Low-molecular-weight heparin in the treatment of venous thromboembolism

The low-molecular-weight heparins (LMWHs) have been evaluated in the prevention and treatment of deep-vein thrombosis and pulmonary embolism. LMWHs have been found to be safe and effective in this clinical setting and have advantages over unfractionated heparin. These advantages include less serious and less frequent therapeutic complications. The favorable pharmacokinetic profile of LMWHs compared with heparin has allowed for safe, effective, and convenient treatment of patients with venous thromboembolism. Use of LMWHs ultimately results in considerable cost savings for the health care system.     

Low-molecular-weight heparin for the prevention and treatment of venous thromboembolism in pregnancy

PURPOSE OF REVIEW: Low-molecular-weight heparins (LMWHs) have largely replaced unfractionated heparins for both prophylaxis and treatment of venous thromboembolism in nonpregnant patients. However, until recently, evidence in pregnant women was lacking, despite the increasing use of LMWHs during pregnancy in clinical practice. This review covers recent literature on the use of LMWHs in relation to pregnancy. RECENT FINDINGS: The main areas covered in this review are the use of LMWHs in both prophylaxis and treatment of venous thromboembolism in pregnancy. The review also considers issues relating to monitoring of LMWHs in pregnancy, and safety from both a maternal and a fetal perspective. SUMMARY: The available evidence demonstrates that LMWHs are of at least equivalent efficacy but have a better safety profile compared with unfractionated heparins in both prophylaxis and treatment of maternal venous thromboembolism, and are more convenient to administer. There is no consensus with respect to whether these agents require monitoring during pregnancy other than periodic checking of the platelet count. The clinical implication from the available evidence is that LMWHs should now be regarded as the anticoagulant agents of choice for both prophylaxis and treatment of maternal venous thromboembolism.     

Low-molecular-weight and unfractionated heparin for prevention of venous thromboembolism in neurosurgery: a meta-analysis

BACKGROUND: Venous thromboembolism is a common, life-threatening complication in neurosurgery, but prophylaxis with anticoagulant agents has not gained wide acceptance because of concern about intracranial bleeding. We performed a meta-analysis of controlled randomized trials on the efficacy and safety of heparin in the prophylaxis of venous thromboembolism in neurosurgery. OBJECTIVE: To review the clinical benefit of prophylaxis of venous thromboembolism with heparin in the controversial setting of neurosurgery. METHODS: Relevant trials evaluating heparin for prophylaxis of venous thromboembolism in neurosurgery were identified by a MEDLINE search, scan of meeting abstracts, and scrutiny of the references of original articles and reviews. Four controlled randomized studies, 3 of which involved low-molecular-weight heparin, were included in the analysis, and 4 uncontrolled studies are commented on in the article. The outcome measure (observed minus expected number of events) and its variance were calculated for each single trial and then summed. Two-tailed P values and 95% confidence intervals (CIs) were calculated. Efficacy was assessed per protocol and safety by intention-to-treat analysis. The homogeneity of the studies was tested with the chi(2) statistic. The results were also expressed as number needed for 1 extra event. RESULTS: A total of 187 thromboembolic events were recorded in 827 patients (22.6%). Heparin prophylaxis resulted in a 45% relative risk reduction of venous thromboembolic events (odds ratio [OR], 0.48; 95% CI, 0.35-0.66; P<. 001). Nineteen major bleedings were recorded in 1022 patients. None were fatal. Heparin treatment resulted in a 71% relative risk increase of major bleeding (OR, 1.72; 95% CI, 0.69-4.27; P =.24). The number needed to treat was 7.7 for venous thromboembolism and 16 for proximal deep vein thrombosis. The number needed to harm was 102 (115 for low-molecular-weight heparin). CONCLUSIONS: Low-molecular-weight and unfractionated heparin have been shown to be effective for prophylaxis of venous thromboembolism in elective neurosurgery without excessive bleeding risk.     

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.     

Low-molecular-weight heparin for the prevention of postoperative venous thromboembolism after abdominal surgery: a review

PURPOSE OF REVIEW: To analyze the effect of low-molecular-weight heparin in abdominal surgery, which carries a significant risk of thrombosis, a risk further increased by cancer. RECENT FINDINGS: Searches in EMBASE and PubMed between 1980 and 2004 were conducted to identify studies of thromboprophylaxis in abdominal surgery patients. Sixteen comparative studies were identified. They showed that low-molecular-weight heparin is as effective as unfractionated heparin in reducing venous thromboembolism and, at appropriate doses, can reduce bleeding complications. In very-high-risk cancer patients, a higher dose of low-molecular-weight heparin may offer increased efficacy without increasing the risk of bleeding. Extending the standard 7-10-day low-molecular-weight heparin prophylaxis period may benefit certain high-risk patient groups. SUMMARY: Patients undergoing abdominal surgery should be stratified according to thromboembolism risk and given prophylaxis accordingly. Low-molecular-weight heparin is a recommended alternative to unfractionated heparin in moderate- or high-risk patients. In patients with cancer, high doses of low-molecular-weight heparin may offer increased efficacy without increased bleeding, and an extended 4-week period of prophylaxis could be beneficial.     

