Appropriate level and length of postthrombotic warfarin treatment: an evaluation of recent developments

Current treatment and secondary prophylaxis of venous thromboembolism has two major drawbacks. During vitamin K antagonist therapy, patients need to be monitored closely to maintain efficacy and minimize the bleeding risk due to fluctuations of the prothrombin time (international normalized ratio, INR), and after cessation of therapy there is the problem of recurrent thrombosis, ie, the catch-up phenomenon. Recent studies indicate that for most patients, vitamin K antagonist therapy aimed at an INR of 2.0 to 3.0 is optimal. For patients with thrombosis due to a temporary risk factor, extending treatment beyond 3 months is not needed, whereas for other patients a minimal duration of 1 year can be advocated. For patients with cancer, it is beneficial to postpone therapy with vitamin K antagonists and prolong initial low-molecular-weight therapy for 3 to 6 months. New developments are aimed at further individualization of the duration of treatment and at the introduction of agents that are suitable for long-term treatment and do not require monitoring.     

Ximelagatran for treatment and prophylaxis of recurrent events in deep vein thrombosis.

The treatment of acute venous thromboembolism and prophylaxis of recurrent events with heparin/low molecular weight heparin followed by vitamin K antagonists is limited by several factors. Oral direct thrombin inhibitors (ODTIs) showed a better pharmacological activity and might be an alternative in the treatment of venous thromboembolism. The Thrombin Inhibition in Venous Thromboembolism (THRIVE) program performed some studies developing the ODTI ximelagatran for this indication, and it is presented in the overview. The aim of the THRIVE I study was the dose finding, and that of the THRIVE IV study the applicability in hemodynamic stabile pulmonary embolism. A prospective, randomized, double blind trial was performed to compare oral ximelagatran with enoxaparin/warfarin for a 6-month treatment of acute venous thrombosis (THRIVE II and V). A second double blind study compared ximelagatran with placebo over 18 months after a 6-month anticoagulant therapy of acute deep vein thrombosis. The efficacy and safety of treatment of patients with acute deep venous thrombosis who received 2 infinity 36 mg ximelagatran was not inferior to that of patients who received a conventional anticoagulant for prophylaxis of recurrent events over 6 months. Ximelagatran 2 infinity 24 mg significantly reduced recurrent thromboembolic events compared to placebo without increasing the risk for hemorrhage. A reversible symptomless increase of alanine aminotransferase occurs in 6% to 9.6% of patients between months 2 and 4. The results of the follow-up studies suggest that thromboembolic events may recur in patients with acute venous thromboembolism after termination of treatment with both vitamin K antagonists and ximelagatran.     

Bleeding risks associated with vitamin K antagonists

Vitamin K antagonists are widely used for the prevention of stroke due to atrial fibrillation, treatment and secondary prevention of venous thromboembolism, prevention of valvular thromboembolism in patients with prosthetic heart valves, and secondary prevention of acute myocardial infarction. The most common adverse event experienced by patients receiving anticoagulant therapy is major bleeding. The incidence of major bleeding in patients receiving long-term anticoagulation with a vitamin K antagonist in contemporary studies is 1–3% per year. To determine if the benefits of anticoagulant therapy outweigh the risk of bleeding in an individual patient, physicians must be aware of the risk factors associated with major bleeding. This narrative review will provide an overview of the incidence of major bleeding in patients receiving therapeutic anticoagulant therapy with vitamin K antagonists, discuss the risk factors for bleeding, and outline the most commonly used clinical prediction rules for bleeding.     

Intensity and duration of anticoagulation therapy in antiphospholipid syndrome

Antithrombotic drugs are the therapeutic cornerstone for patients with antiphospholipid syndrome (APS) and thrombosis. Choosing the specific agent (vitamin K antagonists or antiplatelet drugs), the intensity of anticoagulation (e.g., international normalized ratio [INR] range 2.0 to 3.0 or 3.0 to 4.0), and the duration of treatment has been a recurrent matter of debate. A recent consensus document recommends warfarin to an INR range of 2.0 to 3.0 for patients with a first venous thromboembolic event. Higher anticoagulation intensity is recommended for patients presenting with arterial events. Combined therapy with warfarin and aspirin is another possibility, but some authors recommend standard intensity warfarin or aspirin, either as monotherapy. In general, a more intense regimen is warranted for high-risk patients. On the basis of an increased risk of recurrence during the first 6 months following warfarin withdrawal, long-term anticoagulation is considered the standard treatment. Nevertheless, anticoagulation regimes of shorter duration could be given in selected patients with venous thromboembolism who have transient risk factors and a low-risk profile.     

