The role of low-molecular-weight heparins in the prevention and treatment of venous thromboembolism in cancer patients

Accumulating evidence suggests that low-molecular-weight heparins are the drug of choice for the prevention and treatment of venous thromboembolism in patients with cancer. For prophylaxis in the surgical setting, once-daily subcutaneous injections of low-molecular-weight heparin are as effective and safe as multiple doses of unfractionated heparin. Extending prophylaxis with low-molecular-weight heparins beyond hospitalization was recently found to reduce safely the risk of postoperative thrombosis after abdominal surgery for cancer. For the long-term treatment of deep vein thrombosis and in select patients with pulmonary embolism, recently completed clinical trials have shown that secondary prophylaxis with low-molecular-weight heparin is feasible and more effective than oral anticoagulant therapy in preventing recurrent venous thromboembolism in cancer patients. There is also evidence that low-molecular-weight heparins are effective in cancer patients who develop recurrent thrombosis while on warfarin therapy. Lastly, the potential antineoplastic effects of low-molecular-weight heparins make these agents an attractive option in patients with cancer. Although the management of cancer patients with venous thromboembolism remains challenging, low-molecular-weight heparins have simplified and improved the prevention and treatment of venous thromboembolism in these high-risk patients.     

Optimal therapeutic anticoagulation

The relevant literature on the intensity of anticoagulation needed to prevent the development or growth of thrombi in patients at risk is reviewed. In case of elective surgery, prevention of venous thrombosis is easily attained with heparin or with coumarin alone, at levels of anticoagulation involving only a minor risk of bleeding complications. For posttraumatic prophylaxis, more intensive oral anticoagulation is required, similar to that for the management of active venous thrombosis, for which a combined heparin/coumarin regimen is proposed. A 90% reduction of the incidence of systemic emboli in patients with a high risk of developing intracardiac thrombosis requires high-intensity treatment with a target INR of 4. More intensive anticoagulation would be needed to obtain the same 90% protection in case of arterial (coronary) thrombosis. This is prohibited, however, by the rapidly increasing bleeding risk in cases with INR values greater than 5. With a target INR of 3.5 (sixty-Plus patients), the reinfarction rate will not be lowered by more than two thirds. Antiplatelet drugs given alone or in combination with anticoagulants have not been convincingly successful thus far in the prevention and treatment of thrombosis.     

The Current and Future Role of the Novel Oral Anticoagulants—Indications Beyond Atrial Fibrillation

The direct thrombin inhibitors and Factor-Xa inhibitors are novel oral anticoagulants which are gaining rapid acceptance not only as alternatives to warfarin, but also as recommended first line agents for use as stroke prophylaxis in patients with non-valvular atrial fibrillation.There are, however, other patient settings in which anticoagulation is either indicated or has a potential role. Warfarin is still the predominant anticoagulant used for the treatment and prevention of venous thromboembolic events including deep vein thrombosis and pulmonary embolism as well as in patients with mechanical prosthetic heart valves. In this article, we review the current evidence for the use of dabigatran, rivaroxaban, apixaban and edoxaban in these settings. A summary of suggested regimens utilising these agents is provided. Importantly, in addition, attention is also drawn to clinical scenarios in which use of such agents is considered inappropriate.     

Deep vein thrombosis and pulmonary embolism: prevention, diagnosis, and treatment.

Pulmonary embolism (PE) is a significant cause of mortality in the elderly. More than 90% of pulmonary emboli originate from a thrombus in the deep veins of the legs. Proper diagnosis and treatment of deep vein thrombosis (DVT) are thus essential to prevent PE. Diagnosis of new or recurrent DVT is based on the results of one or more tests, including impedance plethysmography (IPG) or duplex venous scan; venography can often be avoided, based on results of initial testing. For suspected PE, perfusion lung scanning is the initial test of choice, followed by IPG/duplex or venography. Pulmonary angiography is indicated for patients with decreased cardiorespiratory reserve. Decisions governing prophylaxis of DVT are based on individual relative risk; prophylactic therapies include intermittent compression, low-dose heparin, and oral anticoagulants. Management of thromboembolism requires IV and oral anticoagulant therapy.     

