Optimal dosing of subcutaneous unfractionated heparin for the treatment of deep vein thrombosis

Twice-daily, inpatient, subcutaneous unfractionated heparin is at least as effective and safe as continuous intravenous unfractionated heparin for the treatment of acute deep vein thrombosis. Subcutaneous unfractionated heparin therefore may be suitable for outpatient treatment of deep vein thrombosis. The purpose of this study was to develop a dosing nomogram for a dose each 12 hours (2 doses per day) 12-hourly subcutaneous unfractionated heparin that is suitable for outpatient treatment of acute deep vein thrombosis. A cohort study was performed in patients with acute deep vein thrombosis in two phases. In both phases, the first subcutaneous loading dose of unfractionated heparin was 317 U/kg, and the second dose was 231 U/kg. The activated partial thromboplastin time was measured daily, 6 hours after the morning injection, and subsequent doses of unfractionated heparin were adjusted according to a nomogram, which was modified for phase II. Warfarin was started with unfractionated heparin. In phase I (14 outpatients), activated partial thromboplastin time results were frequently subtherapeutic (9:14) the day after starting unfractionated heparin (day 1), and were frequently supratherapeutic (27:40) after the first 2 days of unfractionated heparin therapy. In phase II (21 patients), to explain the frequently subtherapeutic activated partial thromboplastin time results that were obtained on day 1, the activated partial thromboplastin time results were measured after the initial loading dose. Mean activated partial thromboplastin time results of 86 and 61 seconds were obtained 6 and 12 hours after this dose, suggesting that 317 U/kg is a suitable subcutaneous loading dose. In contrast to phase I, in phase II, unfractionated heparin dose was not increased on day 1 in response to a low activated partial thromboplastin time result. This reduced the frequency of supratherapeutic activated partial thromboplastin time results during the early days of therapy without increasing the frequency of subtherapeutic results. Warfarin therapy had a substantal effect on the activated partial thromboplastin time that appeared to account for a high frequency of supratherapeutic results during the later days of unfractionated heparin therapy; the activated partial thromboplastin time increased by 20 seconds (95% CI, 14–27 seconds) with each increase in the International Normalized Ratio of 1.0. We had limited success at developing a dosing nomogram for subcutaneous unfractionated heparin that reliably achieved activated partial thromboplastin time results within the therapeutic range. However, as oral anticoagulants directly increased activated partial thromboplastin time results, we suggest that adjusting unfractionated heparin dose to achieve prespecified activated partial thromboplastin time results may not be appropriate in patients who are receiving concomitant warfarin therapy.     

Subcutaneous low molecular weight heparin versus subcutaneous unfractionated heparin in the treatment of deep vein thrombosis: a Polish multicenter trial.

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.     

Markers of hemostatic system activation during treatment of deep vein thrombosis with subcutaneous unfractionated or low-molecular weight heparin

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.     

Low-molecular-weight heparin in the acute and long-term treatment of deep vein thrombosis

Low molecular weight heparins (LMWHs) are frequently used during acute treatment of deep vein thrombosis, but their utility for long-term treatment needs to be defined. In this multi-centre trial, 378 patients with acute deep vein thrombosis were randomised to intravenous unfractionated heparin (group A), once daily subcutaneous LMWH (bemiparin) for one week (group B) or once daily bemiparin in a therapeutic dose for one week followed by a maintenance dose for 12 weeks (group C). Fifty-two per cent of patients in group A, 72% of group B and 72% of group C showed venographic reduction in thrombus size assessed objectively on day 14; 20% greater improvement in group B and C indicates not only non-inferiority of bemiparin (p = 0.00003) but also superiority (p = 0.004) compared to UFH. Day 84 venographic or Doppler sonographic recanalisation of the affected veins was demonstrated in 75.3%, 79.8% and 81.5% in groups A, B and C respectively. Mortality, recurrent thromboembolic events and bleeding were similar in the three groups. Both bemiparin regimens were more effective than UFH in reducing thrombus size during the acute phase of treatment. The efficacy in terms of recurrence of venous thromboembolism and safety of Bemiparin is similar to UFH. Bemiparin is also an effective alternative to warfarin for long-term treatment.     

