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.     

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.     

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.     

Unfractionated heparin for the treatment of venous thromboembolism: best practices and areas of uncertainty

Nearly 100 years after its discovery, unfractionated heparin (UFH) remains a widely used anticoagulant for the treatment of venous thromboembolism (VTE) and several other thrombotic and prothrombotic conditions. Decades of experience and investigation have contributed to our knowledge of this agent, but crucial questions regarding its optimal use in clinical practice remain unanswered. This review will critically examine the evidence for dosing and laboratory monitoring of UFH in the management of VTE, and highlight areas of uncertainty and future research.     

Treatment of venous thromboembolism with low-molecular-weight heparin

Summary There is now ample evidence to indicate that certain low-molecular-weight heparins given subcutaneously can replace continuous intravenous unfractionated heparin for the initial treatment of venous thromboembolism. The low-molecular-weight heparins have a predictably high absorption rate when given subcutaneously and a prolonged duration of action, permitting them to be given by a once or twice daily injection for the prevention or treatment of venous thrombosis. Furthermore, treatment does not require laboratory monitoring, thus eliminating the need for continuous IV infusion and permitting the early discharge of patients with venous thromboembolism. This should eventually lead to the outpatient treatment of venous thromboembolism. Studies to date indicate that low-molecular-weight heparin is more cost-effective than unfractionated heparin in the treatment of venous thromboembolism and the cost effectiveness will be increased by out-of-hospital treatment. At the present time, the findings associated with any individual lowmolecular-weight heparin preparation cannot be extrapolated to different low-molecular-weight heparins, and therefore each must be evaluated in separate clinical trials. The information to date is that low-molecular-weight heparin is safer and more effective than continuous intravenous unfractionated heparin in the treatment of proximal venous thrombosis. The decreased mortality rate seen in two clinical trials, particularly in patients with metastatic cancer, was quite unexpected. This requires further confirmation in larger prospective randomized trials.     

Community-based treatment of venous thromboembolism with a low-molecular-weight heparin and warfarin

This multicenter, prospective, open label, observational study evaluated practice patterns of physicians using tinzaparin, a low-molecular-weight heparin (LMWH), and warfarin for the treatment of deep venous thrombosis (DVT) with or without pulmonary embolism (PE). Short-term recurrence of venous thromboembolism (VTE) and safety were also evaluated. Patients with an objective diagnosis of DVT, with or without PE, were invited by their physician to participate in this study. Treatment was given according to the approved U.S. package inserts for tinzaparin (175 IU/kg SQ QD) and warfarin and the clinical judgment of the prescribing physician. Baseline patient history including demographic information and the results of tests to confirm the diagnosis of DVT, with or without PE, were collected. Follow-up information included the treatment setting in which each dose of tinzaparin was administered, medical training of the person administering tinzaparin doses, timing of initiation of warfarin with respect to that of tinzaparin, length of overlap of tinzaparin and warfarin therapy, and adverse experiences. A total of 334 patients were enrolled at 65 sites. Patients across a wide age (range 18–93 years old) and body weight (range 40–261 kg) were included. Overall, 27.3% of patients had cancer, and 50% of the overall study population reported more than one VTE risk factor. Mean duration of tinzaparin treatment was 7.61 days. Therapy at home was more common in suburban and rural settings than in urban settings. High proportions of patient, even among the small group with concurrent PE, were treated at home with self-injection. Severity of disease was the primary reason for hospitalization. Home treatment of DVT, with or without PE, with self administration of tinzaparin at 175 IU SQ once-daily was safe and resulted in an acceptably low rate of recurrent venous thromboembolism and adverse events. Home therapy in the usual practice setting should achieve substantial overall cost savings in the treatment of DVT.     

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.     

Secondary prevention of venous thromboembolism: A role for low-molecular-weight heparin.

