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.     

肺癌合并静脉血栓栓塞症的风险评估

静脉血栓栓塞症(venous thromboembolism,VTE)是癌症常见的并发症和最常见的死亡原因之一,主要包括深静脉血栓栓塞症和肺血栓栓塞症.近年来,随着血栓栓塞性疾病研究的深入,肺癌相关性VTE已引起关注.其中,肺癌患者的预防性抗凝治疗具有很大争议性.初级预防能使肺癌相关性VTE发生风险减少,但相关研究同时提示患者出血风险提高.目前尚不推荐对肺癌患者进行常规抗凝,但对血栓风险高、出血风险低的肺癌患者进行选择性抗凝可使其获益.因此,肺癌相关性VTE的风险评估和分级可提高预防性抗凝的临床获益,减少相关出血事件.     

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.     

Extended anticoagulation for unprovoked venous thromboembolism: a majority of patients should be treated

About half of patients with a first unprovoked proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) will have a recurrent venous thromboembolism (VTE) within 10 years if they stop treatment, and randomized trials have shown clear benefit from extended anticoagulant therapy in these patients. Although the risk of recurrence varies among patients with a first unprovoked proximal DVT or PE, and a number of factors can identify patients with a lower risk of recurrence, the safety of routinely stopping anticoagulant therapy based on the presence of these factors needs to be established in prospective studies before this is done in clinical practice. As isolated distal DVT is associated with about half the risk of recurrence of proximal DVT or PE, a first episode of unprovoked distal DVT does not justify extended anticoagulation. High risk for bleeding, and patient preference, are good reasons not to treat unprovoked proximal DVT or PE indefinitely. New anticoagulants, because they are easier to use and may be associated with less bleeding that vitamin K antagonists, have the potential to increase the proportion of patients with unprovoked VTE who are candidates for extended anticoagulant therapy.     

Diagnosis of deep venous thrombosis and pulmonary embolism in pregnancy.

Accurate diagnosis of deep venous thrombosis and pulmonary embolism is required because treatment can be lifesaving, although inappropriate anticoagulation exposes the mother and fetus to hemorrhage and other hazards. Clinicians must be aware of which patients are at risk, as deep venous thrombosis is frequently asymptomatic. Clinical diagnosis is unreliable for deep venous thrombosis and pulmonary thromboembolism; therefore, objective tests are required. Venography is the gold standard test for deep venous thrombosis but is invasive. It has been superseded by less invasive tests such as compression ultrasound. This test, although not yet rigorously scrutinized in pregnancy, is now the first-line investigation. Where doubt remains, venography, CT, and magnetic resonance imaging have a role. Ventilation-perfusion scanning is the pivotal test for pulmonary thromboembolism for pregnancy, and it need not expose the fetus to excess radiation. If the results of this test are unclear, deep venous ultrasound can guide management of suspected pulmonary thromboembolism, thus avoiding pulmonary angiography.     

Workshop: Special problems in anticoagulation therapy: Cancer and venous thromboembolism-temporary discontinuation of warfarin for surgery and invasive procedures

Health care providers monitoring anticoagulated patients are often asked to make recommendations regarding anticoagulant management during periods when illness or treatment may complicate anticoagulant therapy. Two particularly difficult clinical problems concern the indications for and management of anticoagulant therapy in patients with cancer and the management of anticoagulated patients who must undergo some type of surgical procedure. Cancer is a significant risk factor for a variety of thromboembolic disorders, particularly venous thromboembolism. Venostasis from immobility, vessel wall damage from tumor invasion, and especially tumor-mediated activation of the coagulation system are important contributors to the prethrombotic state in cancer patients. The risk of venous thromboembolism is greatest during surgery, chemotherapy, and long-term use of central venous catheters. For selected patients, prophylaxis with subcutaneous heparin, low-intensity warfarin, or very low-intensity warfarin may substantially reduce this risk. A related concern for primary care clinicians is the increasing evidence that idiopathic venous thromboembolism may be the first manifestation of occult cancer. Whether and how these patients should be screened for malignancy is currently uncertain. Prior to surgical procedures in anticoagulated patients, clinicians must compare the risk of bleeding if anticoagulation is continued with the risk of recurrent thrombosis if anticoagulation is stopped. Bleeding risk is influenced by how a specific procedure affects the ability to assess and control bleeding and the intensity of anticoagulation at the time of the procedure. Thromboembolism risk is determined by the specific indication for the anticoagulation and the length of time during which anticoagulant therapy must be discontinued. Guidelines are suggested for perioperative anticoagulant management of patients with different thromboembolic disorders undergoing a variety of surgical procedures.     

