Low-molecular-weight heparin versus unfractionated heparin in the treatment of patients with acute pulmonary thromboembolism

BACKGROUND: Low-molecular-weight heparin (LMWH) appears to be as effective as unfractionated heparin (UFH) for both treatment and prophylaxis of deep vein thrombosis (DVT), but limited data are available for its use in acute pulmonary thromboembolism (PTE). OBJECTIVE: To determine whether enoxaparin, a LMWH, was clinically as efficient and safe as UFH in patients with a diagnosis of acute PTE. MATERIAL AND METHODS: After exclusion of those with massive forms, 59 patients with acute PTE were randomly assigned to either subcutaneous enoxaparin given twice daily (1 mg/kg/dose) or adjusted dose intravenous UFH. Oral anticoagulant treatment was begun on the second day and was given for at least 6 months. We compared the treatment regimens at day 8 and day 90 with respect to a combined end point of major bleeding, recurrent venous thromboembolism (VTE), and death. RESULTS: In the first 8 days of treatment, 1 of 30 patients assigned to receive UFH (3.3%) reached one of the end points (recurrence), as compared with none of 29 patients assigned to enoxaparin. Statistically this difference was not significant (p = 0.508). By day 90, 3 patients assigned to UFH (10%) had symptomatic recurrent VTE, as compared with 1 patient assigned to enoxaparin (3.4%). There was neither major bleeding nor death in the study groups. There was an absolute difference of 6.4 percentage points between the two treatment groups, but the difference was statistically not significant (p = 0.318). CONCLUSION: Initial subcutaneous treatment with enoxaparin appeared to be as effective and safe as UFH in acute PTE.     

Home treatment of deep venous thrombosis with low molecular weight heparin: Long-term incidence of recurrent venous thromboembolism

Outpatient treatment of deep venous thrombosis (DVT) with low molecular weight heparin (LMWH) seems as safe and effective as inpatient treatment with unfractionated heparin (UFH). However, most of the randomized trials comparing a LMWH with UFH described clinical outcomes within 3-6 months. The long-term incidence of recurrent VTE after treatment of DVT with LMWH remains to be established. The primary objective of this retrospective study was to document the long-term incidence of recurrent venous thromboembolism (VTE) in patients with DVT treated with a LMWH, nadroparin in an outpatient basis. The patients were evaluated 46 months after inclusion in two cohorts comparing home treatment with nadroparin (n = 130) with in-hospital treatment with intravenous UFH (n = 149). More than 60% of the patients in the nadroparin group could be treated at home, either entirely or after a short stay in hospital. The age-adjusted thrombosis-free survival was not statistically significant between nadroparin and UFH-treated patients (P = 0.084). There was a nonsignificant trend favoring nadroparin as compared with UFH. The hazard ratio (HR) for recurrent VTE in the nadroparin group with respect to the UFH group was 0.44 (95% confidence interval, 0.17-1.12). No significant differences were observed in overall mortality or major hemorrhage between the two treatment groups. Our study suggests that home treatment of DVT with LMWH is at least as effective and safe as in-hospital UFH after a long-term follow-up period.     

Adjusted subcutaneous heparin or continuous intravenous heparin in patients with acute deep vein thrombosis. A randomized trial

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.     

Recurrent venous thrombosis and heparin therapy: an evaluation of the importance of early activated partial thromboplastin times.