Hereditary protein C deficiency

Hereditary protein C deficiency, which is inherited as an autosomal-dominant trait, predisposes to venous thrombotic disease. Heterozygotes are at risk for superficial thrombophlebitis, deep venous thrombosis and/or pulmonary embolism, which may occur without apparent cause at a young age. Other manifestations are cerebral venous thrombosis and mesenteric vein thrombosis. In severe, often homozygous, protein C deficiency, a purpura fulminans syndrome may occur shortly after birth, resulting in death due to extensive thrombosis, if it is not adequately treated. The thrombotic manifestations in heterozygotes are effectively prevented by coumarin therapy. However, in the initial phase of oral anticoagulant therapy, the patients have an increased risk for the development of coumarin-induced haemorrhagic skin necrosis. The purpura fulminans syndrome can be treated with either replacement therapy or with coumarin therapy. Heparin appears to be ineffective in the prevention of both the purpura fulminans syndrome and the coumarin-induced skin necrosis.     

Oral anticoagulant therapy in subjects with congenital or acquired thrombophilia

Thrombophilia testing is now commonplace. However, testing for heritable thrombophilia does not predict outcome in response to oral anticoagulant therapy. At present there is no conclusive evidence that recurrence on treatment with warfarin with a target International Normalized Ratio of 2.5 is greater in patients with laboratory evidence of heritable thrombophilia compared with those without. Similarly, there is no conclusive evidence that patients with laboratory evidence of heritable thrombophilia are more likely to suffer an earlier recurrence once treatment is stopped. Therefore, the management of patients with familial thrombotic disease and patients with laboratory evidence of heritable thrombophilia should be influenced by their personal and family history rather than the results of laboratory investigations. There is no doubt that the relative risk of thrombosis is increased in affected family members of thrombosis-prone families but this translates to a relatively low absolute risk per year, and long-term primary prophylaxis with oral anticoagulant therapy is not justified in the majority. Evidence of antiphospholipid syndrome is associated with an increased risk of recurrent venous thromboembolism, but there is still uncertainty as to the optimal intensity and duration of oral anticoagulant therapy after an episode of arterial or venous thrombosis in patients with detectable antiphospholipid activity.     

Pulmonary embolism and deep vein thrombosis

Pulmonary embolism is the third most common cause of death from cardiovascular disease after heart attack and stroke. Sequelae occurring after venous thromboembolism include chronic thromboembolic pulmonary hypertension and post-thrombotic syndrome. Venous thromboembolism and atherothrombosis share common risk factors and the common pathophysiological characteristics of inflammation, hypercoagulability, and endothelial injury. Clinical probability assessment helps to identify patients with low clinical probability for whom the diagnosis of venous thromboembolism can be excluded solely with a negative result from a plasma D-dimer test. The diagnosis is usually confirmed with compression ultrasound showing deep vein thrombosis or with chest CT showing pulmonary embolism. Most patients with venous thromboembolism will respond to anticoagulation, which is the foundation of treatment. Patients with pulmonary embolism should undergo risk stratification to establish whether they will benefit from the addition of advanced treatment, such as thrombolysis or embolectomy. Several novel oral anticoagulant drugs are in development. These drugs, which could replace vitamin K antagonists and heparins in many patients, are prescribed in fixed doses and do not need any coagulation monitoring in the laboratory. Although rigorous clinical trials have reported the effectiveness and safety of pharmacological prevention with low, fixed doses of anticoagulant drugs, prophylaxis remains underused in patients admitted to hospital at moderate risk and high risk for venous thromboembolism. In this Seminar, we discuss pulmonary embolism and deep vein thrombosis of the legs.     

Do medical patients need to receive pharmacologic prophylaxis for the prevention of venous thromboembolism?

Acutely ill medical patients with reduced mobility are at increased risk of venous thromboembolism, which can occur during hospitalization or after discharge. A number of clinical trials and meta-analyses have shown that pharmacologic prophylaxis with anticoagulant drugs in these patients significantly reduces the risk of fatal pulmonary embolism as compared to placebo or no treatment, without significant increase in the risk of major bleeding. Thus, the use of anticoagulant prophylaxis is recommended for all high risk medical patients during hospitalization. To identify these high risk patients, clinicians may use the inclusion criteria applied in the trials, with a selection that is mostly qualitative, or risk assessment models, with a selection that is both qualitative and quantitative. With both approaches, about 40 % of medical patients would be at increased risk of venous thrombosis. Because in the real world medical patients tend to be much older and with more comorbidities than in clinical trials, patient selection needs to also take into account risk factors for bleeding. Among others, estimation of creatinine clearance appears to be particularly important to prevent excessive exposure to anticoagulant drugs. Finally, although the risk of venous thrombosis may persist in some patients after hospital discharge, clinical trials assessing extended prophylaxis in this setting have failed to show a convincing clinical benefit with this approach.     