Recurrence risk after anticoagulant treatment of limited duration for late,second venous thromboembolism

Patients with a second venous thromboembolism generally receive anticoagulant treatment indefinitely, although it is known that the recurrence risk diminishes over time while the risk of hemorrhage persists with continued anticoagulation and increases with age. Based on these arguments and limited evidence for indefinitely prolonged treatment, the Dutch guidelines recommend considering treatment of a limited duration (i.e. 12 months) for a ‘late’ second venous thromboembolism, defined by a second venous thromboembolism diagnosed more than 1 year after discontinuing treatment for a first event. It is hypothesized that the risk of continued anticoagulation might outweigh the benefits in such circumstances. We evaluated this management in daily practice. Since 2003, limited duration of treatment was systematically considered at our hospital in consecutive patients, in whom we determined the recurrence risk. Of 131 patients with late second venous thromboembolism, 77 were treated for a limited duration, of whom 26 developed a symptomatic third venous thromboembolism thereafter during a cumulative follow-up of 277 years, resulting in an incidence rate of 9.4/100 patient-years (95% confidence interval: 6.1–14). The incidence rates in patients with unprovoked and provoked venous thromboembolism were 12/100 patient-years (95% confidence interval: 7.4–19) and 5.6/100 patient-years (95% confidence interval: 2.2–12), respectively [adjusted hazard ratio 2.8 (95% confidence interval: 1.1–7.2)]. The recurrence risk after treatment of limited duration for ‘late’ second venous thromboembolism exceeded the risk of hemorrhage associated with extended anticoagulation. Most patients may, therefore, be better served by treatment of indefinite duration, although the risk-benefit ratio of extended anticoagulation should be weighed for every patient.     

Optimal duration of anticoagulation of venous thromboembolism

The optimal duration of anticoagulation after venous thromboembolism (VTE) is determined according to the risk of recurrent VTE after stopping anticoagulant therapy and the risk of anticoagulant-related bleeding while on antivitamin K. Clinical risk factors appears to be determinant to predict the risk of recurrence whereas the influence of biochemical and morphological tests is uncertain. The risk of recurrent venous thromboembolism is low when the initial episode was provoked by a reversible major risk factor (surgery): 3 months of anticoagulation is optimal. Conversely, this risk is high when venous thromboembolism was unprovoked or associated with persistent risk factor (cancer): 6 months or more prolonged anticoagulation is warranted. After this first estimation, the duration of anticoagulation may be modulated according to the presence of additional minor risk factors (major thrombophilia, chronic pulmonary hypertension, massive pulmonary embolism): 6 months if VTE was provoked and 12 to 24 months if VTE was unprovoked. If the risk of anticoagulant related bleeding is high, the duration of anticoagulation should be shortened (3 months if VTE was provoked and 6 or 3 months if it was unprovoked). Lastly, if VTE occurred in the setting of a cancer, anticoagulation should be conducted for 6 months or more while cancer is active or on ongoing treatment. Despite an increasing knowledge of the risk factors of recurrent VTE, a number of issues remain unresolved; randomised trial comparing different duration of anticoagulation are needed.     

Role of thrombophilia in deciding on the duration of anticoagulation

It is now possible to identify hereditary risk factors in a substantial percentage of patients presenting with a venous thrombotic event. Discovery of the factor V Leiden and prothrombin G20210A mutations has greatly increased the percentage of patients in whom venous thrombosis can be attributed to hereditary thrombophilia. There is considerable uncertainty, however, as to how this information should be used in patient management. Although prolonged anticoagulation at an international normalized ratio (INR) of 2 to 3 is highly effective in preventing thrombotic recurrences, this benefit is partially offset by the risk of major bleeding and the inconvenience associated with oral vitamin K antagonists. Although low-intensity anticoagulation at a target INR of 1.5 to 2 has recently been shown to be effective in preventing recurrent venous thromboembolism after 3 to 6 months of treatment at an INR of 2 to 3, it has not been demonstrated to reduce the risk of major bleeding complications. A decision as to the overall benefit of extended anticoagulation therefore continues to require clinical assessment of an individual patient's risk of recurrence in the absence of treatment and the risk of bleeding at the chosen INR target range.     

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.     

