Treating patients with venous thromboembolism: initial strategies and long-term secondary prevention

Therapy for venous thromboembolism (VTE) currently involves a minimum of 3 months of anticoagulation. After cessation of therapy, however, recurrent venous thrombosis occurs at rates of 6 to 9% per year. Clinical trials have demonstrated the benefits of extending anticoagulation beyond 3 months for the prevention of recurrent VTE events. Despite this, many eligible patients do not receive the required thromboprophylaxis and the incidence of recurrent VTE remains too high for a preventable condition. A reason for failure to use prophylaxis is the fear of bleeding complications with current oral anticoagulants such as warfarin. Warfarin has an unpredictable pharmacokinetic profile and a variable dose-response relationship that requires frequent coagulation monitoring and dose adjustments to maintain a target intensity that is both safe and effective. Alternative strategies for long-term prophylaxis, which may potentially provide more consistent anticoagulant responses and reduce coagulation monitoring requirements, include the use of low-molecular-weight heparin (LMWH), treatment with warfarin at a lower intensity, and the introduction of novel anticoagulants. The long-term use of LMWH has been found to be a particularly favorable treatment option for cancer patients in whom it is difficult to control the intensity of anticoagulation. In clinical trials, LMWH significantly reduced the risk of recurrent VTE without increasing bleeding risk. The parenteral administration of the LMWHs, however, is a drawback for long-term use in the outpatient setting. A clinical trial assessing the efficacy and safety of long-term low-intensity warfarin treatment found this therapy to be better than placebo, but another study showed that conventional intensity warfarin was significantly more efficacious than low-intensity warfarin. New therapies in development that may offer improved safety-efficacy profiles are the synthetic pentasaccharides fondaparinux and idraparinux and the oral direct thrombin inhibitor ximelagatran. Parenterally administered fondaparinux has been shown to be as effective as LMWH for the acute treatment (5 to 7 days) of symptomatic deep vein thrombosis. Idraparinux, with once-weekly parenteral dosing, is currently being assessed in phase III clinical trials for the long-term secondary prevention of VTE. Ximelagatran is the first oral agent in the new class direct thrombin inhibitors. With a fast onset of action and oral administration, ximelagatran is a candidate for both acute and chronic therapy. The Thrombin Inhibitor in Venous Thromboembolism (THRIVE) clinical trial program has demonstrated that this agent has a favorable benefit-risk profile compared with standard therapy for the initial treatment (6 months) and secondary prevention (up to 18 months) of VTE. However, in a substantial proportion (6 to 13%) of patients given extended ximelagatran therapy, elevated serum transaminase enzymes developed, typically in the first 2 to 4 months of treatment. Even though these elevations usually abated without clinical sequelae whether or not treatment was continued, their clinical relevance remains unclear. In addition, locally reported coronary events occurred more frequently in ximelagatran-treated patients during the initial 6 months of treatment, the reason for which is yet unclear. The consistent anticoagulant response and fixed oral dosing without coagulation monitoring allows ximelagatran to overcome many of the limitations inherent to current treatment options for VTE treatment and secondary prevention, provided the problem of liver enzyme elevation and coronary events is resolved.     

Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide

Lenalidomide plus dexamethasone is effective in the treatment of multiple myeloma (MM) but is associated with an increased risk of venous thromboembolism (VTE). This prospective, open-label, randomized substudy of a phase 3 trial compared the efficacy and safety of thromboprophylaxis with low-dose aspirin (ASA) or low-molecular-weight heparin (LMWH) in patients with newly diagnosed MM, treated with lenalidomide and low-dose dexamethasone induction and melphalan-prednisone-lenalidomide consolidation. Overall, 342 patients who did not have clinical indications or contraindications to antiplatelet or anticoagulant therapy were randomly assigned to receive ASA 100 mg/d (n = 176) or LMWH enoxaparin 40 mg/d (n = 166). The incidence of VTE was 2.27% in the ASA group and 1.20% in the LMWH group. Compared with LMWH, the absolute difference in the proportion of VTE was 1.07% (95% confidence interval, -1.69-3.83; P = .452) in the ASA group. Pulmonary embolism was observed in 1.70% of patients in the ASA group and none in the LMWH group. No arterial thrombosis, acute cardiovascular events, or sudden deaths were reported. No major hemorrhagic complications were reported. In previously untreated patients with MM receiving lenalidomide with a low thromboembolic risk, ASA could be an effective and less-expensive alternative to LMWH thromboprophylaxis.     