BACKGROUND: After a short initial course of heparin therapy, patients with venous thrombo-embolism (VTE) require continuing anticoagulant therapy for several months after hospital discharge. At present, two small-scale studies have compared the efficacy and safety of low-molecular-weight heparin (LMWH) with warfarin in the secondary prevention of VTE. PATIENTS AND METHODS: We studied 654 consecutive patients, 202 with pulmonary embolism (PE) and 452 patients with deep vein thrombosis (DVT) of the lower limbs. 220/654 patients (34%) were considered to have some contraindications to coumarin, and were discharged on LMWH (dalteparin, Fragmin((R)), 10, 000 IU s.c. once daily). The remaining 434/654 patients were asked to choose between either coumarin or LMWH: 190 patients preferred LMWH and 244 coumarin. Patients were followed up for a 3-month (DVT patients) or 6-month (PE patients) period. RESULTS: 14/654 patients (2%) developed recurrent VTE while on anticoagulant therapy. One in every three recurrent episodes was PE (which was fatal in 2/5 patients), and half of the recurrent DVT were located in the contralateral leg. We failed to find any differences between patients receiving LMWH and those on coumarin therapy, but recurrences were more common in patients with cancer (hazard ratio: 17.15; 95% CI: 4.0-73.5; p < 0.001). 21 patients (3.3%) bled (major bleeding 5 patients; minor bleeding 16). Bleeding was more common in patients on coumarin therapy (hazard ratio: 3.14; 95% CI: 1.20-8.22; p = 0.02). CONCLUSIONS: Long-term LMWH therapy proved to be both effective and safe in the long-term treatment of VTE. Thus, we suggest long-term LMWH therapy should be considered for patients with contraindications to coumarin, or those with difficulties in coming to laboratory control.     

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.     

Unfractionated heparin compared with low-molecular-weight heparin as related to heparin-induced thrombocytopenia

PURPOSE OF REVIEW: Heparin-induced thrombocytopenia is a severe side effect of treatment with unfractionated heparin. The relation of low-molecular-weight heparin to heparin-induced thrombocytopenia is less well understood. This review will summarize what is known about the similarities and differences between thrombocytopenia induced by low-molecular-weight heparin and that induced by unfractionated heparin. RECENT FINDINGS: The pathophysiology of unfractionated heparin-induced thrombocytopenia, caused by the development of antibodies to heparin/platelet factor 4 complexes, holds true for low-molecular-weight heparin because the molecules of the latter are of the same saccharidic structure as those of unfractionated heparin. Owing to their smaller size, however, low-molecular-weight heparin does not interact with platelet factor 4 and platelets as efficiently as does unfractionated heparin. This translates to a two- to threefold lower risk of immune sensitization (antibody generation and occurrence of clinical heparin-induced thrombocytopenia). Low-molecular-weight heparin-induced thrombocytopenia antibodies are more often immunoglobulin A and immunoglobulin M, in contrast to the immunoglobulin G antibodies generated with unfractionated heparin-induced thrombocytopenia, which tend to be more often associated with clinical heparin-induced thrombocytopenia. The clinical expression of low-molecular-weight heparin-induced thrombocytopenia is generally similar to that of unfractionated heparin-induced thrombocytopenia but can have a slower onset, more severe thrombocytopenia, and slower platelet count recovery. Given that low-molecular-weight heparin, of itself, is linked with heparin-induced thrombocytopenia pathophysiology and it can interact with most preexisting heparin-induced thrombocytopenia antibodies generated after exposure to unfractionated heparin, treatment of heparin-induced thrombocytopenia patients with low-molecular-weight heparin is contraindicated. SUMMARY: The risk of the development of heparin-induced thrombocytopenia with low-molecular-weight heparin treatment is reduced relative to the frequency of unfractionated heparin-induced thrombocytopenia, but it is not eliminated, and platelet counts should be monitored with treatment.     

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.     

Heparin and low-molecular-weight heparin therapy for venous thromboembolism. The twilight of anticoagulant monitoring.

