Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism.

BACKGROUND: Low molecular weight heparins (LMWH) have been shown to be effective and safe in preventing venous thromboembolism (VTE), and may also be effective for the initial treatment of VTE. OBJECTIVES: To determine the effect of LMWH compared with unfractionated heparin (UFH) for the initial treatment of VTE. SEARCH STRATEGY: Trials were identified from the Cochrane Peripheral Vascular Diseases Group's Specialised Register, CENTRAL and LILACS. Colleagues and pharmaceutical companies were contacted for additional information. SELECTION CRITERIA: Randomised controlled trials comparing fixed dose subcutaneous LMWH with adjusted dose intravenous or subcutaneous UFH in people with VTE. DATA COLLECTION AND ANALYSIS: At least two reviewers assessed trials for inclusion and quality, and extracted data independently. MAIN RESULTS: Twenty-two studies were included (n = 8867). Thrombotic complications occurred in 151/4181 (3.6%) participants treated with LMWH, compared with 211/3941 (5.4%) participants treated with UFH (odds ratio (OR) 0.68; 95% confidence intervals (CI) 0.55 to 0.84, 18 trials). Thrombus size was reduced in 53% of participants treated with LMWH and 45% treated with UFH (OR 0.69; 95% CI 0.59 to 0.81, 12 trials). Major haemorrhages occurred in 41/3500 (1.2%) participants treated with LMWH, compared with 73/3624 (2.0%) participants treated with UFH (OR 0.57; 95% CI 0.39 to 0.83, 19 trials). In eighteen trials, 187/4193 (4.5%) participants treated with LMWH died, compared with 233/3861 (6.0%) participants treated with UFH (OR 0.76; 95% CI 0.62 to 0.92). Nine studies (n = 4451) examined proximal thrombosis; 2192 participants treated with LMWH and 2259 with UFH. Subgroup analysis showed statistically significant reductions favouring LMWH in thrombotic complications and major haemorrhage. By the end of follow up, 80 (3.6%) participants treated with LMWH had thrombotic complications, compared with 143 (6.3%) treated with UFH (OR 0.57; 95% CI 0.44 to 0.75). Major haemorrhage occurred in 18 (1.0%) participants treated with LMWH, compared with 37 (2.1%) treated with UFH (OR 0.50; 95% CI 0.29 to 0.85). Nine studies (n = 4157) showed a statistically significant reduction favouring LMWH with respect to mortality. By the end of follow up, 3.3% (70/2094) of participants treated with LMWH had died, compared with 5.3% (110/2063) of participants treated with UFH (OR 0.62; 95% CI 0.46 to 0.84). REVIEWERS' CONCLUSIONS: LMWH is more effective than UFH for the initial treatment of VTE. LMWH significantly reduces the occurrence of major haemorrhage during initial treatment and overall mortality at follow up.

Duration of oral anticoagulant treatment in patients with venous thromboembolism and a deficiency of antithrombin, protein C or protein S--a decision analysis.

Patients with a first venous thromboembolic event and a deficiency of the coagulation inhibitors antithrombin, protein C or protein S have an increased risk of recurrent venous thromboembolism compared to patients without such a deficiency. A decision analysis was performed to assess the effect of continuing treatment with vitamin K antagonists on mortality by a reduction in fatal recurrent pulmonary embolism and an induction of fatal haemorrhages associated with their use. The treatment decision involves continuation or discontinuation of vitamin K antagonists in patients with a first spontaneous or secondary venous thromboembolism and an antithrombin, protein C or S deficiency. Although the efficiency of oral anticoagulation is high in all age groups early after the first thromboembolic event, it decreases over time. Our analysis indicates that the optimal treatment duration will vary, depending on the type of the initial event (spontaneous or secondary; deep venous thrombosis or pulmonary embolism), age, and time passed since the initial thromboembolic episode. Moreover, life-long duration of the prophylaxis seems not warranted in all patients.

Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism.