Unexpected high prevalence of silent pulmonary embolism in patients with deep venous thrombosis

In patients presenting with clinically suspected deep vein thrombosis, symptomatic pulmonary embolism is rarely apparent. To assess the prevalence of silent pulmonary embolism in outpatients with proven deep vein thrombosis but without symptoms of pulmonary embolism, perfusion ventilation lung scans were performed in 101 consecutive patients at presentation. Fifty-one percent of these patients had a high probability lung scan at the initiation of treatment. In comparison, in patients referred with suspected venous thrombosis, but who on subsequent objective testing did not have venous thrombosis (n = 44), the prevalence of a high probability-scan for pulmonary embolus was only 5 percent. At repeat lung scanning, performed after one week of anticoagulant treatment, complete to partial improvement was observed in 68 percent of the patients with initially abnormal scans. Lung-scan detected asymptomatic pulmonary embolism occurs frequently in patients presenting with symptomatic deep venous thrombosis, and the majority of these emboli showed significant to complete resolution within one week of anticoagulant treatment.     

Inherited and acquired risk factors for venous thromboembolism

Venous thrombosis, or venous thromboembolism, comprises deep vein thrombosis with or without symptomatic pulmonary embolus. The development of symptomatic venous thrombosis is highly dependent on gene-environment interaction. In most instances this interaction results in hypercoagulability (the intermediate phenotype) sufficient to result in intraluminal clot formation (the disease phenotype). The genetic framework underlying venous thrombosis is complex, and there is a large material contribution from disease and interaction with environmental factors. For example, venous thrombosis is related to recent hospitalization in approximately half of all adult cases. After a first episode of venous thrombosis patients are 40 times more likely to suffer a further event compared with previously unaffected individuals. However, the risk differs between patients. Duration of anticoagulation (lifelong or not) should be made with reference to whether an episode of thrombosis was provoked and the presence of other risk factors. The results of testing for heritable thrombophilia rarely influence duration of treatment.     

Low-molecular-weight heparin for the treatment of venous thromboembolism in the elderly.

Venous thromboembolism (deep vein thrombosis and/or pulmonary embolism) is a common problem in the elderly population. Indeed, increasing age is a significant risk factor for venous thromboembolism. The treatment of venous thromboembolism in the elderly population presents certain unique problems related to aging, such as decreasing body weight, increasing renal insufficiency and numerous comorbid conditions, which complicate therapy. Treatment of venous thromboembolism in the elderly has been complicated by an increased incidence of bleeding, particularly with the use of warfarin. The risk of bleeding may be substantially reduced by carefully adjusting the warfarin dose to maintain a therapeutic INR and for this purpose anticoagulant management clinics have been shown to be useful. The low-molecular-weight heparins have been shown to be efficacious and safe for the treatment of venous thromboembolism in several clinical trials, including many patients in the older age brackets. Furthermore, these agents can safely be used in the out-of-hospital setting. Long-term use of low-molecular-weight heparin is an alternative to the use of oral anticoagulant therapy, particularly in patients with cancer or recurrent venous thromboembolism.     