Electroconvulsive therapy,catatonia, deep vein thrombosis and anticoagulant treatment: a case report

Electroconvulsive therapy (ECT) is considered an effective treatment for pharmacotherapy-resistant severe mental disorders. Catatonia is a complex syndrome characterised by important psychomotor disturbances. Deep vein thrombosis (DVT) and pulmonary embolism (PE) are frequent side effects of prolonged immobility in catatonic patients. Therefore, it is important to resolve the catatonia as soon as possible. ECT is the most effective therapy available and is generally considered a safe procedure. Nevertheless, its use in patients with DVT or PE and anticoagulant treatment remains controversial. We describe a case of a woman in her 40s with a previous diagnosis of bipolar disorder and dysfunctional personality traits. She was hospitalised with persecutory and reference delusions, high emotional lability, anxiety, somatisation and regressive conduct. She later developed catatonic symptoms. No progress was achieved after a month of hospitalisation, despite several pharmacological treatments. She suffered multiple complications of prolonged bedding, such as an extensive DVT of the left common femoral, the external iliac and the common iliac veins. ECT was conducted under treatment with bemiparin. After the third administration, she showed improvement. No major bleeding or PE was developed. The safety of ECT while receiving anticoagulant therapy has been documented, though dosage and type of anticoagulant must be considered. Location of DVT (proximal or distal) may be an important topic to take into account. This report provides further evidence about the efficacy and safety of undergoing ECT in the context of concomitant serious medical conditions, such as DVT and anticoagulant therapy administration.     

Thrombolysis and fibrinolytic parameters during heparin treatment of deep vein thrombosis

Thirty-nine patients with symptomatic, venographically verified deep vein thrombosis (DVT) were studied during treatment with heparin in order to investigate the correlation between the venographic changes and parameters of heparin therapy or fibrinolytic components. Venograms were scored with a 40-grade scale, and after one week a significant improvement with an average reduction of the thrombi of 17% was observed. No statistically significant correlation was found between reduction of thrombus size and duration of heparin treatment, total amount of heparin administered, mean levels of APTT, plasmin-α₂-antiplasmin complex (PAP), tissue plasminogen activator (t-PA) antigen or t-PA-inhibitor. Only a short history of the thrombus was significantly correlated to thrombolysis. The concentrations of PAP and t-PA-inhibitor were not influenced, while that of t-PA antigen showed a significant increase during heparin infusion. Even if statistically significant correlations were not obtained, the patients with pronounced thrombolytic effect had high PAP-levels. Furthermore, patients with high t-PA-inhibitor levels had no lysis. The results suggest, that also other factors than plasminogen dependent fibrinolysis are of importance for the thrombolytic effect.     

Intensive initial oral anticoagulation and shorter heparin treatment in deep vein thrombosis

In order to investigate whether a more intensive initial oral anticoagulation still would be safe and effective, we performed a prospective randomized study in patients with deep vein thrombosis. They received either the conventional regimen of oral anticoagulation ("low-dose") and heparin or a more intense oral anticoagulation ("high-dose") with a shorter period of heparin treatment. In the first part of the study 129 patients were randomized. The "low-dose" group reached a stable therapeutic prothrombin complex (PT)-level after 4.3 and the "high-dose" group after 3.3 days. Heparin was discontinued after 6.0 and 5.0 days respectively. There was no difference in significant hemorrhage between the groups, and no clinical signs of progression of the thrombosis. In the second part of the study another 40 patients were randomized, followed with coagulation factor II, VII, IX and X and with repeated venograms. A stable therapeutic PT-level was achieved after 4.4 ("low-dose") and 3.7 ("high-dose") days, and heparin was discontinued after 5.4 and 4.4 days respectively. There were no clinical hemorrhages, the activity of the coagulation factors had dropped to the same level in both groups at the time when heparin was discontinued and no thromboembolic complications occurred. Our oral anticoagulation regimen with heparin treatment for an average of 4.4-5 days seems safe and reduces in-patient costs.     

