Secondary Prevention Of Venous Thromboembolism Research Articles

Ximelagatran

Despite the significant advances over the last 50 years with regard to anticoagulant therapy, warfarin remains the definitive standard for the long-term prevention of thromboembolic events in at-risk patients, except those with acute coronary syndromes, in which antiplatelets are preferred. Ximelagatran, a prodrug of melagatran, is an orally administered direct thrombin inhibitor whose therapeutic potential has been investigated in venous thromboembolism, acute coronary syndromes and prevention of stroke in atrial fibrillation. Clinical studies have demonstrated ximelagatran to be comparable in efficacy to the oral vitamin K antagonist warfarin and low molecular weight heparin for prophylaxis of venous thromboembolism, comparable to warfarin for stroke prevention in the setting of atrial fibrillation, and, when combined with aspirin, more effective than aspirin alone at preventing major adverse cardiovascular events in patients with a recent myocardial infarction. Double-blind trials have also revealed the efficacy of ximelagatran in the secondary prevention of venous thromboembolism and shown the agent to be as effective as enoxaparin/warfarin in treating patients with acute deep vein thrombosis. Adverse effects with ximelagatran include elevations in alanine transaminase (ALT), which may require monitoring, and bleeding complications. Bleeding complications appear to be less than or at least comparable to those occurring with standard anticoagulant treatments like warfarin or low molecular weight heparin. In addition to its favorable efficacy and safety profile in comparison with standard anticoagulant therapy, the convenience of its oral, fixed-dose administration without the need for anticoagulation monitoring might help encourage a wider use of appropriate anticoagulation using ximelagatran across the population at risk, reducing the incidence of thromboembolic events.

Guidelines on oral anticoagulation (warfarin): third edition – 2005 update

The British Committee for Standards in Haematology (BCSH) published its third edition of Guidelines on Oral Anticoagulation in 1998 (British Committee for Standards in Haematology, 1998). Most of the recommendations made in 1998 remain unchanged and a fourth edition of the guideline is considered unnecessary at the time of writing (June 2005). However, we draw attention to those areas where new informative data have been published. As in the original guideline, the term ‘oral anticoagulant’ used in this update refers to oral vitamin K antagonists (VKA), such as warfarin. New oral non-VKA are currently being evaluated in clinical trials but are not yet licensed for use in the UK. When these drugs become available new guidance will be issued specifically for the use of those drugs. The guideline group was selected to be representative of UKbased medical experts. The drafting group met and communicated by email. MEDLINE was searched systematically for publications in English from 1998. The writing group convenor (T. Baglin) produced the draft guidelines which were subsequently revised by consensus. The guideline was reviewed by a multidisciplinary sounding board, the BCSH and the British Society for Haematology (BSH) and comments incorporated where appropriate. Criteria used to quote levels and grades of evidence are as in Appendix 3 of the Procedure for Guidelines Commissioned by the BCSH (http://www.bcshguidelines.com/process1.asp#App3). The target audience for this guideline is healthcare professionals involved in the management of patients receiving oral anticoagulant therapy.

Malignom und Thrombose: eine wechselseitige klinische Beziehung

Venous thromboembolism (VTE) is the second most common cause of mortality in cancer patients and also points towards unfavourable prognosis. In about 10% of patients with idiopathic VTE there is underlying malignancy. However, the efficacy of extensive tumour screening in those patients is not yet established. Numerous plasmatic and cellular components contribute to the phenomenon of hypercoagulability in cancer patients, including Cancer Procoagulant and activation of coagulation with high levels of coagulation factors. Cancer surgery carries an increased risk compared to non-cancer patients necessating more intensive and longer thromboprophylaxis in those patients. In medical patients active cancer is associated with increased risk for VTE. In the treatment of VTE, cancer patients have a significantly higher recurrence rate for VTE when treated with vitamin K-antagonists (VKA) compared to non-cancer patients. Compared to VKA the use of low molecular weight heparin for long-term secondary prevention is more effective than vitamin K-antagonists. Thus, there is a grade 1A recommendation to use low molecular weight heparin for cancer patients during the first 3-6 months of secondary prevention of VTE. Several studies indicate that low molecular weight heparin may also improve the prognosis of cancer patients quoad vitam, particularly for cancer patients at an earlier stage of disease; this needs to be confirmed in further studies.

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.