Outpatient Management of Venous Thromboembolism

Low molecular weight heparins (LMWHs) have provided the necessary pharmacologic tool to facilitate the outpatient management of selected patients presenting with acute venous thromboembolism. A growing collection of clinical trial results supports the safety and efficacy of this cost-efficient management strategy. However, this approach requires careful patient selection and meticulous care planning. Several randomized multicenter trials have compared a primarily outpatient approach to treating uncomplicated proximal venous thrombosis with a LMWH administered subcutaneously once or twice daily to the inpatient use of unfractionated heparin (UFH). The results have been very encouraging and suggest that the use of subcutaneous LMWH in highly selected, uncomplicated venous thrombosis patients is as safe and effective as intravenous UFH, and that most patients can be treated as outpatient or be discharged early. Irrespective of parenteral anticoagulant approach, warfarin therapy was commenced on day 1 and continued for 3 months. A recent publication by Dedden and colleagues describes a 1-year experience with a pharmacy-managed program for the home treatment of patients presenting with proximal deep vein thrombosis. A plan for coordinated patient care was implemented which included a process for patient referrals, standardized protocol orders, a plan for holding area processing and home healthcare agency follow-up, and subsequent oral anticoagulation management. Results of the program demonstrate a significant healthcare savings (as compared with standard inpatient management) with no significant compromise in patient outcomes. Recently published trials by the Columbus Investigators and Simonneau and colleagues have looked beyond uncomplicated proximal venous thromboembolism to include patients presenting with recurrent venous thrombosis and pulmonary embolism. Results suggest the subcutaneous use of LMWH is as safe and effective as intravenous UFH. Such data begin to lay the scientific foundation for the expanded clinical base of patients who may be candidates for an outpatient management approach. In today's cost-conscience environment, managing the treatment of select venous thromboembolism patients with LMWH(s) and warfarin therapy in an outpatient environment represents an evolving approach that is economically logical, does not compromise patient outcomes, but requires considerable planning to address a myriad of logistical issues.     

Oral anticoagulant therapy. Fundamentals, clinical practice and recommendations.

Oral anticoagulant therapy remains one of the most frequent options for treatment and prevention in patients with arterial and venous thromboembolism. Clinical guidelines have been updated in recent years by various associations such as the American Heart Association (AHA), the American College of Cardiology (ACC) and the European Society of Cardiology (ESC), as well as organizations in several other countries. The authors present a review of therapy with vitamin K antagonists, focusing on their mechanism of action and metabolism, as well as on the fundamentals of such therapy. Clinical recommendations for the most frequent indications are described. One of the most important issues is the use of these drugs for atrial fibrillation therapy, which is a common indication. Prosthetic valvular disease is a compelling indication for anticoagulation, for which there is a broad consensus. Ischemic heart disease is another indication described for oral anticoagulation. Several practical issues in cardiac patients are discussed. These include the appropriate initial dose, schemes for reversal of anticoagulation, and management of surgical patients. Finally, risk factors for deep venous thrombosis and pulmonary embolism are detailed in this review, presenting current clinical recommendations for oral anticoagulation of these patients.     

The significance of venography in the management of patients with clinically suspected pulmonary embolism

The accurate diagnosis of pulmonary embolism causes many problems. Clinical signs are non-specific, and ventilation-perfusion lung scanning has high sensitivity but variable specificity. In more than 90% of cases a pulmonary embolus is derived from deep venous thrombosis in the lower extremities. We have performed a prospective study to evaluate venography in the management of patients with suspected pulmonary embolism. A total of 169 patients were included in the study, and a ventilation-perfusion scan was performed in all cases. Forty-four (26%) patients had a normal scan and treatment was not given (group A). The other 125 (74%) patients, who had an abnormal scan, underwent bilateral venography. Venous thrombosis was demonstrated in 63 patients, and they were treated with oral anticoagulants for 3 months (group B). The remaining 62 patients, who showed no venous thrombosis, did not receive anticoagulant therapy (group C). During follow-up, 1 patient in group A, 3 patients in group B and 1 patient in group C developed a new deep venous thrombosis. One patient in group B suffered a pulmonary embolus. It is concluded that venography of the lower extremities can be of additional value in the management of patients with pulmonary embolism when the lung scan does not provide sufficient information.     