Treatment of deep vein thrombosis and pulmonary embolism

Deep vein thrombosis and pulmonary embolism may be considered as different manifestations of the same disease: venous thromboembolism. Under the condition of entirely stable hemodynamics, treatment follows exactly the same principles. The phase of initial therapy has a duration of 5-10 days and has remained so far a domain of parenteral anticoagulants (low molecular weight heparin, fondaparinux). The phase of early maintenance therapy is instituted with an overlap and has a duration of 3-6 months; vitamin K antagonists with a target INR of 2.0-3.0 are the standard. Patients with a high risk of recurrence and a low risk of bleeding will enter a phase of prolonged or even indefinite maintenance therapy. Again, vitamin K antagonists with a target INR of 2.0-3.0 are the standard. A target INR of 1.5-2.0 may be considered an alternative for patients in whom a very stable anticoagulation with less frequent INR testing is desirable. Clear recommendations can be made for venous thromboembolism treatment in pregnancy, in the post partum and lactation periods, as well as for patients with severe renal impairment. New anticoagulants (thrombin inhibitors, factor Xa inhibitors) have made significant progress in their clinical development and will soon become available as an alternative for all three phases of therapy.     

Therapie der Beinvenenthrombose und der Lungenembolie

Deep vein thrombosis and pulmonary embolism may be considered as different manifestations of the same disease: venous thromboembolism. Under the condition of entirely stable hemodynamics, treatment follows exactly the same principles. The phase of initial therapy has a duration of 5?C10?days and has remained so far a domain of parenteral anticoagulants (low molecular weight heparin, fondaparinux). The phase of early maintenance therapy is instituted with an overlap and has a duration of 3?C6?months; vitamin K antagonists with a target INR of 2.0?C3.0 are the standard. Patients with a high risk of recurrence and a low risk of bleeding will enter a phase of prolonged or even indefinite maintenance therapy. Again, vitamin K antagonists with a target INR of 2.0?C3.0 are the standard. A target INR of 1.5?C2.0 may be considered an alternative for patients in whom a very stable anticoagulation with less frequent INR testing is desirable. Clear recommendations can be made for venous thromboembolism treatment in pregnancy, in the post partum and lactation periods, as well as for patients with severe renal impairment. New anticoagulants (thrombin inhibitors, factor Xa inhibitors) have made significant progress in their clinical development and will soon become available as an alternative for all three phases of therapy.     

Therapie der venösen Thromboembolie

The main objectives in the treatment of venous thromboembolism are to prevent clot extension and pulmonary embolism, to reduce mortality and to prevent recurrent thromboembolic events as well as postthrombotic disorders. Initial and effective anticoagulation with heparin, preferably with low molecular weight heparin (LMWH), or with fondaparinux is the most important measure. Unfractioned heparin (UFH) is as effective as LMWH, but requires coagulation-monitoring and is associated with a higher risk of heparin-induced thrombocytopenia. In patients with renal insufficiency direct determination of anti-factor Xa activity and dose adjustment is recommended, since drug accumulation can occur over time. In those patients UFH instead of LMWH might be favored. Long-term treatment should be administered with vitamin K-antagonists (INR-target range 2–3) for a duration of 3 to 6 months. In case of recurrent venous thromboembolism, indefinite therapy is recommended. Additional treatment with compression stockings is reasonable. Patients who do not require hospital treatment for other conditions, who have a low bleeding risk, no excessive venous congestion and no symptomatic pulmonary embolism can safely be treated at home. In most cases bed rest is not necessary. Thrombolysis or surgical thrombectomy is seldomly indicated in severe thromboembolism.     

The effects of race/ethnicity and sex on the risk of venous thromboembolism

PURPOSE OF THE REVIEW: Recently, studies on large diverse populations have described important ethnic/racial differences in venous thromboembolism incidence, and sex has been reported as an important predictor of recurrence. We review the influence of race/ethnicity and sex on venous thromboembolism, concentrating on articles from 2005 to 2007. RECENT FINDINGS: Most studies found that women have a 40-400% lower risk of recurrent venous thromboembolism than men. Studies of ethnicity/race on risk provide strong evidence that African-American patients are the highest risk group for first-time venous thromboembolism, while Hispanic patients' risk is about half that of Caucasians. African-Americans and Hispanics have a higher risk of recurrence than Caucasians, but sex and the type of index venous thromboembolism event seem to play a role in this risk. Asian/Pacific Islanders have a markedly lower risk of first-time and cancer-associated venous thromboembolism. There is little difference in incidence in African-Americans, Hispanics, and Caucasians diagnosed with cancer. Sex does not seem to be associated with risk in cancer patients. SUMMARY: Sex and race/ethnicity are important factors in the risk of first-time and recurrent venous thromboembolism and need to be included as risk assessment and diagnostic prediction tools are developed or updated.     