BACKGROUND: Low molecular weight heparins have been shown to be effective and safe for prevention of venous thromboembolism. There is accumulating evidence that these new anticoagulants are also effective and safe for treatment of venous thromboembolism. OBJECTIVES: The objective of this review was to determine the effect of fixed-dose, subcutaneous low molecular weight heparins compared with adjusted-dose, intravenous or subcutaneous, unfractionated heparin for initial treatment of acute deep venous thrombosis or pulmonary embolism. SEARCH STRATEGY: Trials were identified from the Cochrane Peripheral Vascular Diseases Group trials register and LILACS. The reviewers contacted colleagues and representatives of pharmaceutical companies for additional information about trials. SELECTION CRITERIA: Randomised trials comparing fixed-dose, subcutaneous low molecular weight heparin with adjusted-dose, intravenous or subcutaneous, unfractionated heparin in patients with venous thromboembolism. DATA COLLECTION AND ANALYSIS: Two reviewers assessed trials for inclusion and quality, and extracted data independently. MAIN RESULTS: Fourteen studies with a total of 4754 patients were included. By the end of follow up in ten trials, thrombotic complications occurred in 86 (4.3%) of the 1998 patients treated with low molecular weight heparin, compared with 113 (5.6%) of the 2021 patients treated with unfractionated heparin (odds ratio 0.76, 95% confidence interval 0.57 to 1.01). In eight trials a reduction in thrombus size was shown by 60% treated with low molecular weight heparin and 54% treated with unfractionated heparin (odds ratio 0.77, 95% confidence interval 0.61 to 0.97). At the end of the initial treatment period, in all 14 of the trials, major haemorrhages occurred in 30 (1.3%) of the 2353 patients treated with low molecular weight heparin, compared with 51 (2.1%) of the 2401 patients treated with unfractionated heparin (odds ratio 0.60, 95% confidence interval 0.39 to 0.93). By the end of follow up in 11 trials, 135 (6.4%) of the 2108 patients treated with low molecular weight heparin had died, compared with 172 (8.0%) of the 2137 patients treated with unfractionated heparin (odds ratio 0.78, 95% confidence interval 0.62 to 0.99). Five studies with a total of 1636 patients examined proximal (above the knee) thrombosis; 814 treated with low molecular weight heparin and 822 with unfractionated heparin. A sub-analysis of these trials showed statistically significant reductions favouring the action of low molecular weight heparin in three areas: thrombotic complications; major haemorrhages; and overall mortality. By the end of follow up 39 (4. 8%) patients treated with low molecular weight heparin had thrombotic complications, compared with 64 (7.8%) treated with unfractionated heparin (odds ratio 0.60, 95% confidence interval 0. 40 to 0.89). Major haemorrhages occurred in 8 (1.0%) treated with low molecular weight heparin, compared with 68 (8.3%) treated with unfractionated heparin (odds ratio 0.44, 95% confidence interval 0. 21 to 0.95). By the end of follow up, 44 (5.4%) treated with low molecular weight heparin had died, compared with 68 (8.3%) treated with unfractionated heparin (odds ratio 0.64, 95% confidence interval 0.43 to 0.93). REVIEWER'S CONCLUSIONS: Low molecular weight heparin is at least as effective as unfractionated heparin in preventing recurrent venous thromboembolism, and significantly reduces the occurrence of major haemorrhage during initial treatment and overall mortality at the end of follow-up. It can be adopted safely as the standard therapy for deep venous thrombosis, and studies comparing individual low molecular weight heparins are merited.

Replacing inpatient care by outpatient care in the treatment of deep venous thrombosis--an economic evaluation. TASMAN Study Group.

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.

Out-of-hospital treatment of venous thrombosis: socioeconomic aspects and patients' quality of life.

Low-molecular-weight heparin has been recommended as the initial treatment of choice for patients with venous thromboembolism who require anticoagulant therapy. In recent studies, outpatient management of these patients has been proposed to be as effective and safe as treatment given in the hospital. This paper outlines the results of these studies and considers the feasibility of home treatment and the consequences of such a strategy. It is concluded that home treatment with low-molecular-weight heparin in patients with venous thromboembolism leads to significant benefits in terms of increase in the quality of life of the patients and a reduction in the duration of hospital stay, thus improving healthcare efficiency.

Recurrence of venous thromboembolism in patients with familial thrombophilia.