Reviewing the reality: why we need to change

For nearly 60 years, vitamin K antagonists (VKAs) such as warfarin have been the mainstay of oral anticoagulation in a range of thromboembolic disorders, ranging from stroke prevention in atrial fibrillation (AF) to the treatment and secondary prevention of venous thromboembolism. Although highly effective, warfarin has numerous limitations that have resulted in its underuse and the imposition of considerable burdens on both patients and healthcare systems. In the case of stroke prevention in AF, the argument has been made that warfarin use can be maximized and its limitations minimized by using several strategies, such as improving international normalized ratio (INR) control through greater use of anticoagulation clinics or patient self-management, and greater adherence to relevant treatment guidelines.1 But is this realistic? Can the limitations of VKAs such as warfarin really be effectively and properly minimized in everyday clinical practice? In this article, the author provides a counter-argument that warfarin is difficult to use in clinical practice, that its limitations make it difficult to manage, and that we need new oral agents with improved benefit–risk profiles and increased consistency and predictability when compared with warfarin. To understand the need for new agents, one must first understand how warfarin works. To this end, it is necessary to review the history of warfarin, and its pharmacodynamic and pharmacokinetic profiles, so that it becomes clear that the concerns and challenges that face physicians and patients are very real and are a direct result of the characteristics of warfarin. More than 80 years ago, livestock farmers in North Dakota, United States, observed severe, unexplained bleeding in cattle, which was later linked to their diet of fermented hay or silage made from sweet clover, grown as a substitute for corn at this time.2 In 1939, the coumarin dicoumarol was identified as the active agent …

Extended Anticoagulation Therapy for the Primary and Secondary Prevention of Venous Thromboembolism

Extending the period of anticoagulation is an active area of investigation in both primary and secondary prevention of venous thromboembolic disease. In orthopaedic surgery, particularly in patients undergoing hip surgery, there is a growing interest in using extended anticoagulation beyond that traditionally given in the postoperative period using low-molecular weight heparin, oral anticoagulants, or newer agents such as fondaparinux sodium. Most studies show a benefit to extending anticoagulation without a considerable increase in major bleeding. There have been several large clinical trials addressing the question of extending oral anticoagulation in secondary prevention of venous thromboembolism (VTE). Just how long anticoagulation should be given in the treatment of venous thromboembolic disease remains an open question, depending on the nature of the initial VTE, associated patient risk factors and the risks of major bleeding. Future directions include the use of newer agents for anticoagulation as well as methods of better defining who will benefit most from extended anticoagulation based on an identification of risk factors with the aid of markers such as D-dimer or residual vein thrombosis.

Warfarin Versus Low-Molecular-Weight Heparin Therapy in Cancer Patients

The association between cancer and venous thromboembolism (VTE) is well established. Importantly, VTE is a significant cause of mortality in cancer patients. Although long-term warfarin (Coumadin(trade mark); Bristol-Myers Squibb; New York, NY) therapy is the mainstay of treatment for cancer patients with VTE, there are many practical problems with its use in this population. In particular, achieving therapeutic drug levels is difficult in cancer patients due to the increased risk of drug interactions, malnutrition, vomiting, and liver dysfunction in these patients. Moreover, cancer patients are at an increased risk of adverse effects of warfarin therapy. In contrast, low-molecular-weight heparins (LMWHs) are associated with a lower risk of adverse events compared with warfarin in patients with cancer. These agents also offer practical advantages compared with warfarin, including more predictable anticoagulant effects and ease of administration in addition to possible antineoplastic effects. Several LMWHs have demonstrated superior efficacy to warfarin in the secondary prevention of VTE. In particular, the LMWH, dalteparin (Fragmin; Pfizer; New York, NY), has recently been shown to have superior efficacy to warfarin in a large trial of patients with cancer and VTE without increasing the risk of bleeding. A randomized trial of dalteparin has also shown improved response rates and survival in patients with small cell lung cancer. In view of the availability of more effective and reliable alternatives to warfarin therapy in cancer patients, it is appropriate to reassess the role of warfarin therapy in patients with cancer and VTE. Further evaluation of the LMWHs for effects on cancer outcome is indicated.