BACKGROUND: The presence of an association between early subtherapeutic activated partial thromboplastin times (aPTTs) and recurrent venous thromboembolism (VTE) remains controversial. OBJECTIVE: To determine the relation between early subtherapeutic aPTTs and recurrent VTE in patients who were treated with intravenous (i.v.) unfractionated heparin (UFH). PATIENTS AND METHODS: We studied 961 patients with acute VTE who received i.v. UFH in 3 randomized trials that compared the use of i.v. UFH (loading dose: 5000 U i.v.; initial infusion, 1250-1280 U/h) with that of subcutaneous low-molecular-weight heparin. According to aPTT criteria, patients were classified as being in a subtherapeutic or a therapeutic state during the first 24 and 48 hours of treatment. All episodes of possible recurrent VTE were adjudicated by an independent committee that was unaware of the aPTTs. RESULTS: At 24 hours, in 886 patients who were eligible for the analysis, the rate of recurrent VTE in the subtherapeutic group was 6.7% (11/163) compared with 5.3% (38/723) in the therapeutic group. The odds ratio for recurrence in patients in the subtherapeutic vs the therapeutic group at 24 hours was 1.30 (95% confidence interval: 0.64-2.63; P = .46). At 48 hours, in 917 patients who were eligible for the analysis, the rate of recurrent VTE in the subtherapeutic group was 7.8% (5/64) compared with 5.7% (49/853) in the therapeutic group. The odds ratio for recurrence in patients in the subtherapeutic vs the therapeutic group at 48 hours was 1.32 (95% confidence interval: 0.51-3.44; P = .56). CONCLUSION: In patients with acute VTE who receive an i.v. bolus of 5000 U, followed by a starting dose of at least 1250 U/h of UFH, a subtherapeutic aPTT response during the first 48 hours of treatment is not associated with a large increase in the risk of recurrent VTE.     

Unfractionated heparin and low-molecular-weight heparin for the initial treatment of acute venous thromboembolism

Anticoagulant drugs represent the therapy of choice for the initial treatment of venous thromboembolism. Unfractionated heparin (UFH) in adjusted doses and low-molecular-weight heparin (LMWH) in fixed doses are equally as effective and safe. Proper use of UFH requires considerable expertise, can cause inconvenience and has limitations. The use of LMWHs has multiple advantages over UFH including a more predictable dose-response and fixed administration dose. These properties make the treatment of suitable patients feasible in an outpatient setting. In two major clinical trials addressing the treatment of deep vein thrombosis, outpatient management with LMWH was associated with a substantial cost reduction compared with inpatient treatment using UFH. Recent studies have also shown that LMWHs are at least as effective and safe as UFH for the treatment of non-critical patients with pulmonary embolism. Whether or not home treatment of pulmonary embolism is feasible and safe remains to be demonstrated.     

Reduction in thrombus extension and clinical end points in patients after initial treatment for deep vein thrombosis with the fixed-dose body weight-independent low molecular weight heparin certoparin.

Low molecular weight heparin (LMWH) is effective in the treatment of acute deep vein thrombosis (DVT) in adults. This has not been demonstrated for one LMWH alone. The relationship between venographic changes due to LMWH therapy and clinical outcome in the initial treatment period has not been reported. A pooled analysis of two clinical trials was performed. The trials compared a fixed-dose, body weight-independent, subcutaneous LMWH, certoparin (8000 antifactor Xa [aXa] U twice a day [b.i.d.]), with an adjusted-dose intravenous unfractionated heparin (UFH) with respect to venographic changes expressed as Marder score and occurrence of recurrent venous thromboembolism, major bleeding, and mortality. The Marder score was 23.2 +/- 8.4 in patients randomized to LMWH (n = 299 paired phlebograms) and 23.9 +/- 8.9 in patients allocated to UFH (n = 297 paired phlebograms) at entry (2p = 0.23) and 18.9 +/- 9.7 and 20.5 +/- 9.9 at the end of the initial therapy (2p = 0.04), respectively. The composite outcome of recurrent venous thromboembolism, major bleeding, and mortality occurred less frequently during treatment with LMWH (n = 393) than it did with UFH (n = 404, 1.3% versus 5.0%, risk reduction [RR] 0.26, 95% confidence interval [CI] 0.11 to 0.63, 2p = 0.004). Single events of recurrent thromboembolism (2p = 0.12), major bleeding (2p = 0.03), and mortality (2p = 0.12) were observed less frequently with LMWH. A trend toward a lack of regression of thrombus size was observed in recurrent venous thromboembolism (2p = 0.08). Body weight-independent LMWH significantly reduces thrombus size and the incidence of composite outcome during the initial treatment of acute proximal venous thrombosis compared with adjusted dose intravenous UFH. The data indicate a relation between an unimproved Marder score and a recurrent venous thromboembolism.     