Treatment of venous thromboembolism

Venous thromboembolism (VTE), comprised of pulmonary embolism (PE) and deep vein thrombosis (DVT), is a disease entity with a significant morbidity and mortality. Anticoagulation, initially with intravenous heparin and followed with long term warfarin treatment is the traditional therapy for VTE. Low molecular weight heparin, (LMWH) has a greater bioavailability than unfractionated heparin and can be administered subcutaneously. LMWH has resulted in shorter hospitalizations, reduced inicidents of major bleeding complications, and has moved the treatment of VTE for selected patients to the out-patient setting. Thrombolytic therapy has been recommended in patients with life threatening PE such as those with right ventricular dysfunction or hypotension. There are advances in the technology for clot removal with catheter embolectomy and clot fragmentation. Inferior vena cava filters can be place percutaneously in patients who are at high risk for VTE or those in whom anticoagulation is contraindicated. Since VTE is often asymptomatic, prevention is the most effective means to reduce morbidity and mortality.     

Treatment of venous thromboembolism in cancer patients

Venous thromboembolism (VTE) is a common complication in patients with malignant disease. Its management remains challenging because patients with a cancer-associated thrombosis are at higher risk of recurrent VTE than are noncancer subjects with thrombosis and also have a greater risk for anticoagulant-associated bleeding complications while receiving therapy to prevent recurrent VTE. Recently, anticoagulant strategies based on the administration of low-molecular-weight heparin (LMWH) rather than vitamin K antagonists for up to 6 days to prevent recurrent VTE have been evaluated. These studies indicate that LMWH is associated with a lower rate for recurrent VTE and similar rates of bleeding when compared with oral anticoagulant therapy. Chronic exposure to LMWH may also prolong survival of cancer patients.     

How I treat venous thromboembolism in patients with cancer

Venous thromboembolism (VTE) is a frequent complication in cancer patients and represents an important cause of morbidity and mortality. Especially in patients who have a poor life expectancy, preventing death from pulmonary embolism is the mainstay of treatment. Critically ill patients should promptly be administered thrombolytic drugs. Except for selected patients requiring aggressive therapy, the initial VTE treatment should be conducted with either adjusted-dose unfractionated heparin or fixed-dose low-molecular-weight heparin (LMWH). LMWHs have the potential to greatly simplify the initial treatment of VTE, making the treatment of suitable patients feasible in an outpatient setting. During anticoagulant therapy, cancer patients have a 2- to 4-fold higher risk of recurrent VTE and major bleeding complications when compared with noncancer patients. The long-term administration of LMWH should be considered as an alternative to anti-vitamin K drugs in patients with advanced disease and in those with conditions limiting the use of oral anticoagulants. Prolongation of anticoagulation should be considered for as long as the malignant disorder is active. The evidence of lowered cancer mortality in patients on LMWH has stimulated renewed interest in these agents as antineoplastic drugs and raises the distinct possibility that cancer and thrombosis share common mechanisms.     