Cerebral venous sinus thrombosis as a recurrent thrombotic event in a patient with heterozygous prothrombin G20210A genotype after discontinuation of oral anticoagulation therapy: How long should we treat these patients with warfarin?

Background

Cerebral venous sinus thrombosis is an uncommon condition with many clinical manifestations, and hereditary prothrombotic conditions such as factor Leiden V, deficiency of protein S, protein C and antithrombin III, as well as prothrombin gene mutation, may account for 10–15% of cases. To date, conflicting results have been reported for recurrent venous thrombosis in the patients with factor V Leiden and prothrombin G20210A mutation, since some studies have shown a higher risk for recurrent venous thrombosis in carriers of these two mutations than in non-carriers, and the last study showed higher risk only for carriers of double defect (homozygous or double heterozygous for this mutations).

Methods

Case report is presented.

Results

We report a case of cerebral sinus thrombosis as a recurrent thrombotic event in a patient with heterozygous prothrombin G20210A genotype after discontinuation of oral anticoagulation therapy.

Conclusion

Since many facts are controversial, the use of secondary prophylaxis for thrombosis in these patients is still a matter of debate without clear consensus recommendation. Data on the risk of recurrent thrombotic events in thrombophilic patient is insufficient. The main unclear question concerning these patients is: how long and whom should we treat with long-term anticoagulant therapy as secondary prophylaxis of DVT? The problem for practitioner is that we do not have guidelines and precise recommendations for secondary thromboprophylaxis in this or similar cases. This case is remarkable for its favorable and quick outcome and its rarity, because CSVT is an uncommon condition and heterozygous prothrombin G20210A genotype was only found predisposing factor for CSVT. Further studies of risk of recurrent venous thrombosis in patients with heterozygous prothrombin G20210A genotype with the larger sample size are required.

     

Pharmacology of the new oral anticoagulants

New oral anticoagulants, such as dabigatran, rivaroxaban, apixaban, and edoxaban display pharmacologic and pharmacodynamic data similar to low molecular weight heparins. Peak levels are found 2-4?h after oral ingestion and elimination half-lives are in the range of 7-14?h. The drugs differ primarily concerning renal elimination. Dose adjustment is only performed in patients with impaired renal function, high risk of bleeding and patients with co-medications which influence the metabolism or anticoagulant effect of the drugs. Due to the short half-life, perioperative bridging is not necessary. Currently, no specific antidotes are available: however, assay systems are available for measuring the plasma concentration of dabigatran and rivaroxaban. In emergency cases a normal thrombin time excludes relevant levels of dabigatran, whereas a normal anti-factor Xa assay result excludes relevant levels of factor Xa inhibitors.The new anticoagulants are being used for prophylaxis of venous thrombosis in elective hip and knee surgery, as well as for treatment of venous thrombosis and for prevention of stroke and systemic embolism in patients with atrial fibrillation. Additional indications are to follow. Dabigatran is given at a dose of 110?mg initially 1-4?h after surgery followed by 220?mg once daily for prophylaxis of thrombosis and at doses of 110?mg or 150?mg twice daily for therapeutic anticoagulation. The prophylactic and therapeutic doses of rivaroxaban are 10 and 20?mg and, of apixaban 2.5?mg and 5?mg twice daily, respectively.     

Thrombophilic conditions in the pathogenesis of venous thromboembolism

Thrombophilic conditions are congenital or acquired hemostatic disorders pathophysiologically or statistically associated with higher risk of thrombosis. Their most important clinical manifestation is venous thromboembolism. In more than 50% of persons with non-induced thrombosis, some of the known thrombophilias can be found. Persons with congenital thrombophilias have, contrary to those without any thrombophilias, most of all an increased risk of an initial thromboembolic event while the impact of congenital thrombophilic conditions on their recurrence is not so clear. In patients with idiopathic thrombosis is the risk of recurrence 7-10% a year even at the absence of known thrombophilias. The risk of a recurrent event is influenced by a set of other factors (prevailing or undetected trigger factor, proximal thrombosis and pulmonary embolism, incomplete rechanneling of a thrombotic vein, presence of some thrombophilias, high level of D-dimers after discontinuation of the anticoagulant treatment). Their identification and consequent monitoring are decisive in the choice of an optimum treatment and the duration of their administration in secondary prevention of venous thromboembolism. In the primary venous thrombosis prevention, the knowledge of general trigger factors and the individual risk characteristics of the given patient is important, which means also timely detection of thrombophilic conditions in patients who profit from it, i.e. if they display at least medium probability of detection. A universal long-term prophylaxis in so far asymptomatic carriers of congenital thrombophilias is not indicated with regard to potential complications of anticoagulant treatment. Women with thrombophilic disorders are under an increased risk of a thromboembolic event when using hormonal contraceptives and during pregnancy. There is also a higher incidence of pregnancy complications connected with disorders in blood circulation of placental vascular tree.     

