Outpatient management of patients with venous thromboembolic disease

Background

Deep venous thrombosis (DVT), because of its sequelae, which include the risk of pulmonary embolism and posthrombotic syndrome, is a serious disease. Its incidence increases with age and accounts for between 1-3 cases per 1000 adult subjects (1). Until 10 years ago, DVT and pulmonary embolism (PE), with joint expression of venous thromboembolism (VTE) were strictly treated in hospital for 1-2 weeks. There were various reasons for such management of venous thrombosis and pulmonary embolism. One was the prevailing opinion that patients with VTE need strict bed rest to prevent thrombus mobilisation from the thrombosed peripheral veins leading to pulmonary embolism. Further, the limited treatment options of the acute disease with unfractionated heparin (UFH) were applicable only in hospital. Since, evidence has shown that bed rest does not prevent complications, including PE, and new anticoagulant drugs, particularly low-molecular weight heparin (LMWH), promote safe and effective treatment of DVT at home and in the out-patient department.

1 - Change in treatment

Many years ago it was shown that the anticoagulant drugs heparin and vitamin K antagonist significantly reduce thromboembolic complications (PE and mortality).(2) Patients used to be treated for VTE for at least one week in hospital with intravenous infusions of UFH. Simultaneously they received warfarin during the acute phase of the disease or longer - for at least three months. Such a treatment involves frequent regulatory check-ups to determine the optimal dosage of the drug for the individual patient. Therefore, treatment of this disease was possible only in hospital.
However, with the development of new parenteral anticoagulant drugs (LMWHs) two decades ago, and the recognition that early mobilisation does not increase the frequency of PE (3) the management of patients with VTE (4) changed significantly. Furthermore, low molecular weight heparin in comparison to UFH has many advantages; better bioavailability, a more standard and predictable anticoagulant effect and consequently regular check-ups of anticoagulant effects are not needed.
In parallel, studies have confirmed expectations that home treatment of patients with acute DVT with LMWH is as safe and effective as in-hospital treatment with UFH or LMWH (5). It was also shown that patients with DVT accompanied by PE without significant haemodynamic consequences can be safely treated at home (6,7).  
Further, in the last decade new oral anticoagulant agents (direct factor Xa and thrombin inhibitors) have demonstrated advantages over traditional anticoagulants, including administration at fixed doses, fewer food and drug interactions, and no requirement for routine coagulation monitoring. Rivaroxaban, apixaban and dabigatran have been investigated in a number of phase III trials for VTE treatment. Studies comparing efficacy of warfarin therapy with dabigatran have confirmed that at optimal dosing, dabigatran is at least as effective as warfarin (8). Similarly, rivaroxaban, a direct oral factor Xa inhibitor, is effective in treatment of DVT and it has non-inferior efficacy in respect to enoxaparin followed by vitamin K antagonist - with the same safety profile (9). In patients with acute DVT, apixaban, a direct oral factor Xa inhibitor, showed efficacy and safety similar to low-molecular-weight heparin followed by vitamin K antagonist, and was associated with significantly less bleeding (10). There are different therapeutic protocols for management of DVT with new oral anticoagulants: rivaroxaban and apixaban allow a single-drug regimen even in the acute phase of the disease; rivaroxaban 15 mg bid for 3 weeks, then rivaroxaban 20 mg od; apixaban 10 mg bid for 7 days, then apixaban 5 mg bid; while dabigatran requires 5–7 days of initial heparin treatment followed by dabigatran 150 mg bid. However, only rivaroxaban has been approved in Europe for the treatment of acute DVT and prevention of recurrent VTE. 

2 - Outpatient treatment

This shift in the type of treatment of DVT and the shift from hospital to outpatient department was enabled after the introduction of LMWH and after numerous controlled studies confirmed that outpatient treatment with LMWH is as effective and safe as traditional hospital treatment with UFH. In the mid-nineties, two randomised studies confirmed that a fixed dose of subcutaneous LMWH is as effective and safe as an adjusted dose of intravenous UFH for the initial management of VTE, regardless of whether the patient has PE or a history of VTE (11, 12). In both studies, the recurrent rate of VTE was low and comparable between the groups. The Vascular Midi Pyrenees Study confirmed the efficacy and safety of home treatment of DVT. One group was treated with LMWH at home from the start, whereas patients from the second group were first treated with LMWH in hospital for one week and in the outpatient department after that. There were no significant differences in the efficacy of treatment and complications (including major bleeding) (13). It seems that outpatient treatment of DVT is simpler. Nevertheless, outpatient treatment of DVT is based on the ability to coordinate multiple services, while hospitals have an integrated model of healthcare so that it is easy to manage patients with DVT in hospitals. Meanwhile, outpatient DVT management provides more patient satisfaction than inpatient treatment, and is associated with higher levels of physical activity, better social functioning and a more rapid return to active every-day life (14). Home treatment of DVT is also less costly than in-hospital treatment (15, 16). The new anticoagulant drugs will probably further simplify treatment of thromboembolic disorders in the outpatient setting.

3 - Selection criteria

Most patients with objectively confirmed DVT and patients with asymptomatic pulmonary embolism could be safely treated in an outpatient department or at home. The decision for in- or outpatient treatment depends on various factors; the extension of the thromboembolic process, accompanying internal or surgical diseases, the patient’s haemodynamic status, active bleeding, the patient’s adherence of the type of treatment and the support of family members and other services. 
Exclusion criteria for home treatment of DVT comprise: 

• Active bleeding or known haemorrhagic disease
• Recent stroke or a neural surgical procedure (in the last month)
• Acute DVT in spite of adequate anticoagulant treatment, 
• Heparin-induced thrombocytopenia (HIT) during previous heparin treatment
• Serum creatinine >200 μmol/L or a glomerular filtration rate (GFR) <30 ml/minpatient’s non-cooperation
• Accompanying other diseases hospital treatment

Conclusions

In the past, conventional management of an acute DVT consisted of initiating continuous infusion of intravenous unfractionated heparin in hospital, and patient bed rest. The advent of low molecular weight heparin, which exhibits prolonged bioavailability and easy dosing, has enabled outpatient management of DVT. Outpatient management of DVT has several advantages; it enables a higher level of physical activity, better social functioning and is less costly than hospital treatment. With only a few exceptions, most patients with DVT and low-risk symptomatic pulmonary embolism can be safely treated in the outpatient department.