Approach to Venous Thromboembolism in the Cancer Patient

Venous thromboembolism (VTE) is frequently encountered in cancer patients, acts as an important cause of morbidity and mortality, and may be a predictor of worse prognosis. In cancer patient who have a poor life expectancy, preventing death from pulmonary embolism is the mainstay of treatment. Patients who present with severe hypotension or other clinical manifestations suggestive of critical pulmonary embolism and do not have contraindications to thrombolysis should promptly be administered thrombolytic drugs. Except for selected cases requiring aggressive therapy, treatment of VTE in patients with cancer should not differ from that of patients without malignancy; the initial treatment should be conducted with adjusted dose of unfractionated heparin (UH), fixed dose of low-molecular-weight heparins (LMWH), or fondaparinux. LMWHs and fondaparinux have the potential to greatly simplify the initial treatment of VTE, making the management of the pathology feasible in an outpatient setting for selected patients. Traditionally, in cancer as well as in non-cancer patients, UH or LMWH or fondaparinux are overlapped by oral anticoagulation, targeted to reach an International Normalized Ratio (INR) between 2.0 and 3.0, and then followed by oral anticoagulants. However, during oral anticoagulant therapy, cancer patients exhibit a two- to fourfold higher risk of recurrent VTE and major bleeding complications when compared to non-cancer patients. Studies performed during the current decade have demonstrated that LMWHs offer several advantages in terms of efficacy in preventing VTE recurrences without increasing the bleeding risk. According to International Guidelines, the long-term administration of LMWH should be considered an alternative to anti-vitamin K drugs in patients with advanced disease and in those with conditions limiting the use of oral anticoagulants. The targeted policy is to administer LMWH at full therapeutic doses for the first month of treatment and then 75% of the initial dose for at least the following 5 months of therapy. Prolongation of anticoagulation should be considered for as long as the malignant disorder is active. In patients with acute deep venous thrombosis and contraindications to anticoagulation, vena cava filters should be considered. If anticoagulation is temporarily contraindicated, retrievable filters should be considered. Only patients who are actively bleeding or who are at extremely high risk for bleeding should receive a filter without anticoagulation coverage.     

Prevention of venous thromboembolism in neurosurgery: a metaanalysis

BACKGROUND: Venous thromboembolism (VTE) is an important complication of neurosurgery. Current guidelines recommend pharmacologic prophylaxis in this setting with either unfractionated heparin or low-molecular-weight heparin (LMWH). We conducted a systematic review asking, "Among patients undergoing neurosurgical procedures, how safe and effective is the prophylactic use of heparin and mechanical devices?" METHODS: We searched the medical literature to identify prospective trials reporting on VTE prevention (either mechanical or pharmacologic). The rates of VTE and bleeding were our primary end points and were pooled using a random-effects model. RESULTS: We identified 30 studies reporting on 7,779 patients. There were 18 randomized controlled trials and 12 cohort studies. The results of pooled relative risks (RRs) showed LMWH and intermittent compression devices (ICDs) to be effective in reducing the rate of deep vein thrombosis (LMWH: RR, 0.60; 95% confidence interval [CI], 0.44 to 0.81; ICD: RR, 0.41; 95% CI, 0.21 to 0.78). Similar results were seen when pooled rates from all 30 trials were analyzed. In head-to-head trials, there was no statistical difference in the rate of intracranial hemorrhage (ICH) between therapy with LMWH and nonpharmacologic methods (RR, 1.97; 95% CI, 0.64 to 6.09). The pooled rates of ICH and minor bleeding were generally higher with heparin therapy than with non-heparin-based prophylactic modalities. CONCLUSIONS: In a mixed neurosurgical population, LMWH and ICDs are both effective in the prevention of VTE. Sensitivity analyses have suggested that isolated high-risk groups, such as those with patients undergoing craniotomy for neoplasm, may benefit from a combination of prophylactic methods, suggesting the need for a more individualized approach to these patients.     

Anticoagulants in Pregnancy

Venous thromboembolic (VTE) complications are a leading cause of maternal mortality in the developed world. To reduce the incidence of VTE in pregnancy, and improve outcomes, a wider understanding of the risk factors involved and a better identification of women at risk of thrombosis coupled with effective thromboprophylaxis and treatment of VTE are required. As coumarin is unsuitable for use in pregnancy because of problems with embryopathy and risk of fetal bleeding, anticoagulation therapy in pregnancy centres on the use of low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH). There is now extensive experience of the safety and efficacy of LMWH in pregnancy. LMWH's, such as enoxaparin and dalteparin, have clinical and practical advantages compared with UFH in terms of improved safety (significantly lower incidence of osteoporosis and heparin induced thrombocytopenia), and patient convenience with once daily dosing for the majority of women. Such therapy is not restricted only to prevention and treatment of VTE but is now being assessed in additional clinical situations such as the prevention of pregnancy complications.     

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.     