Pharmakologie der neuen oralen Antikoagulanzien

New oral anticoagulants, such as dabigatran, rivaroxaban, apixaban, and edoxaban display pharmacologic and pharmacodynamic data similar to low molecular weight heparins. Peak levels are found 2–4?h after oral ingestion and elimination half-lives are in the range of 7–14?h. The drugs differ primarily concerning renal elimination. Dose adjustment is only performed in patients with impaired renal function, high risk of bleeding and patients with co-medications which influence the metabolism or anticoagulant effect of the drugs. Due to the short half-life, perioperative bridging is not necessary. Currently, no specific antidotes are available: however, assay systems are available for measuring the plasma concentration of dabigatran and rivaroxaban. In emergency cases a normal thrombin time excludes relevant levels of dabigatran, whereas a normal anti-factor Xa assay result excludes relevant levels of factor Xa inhibitors. The new anticoagulants are being used for prophylaxis of venous thrombosis in elective hip and knee surgery, as well as for treatment of venous thrombosis and for prevention of stroke and systemic embolism in patients with atrial fibrillation. Additional indications are to follow. Dabigatran is given at a dose of 110?mg initially 1–4?h after surgery followed by 220?mg once daily for prophylaxis of thrombosis and at doses of 110?mg or 150?mg twice daily for therapeutic anticoagulation. The prophylactic and therapeutic doses of rivaroxaban are 10 and 20?mg and, of apixaban 2.5?mg and 5?mg twice daily, respectively.     

Venous thromboembolism prophylaxis in medical patients

PURPOSE OF REVIEW: Venous thromboembolism, including deep vein thrombosis and pulmonary embolism, represents a significant source of morbidity and mortality in the United States and worldwide. Most acutely ill medical patients are at risk for venous thromboembolism, and prophylaxis is recommended. However, acutely ill medical patients are heterogeneous, and the degrees of risk, the length of prophylaxis, as well as the most safe and efficacious strategies to prevent venous thromboembolism in specific medical patients continue to evolve. RECENT FINDINGS: Most medically ill patients in the hospital do not receive any form of venous thromboembolism prophylaxis despite evidence that their venous thromboembolism risk is similar to surgical patients. Low-molecular weight heparins demonstrate at least equal efficacy and improved safety over standard unfractionated heparin for the prevention of venous thromboembolism in medical patients. Patients with renal impairment, obesity, or those who are critically ill are special populations for prophylaxis that require individual approaches. Many patients recently discharged from the hospital remain at high risk for thrombosis. SUMMARY: All hospitalized patients should be assessed for venous thromboembolism risk. Most acutely ill medical patients will be in the high- to very high-risk category for thrombosis. Patients who have an estimated thrombosis risk greater than bleeding risk should receive pharmacologic prophylaxis. Low-molecular weight heparin is the preferred drug-based approach over standard unfractionated heparin for the prevention of venous thromboembolism in the acutely ill medical patient. Patients with higher risks for bleeding than thrombosis should receive mechanical methods of prophylaxis. Patients who have not returned to baseline health should be considered for extended venous thromboembolism prophylaxis out of the hospital.     

Therapy of deep vein thrombosis

Adequate anticoagulation treatment in patients with deep vein thrombosis reduces the risk of thrombus extension or embolization to less than 5%. Thrombolytic treatment may possibly prevent subsequent postthrombotic syndrome. Heparin is the initial treatment of choice for most patients with deep vein thrombosis. The dose is adjusted according to the results of tests such as the whole blood clotting time, thrombin clotting time, activated partial thromboplastin time or plasma heparin concentration. The most commonly used test is the activated partial thromboplastin time which should be maintained at 1 1/2 to two times the control level. Initially the test should be performed two to three times daily and when optimal adjustment has been established, clotting studies are required only at 24-hour intervals. In general, treatment with intravenous heparin should be continued for seven to ten days. Thereafter, for secondary prophylaxis, treatment with oral anticoagulants is carried out for six to eight weeks for symptomatic lower leg thrombosis, for twelve weeks in the case of proximal venous thrombosis and pulmonary embolism. Oral anticoagulant therapy with warfarin should be given overlapping the last few days of heparin with the dose adjusted to prolong the prothrombin time to 1.3 to 1.5 times control. Initially, the prothrombin time should be monitored weekly, thereafter at intervals of two to three weeks. If oral anticoagulant therapy is contraindicated, secondary prophylaxis with subcutaneous heparin given twice daily in doses sufficient to prolong the activated partial thromboplastin time to 1 1/2 times control is an effective and safe alternative. The major side effect of oral anticoagulant therapy, as well as that of heparin, is bleeding.(ABSTRACT TRUNCATED AT 250 WORDS)     