Nadroparin for the prevention of venous thromboembolism in nonsurgical patients: a systematic review and meta-analysis

Anticoagulant thromboprophylaxis with low molecular weight heparin is widely used in nonsurgical settings. To obtain best estimates of the effects of nadroparin for the prevention of venous thromboembolism (VTE) in nonsurgical patients, we conducted a systematic review and meta-analysis. Data sources were Medline, Embase, and Cochrane Library supplemented with conference abstracts, without language restrictions. Selection criteria were randomized controlled trials with nadroparin at prophylactic dose in adult nonsurgical patients. Main efficacy outcomes were major VTE (the composite of symptomatic deep vein thrombosis, symptomatic pulmonary embolism, asymptomatic proximal deep vein thrombosis and VTE-related death) and symptomatic VTE. The main safety outcome was major bleeding. We expressed treatment effects as risk ratios. Ten studies (4 vs. placebo or no treatment, 4 vs. UFH, 1 vs. fondaparinux and 1 vs. warfarin) enrolling a total of 7658 patients were included. In comparison with placebo, nadroparin reduced major VTE by about one-half (RR 0.48, 95% CI 0.24–0.97) with a consistent effect on symptomatic VTE (RR 0.69, 95% CI 0.46–1.05) and no increase in major bleeding (RR 1.51, 95% CI 0.40–5.79). In comparison with other pharmacological prophylaxis, nadroparin was similarly efficacious for prevention of major VTE (RR 1.14, 95% CI 0.63–2.10) and symptomatic VTE (RR 1.10, 95% CI 0.51–2.35) and produced similar effects on major bleeding (RR 0.60, 95% CI 0.25–1.50). Five studies were open label, and for three of these the adjudication method was not described or not blinded. In nonsurgical populations at risk of VTE, nadroparin reduced VTE by about one half compared with placebo or no treatment and appeared similarly effective and safe as other prophylactic anticoagulants.     

Heparin and low molecular weight heparin for treatment of acute pulmonary embolism.

Pulmonary embolism occurs in more than 175,000 patients each year in the United States. The objectives of treatment are to prevent death from the existing embolus, to prevent death and morbidity from recurrent pulmonary embolism, and to prevent morbidity from recurrent deep-vein thrombosis. For patients with adequate cardiorespiratory reserve, the primary objective is to prevent recurrent pulmonary embolism. Anticoagulant therapy with intravenous unfractionated heparin or subcutaneous low molecular weight heparin followed by oral anticoagulant treatment for at least 3 months is the treatment of choice for most of these patients. Clinical trials indicate that the effectiveness of intravenous heparin depends on achieving an adequate heparin effect (activated partial thromboplastin time above lower limit) during the initial 24 hours. A validated protocol for intravenous heparin should be used to lessen the likelihood of delayed heparinization. Low molecular weight heparin given subcutaneously either once or twice daily is as effective as intravenous heparin for the treatment of patients with deep-vein thrombosis and submassive pulmonary embolism. Low molecular weight heparin enables many patients with uncomplicated deep-vein thrombosis to be treated in an outpatient setting.     

Treatment of symptomatic venous thromboembolism: improving outcomes

Antithrombotic therapy with unfractionated heparin (UFH) and warfarin for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) became widely accepted in the early 1960s. Subsequent clinical trials have focused on the importance of early intravenous UFH in the treatment of venous thromboembolic events, the method of heparin administration, the importance of rapid anticoagulation to prevent recurrent venous thromboembolism (VTE), and the optimal duration of UFH administration. Low-molecular-weight heparin (LMWH) represents a significant advance over UFH therapy for VTE. Developed in the late 1980s, LMWH has become an excellent alternative to UFH because it offers superior efficacy and safety, improved pharmacokinetics, longer half-life, and once- or twice-daily subcutaneous administration without the need for laboratory monitoring. Fondaparinux is the first of a new class of antithrombotic agents that targets factor Xa. Based on studies of the heparin binding site of antithrombin, this novel pentasaccharide has superior pharmacokinetics and bioavailability when compared with LMWH and can be administered once daily. Studies in patients undergoing major orthopedic surgery and in those with proximal DVT indicate that the efficacy and safety of fondaparinux may represent an improvement over those of LMWH.     