Fixed-dose, body weight-independent subcutaneous LMW heparin versus adjusted dose unfractionated intravenous heparin in the initial treatment of proximal venous thrombosis. EASTERN Investigators

BACKGROUND: Body weight-adjusted subcutaneous low-molecular-weight heparin (LMWH) has been proven to be at least as effective and safe as dose-adjusted intravenous unfractionated heparin (UFH) for the treatment of patients with venous thromboembolism. However, body weight-adjusted dosage of low-molecular-weight heparin may be cumbersome and could lead possibly to incorrect dosing. Therefore a fixed LMWH dose, independent of body-weight, might rationalize initial treatment for venous thromboembolism. METHODS: Patients with proven proximal deep-vein thrombosis were randomly assigned to fixed dose subcutaneous LMWH Certoparin (8,000 anti-factor Xa U b.i.d.; 265 patients) or to adjusted dose i.v. UFH (273 patients) for 12 days. Vitamin K antagonists were started between day 3 and 7 and continued for up to 6 months. The primary outcome measure was a 30 percent or greater improvement in the Marder Score, as revealed by repeated venography on day 12 (end of the initial treatment). The secondary composite outcome measure included death, recurrent venous thromboembolism and major bleeding and was assessed at day 12 and after 6 months by a blinded adjunction committee. RESULTS: The Marder score improved by 30% or more in 30.3% and 25.0% of patients assigned to LMWH (198 paired venograms) and UFH (192 paired venograms), respectively (2p = 0.26). At the end of the initial treatment, the composite outcome was observed in 4 of the 265 patients (1.5%) randomized to LMWH, as compared with 14 of the 273 patients (5.1%) randomized to UFH (2p = 0.03). At 6 months these figures were 6.8% and 12.8%, respectively (risk reduction 0.53, confidence interval 0.31-0.90, 2p = 0.02). CONCLUSION: Fixed dose subcutaneous LMWH certoparin is at least as efficacious as UFH in resolving proximal vein thrombosis.     

Fixed-dose,body weight-independent subcutaneous low molecular weight heparin Certoparin compared with adjusted-dose intravenous unfractionated heparin in patients with proximal deep venous thrombosis

Subcutaneous body weight-adjusted low molecular weight heparin (LMWH) has been proven as effective and safe as intravenous aPTT-adjusted unfractionated heparin (UFH) for the treatment of patients with acute deep venous thrombosis (DVT). In this study we evaluate the efficacy of the initial treatment of proximal DVT with a fixed-dose, body weight-independent application of the LMWH Certoparin with a six month follow-up. In a prospective, multicentre, randomized, active-controlled study 1220 patients with objectively diagnosed proximal DVT were randomly assigned to subcutaneous 8000 U anti-factor Xa of Certoparin twice daily for 10 to 14 days or intravenous aPTT-adjusted UFH for 5 to 8 days. Both regimen were followed by oral anticoagulation for 6 months. The primary end point was the rate of symptomatic and objectively confirmed thromboembolic events within 6 months. The aim of the study was to demonstrate the non-inferiority of the Certoparin regimen as compared to UFH. The per-protocol analysis revealed 22 (3.8%) thromboembolic events in the Certoparin group and 24 (4.3%) in patients assigned to UFH within 6 months, thereby proving the non-inferiority (p<0.01), confirmed by intent-to-treat analysis (p<0.001). Major bleeding occurred in 6 and 7 patients started on Certoparin or UFH during the treatment period. Thromboembolic events were equally distributed in body weight categories with < 50, 50-80 and >80 kg as followed: 0, 3.6% and 4.1% of patients for the Certoparin group and 0, 4.6% and 4.2% of patients for the UFH group. The same was true for major bleeding complications with 0, 2.9% and 1.5% for Certoparin and 0, 3.5% and 4.2% for UFH. Overall mortality was 1.9% in the Certoparin group and 2.7% in the UFH group. Fixed-dose body weight-independent subcutaneous LMWH Certoparin is at least as efficacious and safe as intravenous aPTT-adjusted UFH for the initial treatment of acute proximal DVT. This effect is maintained during a 6-months follow-up of treatment with oral anticoagulation.     

Intermittent plasminogen-streptokinase treatment of deep vein thrombosis.

The fibrinolytic response of 12 patients receiving single daily infusions of 600,000 units of streptokinase (SK) and 90 mg of plasminogen for the treatment of DVT has been studied. The mean plasminogen concentration was maintained throughout the treatment period (4-6 days) at between 20-40% the initial value, while mean circulating plasmin concentration rose to only about twice initial plasma levels. The degradation of fibrinogen as indicated by a fall in clottable fibrinogen did not fall below 1 mg/ml and serum FDP rose to greater than 1 mg/ml. Limited fibrinogenolysis occurred in 2 patients, while in another patient who bled there was immediate and extensive depletion to below 0.5 mg/ml. The beneficial clinical results obtained with this regimen (Kakkar et al. 1975), which produces only limited systemic plasminaemia, suggest that thrombolysis may be facilitated by higher levels of plasminogen than those maintained during conventional SK treatment.     