Recent improvements in the methods of clinical trials and the use of accurate objective tests to detect venous thromboembolism have made possible a series of randomized trials to evaluate various treatments for venous thromboembolism. The results of these trials have resolved many of the uncertainties a clinician confronts in selecting an appropriate course of anticoagulant therapy. These trials have shown that the intensity of both initial heparin treatment and long-term anticoagulant therapy must be sufficient to prevent unacceptable rates of recurrence of venous thromboembolism. Patients with proximal deep vein thrombosis who receive inadequate anticoagulant therapy have a risk of clinically evident, objectively documented recurrent venous thromboembolism that approaches 20% to 25%. The need for therapy with heparin and the importance of monitoring blood levels of the effect of heparin have been established. The importance of achieving adequate heparinization was suggested by a nonrandomized trial in 1972 and randomized trials in the 1980s have confirmed this finding. Furthermore, randomized trials have demonstrated the importance of achieving adequate heparinization early in the course of therapy. Unfractionated intravenous heparin has provided an effective therapy for more than half a century, but the need to monitor therapy and establish therapeutic levels is a fundamental problem. It is evident that validated heparin protocols are more successful in establishing adequate heparinization than intuitive ordering by the clinician. However, even with the best of care using a heparin protocol, some patients treated with intravenous heparin will receive subtherapy. In this context, subtherapy reflects a practical limitation of the use of unfractionated heparin, rather than a poor standard of care. Furthermore, it is recognized that the practical difficulties associated with heparin administration are compounded by the substantive practical difficulties of standardizing APTT testing and the therapeutic range. Our findings emphasize the confounding effect that initial heparin treatment has on long-term outcome. In future trials of longterm therapy, it is imperative that the initial therapy is of adequate intensity and duration; failure to administer adequate initial treatment may lead to a poor outcome that is falsely attributed to the long-term therapy under evaluation. Therapy with low-molecular-weight heparin, which does not require monitoring and dose finding, is the likely practical solution to these dilemmas. Based on the experience of difficulties achieving adequate therapy with subcutaneous unfractionated heparin dosing, we administered a low-molecular-weight heparin formulation in a single daily dose, rather than splitting the treatment into 2 equal doses. The initial intensity of therapy was thereby maximized. Therapy with low-molecular-weight heparin proved to be better than therapy with unfractionated heparin.     

Economic analysis of low-dose heparin vs the low-molecular-weight heparin enoxaparin for prevention of venous thromboembolism after colorectal surgery.

BACKGROUND: Low-dose heparin and low-molecular-weight heparin are effective strategies for preventing venous thromboembolism in colorectal surgery. The economic attractiveness of these 2 strategies in North America is unknown. We conducted an economic analysis of low-dose heparin calcium compared with enoxaparin sodium, a low-molecular-weight heparin, for thromboembolism prophylaxis after colorectal surgery. METHODS: We used decision analysis, with an economic perspective of a third-party payer. Efficacy data were obtained from the Canadian Multicentre Colorectal Deep Vein Thrombosis Prophylaxis Trial and a literature review. Canadian costs for diagnosis and treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and major bleeding were obtained from chart review and a national hospital database of colorectal surgery; American costs were obtained from published literature. The main outcomes were incremental benefits (symptomatic DVTs, symptomatic PEs, and major bleeding events avoided) and incremental costs for every 1000 patients treated. RESULTS: In the Canadian Colorectal Trial, the relative risk of DVT and PE for enoxaparin compared with low-dose heparin was 1.0 (95% confidence interval, 0.7-1.5), and the relative risk of major bleeding was 1.8 (95% confidence interval, 0.8-3.9). With the use of these data in the baseline analysis, a strategy of enoxaparin prophylaxis was associated with equal numbers of symptomatic DVTs and PEs, and an excess of 12 major bleeding episodes for every 1000 patients treated, with an additional cost of $86 050 (Canadian data) or $145 667 (US data). In a sensitivity analysis using optimal assumptions for efficacy and safety of enoxaparin (relative risk of DVT, 0.8; relative risk of PE, 0.4; relative risk of major bleeding, 1.0), a strategy of enoxaparin prophylaxis was associated with 0.8 fewer symptomatic DVT, 3 fewer symptomatic PEs, and equal numbers of major bleeding episodes for every 1000 patients treated, with an additional cost of $15 217 (Canadian data) or $107 614 (US data). CONCLUSION: Although heparin and enoxaparin are equally effective, low-dose heparin is a more economically attractive choice for thromboembolism prophylaxis after colorectal surgery.