A meta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism: examining some unanswered questions regarding location of treatment, product type, and dosing frequency

OBJECTIVES: To compare the efficacy and safety of unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) and to examine current controversies in the treatment of venous thromboembolism (VTE) (ie, setting, product type, and frequency of administration). METHODS: Data were abstracted from MEDLINE, HEALTH, previous reviews, personal files, clinical experts, and conference abstracts. Randomized controlled trials of patients diagnosed with acute VTE that compared LMWHs with UFH were included. Independent duplicate assessment was done for methodological quality and data extraction. Data are reported as pooled relative risks (RRs) and 95% confidence intervals (CIs) comparing LMWHs with UFH as determined by the random effects model. RESULTS: Thirteen studies were included. There was no statistically significant difference in risk between UFH and LMWHs for recurrent VTE (RR, 0.85 [95% CI, 0.65-1.12]), pulmonary embolism (RR, 1.02 [95% CI, 0.64-1.62]), major bleeding (RR, 0.63 [95% CI, 0.37-1.05]), minor bleeding (RR, 1.18 [95% CI, 0.87-1.61]), and thrombocytopenia (RR, 0.85 [95% CI, 0.45-1.62]). There was a statistically significant difference for risk of total mortality (RR, 0.76 [95% CI, 0.59-0.98]) in favor of LMWHs. Inpatient treatment may reduce the risk of major bleeding vs outpatient therapy. Once-daily therapy is as safe and effective as twice-daily therapy when compared indirectly. Different products could not be statistically compared, but qualitative analysis shows that there are no apparent differences in efficacy and safety. CONCLUSIONS: Low-molecular-weight heparins are at least as effective as UFH in preventing recurrent VTE. It is unlikely that LMWHs are superior in the treatment of VTE, but they do show a statistically significant decrease in total mortality. No differences were seen in the development of recurrent VTE dependent on treatment setting. There were no apparent differences between once-daily and twice-daily therapy or among products. Inpatient therapy may be associated with less major bleeding; therefore, if LMWHs are given in the outpatient setting, patients should be rigorously monitored.     

Subcutaneous enoxaparin following thrombolysis and intravenous unfractionated heparin in ST-elevation acute myocardial infarction: safety and efficacy of low vs full dose

AIM: In ST-segment elevation myocardial infarction (STEMI) treated with fibrin-specific thrombolytic agents, early intravenous unfractionated heparin (UFH) is warranted. Low molecular weight heparin Enoxaparin currently represents an alternative to UFH, to be used until hospital discharge. Since optimal dosing of subcutaneous Enoxaparin is not standardized, we conducted an observational study to compare safety and efficacy of low (4,000 U once daily) vs full dose (100 U/kg twice daily) regimens. METHODS: All STEMI patients successfully treated with tenecteplase and intravenous UFH and referred to the Catheterization Laboratory between June 2002-November 2003 for predischarge coronary angiography, were evaluated. The primary end-point was the composite of hemorrhages and residual angina/reinfarction during Enoxaparin administration, whereas secondary end-points were occurrence of venous thromboembolism (VTE) during Enoxaparin administration, and infarct-related artery (IRA) patency rate at predischarge coronary angiography. RESULTS: Out of 123 patients, 57 (M/F 45/12, mean age 65.8+/-8.1 years) received low dose, and 66 (men/women 45/21, mean age 62.6+/-11.8 years) full dose subcutaneous Enoxaparin. The incidence of the composite primary end-point was comparable in both groups (19% vs 26%; P=NS). Also, null was the occurrence of VTE, whereas the IRA patency rate did not significantly differ in the 2 groups (84% vs 86% TIMI 3 and 11% vs 9% TIMI 2 flow grades; P=NS). CONCLUSIONS: In patients with STEMI undergoing successful recanalization with tenecteplase and intravenous UFH, low dose subcutaneous Enoxaparin appears preferable to full dose, in the light of comparable safety and clinical efficacy and superior easiness of use.     