Ximelagatran for the prevention of venous thromboembolism following elective hip or knee replacement surgery

Patients undergoing major lower-extremity orthopedic surgery such as total hip replacement (THR) and total knee replacement (TKR) are at an increased risk of venous thromboembolism (VTE). Routine prophylaxis is necessary to reduce the risk of deep vein thrombosis (DVT), which may progress to potentially fatal pulmonary embolism and secondary complications such as postthrombotic syndrome, recurrent DVT, and chronic pulmonary hypertension. Prophylaxis in patients undergoing TKR, THR, and hip fracture surgery is now standard practice and generally involves anticoagulant treatment with either low-molecular-weight heparin (LMWH) or warfarin for a period of 7 to 10 days, with extended prophylaxis in those with ongoing risk factors such as obesity, cancer, or previous VTE. Data from clinical practice suggest that there is a general trend toward longer postsurgical prophylaxis and shorter hospital stays, making practicality of treatment an important consideration. LMWH is effective for the prophylaxis of VTE, but the parenteral route of administration is not convenient for use in the outpatient setting. Warfarin, on the other hand, can be administered orally but requires the infrastructure for careful patient monitoring and dose adjustments because of its unpredictable dose-response relationship. The development of new anticoagulants has been pursued with the aim of improving efficacy, predictability, consistency of response, safety, and convenience. A recently approved anticoagulant, fondaparinux, has been proven to provide superior efficacy for the prevention of VTE compared with LMWH, but this agent requires parenteral administration and does not overcome the convenience issue. Ximelagatran is the oral form of the direct thrombin inhibitor melagatran, which is available for subcutaneous administration. Ximelagatran has a consistent anticoagulant response allowing fixed oral dosing without the need for coagulation monitoring. The efficacy and safety profile of melagatran/ximelagatran prophylaxis for VTE following THR and TKR has compared favorably with standard LMWH prophylaxis, as seen in the European METHRO II and III trials and EXPRESS trial, and with warfarin prophylaxis, as seen in the North American EXULT A and B trials. Several prophylactic treatment regimens have been evaluated in the European trials to determine the optimal dosing and timing of first dose of melagatran to achieve the best balance of efficacy and safety. Preoperative initiation of melagatran was more effective than when prophylactic treatment was initiated postoperatively, and the lowest rates of bleeding were associated with a postoperative initiation of prophylaxis. Early administration of the first postoperative melagatran dose (4 to 8 hours) was also associated with better prophylactic efficacy relative to a later postoperative start (8 to 12 hours). The results of the comprehensive international clinical trial program and in particular the optimal balance of efficacy/safety data provided by the METHRO III study have led to approval of melagatran/ximelagatran in 2004 in the European Union for the prevention of VTE in patients undergoing elective hip or knee replacement surgery. Ximelagatran has the potential to maximize the use of anticoagulation in patients discharged following major lower-extremity orthopedic surgery.     

Deep vein thrombosis

Initially, patients with deep vein thrombosis (DVT) should be treated with a 5- to 7-day course of heparin or low-molecular-weight heparin (LMWH). They can be administered LMWH as outpatients. Patients with extensive iliofemoral thrombosis, major pulmonary embolism, or concomitant medical illness, and those at high risk for bleeding, should be treated as inpatients. Thrombolytic therapy may be considered for patients with extensive iliofemoral thrombosis if there is no contraindication to the use of thrombolytic drugs. Oral anticoagulants can be started within 24 hours of the initiation of heparin or LMWH. Warfarin is started at a dose of 5 mg, and subsequent doses are given in amounts sufficient to achieve an international normalized ratio of 2.0 to 3.0. Inferior vena caval filters should be considered for patients with overt bleeding or for those at high risk for hemorrhage. Warfarin can be used for secondary prophylaxis in most patients. Patients in whom there are contraindications to the use of oral anticoagulants and patients in whom recurrent venous thromboembolism (VTE) develops while they are receiving therapeutic doses of warfarin can be safely and effectively treated with LMWH. Patients with idiopathic DVT should be treated with anticoagulants for at least 6 months. Those with calf DVT or proximal DVT that complicates surgery or medical illness can be treated with anticoagulants for 6 weeks and 3 months, respectively, provided that there are no ongoing risk factors for recurrent VTE. Oral anticoagulants are teratogenic and should be avoided by patients who are pregnant; unfractionated heparin or LMWH are safe alternatives. Unfractionated heparin, LMWH, and oral anticoagulants can be safely administered to nursing mothers.     