Current and future prospects for anticoagulant therapy: inhibitors of factor Xa and factor IIa

Indirect systemic and direct oral factor Xa and direct oral factor IIa inhibitors with improved pharmacologic profiles compared with heparins and vitamin K antagonists are currently in clinical development. This overview focuses on the indirect antithrombin dependent pentasaccharide derivatives of idraparinux and on the most advanced oral direct inhibitors to factor Xa (rivaroxaban and apixaban) and IIa (dabigatran). Specifically, the results of dose-finding studies for the prevention of venous thromboembolism after elective orthopedic surgery, the results of dose-finding studies for treatment of acute venous thromboembolism including prolonged prophylaxis of recurrent events, and the designs of ongoing clinical trials are reviewed.     

The optimal duration of anticoagulant treatment following pulmonary embolism

The optimal course of oral anticoagulant therapy is determined according to the risk of recurrent venous thromboembolism after stopping therapy and the risk of anticoagulant-related bleeding. Clinical risk factors appear to be important in predicting the risk of recurrence whereas the influence of biochemical and morphological tests is uncertain. The risk of recurrent venous thromboembolism is low when the initial episode was provoked by a reversible major risk factor (surgery): 3 months of anticoagulation is sufficient. Conversely, the risk is high when venous thromboembolism was unprovoked or associated with persistent risk factor (cancer): 6 months or more prolonged anticoagulation is necessary. After this first estimation, the duration of anticoagulation may be modulated according to the presence or absence of certain additional risk factors (major thrombophilia, chronic pulmonary hypertension, massive pulmonary embolism): 6 months if pulmonary embolism was provoked and 12 to 24 months if pulmonary embolism was unprovoked. If the risk of anticoagulant-related bleeding is high, the duration of anticoagulation should be shortened (3 months if pulmonary embolism was provoked and 3 to 6 months if it was unprovoked). Lastly, if pulmonary embolism occurred in association with cancer, anticoagulation should be conducted for 6 months or more if the cancer is active or treatment is on going. Despite an increasing knowledge of the risk factors for recurrent venous thromboembolism, a number of issues remain unresolved. Randomised trials comparing different durations of anticoagulation are needed.     

How should we determine length of anticoagulation after proximal deep vein thrombosis of the lower limbs?

The current approach for deciding the duration of vitamin K antagonist (VKA) treatment after an episode of venous thrombo-embolism (VTE) is mainly based on the characteristic of the index event (3 months or longer in case of unknown/persistent risk factors, 3 months or less in case of removable causes). However, the length of anticoagulation should be tailored on the patient's risk for recurrent thrombosis as well as for bleeding, but such 'time for decision' is often unclear and the optimal duration of VKA remains debatable. The presence of persistent residual vein thrombosis and increased d -dimer levels after stopping therapy are predictors for recurrent deep vein thrombosis (DVT). Management strategies based on these parameters have been demonstrated to optimize the decision for VKA duration, as they establish the patient's intrinsic risk for recurrent events. This annotation discusses current practice and upcoming approaches regarding the length of VKA treatment after a first episode of DVT.     

Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors

BACKGROUND: The recurrence rate after deep vein thrombosis (DVT) is high and the risk factors for recurrent thromboembolic events have only been investigated on a small scale. OBJECTIVES: To estimate the cumulative incidence of recurrent venous thromboembolic events after a first or a second DVT and to identify possible risk factors for recurrent venous thromboembolism. METHODS: We prospectively followed up 738 consecutive patients with an objectively verified symptomatic DVT for 3.7 to 8.8 years. Medical records and death certificates for all patients were reviewed during follow-up and recurrent DVT and pulmonary embolism were registered. RESULTS: The 5-year cumulative incidence of recurrent venous thromboembolic events was 21.5% (95% confidence interval [CI], 17.7%-25.4%) after a first DVT and 27.9% (95% CI, 19.7%-36.1%) after a second DVT. The 5-year cumulative incidence of fatal pulmonary embolism was 2.6% (95% CI, 1.1%-4.1%) after a first DVT. Proximal DVT (relative risk [RR], 2.40; 95% CI, 1.48-3.88; P<.001), cancer (RR, 1.97; 95% CI, 1.20-3.23; P<.001), and history of a venous thromboembolism (RR, 1.71; 95% CI, 1.16-2.52; P<.01) predicted an independently increased risk of recurrent events in multivariate survival analysis. Postoperative DVT (RR, 0.27; 95% CI, 0.13-0.55; P<.001) and a long duration of oral anticoagulation therapy (RR, 0.95; 95% CI, 0.92-0.98; P<.01) involved a smaller risk of recurrent events. Sex, age, initial antithrombotic therapy, or immobilization did not affect the risk of a recurrent event. CONCLUSIONS: The recurrence rate after a symptomatic DVT is high. Patients with proximal DVT, diagnosed cancer, short duration of oral anticoagulation therapy, or a history of thromboembolic events had a higher risk of recurrent events, while patients with postoperative DVT had a lower recurrence rate. This knowledge could help identify patients who might benefit most from prolonged prophylactic treatment in various risk situations.     