Subcutaneous unfractionated heparin for the treatment of venous thromboembolism

PURPOSE OF REVIEW: When unfractionated heparin is used to treat acute venous thromboembolism, it is usually given by intravenous infusion with dose adjustment in response to activated partial thromboplastin time measurements. These two requirements are a barrier to treatment of venous thromboembolism with unfractionated heparin, and it is uncertain if they are necessary. RECENT FINDINGS: Two recent studies compared subcutaneous unfractionated heparin and subcutaneous low-molecular-weight heparin, each given twice-daily, for the acute treatment of venous thromboembolism. The Galilei study used an initial dose of unfractionated heparin that was partially weight-adjusted, with subsequent dosing based on activated partial thromboplastin time results. The FIDO study treated patients with a first dose of unfractionated heparin of 333 IU/kg, followed by 250 IU/kg twice-daily without dose adjustment in response to the activated partial thromboplastin time or other coagulation tests. There was no difference in either study between the unfractionated heparin and low-molecular-weight heparin groups at the end of 3 months, for recurrent venous thromboembolism (Galilei: 4.2 vs. 3.9%; relative risk (RR) 1.1, 95% confidence interval (CI) 0.5 to 2.2. FIDO: 3.8 vs. 3.4%; RR 1.1, 95% CI 0.5 to 2.3) or major bleeding (Galilei: 1.4 vs. 1.9%; RR 0.7, 95% CI 0.2 to 2.2. FIDO: 1.7 vs. 3.4%; RR 0.5, 95% CI 0.2 to 1.3). SUMMARY: Recent studies suggest that twice-daily subcutaneous unfractionated heparin is as effective and safe as low-molecular-weight heparin for the acute treatment of venous thromboembolism, and that adjustment of unfractionated heparin dose in response to activated partial thromboplastin time measurements is not necessary with a weight-adjusted dose of unfractionated heparin.     

Rivaroxaban and usual care had similar rates of recurrent VTE and bleeding in symptomatic PE

QUESTION In patients with symptomatic pulmonary embolism (PE), what are the effects of rivaroxaban compared with usual care on recurrent venous thromboembolism (VTE) and bleeding? METHODS DESIGN Randomized controlled trial (EINSTEIN-Pulmonary Embolism Study). ClinicalTrials.gov NCT00439777. ALLOCATION Concealed.* BLINDING Blinded* (outcome adjudication committee and {data analysts}?). FOLLOW-UP PERIOD Mean 9 months. SETTING 263 sites in 38 countries. PATIENTS 4833 adults (mean age 58 y, 53% men) with acute, symptomatic, objectively verified PE with or without symptomatic deep venous thrombosis (DVT). Exclusion criteria included low-molecular-weight heparin, fondaparinux, or unfractionated heparin for >?48 hours, or >?1 dose of a vitamin K agonist (VKA) before randomization; or another indication for VKA treatment. INTERVENTION Oral rivaroxaban, 15 mg twice daily for 3 weeks and then 20 mg once daily (n =?2420); or usual care with enoxaparin, 1.0 mg/kg body weight twice daily (for ≥?5 d until international normalized ratio [INR] was ≥?2.0 for 2 consecutive d) plus a VKA (warfarin or acenocoumarol) started within 48 hours of randomization, with dose adjusted to maintain INR at 2.0 to 3.0 (n =?2413). OUTCOMES Primary efficacy outcome was symptomatic recurrent VTE (composite of fatal or nonfatal PE or DVT). Primary safety outcome was clinically relevant bleeding (composite of major or clinically relevant nonmajor bleeding). Secondary outcomes included major bleeding (clinically overt bleeding; decrease in hemoglobin level ≥?2.0 g/dL; transfusion of ≥?2 units of red cells; or if bleeding was intracranial or retroperitoneal, occurred in other critical sites, or contributed to death). PATIENT FOLLOW-UP 99.6% (intention-to-treat analysis). MAIN RESULTS The main results are in the Table. {Results are consistent with an absolute reduction in recurrent VTE with rivaroxaban of 5 per 1000 patients or an increase of 10 per 1000 patients, and a reduction in clinically relevant bleeding of 28 per 1000 patients or an increase of 7 per 1000 patients}?. CONCLUSION Rivaroxaban and usual care had similar rates of recurrent venous thromboembolism and clinically relevant bleeding in patients with symptomatic pulmonary embolism.Rivaroxaban vs usual care for symptomatic pulmonary embolism§OutcomesRivaroxabanUsual careAt a mean 9 moRRI (95% CI)NNH (CI)Recurrent VTE2.1%1.8%12% (-25 to 67)NSRRR (CI)NNT (CI)Clinically relevant bleeding||?10.3%11.4%9% (-7 to 23)NSMajor bleeding||**1.1%2.2%51% (21 to 69)92 (68 to 223)§NS = not significant; VTE = venous thromboembolism; other abbreviations defined in Glossary. RRI, RRR, NNH, NNT, and CI calculated from control event rates and hazard ratios in article. Analyses were adjusted for cancer at baseline.||Patients receiving ≥?1 dose of study drug (n =?4817).?Composite of major or clinically relevant nonmajor bleeding.**Clinically overt bleeding; decrease in hemoglobin level ≥?2.0 g/dL; transfusion of ≥?2 units of red cells; or if bleeding was intracranial or retroperitoneal, occurred in other critical sites, or contributed to death.     