Prophylaxe und Therapie venöser Thromboembolien bei Tumorerkrankungen

Venous thromboembolism (VTE) is a common complication in patients with cancer. Because of their improved subcutaneous bioavailability and reliable antithrombotic efficiency low-molecular-weight heparins (LMWH) are preferably used for prevention and treatment of cancer-related VTE. Thromboprophylaxis with LMWH is well established in patients undergoing cancer surgery and hospitalized cancer patients, while outpatient prophylaxis remains contentious. LMWH are recommended over unfractionated heparins and vitamin K antagonists for initial treatment and secondary prophylaxis (3–6 months) after cancer-related VTE. Long-term secondary prophylaxis should be considered for patients with ongoing active malignancy and low bleeding risk. Due to absence of clinical studies in cancer patients, the use of novel oral anticoagulants is currently not recommended.     

Treatment modalities in cancer-associated venous thromboembolism (VTE)

Anticoagulation is the cornerstone of cancer-associated VTE treatment, including vitamin K antagonists (VKA), unfractionated heparin (UFH), fondaparinux, low-molecular-weight heparins (LMWH) and direct oral anticoagulants (DOACs). The goals of anticoagulant therapy in cancer patients with cancer-associated thrombosis (CAT) are to improve symptoms, reduce risk of recurrent VTE or fatal pulmonary embolism (PE), and decrease the risk of post-thrombotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension. Although LMWH have been the standard of care for a long time for VTE treatment in cancer patients, showing superiority over the classic VKA, in the recent years the landscape of anticoagulant therapy has significantly changed with the inclusion of DOACs in this population.     

New treatments for venous thromboembolic disease

Following the landmark study by Barritt and Jordan in 1960, in which patients with venous thromboembolism (VTE) were randomized to no treatment or a combination of heparin and warfarin, antithrombotic therapy for this disease became widely accepted. This study was stopped prematurely because half of the non-treated patients had recurrent pulmonary embolism (PE), or died. It was subsequently found that after a VTE, patients given warfarin alone had a 3-4-fold higher incidence of recurrent VTE than patients given both heparin and warfarin. Since the 1990 s, standard therapy for VTE has comprised an initial 5-7 day course of parenteral anticoagulant plus warfarin continued for at least 3 months. Recently, several orally active small molecules have been evaluated in the treatment of VTE, including a direct thrombin inhibitor and direct Factor Xa inhibitors. Other novel oral agents are also in development for VTE treatment. Although the DTI ximelagatran, the first oral agent to be introduced since warfarin was withdrawn from the market in Europe because of hepatotoxicity, evidence from clinical trial evaluating other single target-specific oral agents in the treatment of VTE is encouraging. It is therefore likely that use of warfarin in the treatment and secondary prevention of VTE will decrease should these novel oral agents be introduced for these indications. Additionally, there will be less distinction between initial and long-term therapy, and a great majority of patients will be treated on an outpatient basis for prolonged periods of time. Recently these expectations were fulfilled by the results of two Phase III studies in patients with VTE. The Recover I study indicated that Dabigatran (150 mg b.d.) following an initial course of LMWH was non-inferior to the standard treatment of LMWH plus warfarin, with also a similar safety profile. The Einstein DVT study revealed that Rivaroxaban as a single agent can safely replace the standard treatment in patients with DVT. Taken together these studies and a few others that have or are about to be completed will indeed introduce a paradigm shift in the way patients with VTE will be treated.     

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.     

