of those receiving subcutaneous heparin had some bruising at the injection site. This study showed that subcutaneous calcium heparin was more effective in helping lyse existing thrombus and preventing its propagation than intravenous sodium heparin. 271 patients with acute symptomatic deep venous thrombosis of lower limbs, confirmed by strain-gauge plethysmography and/or venography, were randomly assigned to receive intermittent subcutaneous heparin calcium or heparin sodium by continuous intravenous infusion for 6-10 days. Heparin dosage was adjusted to maintain activated partial thromboplastin time values (Thrombofax reagent) at 1.3-1.9 times the basal ones. Strain-gauge plethysmography was repeated at the end of heparin treatment, and evaluation of therapy was performed by comparing the indexes of venous hemodynamics and by assessing the incidence of pulmonary embolism and of bleeding complications. In the intravenous group, Maximal Venous Outflow (MVO) increased from 20.8 +/- 12.8 to 28.4 +/- 17.5 ml/min per 100 ml of tissue and Venous Capacitance (VC) from 1.39 +/- 0.92 to 1.94 +/- 1.0 ml/100 ml of tissue (mean +/- SD). In the subcutaneous group, MVO increased from 21.0 +/- 12.7 to 27.5 +/- 18.1 and VC from 1.60 +/- 0.86 to 2.06 +/- 1.0. The median improvement of MVO and VC were 22% and 36% respectively in the IV group and 20% and 24% in the SC group. Clinical pulmonary embolism occurred in 2 patients in the intravenous group (1 fatal) and in 4 in the subcutaneous group (1 fatal). 9 major bleeding complications occurred in the intravenous group (1 fatal) and 5 in the subcutaneous group (1 fatal). The differences were not significant at the statistical analysis. The results suggest that subcutaneous intermittent heparin has a comparable efficacy to continuous intravenous heparin in the treatment of deep venous thrombosis. To the same conclusion points an overview of the seven randomized trials which compared these treatment modalities. In this study, 294 patients with acute proximal DVT (deep venous thrombosis) were randomly assigned to receive intravenous standard heparin in the hospital (98 patients) or low-molecular-weight heparin (LMWH) (nadroparin 0.1 mL [equivalent to 100 AXa IU] per kg of body weight subcutaneously twice daily) administered primarily at home (outpatients) or alternatively in hospital (97 patients) or subcutaneous calcium heparin (SCHep) (99 patients, 0.5 mL bid) administered directly at home. The study design allowed outpatients taking LMWH heparin to go home immediately and hospitalized patients taking LMWH to be discharged early. Patients treated with standard heparin or LMWH received the oral anticoagulant starting on the second day, and heparin was discontinued when the therapeutic range (INR 2-3) had been reached. Anticoagulant treatment was maintained for 3 months. Patients treated with SCHep were injected twice daily for 3 months without oral anticoagulants. Patients were evaluated for inclusion and follow-up with color duplex scanning. Venography was not used. In case of suspected pulmonary embolism (PE) a ventilatory-perfusional lung scan was performed. Endpoints of the study were recurrent or extension of DVT, bleeding, the number of days spent in hospital, and costs of treatments. Of the 325 patients included, 294 completed the study. Dropouts totaled 31 (10.5%); six of the 325 included patients (1.8%) died from the related, neoplastic illness. Recurrence or extension of DVT was observed in 6.1% of patients in the LMWH group, in 6.2% in the standard heparin group, and in 7.1% in the SCHep group. Most recurrences (11/17) were in the first month in all groups. Bleedings were all minor, mostly during hospital stay. Hospital stay in patients treated with LMWH was 1.2+/-1.4 days in comparison with 5.4+/-1.2 in those treated with standard heparin. There was no hospital stay in the SCHep group. Average treatment costs in 3 months in the standard heparin group (US $2,760) were considered to be 100%; in comparison costs in the LMWH group was 28% of the standard heparin and 8% in the SCHep group. This study indicated that LMWH and SCHep can be used safely and effectively to treat patients with proximal DVT at home at a lower cost.