Differences between low-molecular-weight and unfractionated heparin for venous thromboembolism prevention following ischemic stroke: a metaanalysis

BACKGROUND: Venous thromboembolism (VTE) remains a major cause of morbidity following stroke. The optimal form of pharmacologic prophylaxis following stroke is unknown. METHODS: We identified randomized trials comparing unfractionated heparin (UFH) to low-molecular-weight heparin (LMWH) for VTE prevention in ischemic stroke patients. We focused on the risk for VTE, pulmonary embolism (PE), bleeding, and mortality as a function of the type of agent used for prophylaxis. Findings were pooled with a random-effects model. RESULTS: We identified three trials including 2,028 patients. Two of the studies were blinded, two studies relied on enoxaparin, while one study utilized certoparin. In two studies, UFH was administered three times a day, while it was administered twice daily in the remaining study. The use of LMWH was associated with a significant risk reduction for any VTE (odds ratio [OR], 0.54; 95% confidence interval [CI], 0.41 to 0.70; p < 0.001). Limiting the analysis to proximal VTEs also indicated that LMWHs were superior (OR with LMWH vs UFH, 0.53; 95% CI, 0.37 to 0.75; p < 0.001). LMWH use led to fewer PEs as well (OR, 0.26; 95% CI, 0.07 to 0.95; p = 0.042). There were no differences in rates of overall bleeding, intracranial hemorrhage, or mortality based on the type of agent employed. Restricting the analysis to the reports employing enoxaparin did not alter our findings. CONCLUSIONS: The prophylactic use of LMWH compared to UFH following ischemic stroke is associated with a reduction in both VTE and PE. This benefit is not associated with an increased incidence of bleeding. Broader use of LMWH for VTE prevention after ischemic stroke is warranted.     

Perspectives on antithrombotic agents: from unfractionated heparin to new antithrombotics

BACKGROUND AND OBJECTIVES: Unfractionated heparin (UFH) has been the antithrombotic agent of choice for the prevention and treatment of venous thromboembolism (VTE) for a long time. UFH is also widely used for the treatment of patients with acute coronary syndromes. However, UFH has some limitations such as the need for parenteral administration and close monitoring of its anticoagulant effect. UFH is also associated with bleeding, heparin-induced thrombocytopenia and osteoporosis. EVIDENCE AND INFORMATION SOURCES: Low molecular weight heparins (LMWHs) are produced by the depolymerization of UFH. LMWHs have pharmacologic advantages over UFH: a better bioavailability after subcutaneous administration, a longer plasma half-life and a more predictable anticoagulant effect. These improved features allow once or twice daily subcutaneous injection of weight-adjusted doses of LMWHs without requiring laboratory monitoring in patients with VTE or unstable angina. PERSPECTIVES: A number of new antithrombotic agents are currently under development. These include direct antithrombins and factor Xa inhibitors. The results of the main clinical trials with LMWHs as well as those of the studies with the new antithrombotic agents will be reviewed in this article.     

Thrombolysis vs heparin in the treatment of pulmonary embolism: a clinical outcome-based meta-analysis