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.     

Low-molecular-weight heparin versus warfarin for secondary prophylaxis of venous thromboembolism: a cost-effectiveness analysis

PURPOSE: To compare the cost effectiveness of low-molecular-weight heparin with that of oral anticoagulants in preventing recurrences after an episode of venous thromboembolism. METHODS: A decision tree was used to assess the cost and the expected quality-adjusted years of life (QALY) after treatment with either low-molecular-weight heparin or warfarin, based on pooled data from six published trials. Preferences were elicited with a modified time trade-off method in a sample of patients attending an anticoagulation clinic. RESULTS: Compared with warfarin, low-molecular-weight heparin significantly decreased the rate of minor bleeding (odds ratio [OR] = 0.24; 95% confidence interval [CI]: 0.14 to 0.43) but not recurrent deep vein thromboses (OR = 0.77; 95% CI: 0.43 to 1.35). Patients' preference for warfarin (0.988, on a 0 to 1 scale) was lower than that for low-molecular-weight heparin (0.992), but the difference was not statistically significant. A Monte Carlo analysis estimated that low-molecular-weight heparin saved an average of 13 quality-adjusted days compared with warfarin, at a cost of $6,583 per QALY (95% CI: $5,525 to $7,625) based on costs in Italy and $28,231 per QALY (95% CI: $20,872 to $36,773) based on costs in the United States. When we included rebound recurrences after interruption of therapy, which were more common with low-molecular-weight heparin, treatment with low-molecular-weight heparin cost $53,166 per QALY in Italy and $177,166 per QALY in the United States. CONCLUSIONS: Low-molecular-weight heparin might be a cost-effective drug for secondary prophylaxis of venous thromboembolism, especially in patients at high risk of recurrence and where the drug's cost is lower. The apparent increase in recurrence after interruption of therapy needs to be investigated more thoroughly before low-molecular-weight heparin can be recommended routinely.     

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.     

Subcutaneous unfractionated heparin compared with low-molecular-weight heparin for the initial treatment of venous thromboembolism

PURPOSE OF REVIEW: Low-molecular-weight heparin is the preferred choice for the initial treatment of acute, uncomplicated venous thromboembolism. In this context, unfractionated heparin is as safe and effective as low-molecular-weight heparin but requires strict laboratory monitoring. Twice-daily subcutaneous unfractionated heparin is more effective than, and as safe as, intravenous unfractionated heparin and may simplify patient treatment in or out of the hospital, being possibly cost saving, especially if it is used in weight-based, fixed, unadjusted doses. The present review focuses on the relative values of low-molecular-weight heparin and subcutaneous unfractionated heparin for the initial treatment of venous thromboembolism. RECENT FINDINGS: The major advantages of low-molecular-weight heparin over unfractionated heparin seem to be ease of administration and cost savings associated with home therapy or early hospital discharge; however, many patients with venous thromboembolism are still admitted to the hospital for treatment, and unfractionated heparin is extensively used to this purpose, especially in the United States. Subcutaneous unfractionated heparin, adjusted according to activated partial thromboplastin time algorithms, is as safe and effective as low-molecular-weight heparin for the treatment of venous thromboembolism, allows for quick mobilization and early discharge of suitable patients, and represents a cost-effective strategy. Fixed-dose unfractionated heparin, like low-molecular-weight heparin, may be used for the home treatment of deep vein thrombosis. SUMMARY: Subcutaneous unfractionated heparin, targeted on activated partial thromboplastin time results or in fixed doses, may be used in or out of the hospital for the treatment of venous thromboembolism, being possibly cost effective; however, these findings need confirmation through appropriate, large-sample, randomized clinical trials.     

Long-term treatment of venous thromboembolism with low-molecular-weight heparin

Vitamin K antagonists are the most widely used form of long-term treatment of patients with venous thromboembolism (VTE). In certain patients, however, the desire to initiate oral anticoagulant therapy is tempered by concern about the risk of bleeding. In these cases, consideration should be given to alternative forms of treatment. Unfractionated heparin (UFH) may be an alternative, but it requires twice-daily subcutaneous administration, and the dosage must be adjusted after periodic blood tests. Therapy with low-molecular-weight heparin (LMWH) is the likely practical solution to this dilemma. Up to now, four small randomized trials have compared the efficacy and safety of LMWH therapy as an alternative to oral anticoagulants. When the results of the four studies are combined, a significant decrease is found in the bleeding rate in patients receiving LMWH. Two further studies by our group confirm this lower bleeding rate in patients on LMWH therapy. According to these data, we suggest that LMWH could be an alternative to oral anticoagulants in patients who cannot attend the laboratory for prothrombin time monitoring, as well as those who are at high risk for bleeding.     