Recurrent intracardiac thrombosis as an unusual manifestation of inherited thrombophilia

Patients with inherited thrombophilia are at high risk for the development of venous thrombosis that manifests mainly as deep venous thrombosis of the legs and/or pulmonary embolism. We report spontaneous right-sided intracardiac thrombosis in a young man as an unusual manifestation of inherited thrombophilia. The diagnosis of thrombophilia was confirmed by demonstration of the prothrombin-G20210A-mutation in the homozygous state. A second spontaneous intracardiac thrombosis occurred 3 years after discontinuation of oral anticoagulant treatment. This indicates the high risk for recurrence in patients developing intracardiac thrombosis in the absence of an underlying cardiac disease and warrants long-term oral anticoagulant treatment.     

Warfarin resistance associated with parenteral nutrition

Warfarin is widely used as an oral anticoagulant for the prevention and long-term treatment of venous thromboembolism and for the prevention of thromboembolic complications associated with atrial fibrillation, heart valve replacement and myocardial infarction. Warfarin exerts its anticoagulation effect by inhibiting the enzymes responsible for the cyclic interconversion of vitamin K in the liver. Vitamin K serves as a cofactor required for the carboxylation of the vitamin K-dependent coagulation proteins. By inhibiting the supply of vitamin K in the production of these proteins, warfarin indirectly slows their rate of synthesis. The authors describe a 46-year-old patient readily anticoagulated for a deep venous thrombosis who then required large doses of warfarin after initiation of total parenteral nutrition, which included lipid preparation that contained vitamin K, in addition to vitamin K required for the daily parenteral nutrition. The effect of total parenteral nutrition with vitamin K on anticoagulation is discussed.     

Short-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of prospective studies investigating symptomatic outcomes

BACKGROUND: The prevalence of asymptomatic deep vein thrombosis diagnosed by venography after hip or knee replacement remains high despite 7 to 10 days of anticoagulant prophylaxis. However, the risk of symptomatic events in such patients is unclear. We performed a meta-analysis to provide reliable estimates of the risk of symptomatic venous thromboembolism occurring within 3 months of hip or knee replacement in patients who received short-duration (7-10 days) anticoagulant prophylaxis. METHODS: The MEDLINE, EMBASE, and Cochrane databases were searched from January 1993 to March 2001, supplemented by a manual search of bibliographies and conference abstracts, to identify prospective studies of patients undergoing hip or knee replacement who received short-duration prophylaxis (ie, 7-10 days of fixed-dose low-molecular-weight heparin or adjusted-dose warfarin, with a target international normalized ratio of 2.0-3.0). Studies were classified as clinical outcome studies if the outcome was symptomatic venous thromboembolism or as venographic outcome studies if the outcome was asymptomatic deep vein thrombosis diagnosed after bilateral venography. RESULTS: There were 4 clinical outcome studies with 6089 patients who had 3 months of follow-up, and 13 venographic outcome studies with 7080 patients who had venography 7 to 10 days after surgery. In clinical outcome studies, the 3-month incidence of nonfatal venous thromboembolism was 3.2% (95% confidence interval [CI], 2.0%-4.4%), and the 3-month incidence of fatal pulmonary embolism was 0.10% (95% CI, 0.02%-0.20%). The postprophylaxis incidence of nonfatal venous thromboembolism was 2.2% (95% CI, 1.4%-3.0%), and the incidence of fatal pulmonary embolism was 0.05% (95% CI, 0%-0.12%). The postprophylaxis incidence of symptomatic venous thromboembolism was higher after hip than after knee replacement (2.5% vs 1.4%; P=.02). In venographic outcome studies, the prevalence of deep vein thrombosis (total and proximal) was higher after knee than after hip replacement (total: 38.8% vs 16.4%; P<.001; proximal: 7.6% vs 3.8%; P<.001). CONCLUSIONS: In patients who undergo hip or knee replacement and receive short-duration anticoagulant prophylaxis, symptomatic nonfatal venous thromboembolism will occur in about 1 of 32 patients and fatal pulmonary embolism will occur in about 1 of 1000 patients within 3 months of the surgery. Although the prevalence of asymptomatic deep vein thrombosis is more than 2-fold higher after knee replacement than after hip replacement 7 to 10 days after surgery, in the subsequent 3 months, symptomatic venous thromboembolism is more likely to occur after hip replacement.     