BACKGROUND: In patients with acute pulmonary embolism, thrombolysis results in a more rapid resolution of pulmonary emboli than heparin treatment. Whether this advantage results in an improved clinical outcome is unclear. We sought to perform a clinical outcome-based meta-analysis of studies comparing thrombolytic and heparin treatment in patients with pulmonary embolism. METHODS: Data concerning adverse outcome events (death, recurrent pulmonary embolism, and major bleeding events) were extracted from the identified randomized studies. RESULTS: A total of 56 (23.2%) of 241 patients treated with thrombolytic agents in 9 randomized trials experienced an adverse outcome event compared with 57 (25.9%) of 220 patients treated with heparin (relative risk [RR], 0.9; 95% confidence interval [CI], 0.57-1.32). In the thrombolysis group, 11 patients (4.6%) died compared with 17 (7.7%) in the heparin group (RR, 0.59; 95% CI, 0.27-1.25). Thirty-one patients (12.9%) undergoing thrombolysis had a major bleeding episode compared with 19 patients (8.6%) treated with heparin (RR, 1.49; 95% CI, 0.85-2.81). Five fatal bleeding episodes (2.1%) occurred in the thrombolysis group and none in the heparin group. Six studies provided data on recurrent pulmonary embolism. A recurrence occurred in 14 (6.6%) of 214 patients treated with thrombolytic agents and in 22 (10.9%) of 201 patients treated with heparin (RR, 0.60; 95% CI, 0.29-1.15). Recurrence and/or death occurred in 25 (10.4%) of 241 and in 38 (17.3%) of 220 patients treated with thrombolytic agents and heparin, respectively (RR, 0.55; 95% CI, 0.33-0.96; P =.03). CONCLUSIONS: In patients with pulmonary embolism, thrombolysis had a lower composite end point of death/recurrence than heparin treatment. Excessive bleeding is the trade-off for improved efficacy. A comparative clinical outcome trial of thrombolysis and heparin treatment is warranted in patients with pulmonary embolism and selected for high risk of death and/or recurrence and low risk of bleeding.     

Frequency of major hemorrhage in patients treated with unfractionated intravenous heparin for deep venous thrombosis or pulmonary embolism: a study in routine clinical practice

BACKGROUND: The rate of major hemorrhage during the initial treatment with unfractionated heparin (UFH) in patients with deep venous thrombosis (DVT) and pulmonary embolism (PE) in routine clinical practice is understudied. In recent clinical trials an overall average of 3.8% was reported. However, the incidence of this complication in routine patient care might be higher owing to less strict patient selection and lack of standardization in the administration of heparin. We have determined major bleeding rates during heparin treatment for DVT or PE in routine practice and compared these rates with data from clinical trials. METHODS: Data on the occurrence of major hemorrhage were retrieved according to strict criteria from the records of patients who had received continuous intravenous UFH therapy to treat objectively documented DVT or PE in 3 hospitals. RESULTS: After exclusion of 29 patients because of lack of objective diagnosis of DVT or PE and 25 patients because of initial treatment with low-molecular-weight heparin, 424 consecutive patients were available for detailed analysis. Among them, 17 patients (4.0%; 95% confidence interval, 2.1%-5.9%) experienced major hemorrhage during UFH treatment, which in most patients occurred at the end of planned heparin therapy; one of the hemorrhages was fatal. Six patients (1.4%; 95% confidence interval, 0.3%-2.5%) developed clinically suspected recurrent venous thromboembolism (fatal in 1 case) during UFH treatment or within 7 days' cessation. CONCLUSIONS: Administration of continuous intravenous UFH in patients with DVT or PE in routine clinical practice leads to a major bleeding rate of 4.0%. This rate is comparable to the rate of major bleeding in patients who received UFH in clinical trials. Our findings are relevant to the discussion of major bleeding rates in patients with DVT and PE treated in daily clinical practice with subcutaneous low-molecular-weight heparin and newer antithrombotic drugs.     

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.

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.     

Fixed-dose versus adjusted-dose low molecular weight heparin for the initial treatment of patients with deep venous thrombosis

Patients with acute deep vein thrombosis (DVT) were treated with a body-weight independent dosage of 2 x 8000 aXa IU low-molecular-weight heparin (LMWH) Certoparin. After the subcutaneous administration of 8000 IU Certoparin, pharmacodynamic parameters did not differ between patients and healthy volunteers, and the AUC of the anticoagulant effects were not related to body weight. Two clinical trials demonstrated a greater regression of thrombi and a lower occurrence of recurrent venous thromboembolism (VTE), major bleeding, and mortality within 14 days of initial therapy compared with intravenous heparin. D-dimer decreased, and anti-Xa activity increased in those patients with a regression of thrombosis. The benefit of the reduced occurrence of recurrent VTE, major bleeding, and mortality was maintained up to 6 months. Major bleeding was not related to the body weight in either treatment group. Treatment of acute DVT in adults with fixed dose of 2 x 8000 aXa IU LMWH Certoparin is more effective and safer than heparin.