Venous thromboembolism in cancer patients: expanding horizons

Venous thromboembolism (VTE) and particularly idiopathic VTE may be paraneoplastic phenomena. The merits of screening patients with idiopathic VTE for occult cancer are still under debate, and randomized studies are required to establish its potential cost-effectiveness. Cancer and its related surgery greatly increase the risk of VTE. Thromboprophylaxis using agents such as low-molecular-weight heparin (LMWH) has proved to be safe and effective in reducing the incidence of postoperative VTE. The ENOXACAN II study has shown that prolonging the standard 1-week regimen of the LMWH enoxaparin to 4 weeks may further reduce the incidence of postoperative VTE. Enoxaparin has also shown potential benefits in the secondary prevention of VTE and the reduction of bleeding complications. Emerging data indicate that LMWH may improve survival rates in cancer patients with VTE, making this a very important area for future research.     

Cancer and venous thromboembolism: prevention, treatment and survival

Venous thromboembolism (VTE) occurs frequently in patients with cancer. It can be difficult to manage, sometimes delay cancer therapy and predicts for a worse prognosis. Hence, effective methods to prevent and treat VTE can reduce morbidity and mortality. Prophylaxis with anticoagulants is recommended for patients hospitalized for surgery or medical conditions, but is not routinely administered in the ambulatory setting. Traditional anticoagulation with a heparin followed by vitamin K antagonist therapy for cancer patients with acute VTE is associated with a high frequency of treatment failure and bleeding complications. Low molecular weight heparins (LMWHs) have simplified and improved the management of VTE, and recent studies suggest these agents may improve survival in patients with limited or early stage disease. This brief review will provide an update on the primary prevention and treatment of VTE and discuss the evidence for the survival advantage associated with LMWH use in patients with malignancy.     

Effective prophylaxis of thromboembolic complications with low molecular weight heparin in relapsed multiple myeloma patients treated with lenalidomide and dexamethasone

The immunomodulatory drugs thalidomide and lenalidomide have enhanced activity in patients with multiple myeloma (MM). Their efficacy is increased with the addition of dexamethasone, but significant rates of venous thromboembolism (VTE) are a severe side effect. Based on this evidence, it is recommended that VTE prophylaxis be prescribed in these patients. However, the optimal prophylaxis remains controversial. We analyzed 45 patients with relapsed MM who were treated with lenalidomide and dexamethasone at our center. The 45 patients received a total number of 192 cycles, respectively a median of three cycles; the median dosage of dexamethasone was 240 mg per cycle. All patients received prophylactic anticoagulation with low molecular weight heparin (LMWH). Moreover, 86.6% of patients had at least one additional VTE risk factor beside the myeloma-related risk. One out of 45 patients developed a deep vein thrombosis and pulmonary embolism. None of the other 44 patients had clinical signs of thrombosis or embolism and none of all patients experienced complications or side effects due to anticoagulation. Our results indicate that prophylactic anticoagulation with LMWH is safe and effective. Therefore, we propose LMWH should be used in patients being treated with lenalidomide and dexamethasone at least for the first 3 months of treatment until randomized trials have proven the equality of other pharmacological prophylaxis.     

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.     

Heparin and low-molecular-weight heparin therapy for venous thromboembolism: will unfractionated heparin survive?

Recent improvements in clinical trials methodology and the use of accurate objective tests to detect venous thromboembolism (VTE) have made it possible to carry out a series of randomized trials to evaluate various treatments for VTE. The results of these trials have resolved many of the uncertainties a clinician confronts in selecting the 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 VTE. Patients with proximal deep vein thrombosis who receive inadequate anticoagulant therapy have a risk of clinically evident, objectively documented recurrent VTE that approaches 20% to 25%. The need for adequate 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 heparin by continuous intravenous infusion 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 subtherapeutic treatment. In this context, subtherapeutic treatment 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 activated partial thromboplastin time (aPTT) testing and the therapeutic range. Our findings have emphasized the confounding effect that initial heparin treatment has on long-term outcome. In all trials of long-term treatment, 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. Treatment with low-molecular-weight heparin (LMWH), which does not require monitoring or dose finding, has largely replaced unfractionated heparin for the initial management of VTE. Efficacy in terms of recurrent VTE or extension of thrombus has been at least as good with LMWH as unfractionated heparin and there is evidence that the incidence of major bleeding, heparin-induced thrombocytopenia, and osteoporosis are less with LMWH as compared with unfractionated heparin. Although unfractionated heparin may survive as a treatment option for acute VTE, its use has been largely supplanted by LMWH.