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.     

Prevention of venous thromboembolism in high-risk surgical and medical patients

Although pharmacologic prophylaxis against venous thromboembolism has become the standard of care following total hip and knee replacement, prophylaxis among patients undergoing surgery for hip fracture and other lower extremity trauma remains underutilized. Available experience consistently supports the view that low-molecular-weight heparins are more effective than unfractionated heparin for prevention of proximal deep vein thrombosis (DVT) with no additional hemorrhagic risk and more effective than oral anticoagulants for prevention of in-hospital (mostly distal) venous thrombosis at the price of a higher surgical site bleeding and wound hematoma. The choice between low-molecular-weight heparin and warfarin should be tailored to the individual patients based on the clinical assessment of postoperative thrombosis and bleeding risk as well as the prophylaxis-specific cost and convenience. Whether thromboprophylaxis should be continued for a few additional weeks after hospital discharge is controversial. The overall incidence of postoperative DVT in patients with cancer is about twice as high as that of patients free of malignancy. Accordingly, they require prophylactic measures comparable with those usually recommended for major orthopedic surgery. In this setting, dermatan sulfate shows promise. In contrast to surgical patients, prevention of venous thromboembolism is less well studied in hospitalized medical patients. In a recent controlled randomized trial, enoxaparin in high prophylactic doses was an effective and safe measure of thromboprophylaxis in ordinary bedridden patients.     

Treatment of DVT: how long is enough and how do you predict recurrence

Abstract Currently available anticoagulants are effective in reducing the recurrence rate of venous thromboembolism (VTE). However, anticoagulant treatment is associated with an increased risk for bleeding complications. Thus, anticoagulation has to be discontinued when benefit of treatment no longer clearly outweigh its risks. The duration of anticoagulant treatment is currently framed based on the estimated individual risk for recurrent VTE. The incidence of recurrent VTE can be estimated through a two-step decision algorithm. Firstly, the features of the patient (gender), of the initial event (proximal or distal deep vein thrombosis or pulmonary embolism), and the associated conditions (cancer, surgery, etc) provide essential information on the risk for recurrence after anticoagulant treatment discontinuation. Secondly, at time of anticoagulant treatment discontinuation, d-dimer levels and residual thrombosis have been indicated as predictors of recurrent VTE. Current evidence suggests that the risk of recurrence after stopping therapy is largely determined by whether the acute episode of VTE has been effectively treated and by the patient’s intrinsic risk of having a new episode of VTE. All patients with acute VTE should receive oral anticoagulant treatment for three months. At the end of this treatment period, physicians should decide for withdrawal or indefinite anticoagulation. Based on intrinsic patient’s risk for recurrent VTE and for bleeding complications and on patient preference, selected patients could be allocated to indefinite treatment with VKA with scheduled periodic re-assessment of the benefit from extending anticoagulation. Alternative strategies for secondary prevention of VTE to be used after conventional anticoagulation are currently under evaluation. Cancer patients should receive low molecular-weight heparin over warfarin in the long-term treatment of VTE. These patients should be considered for extended anticoagulation at least until resolution of underlying disease. Abbreviated abstract The risk for recurrent venous thromboembolism can be estimated through a two-step algorithm. Firstly, the features of the patient (gender), of the initial event (proximal or distal deep vein thrombosis or pulmonary embolism), and the associated conditions (cancer, surgery, etc) are essential to estimate the risk for recurrence after anticoagulant treatment discontinuation. Secondly, a correlation has been shown between d-dimer levels and residual thrombosis at time of anticoagulant treatment discontinuation and the risk of recurrence. Currently available anticoagulants are effective in reducing the incidence of recurrent venous thromboembolism, but they are associated with an increased risk for bleeding complications. All patients with acute venous thromboembolism should receive oral anticoagulant treatment for three months. At the end of this treatment period physicians should decide for definitive withdrawal or indefinite anticoagulation with scheduled periodic re-assessment of the benefit from extending anticoagulation.