BACKGROUND: Treatment of patients with deep vein thrombosis and an antithrombin or protein C or S deficiency is based on case reports and personal experience. OBJECTIVE: To systematically assess the risk for recurrence of venous thromboembolism after a first episode in patients with these deficiencies, a literature review and retrospective family cohort study were performed. METHODS: For the literature review, the annual incidence of a first recurrent venous thromboembolism was assessed for each deficiency by dividing the number of venous thromboembolic events by the number of years at risk. For the family cohort study, 1- and 5-year cumulative incidences of first recurrence were calculated based on medical histories taken in relatives of consecutive patients in whom venous thromboembolism and a deficiency were diagnosed. RESULTS: For the literature review, the annual incidence of a first recurrent venous thromboembolism in patients with antithrombin or protein S deficiency ranged from 13% to 17% and 14% to 16%, respectively. For the family cohort study, the 1- and 5-year cumulative incidences of recurrent venous thromboembolism were 10% (95% confidence interval, 1%-19%) and 23% (95% confidence interval, 10%-36%), respectively. Warfarin sodium (Coumadin) prophylaxis was associated with 2 venous thromboembolic events in 141 years at risk (1.4% per year), in contrast with 19 events in 709 years at risk (2.7% per year) without prophylaxis (difference, -1.3%; 95% confidence interval, -3.5% to 1.0%). CONCLUSIONS: The annual incidence of recurrent venous thromboembolism is high during the first years following a first episode, but seems to decline thereafter. Therefore, our results challenge current practice of prescribing lifelong warfarin therapy after a first or second episode of venous thromboembolism in patients with antithrombin or protein C or S deficiency.

Antithrombotic therapy in acute ischaemic stroke: an overview of the completed randomised trials.

A formal statistical overview of all truly randomised trials was undertaken to determine whether antithrombotic therapy is effective and safe in the early treatment of patients with acute stroke. There were 15 completed randomised controlled trials of the value of early antithrombotic treatment in patients with acute stroke. The regimes tested in acute presumed or confirmed ischaemic stroke were: heparin, 10 trials with 1047 patients: oral anticoagulants, one trial with 51 patients: antiplatelet therapy, three trials with 103 patients. Heparin was tested in one trial with 46 patients with acute haemorrhagic stroke. Outcome measures were deep venous thrombosis (confirmed by I125 scanning or venography), pulmonary embolism, death from all causes, haemorrhagic transformation of cerebral infarction, level of disability in survivors. In patients with acute ischaemic stroke, allocation to heparin was associated with a highly significant 81% (SD 8, 2p < 0.00001) reduction in deep venous thrombosis detected by I125 fibrinogen scanning or venogram. Only three trials systematically identified pulmonary emboli, which occurred in 6/106 (5.7%) allocated control vs 3/132 (2.3%) allocated heparin, a non-significant 58% reduction (SD 45.7, 2p > 0.1). There were relatively few deaths in the trials in patients with presumed ischaemic stroke: 94/485 (19.4%) among patients allocated to the control group vs 79/497 (15.9%) among patients who were allocated heparin. The observed 18% (SD 16) reduction in the odds of death was not statistically significant. The least biased estimated of the effect of treatment on haemorrhagic transformation of the cerebral infarct (HTI) comes from trials where all patients were scanned at the end of treatment, irrespective of clinical deterioration; using this analysis, haemorrhagic transformation occurred in 7/102 (6.9%) control vs 8/106 (7.5%) treated, a non-significant 12% increase (SD 56, 2p > 0.1). These data cannot exclude the possibility that heparin substantially increases the risks of HTI. No data on disability in survivors could be obtained. Early heparin treatment might be associated with substantial reductions in deep venous thrombosis (and probably also pulmonary embolism) and possibly a one fifth reduction in mortality (equivalent to the avoidance of 20-40 early deaths per thousand patients treated.) However, the data were wholly inadequate on safety, particularly on the risk of haemorrhagic transformation of the infarct and on the hazards of heparin therapy in patients with known intracerebral haemorrhage. The trials of oral anticoagulants (15 deaths among 57 patients) and antiplatelet therapy (two deaths among 103 patients) were too small to be informative. Much larger randomized trials-comparing aspirin, heparin and the combination of both drugs against control-in patients with acute ischaemic stroke are justified (and several are now planned or underway).