Prophylactic use of heparin for deep vein thrombosis in restrained psychiatric patients: a chart review

ObjectivePhysical restraint sometimes causes deep vein thrombosis (DVT) and pulmonary embolism. Although unfractionated heparin (UFH) is used for the prophylaxis of DVT, its effectiveness remained unknown for restrained patients.MethodWe conducted a chart review of restrained inpatients at Sakuragaoka Memorial Hospital in Japan. Restrained patients received subcutaneous injection of UFH 5000 IU bid from December 2008 to September 2010 [heparin (+) period] while UFH was not used from December 2010 to September 2012 [heparin (−) period]. A Doppler ultrasound scanning was performed to examine the presence of DVT. The incidence of DVT was compared between the two periods by chi-square test. A multiple logistic regression model was used to examine effects of demographic and clinical characteristics on the incidence of DVT.ResultsNo significant difference was found in the incidence of DVT between the heparin (+) and (−) periods [11.8% (11/93) vs. 11.1% (13/117)]. Sedation [odds ratio (OR)=3.78], physical comorbidities (OR=6.29) and a longer duration of restraint (OR=1.22) were associated with the incidence of DVT.ConclusionThe use of UFH was not associated with any reduction in the incidence of DVT in restrained psychiatric patients.     

The efficacy and safety of low-molecular-weight heparin and unfractionated heparin in the treatment of cerebral venous sinus thrombosis

Objective:

To compare the efficacy and safety of low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) in the treatment of patients with cerebral venous sinus thrombosis (CVST), and to provide an appropriate treatment option in these patients.

Method:

This is a randomized double blind clinical trial conducted between December 2013 and December 2014. The subjects were selected among patients referred to Neurology Department, Imam Reza Hospital; affiliated to Kermanshah University of Medical Sciences, Kermanshah, Iran. Fifty-two cases of CVST were included in this study and randomly divided into 2 groups. Twenty-six cases received LMWH and the other 26 cases received UFH. The primary outcomes include hospital mortality rate and neurologic deficits as assessed by the National Institutes of Health Stroke Scale (NIHSS). The secondary end point was disability as measured by the Modified Rankin Scale (MRS).

Results:

We observed the rate of mortality and neurological deficits and disability based on NIHSS, and the MRS did not differ between the 2 groups.

Conclusion:

The efficacy of LMWH and UFH in reduction of neurologic deficit and functional disability in patients with CVST are similar.Cerebral venous sinus thrombosis (CVST) is an uncommon stroke that, unlike arterial stroke, occurs mostly in adolescent and young children.1,2 The outcome of patients with CVST is variable from complete recovery to persistent neurological damage.3 Regardless of the fact that most patients have a complete or partial recovery, 10% are observe to have persistent neurological damage by 12 months of follow-up.3 According to information from clinical trials and observational studies, anticoagulation is advised as safe and effective treatment for cerebral venous thrombosis.3-5 Anticoagulants can also prevent pulmonary embolism, which makes sinus thrombosis is highly complicated.4-7 However, there is no agreement on what type of heparin to use: low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH).7,8 The advantage of using UFH is that it acts rapidly due to inhibition of IIa factor, and its effects are reversible by administering protamine sulfate; however, binding to plasma proteins, platelet (platelet factor 4), macrophages, and endothelial cells limit its bioavailability and account for the highly variable anticoagulant response and requires dose adjustments based on activated partial-thromboplastin time values.8,9 The clinical benefits of LMWH comprise higher bioavailability more predictable pharmacokinetic profile, dose-dependent plasma levels, a longer half-life, the lower risk of bleeding and immune-mediated thrombocytopenia and heparin-induced osteoporosis.8,9 Because of these clinical advantages, LMWHs have gradually replaced UFH for most indications. Several clinical trials, in patients with deep venous thrombosis and pulmonary embolism indicates that LMWH is as effective as UFH and associated with the fewest hemorrhagic complications.8,10 There are already limited data directly comparing LMWH with UFH in CVST patients. It is critical for the clinician to understand which drugs are most effective and associated with the fewest adverse events. The aim of this study was to compare the efficacy and safety of these 2 types of heparins in the treatment of patients with CVST to provide an appropriate treatment option in such patients.     