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.     

Venous thromboembolism in cystic fibrosis

The incidence of venous thromboembolism (VTE) is increasing in the pediatric population. Individuals with cystic fibrosis (CF) have an increased risk of thrombosis due to central venous catheters (CVCs), as well as acquired thrombophilia secondary to inflammation, or deficiencies of anticoagulant proteins due to vitamin K deficiency and/or liver dysfunction. CVC-associated thrombosis commonly results in line occlusion, but may develop into serious life-threatening conditions such as deep venous thrombosis (DVT), superior vena cava syndrome or pulmonary embolism (PE). Post-thrombotic syndrome (PTS) may be a long complication. Local occlusion of the catheter tip may be managed with instillation of thrombolytics (such as tPA) within the lumen of the catheter; however, CVC-associated thrombosis involving the proximal veins is most often is treated with systemic anticoagulation. Initial treatment with heparin is a standard approach, but thrombolytic therapy, which may carry higher bleeding risks, should be considered for life and limb threatening episodes of VTE. Recommended duration of anticoagulation with low molecular weight heparin (LMWH) or warfarin ranges from 3 to 6 months for major removable thrombotic risks; longer anticoagulation is considered for recurrent thrombosis, major persistent thrombophilia, or the continued presence of a major risk factor such as a CVC. While CVCs are the most common risk for development of VTE in children, studies have not demonstrated a clear benefit with routine use of systemic thromboprophylaxis. The incidence and risk factors of VTE in CF patients will be reviewed and principles of diagnosis and management will be summarized.     

The use of D-dimer in specific clinical conditions: A narrative review

The use of D-dimer in combination with a clinical decision rule has been widely investigated in pulmonary embolism and deep venous thrombosis. Although it has been shown to be safe in excluding venous thromboembolism, the clinician is often faced with specific situations in which the use of D-dimer is controversial. We review the best available evidence on these patients. We conclude that it is not safe to use D-dimer testing in patients with symptoms of a venous thromboembolism for over 14 days, patients receiving therapeutic heparin treatment and patients with suspected deep venous thrombosis during oral anticoagulant therapy. In these populations the levels of D-dimer can be lower then expected giving rise to false-negative results. It is safe to use D-dimer testing in combination with a clinical decision rule in patients of all ages, patients presenting with a suspected recurrent venous thromboembolism or inpatients with suspected pulmonary embolism. As patients with recurrent venous thromboembolism, elderly patients and inpatients have higher levels of D-dimer, D-dimer testing has a low specificity and the need for additional radiological testing is increased.     

Treatment of venous thrombosis in the cancer patient

Venous thromboembolism is a common complication in patients with cancer. The management of deep vein thrombosis and pulmonary embolism can be a considerable challenge in patients with cancer. The cancer itself and associated treatments contribute to an ongoing thrombogenic stimulus, while cancer patients are thought to be at increased risk for anticoagulant-induced bleeding. Initial treatment of acute thromboembolism is with intravenous unfractionated heparin or subcutaneous low molecular weight heparin. Treatment at home with low molecular weight heparin is an attractive option in patients with malignant disease. Long-term treatment of acute venous thromboembolism has traditionally been with oral anticoagulants. However, the inconvenience and narrow therapeutic window of oral anticoagulants make such therapy unattractive and problematic in cancer patients. Low molecular weight heparins are being evaluated as an alternative for long-term therapy because their anticoagulant effects are more predictable and laboratory monitoring is unnecessary. Although many clinical issues remain unresolved in the treatment of cancer patients with venous thromboembolism, the future holds much promise as new antithrombotic agents, including factor Xa antagonists and oral thrombin inhibitors, are being tested in clinical trials.     

Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians

Venous thromboembolism is a common condition affecting 7.1 persons per 10,000 person-years among community residents. Incidence rates for venous thromboembolism are higher in men and African Americans and increase substantially with age. It is critical to treat deep venous thrombosis at an early stage to avoid development of further complications, such as pulmonary embolism or recurrent deep venous thrombosis. The target audience for this guideline is all clinicians caring for patients who have been given a diagnosis of deep venous thrombosis or pulmonary embolism. The target patient population is patients receiving a diagnosis of pulmonary embolism or lower-extremity deep venous thrombosis.     

Advanced management of acute iliofemoral deep venous thrombosis: emergency department and beyond

Recent attention to the increasing incidence of venous thromboembolism has included a call to action from the surgeon general and new guidelines from various specialty organizations. The standard of care for treatment of deep venous thrombosis in the emergency department (ED), supported by the 2008 American College of Chest Physicians (ACCP) guidelines, involves initiation of anticoagulation with low-molecular-weight heparin, pentasaccharide, or unfractionated heparin. For selected appropriate patients with extensive acute proximal deep venous thrombosis, the ACCP guidelines now recommend thrombolysis in addition to anticoagulation to reduce not only the risk of pulmonary embolism but also the risk of subsequent postthrombotic syndrome and recurrent deep venous thrombosis. Postthrombotic syndrome is a potentially debilitating chronic cluster of lower-extremity symptoms occurring in 20% to 50% of deep venous thrombosis patients subsequent to the acute insult, sometimes not until years later. A strategy of early thrombus burden reduction or frank removal might reduce the incidence of postthrombotic syndrome, as per natural history studies, venous thrombectomy data, observations after systemic and catheter-directed thrombolysis, and the still-limited number of randomized trials of catheter-directed thrombolysis (with anticoagulation) versus anticoagulation alone. Contemporary invasive (endovascular) treatments mitigate the drawbacks historically associated with thrombolytic approaches by means of intrathrombus delivery of drugs with greater fibrin specificity and lower allergenicity, followed by mechanical dispersion to accelerate lysis and then aspiration of remaining drug and clot debris. With a 2016 target completion date, the National Heart, Lung, and Blood Institute--sponsored Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis trial is comparing the safety and efficacy, in terms of both deep venous thrombosis and postthrombotic syndrome parameters, of the most evolved pharmacomechanical catheter-directed thrombolysis devices versus standard anticoagulation therapy alone. This article reviews the grounds for use of adjunctive thrombolysis in patients with acute proximal deep venous thrombosis and begins to identify types of deep venous thrombosis patients encountered in the ED who might benefit most from multidisciplinary consideration of early referral for possible endovascular therapy.     

Recurrent thromboembolism in cancer patients: incidence and risk factors

In contrast with the paucity of data on the risk of a first episode of thrombosis in cancer patients, the frequency of recurrent thromboembolism in patients with malignancy has been extensively investigated, both during anticoagulation and after its cessation. Cancer patients are more likely to develop recurrent thromboembolism and major bleeding during anticoagulation than patients without malignancies. These events are more pronounced during the first weeks of treatment and increase with cancer severity. Since they are not associated with anticoagulant intensities outside the therapeutic range, possibilities for improvement using the current paradigms of anticoagulation seem limited and new treatment strategies should be developed. In this regard, the use of low-molecular-weight heparins for initial treatment and long-term anticoagulation in cancer patients with venous thrombosis seems promising. Furthermore, patients with active cancers exhibit a particularly high risk of recurrent venous thromboembolism after the cessation of anticoagulation. In view of the persisting high risk for recurrent thrombotic events in cancer patients, and the acceptable risk of bleeding, prolonged warfarin treatment should be considered in such patients for as long as the cancer is active.