Prognostic factors for recurrence of venous thromboembolism (VTE) or bleeding during long-term secondary prevention of VTE with ximelagatran

The oral direct thrombin inhibitor ximelagatran (24 mg twice daily) has been shown to significantly reduce the incidence of recurrent venous thromboembolism (VTE) vs. placebo over 18 months, with no significant influence on bleeding (THRIVE III). The influence of potential prognostic factors on the risk of recurrent VTE or major and/or minor bleeding and their impact on ximelagatran treatment was evaluated in the THRIVE III study population. The effect of sex, age, body weight, renal function, malignancy, type of initial VTE event, and history of previous VTE events was investigated in the intention-to-treat population using Cox proportionate hazard modelling. Ximelagatran was administered to 612 patients and placebo to 611 patients. Within the placebo group, risk of recurrent VTE was higher among men than women (hazard ratio [HR]: 2.50,95% confidence interval [CI] 1.49,4.17), and in patients with one or more than one previous VTE event (HR: 1.73,95% CI 1.00, 2.99). There was a higher risk of bleeding among women than men in both the ximelagatran (HR: 1.49, 95% CI 1.06, 2.09) and placebo (HR: 1.48, 95% CI 1.01, 2.15) groups, and in placebo-treated patients with an initial pulmonary embolism (HR: 1.53, 95% CI 1.06,2.23) compared to those with initial deep vein thrombosis. There were no significant interactions between treatment effect and any of the potential prognostic factors. In conclusion, the superior efficacy of ximelagatran vs. placebo was maintained in all subgroups. Long-term use of oral ximelagatran, without coagulation monitoring or dose adjustment, should be feasible and well tolerated in a wide cross-section of patients for the secondary prevention of VTE.

Ximelagatran for the secondary prevention of venous thromboembolism

In the randomized, double-blind THRIVE III trial, the oral direct thrombin inhibitor ximelagatran (24 mg twice daily) significantly reduced the incidence of recurrent venous thromboembolism (VTE) versus placebo over 18 months or until premature study drug discontinuation. A complementary follow-up analysis (intention-to-treat) was conducted post-study to evaluate the cumulative risks of locally-confirmed recurrent VTE and death (Kaplan-Meier procedure) over the full 18-month study period, regardless of whether patients discontinued study drug prematurely. Hazard ratios (HRs) between treatments were estimated using Cox proportional hazard modeling. Of 612 and 611 patients receiving ximelagatran and placebo, respectively, 149 and 181 discontinued treatment prematurely. Of these discontinuations, further information could not be collected for 14 and 13 patients in the ximelagatran and placebo groups, respectively; among the remaining patients, four VTE events and four deaths occurred in the ximelagatran group, and one VTE event and five deaths occurred in the placebo group. The resulting cumulative risks of VTE (3.2% vs. 12.7%; HR 0.21; 95% confidence interval [CI], 0.12, 0.36; P < 0.0001) and pulmonary embolism (0.8% vs. 5.2%; HR 0.13; 95% CI 0.04, 0.36; P < 0.0001) were significantly lower in the ximelagatran than in the placebo group over 18 months. Death from any cause over 18 months occurred in 10 and 12 patients, respectively (HR 0.83;95% CI 0.36, 1.93; P = 0.7). This complementary follow-up analysis confirms the benefit of oral ximelagatran 24 mg twice daily, administered without coagulation monitoring or dose adjustment, for the long-term secondary prevention of VTE.

Ximelagatran vs. Enoxaparin/Warfarin for VTE

Ximelagatran, an oral direct thrombin inhibitor that does not require coagulation monitoring, has been shown to be effective for long-term secondary prevention of venous thromboembolism (VTE; Journal Watch Cardiology Feb 13 2004). Now, researchers have conducted a multinational, manufacturer-funded, randomized trial of ximelagatran (36 mg twice daily) versus standard therapy …

Venous thromboembolism prophylaxis guidelines: Use by primary care physicians

Venous thromboembolism (VTE), a prevalent, costly medical condition, is one of the most common causes of death in the United States. Although risk factors for VTE are well known, thromboembolic events cannot be predicted because patients are asymptomatic and screening methods have limitations. Anticoagulant therapy (eg, low-molecular-weight heparin, unfractionated heparin, selective factor Xa inhibitors) has proved effective for preventing thromboembolism, including deep vein thrombosis and pulmonary embolism. While quality care for VTE entails prophylaxis for all relevant patients, many high-risk patients are undertreated or treated incorrectly. Both primary and secondary prevention of VTE remain inadequate for several reasons, including lack of awareness of the American College of Chest Physicians guidelines, of the seriousness of VTE, of the benefits of prophylaxis, and of the relatively low risk of bleeding complications. To provide appropriate treatment, physicians must assess the numbers and types of risk factors for each patient, the underlying illness or surgical procedure, and the benefits and risks of possible therapies. The problem of VTE will grow as the US population ages, as surgery is performed on increasingly sick patients, and as the length of hospital stays continues to decrease.

