Nonoperative Treatment of Acute Lower Extremity Venous Thrombosis

Russel D. Hull

Patients with Deep Vein Thrombosis

The classic long-term treatment for deep vein thrombosis (DVT) is vitamin K–antagonist therapy overlapped with initial heparin or low-molecular-weight heparin (LMWH) therapy. Accurate, objective tests to detect venous thromboembolism (VTE) have led to randomized trials evaluating short-term therapy and long-term anticoagulant therapy for venous thrombosis, which have advanced our therapeutic understanding.

Initial short-term LMWH therapy is effective and is preferred over intravenous heparin because anticoagulant monitoring is not required, thus facilitating outpatient therapy. For vitamin K–antagonist therapy the importance of maintaining a therapeutic international normalized ratio (INR) is well documented; this necessitates frequent INR monitoring. The international consensus recommendations and American College of Chest Physicians (ACCP) consensus recommendations established that the use of initial LMWH therapy is a Grade A recommendation for 5 days or so. Long-term oral anticoagulant therapy is commenced immediately at the onset of initial therapy with a crossover interval of 4 to 5 days, with cessation of LMWH once the INR has been therapeutic on 2 consecutive days.

The need for and use of long-term oral anticoagulant therapy is also a Grade A recommendation. The duration of long-term anticoagulant therapy using a vitamin K antagonist is patient specific, and the guidelines are clearly established in the international consensus report and the ACCP guidelines. A comprehensive, detailed review of the nonoperative treatment of DVT, which includes both anticoagulant treatment and thrombolytic therapy, exists in the recommendations by the ACCP and the international consensus report. These highly regarded consensus guidelines provide detailed recommendations for initial type of therapy, duration of initial therapy, the type of long-term therapy, the intensity of long-term therapy using a vitamin K antagonist, and the duration of long-term therapy. Special recommendations are also provided for patients undergoing treatment for DVT who also have cancer.

International guideline suggests all patients should receive long-term antithrombotic therapy for at least 3 months. In patients with a major provoking risk factor that has been removed 3 months is sufficient. In patients with an unknown risk factor, the duration of anticoagulant therapy may be indefinite. The decision as to the length of therapy is based upon the balance of benefit and harm/bleeding and the patient’s preference. Patients on continued therapy should undergo periodic reconsideration. The review process involves balance of benefit and harm. In patients at lower risk of bleeding and continuing with VKA treatment, patient preferences are considered. In patients with a minor provoking risk factor, the duration of anticoagulant therapy is uncertain and should be based once again upon the same principles. In patients with more than 1 episode of VTE, the duration of anticoagulant therapy is indefinite. New oral antithrombotic regimens that do not require INR monitoring may provide an alternative long term therapy. Such antithrombotic include rivaroxaban, apixaban, edoxaban or dabigatran and may became an alternative therapy in countries where they have been approved for the indication.

There has been a paradigm shift in the treatment of two discrete domains, which are composed of DVT patients who have cancer or who suffer from the postthrombotic syndrome (PTS). VTE is a major therapeutic issue in cancer patients. It affects 15% to 20% of patients with cancer and is an independent prognostic factor and a leading cause of death. The onset of VTE during the course of active cancer also appears to be an independent prognostic factor for survival, being the second leading cause of mortality in these patients. Therefore, treatment in cancer patients represents a major therapeutic challenge. Renewed interest in the interaction of antithrombotic regimens on the survival of cancer patients resulted from findings of randomized trials evaluating LMWH treatment of DVT, which revealed a reduction in cancer mortality. Subsequently, this revived interest in antithrombotic therapy in cancer patients has been reinforced by the outcomes of multiple trials evaluating long-term LMWH therapy. Vitamin K–antagonist therapy is less effective than LMWH in cancer patients with a DVT, and it may be associated with an excessive bleeding in such patients.

Two independent trials benchmarked the observation that LMWH was more effective than vitamin K–antagonist treatment for preventing recurrent VTE in cancer patients. Further clinical trial evidence suggests that LMWH therapy in this context is superior because patients with DVT are resistant to vitamin K–antagonist therapy. A brief course of subcutaneous LMWH was shown to be favorably influencing survival in patients with advanced malignancy. Individual trial findings for efficacy and safety with regard to recurrent VTE and hemorrhagic complications exist (Figure 1).

The aggregate findings of these trials provide strong support for the use of long-term LMWH for 3 to 6 months in patients who have cancer and who are undergoing long-term treatment for DVT. An issue that is debated is what to do after the long-term course of LMWH in patients who remain at risk with active cancer. Given that such patients are resistant to vitamin K antagonist, the continued use of LMWH is entirely rational. The most appropriate course of action after completing the 3 to 6 months of long-term LMWH therapy is to involve the patient and ask the patient’s preference. A clinical trial has shown higher patient satisfaction when using LMWH compared with long-term vitamin K–antagonist therapy. Patients were more satisfied because long-term LMWH treatment did not interfere with employment and did not interfere with lifestyle activities. Accordingly, although the treatment is counterintuitive, patients preferred to self-inject than to be on vitamin K–antagonist and dependent on INR monitoring.

An expert review adds an important understanding of the pressing need for patients who have cancer and DVT to receive long-term LMWH. Several meta-analyses that focused on the treatment of venous thromboembolism in cancer patients confirmed the importance of these pivotal trials. Cancer patients often present with a variety of risk factors and comorbidities, and specific oncology guidelines exist on the subject based on various methodologic approaches. These guidelines for treating VTE in cancer patients were published first by the Italian Association of Medical Oncology in 2006, subsequently in the United States by the National Comprehensive Cancer Network and the American Society of Clinical Oncology, and in Europe by the French National Cancer Institute and by the European Society of Medical Oncology.

In addition, several scientific societies and organizations, including the ACCP and the Agence Française de Sécurité Sanitaire des Produits de Santé (French Agency for the Safety of Health Products) (AFSAPS), have issued detailed guidelines for preventing and treating VTE in the general population, with particular recommendations for cancer patients. Despite these well-established guidelines, many clinicians are reluctant to modify their practice or still have doubts regarding the tolerability and acceptance of long-term daily subcutaneous LMWH when applying standard therapeutic recommendations.

These organizations’ recommendations are almost identical, but despite clear and well-formulated guidelines, their rapid implementation was low. More recent anecdotal evidence suggests that their incorporation into practice may be happening much more quickly. The author’s experience also is that patients’ preferences are very important when the patient is presented with the choice of LMWH or vitamin K–antagonist therapy. In the long term, particularly after the initial course of LMWH, the patient’s preference is usually to remain on it. The apparent obstacle of a parenteral over an oral medication is usually not a barrier. Another important step is to have institutional or practice-based guidelines providing clear guidance concerning initial and long-term treatment of patients with DVT and cancer. The use of such guidelines will encourage a local standard of care and by the use of long-term LMWH will improve the outcome for patients with DVT and cancer.

A substantial clinical need also exists for an alternative to vitamin K–antagonist therapy for treating DVT in many patients other than cancer patients. A randomized trial evaluating self-managed LMWH therapy has provided further evidence on the balance of benefits and harms of its long-term use compared with long-term vitamin K–antagonist therapy suggested that LMWH had effectiveness similar to the usual vitamin K–antagonist treatment for preventing recurrent VTE in a broad spectrum of patients. Important clinically, however, is that long-term LMWH caused less harm as a result of bleeding and thus enhanced the clinicians’ therapeutic options for patients with DVT (Figure 2). This suggests the possibility of a broader range for long-term LMWH in selected patients without cancer.

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