Secondary prevention in thrombotic antiphospholipid syndrome

Secondary prevention of venous thromboembolism in antiphospholipid syndrome (APS) is usually made using vitamin K antagonists (VKAs) to maintain an international normalized ratio (INR) between 2.0 and 3.0. The optimal intensity of anticoagulation was determined in two prospective randomized controlled trials, both excluding the benefit of more intense anticoagulation. The same regimen is also recommended in patients with APS and arterial thromboembolism as aspirin does not appear to protect against recurrences. The duration of treatment is usually indefinite because of a substantial risk of recurrence.     

Periprocedural Bridging in Patients with Venous Thromboembolism: A Systematic Review

BackgroundVitamin K antagonists (VKA) are the most widely used anticoagulants, and bridging is commonly administered during periprocedural VKA interruption. Given the unclear benefits and risks of periprocedural bridging in patients with previous venous thromboembolism, we aimed to assess recurrent venous thromboembolism and bleeding outcomes with and without bridging in this population.MethodsWe performed a systematic review searching the PubMed and Embase databases from inception to December 7, 2017 for randomized and nonrandomized studies that included adults with previous venous thromboembolism requiring VKA interruption to undergo an elective procedure, and that reported venous thromboembolism or bleeding outcomes. Quality of evidence was graded by consensus.ResultsWe included 28 cohort studies (20 being single-arm cohorts) with, overall, 6915 procedures for analysis. In 27 studies reporting perioperative venous thromboembolism outcomes, the pooled incidence of recurrent venous thromboembolism with bridging was 0.7% (95% confidence interval [CI], 0.4%-1.2%) and 0.5% (95% CI, 0.3%-0.8%) without bridging. Eighteen studies reported major or nonmajor bleeding outcomes. The pooled incidence of any bleeding was 3.9% (95% CI, 2.0%-7.4%) with bridging and 0.4% (95% CI, 0.1%-1.7%) without bridging. In bridged patients at high thromboembolic risk, the pooled incidence for venous thromboembolism was 0.8% (95% CI, 0.3%-2.5%) and 7.5% (95% CI, 3.1%-17.4%) for any bleeding. Quality of available evidence was very low, primarily due to a high risk of bias of included studies.ConclusionsPeriprocedural bridging increases the risk of bleeding compared with VKA interruption without bridging, without a significant difference in periprocedural venous thromboembolism rates.     

Management der Lungenembolie

Venous thromboembolism is often triggered by transient episodes of increased risk but may occur spontaneously in patients with permanently increased risk. Pulmonary embolism may cause impairment of respiratory and circulatory function which can vary in severity from silent to catastrophic. The diagnosis can be feasibly established by detecting vein thrombosis. If this approach fails, demonstration of pulmonary emboli by lung scans becomes necessary to establish the diagnosis. A D-dimer-test can select patients in whom imaging of pulmonary perfusion is required. Immediate therapeutic anticoagulation with heparins is mandatory in confirmed thromboembolism, and is followed by a vitamin K antagonist. In the initial work-up, patients also have to be evaluated for systemic thrombolytic therapy by hemodynamic parameters and echocardiography. In a triggered episode of venous thromboembolism, duration of anticoagulation is confined to several months while spontaneous or recurrent events require prolonged or indefinite treatment.     

Management of pulmonary embolism

Venous thromboembolism is often triggered by transient episodes of increased risk but may occur spontaneously in patients with permanently increased risk. Pulmonary embolism may cause impairment of respiratory and circulatory function which can vary in severity from silent to catastrophic. The diagnosis can be feasibly established by detecting vein thrombosis. If this approach fails, demonstration of pulmonary emboli by lung scans becomes necessary to establish the diagnosis. A D-dimer-test can select patients in whom imaging of pulmonary perfusion is required. Immediate therapeutic anticoagulation with heparins is mandatory in confirmed thromboembolism, and is followed by a vitamin K antagonist. In the initial work-up, patients also have to be evaluated for systemic thrombolytic therapy by hemodynamic parameters and echocardiography. In a triggered episode of venous thromboembolism, duration of anticoagulation is confined to several months while spontaneous or recurrent events require prolonged or indefinite treatment.