Low molecular weight heparin versus unfractionated heparin in the initial treatment of venous thromboembolism

In this review, we analyze data from randomized trials in which low molecular weight heparin was compared with unfractionated heparin, both to estimate the treatment effect of low molecular weight heparin in the initial treatment of venous thromboembolism and to evaluate the effect of the varied proportion of included cancer patients (6% to 22.7%) on the incidence of outcome events (recurrence of venous thromboembolism, bleeding, and mortality) and on the estimated treatment effect. Low molecular weight heparin has been extensively investigated in patients with deep vein thrombosis, but few trials have included patients with pulmonary embolism. The risk of recurrence of venous thromboembolism (odds ratio, 0.77; 95% CI, 0.56-1.04), major bleeding (odds ratio, 0.60; 95% CI, 0.38-0.95), and mortality (odds ratio, 0.72; 95% CI, 0.55-0.96) was less with low molecular weight heparins compared with unfractionated heparin. The proportion of cancer patients in these studies had a statistically significant effect on the incidence of recurrent venous thromboembolism (P = 0.03) and mortality (P = 0.002), but no influence on the estimated treatment effects of low molecular weight heparins. Low molecular weight heparin is effective and safe in the initial treatment of venous thromboembolism.     

Subcutaneous adjusted-dose unfractionated heparin vs fixed-dose low-molecular-weight heparin in the initial treatment of venous thromboembolism

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Prevention and treatment of venous thromboembolism in the elderly patient

Venous thromboembolism (VTE) is a common complication among hospitalized patients. Pharmacological thromboprophylaxis has emerged as the cornerstone for VTE prevention. As trials on thromboprophylaxis in medical patients have proven the efficacy of both low-molecular-weight heparins (LMWHs) and unfractionated heparin (UFH), all acutely medical ill patients should be considered for pharmacological thromboprophylaxis. Unlike in the surgical setting where the risk of associated VTE attributable to surgery is well recognized, and where widespread use of pharmacological thromboprophylaxis and early mobilization has resulted in significant reductions in the risk of VTE, appropriate VTE prophylaxis is under-used in medical patients. Many reasons for this under-use have been identified, including low perceived risk of VTE in medical patients, absence of optimal tools for risk assessment, heterogeneity of patients and their diseases, and fear of bleeding complications. A consistent group among hospitalized medical patients is composed of elderly patients with impaired renal function, a condition potentially associated with bleeding. How these patients should be managed is discussed in this review. Particular attention is devoted to LMWHs and fondaparinux and to measures to improve the safety and the efficacy of their use.     

Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A cost-effectiveness analysis.

BACKGROUND: Low-molecular-weight heparins are effective for treating venous thrombosis, but their cost-effectiveness has not been rigorously assessed. OBJECTIVE: To evaluate the cost-effectiveness of low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. DESIGN: Decision model. DATA SOURCES: Probabilities for clinical outcomes were obtained from a meta-analysis of randomized trials. Cost estimates were derived from Medicare reimbursement and other sources. TARGET POPULATION: Two hypothetical cohorts of 60-year-old men with acute deep venous thrombosis. TIME HORIZON: Patient lifetime. PERSPECTIVE: Societal. INTERVENTION: Fixed-dose low-molecular-weight heparin or adjusted-dose unfractionated heparin. OUTCOME MEASURES: Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. An in-patient hospital setting was used for the base-case analysis. Secondary analyses examined outpatient treatment with low-molecular-weight heparin. RESULTS OF BASE-CASE ANALYSIS: Total costs for inpatient treatment were $26,516 for low-molecular-weight heparin and $26,361 for unfractionated heparin. The cost of initial care was higher in patients who received low-molecular-weight heparin, but this was partly offset by reduced costs for early complications. Low-molecular-weight heparin treatment increased quality-adjusted life expectancy by approximately 0.02 years. The incremental cost-effectiveness of inpatient low-molecular-weight heparin treatment was $7820 per QALY gained. Treatment with low-molecular-weight heparin was cost saving when as few as 8% of patients were treated at home. RESULTS OF SENSITIVITY ANALYSIS: When late complications were assumed to occur 25% less frequently in patients who received unfractionated heparin, the incremental cost-effectiveness ratio increased to almost $75,000 per QALY gained. When late complications were assumed to occur 25% less frequently in patients who received low-molecular-weight heparin, this treatment resulted in a net cost savings. Inpatient low-molecular-weight heparin treatment became cost saving when its pharmacy cost was reduced by 31% or more, when it reduced the yearly incidence of late complications by at least 7%, when as few as 8% of patients were treated entirely as outpatients, or when at least 13% of patients were eligible for early discharge. CONCLUSIONS: Low-molecular-weight heparins are highly cost-effective for inpatient management of venous thrombosis. This treatment reduces costs when small numbers of patients are eligible for outpatient management.