Secondary Prevention of Venous Thromboembolism with the Oral Direct Thrombin Inhibitor Ximelagatran

The authors conducted a study to determine the effects of oral ximelagatran for the extended prevention of venous thromboembolism because the protection of anticoagulation therapy does not extend beyond six months owing to the risk of major bleeding. Patients with venous thromboembolism who had undergone six months of anticoagulant therapy were randomized to treatment with 24 mg ximelagatran (twice daily) (612 patients) or placebo (611 patients). The regimen lasted 18 months during which time coagulation was not monitored. Symptomatic recurrent venous thromboembolism occurred in 12 patients on the ximelagatran regimen and 71 patients in placebo. In the ximelagatran group, 6.4% of patients had transient elevation of alanine aminotransferase level to more than three times compared with 1.2% in the placebo group. The authors concluded that oral ximelagatran was superior to placebo for the extended prevention of venous thromboembolism.

Emerging Options in The Treatment of Venous Thromboembolism

The long-term consequences of recurrent venous thromboembolism (VTE) and post-thrombotic syndrome, clinical profiles of traditional and novel antithrombotic agents used to treat VTE, current treatment recommendations for acute symptomatic VTE, clinical experience with newer antithrombotic agents for acute treatment and extended secondary prevention of VTE, and an emerging VTE treatment paradigm are discussed. Novel antithrombotic agents, with more specific activity on the coagulation cascade, more predictable pharmacodynamics and pharmacokinetics, simpler dosing regimens, and few or no laboratory monitoring requirements, have been developed to overcome limitations associated with some of the nonspecific traditional anticoagulants. Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are currently the recommended options for initial anticoagulation in patients with acute VTE. Warfarin is the most commonly used agent for chronic anticoagulation. Emerging evidence now also supports the role of factor-Xa inhibitors and oral direct thrombin inhibitors in the acute treatment and extended secondary prevention of VTE. In recent clinical trials, fondaparinux (a synthetic factor-Xa inhibitor) was comparable in efficacy and safety to unfractionated heparin for the treatment of acute symptomatic PE and to the LMWH enoxaparin for treating acute DVT. Ximelagatran, an oral direct thrombin inhibitor, was comparable in safety and efficacy to enoxaparin plus warfarin for treatment of acute VTE (DVT with or without PE). In addition, ximelagatran has been demonstrated to be superior to placebo for the extended secondary prevention of VTE, when continued for an additional 18 months beyond an initial six months of therapy. The benefits of extended anticoagulation for secondary VTE prevention have also been recently demonstrated with both low (INR 1.5-2.0) and regular intensity (INR 2.0-3.0) warfarin therapy. A new paradigm for treating VTE is evolving based on the results of recent research to incorporate the use of emerging antithrombotic therapies in the acute treatment period and both traditional and novel agents in the chronic, extended-treatment period.

Fixed‐dose low‐molecular‐weight heparin for secondary prevention of venous thromboembolism in patients with disseminated cancer: a prospective cohort study

Secondary prevention of venous thromboembolism (VTE) with vitamin K antagonists is often problematic in patients with cancer. We prospectively evaluated the effectiveness and safety of long-term subcutaneous dalteparin in a series of consecutive patients with symptomatic VTE and metastatic cancer. The study included 203 patients, aged 36-96 years. The initial treatment consisted of a 7-day course of subcutaneous dalteparin according to body weight. Then, patients received a fixed dose of 10 000 IU dalteparin once daily for at least 3 months. In patients developing transient thrombocytopenia the dose was reduced to 5000 IU daily while the platelet count remained <50,000; and to 2500 IU daily while it remained <10 000. Patients undergoing any surgical intervention during the study were put on 5000 IU daily during the first 4 days, switching thereafter to 10,000 IU. Patients undergoing any other invasive procedure (i.e. biopsies, punctures) received a 5000 IU dose the same day, instead of 10 000 IU. Eleven patients (5.4%) developed major bleeding complications (6 fatal) during the 3-month study period, and 18 patients (8.9%) developed VTE recurrences (2 patients died). There were no higher complication rates in patients with either liver or brain metastases, nor during thrombocytopenia, surgery or invasive procedures. Fixed dose 10,000 IU subcutaneous dalteparin once daily for 3 months was not associated with more complications in patients with liver or brain metastases. The dose adjustment for patients with thrombocytopenia, surgery or invasive procedures was safe too.