A comparative study of low doses of heparin and a heparin analogue in the prevention of postoperative deep vein thrombosis

The efficacy of heparin and a semi-synthetic heparin analogue as compared for the prevention of postoperative deep vein thrombosis (DVT) in a prospective, randomized trial involving 200 patients. 12 (12.5%) out of 95 patients in the heparin group developed DVT compared to 6 (6.3%) out of 94 patients who received the analogue. Serious bleeding did not occur in any of the patients in either group and the difference in the operative and postoperative bleeding was not statistically significant. In this entire series of 190 patients, wound haematoma developed in 3, and all were in the heparin group. In 50 patients (25 in each group) plasma heparin levels, kaolincephalin clotting time (KCCT) and antithrombin III (At IIII) activity were measured in the samples withdrawn before, during and immediately after surgery and also on the first postoperative day. Significantly higher mean plasma heparin levels were obtained in the pat-ients receiving the analogue than those receiving heparin. Yet there was no difference in the prolongation of the KCCT observed in the two groups when measured by the clotting assay; the analogue had greater potentiating effect on At III activity as compared to heparin; the difference being statistically significant (p < 0.005). These findings provide further evidence for our preliminary observations that the heparin analogue selectively potentiates antithrombin III activity $\text{in vivo}$ while having little effect on overall clotting. The results presented indicate that it is as effective as heparin in preventing postoperative DVT.     

Long-term clinical follow-up in 265 patients with deep venous thrombosis initially treated with either unfractionated heparin or dalteparin: a retrospective analysis.

The primary objective of this retrospective study was to describe the frequency of a post-thrombotic syndrome in 265 patients previously treated for deep venous thrombosis (DVT). The secondary objectives were to document the frequency of recurrent venous thromboembolism (VTE) and mortality, especially from malignant disease. The patients were evaluated 5-14 years after inclusion in three randomized trials comparing continuous intravenous (i.v.) infusion of unfractionated heparin (UFH) (n = 85) with a low molecular weight heparin (LMWH), dalteparin (n = 180). The median post-thrombotic score at follow-up was 2 (range 0-8). In a multiple step-wise regression analysis the postthrombotic score was significantly higher among patients with initial proximal DVT (p = 0.0001) as compared with those who had distal DVT. A recurrent venous thromboembolic event was diagnosed in 29.4% of the patients treated with dalteparin and in 23.5% of the patients treated with UFH (ns). A secondary risk factor for venous thromboembolism and a longer duration of treatment with oral anticoagulants (OAC) were significantly associated with a lower risk for recurrent VTE, whereas malignant disease diagnosed during follow-up was associated with a higher risk. During follow-up a total of 40.7% of patients had died. No difference in total mortality or mortality from malignant disease was demonstrated between the two drugs. In conclusion, a severe post-thrombotic syndrome occured relatively infrequent. considering the long observation period. Proximal DVT was significantly associated with a more severe post-thrombotic syndrome. After 14 years follow-up, no significant differences were observed in overall mortality, mortality from malignant disease or recurrent VTE between UFH- and dalteparin-treated patients. Malignant disease was a risk factor for recurrent VTE, the presence of a secondary risk factor and a longer duration of treatment with OAC decreased the risk for recurrent VTE.     

Controlled multicenter pilot study of urokinase- heparin and streptokinase in deep vein thrombosis

Thirty-three patients with acute iliofemoral thrombosis were randomly assigned to three treatment groups in a pilot dose-ranging study of thrombolytic therapy in deep vein thrombosis. One group received tissue culture urokinase in a dose of 2,200 I.U./kg/hr, and a second group in a dose of 1,100 I.U./kg/hr following a loading dose of 4,400 I.U./kg given in ten min. Urokinase was administered for 12 hr periods, alternating with 12 hr periods of heparin. A third group received an initial dose of 250,000 I.U. of streptokinase in 20 min, followed by 100,000 I.U./hr. Treatment of all patients continued for three days. At the end of this period little improvement, evaluated by "blinded" interpretation of pre- and post-treatment phlebograms, was found in five out of ten of the higher-dose urokinase patients, seven out of eleven of lower-dosage urokinase patients, and six out of ten of streptokinase patients. Optional treatment for another three days showed little further improvement of urokinase-patients and moderate further improvement in the streptokinase-patients. Neither of the 2 dosage schemes at intermittent application of urokinase appeared to be advantageous. Urokinase treated patients experienced fewer adverse reactions.