Secondary Prevention of Venous Thromboembolism With the Oral Direct Thrombin Inhibitor Ximelagatran

Survey of Anesthesiology: August 2004 - Volume 48 - Issue 4 - p 174-175 doi: 10.1097/01.sa.0000131998.02363.38

The effect of anticoagulant drugs on cancer

The effect of anticoagulant drugs on cancer

A Potentially Better Means of Preventing Recurrent Venous Thromboembolism Is on the Horizon

Synopsis: In patients with venous thromboembolism, treatment with long-term ximelagatran following 6 months of anticoagulant therapy may safely and effectively reduce the risk of recurrent thromboembolic events. Source: Schulman S et al. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med. 2003;349:1713–1721.

Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor Ximelagatran

Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor Ximelagatran

Therapy and secondary prevention of venous thromboembolism with vitamin K antagonists

Oral anticoagulation with vitamin-K-antagonists is very effective in secondary prevention of venous thromboembolism. In Germany, most commonly Phenprocoumon is used, while most of the evidence-based data are available for Warfarin. The initial treatment of acute venous thromboembolism requires immediate anticoagulation with heparin and a subsequent overlapping treatment with oral anticoagulants. During this phase, anticoagulation may be unstable with increased risk for bleeding. An INR target range between 2 and 3 provides effective protection with minimal risk for major bleeding. The individual risk for bleeding may be estimated by a clinical score. Six months of oral anticoagulation is the standard duration for a first episode of venous thromboembolism, while recurrencies are treated for at least one to two years. The duration may be tailored to the individual patient according to underlying risk factors for recurrencies and for bleeding. Because of a plethora of practical problems and the narrow therapeutic window, there is a need for new antithrombotic agents. These may allow a longer duration of secondary prevention with improved protection against recurrencies without sacrificing safety.

The management and outcome of acute venous thromboembolism: a prospective registry including 4011 patients.

To obtain a realistic overview of management and clinical outcomes of patients with venous thromboembolism (VTE) in Spain on the basis of data from a national multicenter registry. A prospective registry was initiated in Spain in March 2001. Data were collected from patients with objectively confirmed deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and entered into the online registry by physicians who were responsible for the management of these patients. As of August 2002, 4011 patients with confirmed VTE were included in the registry: 60% with DVT, 23% with PE, and 17% with both DVT and PE. Diagnostic methods for VTE included compression ultrasonography (86%), venography (10%), V/Q lung scans (42%), computed tomography scan (28%), and pulmonary angiography (0.9%). D-dimer testing was performed in 61% of cases and was positive in 92% of patients with confirmed VTE. The majority of DVT (95%) were located in the lower extremities (82% proximal and 4% bilateral), while 4.8% were located in the upper extremities or neck veins. Most patients (90.5%) were admitted to hospital. In the acute phase, treatment consisted of low molecular weight heparin (LMWH) in 88%, unfractionated heparin (UFH) in 11%, and fibrinolysis in 0.8%. Cava filters were inserted in 2% of patients, mainly because of active bleeding (13%), increased hemorrhagic risk (38%), or recurrent VTE (29%). Absolute bed rest was recommended to 63% of patients. Secondary prevention of VTE included oral anticoagulants (75%) and LMWH (24.5%). Therapeutic compression stockings were prescribed to 53% of patients at the time of hospital discharge. Regarding the main clinical outcomes during an average (+/-SD) follow-up period of 156 +/- 95 days, 19% had adverse events: 12.5% of patients died, 5.5% had clinically confirmed VTE recurrence, and 9.8% suffered bleeding complications (44% with major bleeding). This prospective observational multicenter registry provides a large database reflecting the actual day-to-day clinical practice regarding VTE management in a European country. The most important findings were the increasing use of spiral computed tomography for PE diagnosis, the unexpectedly high proportion of patients admitted to hospital despite the use of LMWH in almost 90% of cases in the acute phase, and the utilization of LMWH for secondary prevention in almost 25% of cases. On the other hand, this large-scale prospective registry permits on-line consultation of high-risk situations to assess how difficult cases were treated and what their outcomes were. This will provide a most useful tool for the practicing physician responsible for the management of VTE patients.