Abstract
The post-thrombotic syndrome (PTS) is the major chronic sequel of deep vein thrombosis (DVT) of the leg, and is a major socioeconomic challenge. In addition to systematic prophylaxis of DVT in hospitalized patients, effective management of DVT is important to reduce the incidence of PTS. Thrombolysis and thrombectomy are not indicated routinely. Optimal anticoagulation, usually with heparins initially and then with oral warfarin, is important to prevent recurrent DVT, which is a major risk factor for PTS. Following a routine three-month period of anticoagulation, patients with proximal idiopathic DVT should be individually assessed for the benefits and risks of continued oral anticoagulation, including patient preferences. Risk factors for recurrent DVT include active cancer, pregnancy, continued use of oral oestrogens, male sex, obesity, recurrent thrombosis, established PTS, permanent inferior vena caval filters, residual DVT, high fibrin D-dimer and other thrombophilias. Early walking, continued high levels of physical activity and wearing compression stockings for up to two years may also reduce the risk of PTS.
Introduction
The post-thrombotic syndrome (PTS) is a cluster of leg symptoms (heaviness, pain, cramps, itch, paraesthesiae) and signs (oedema; skin induration, hyper-pigmentation, redness, venous ectasia and ulceration; and pain during calf compression), which develops after one or more episodes of deep vein thrombosis (DVT). While variable in severity, overall it is an important chronic cardiovascular disease that imposes a major social and economic burden on patients and their health-care systems.1–3
The incidence of PTS varies widely in published studies. 1 Recent prospective studies suggest that the incidence appears lower than in previous reports (10–20% by 2 years following a first, objectively confirmed symptomatic episode of DVT), especially if patients are adequately treated with anticoagulant therapy for at least three months, and are prescribed elastic compression stockings for at least two years.1,4–8 The initial extent, and degree of occlusion of DVT have been associated with risk of PTS in some reports9,10 but not in others. 1 However, recurrence of DVT in the ipsilateral leg is consistently reported as a major risk factor for PTS.1,5,9,11
Reducing the incidence of PTS in the UK by optimal management of DVT involves three national strategies:
Optimal prophylaxis of DVT. About 50% of cases of DVT occur following hospitalization (hospital-acquired DVT), and most of these could be prevented by routine risk assessment of all patients admitted to hospital, followed by prescription of effective thromboprophylaxis to all patients at significant risk. This is now mandated across the UK;12–14
Antithrombotic treatment of DVT;
Physical activity and use of elastic compression stockings by patients with DVT.
The remainder of this article considers (b) and (c).
Antithrombotic treatment of DVT
Thrombolysis and thrombectomy
Thrombolysis or thrombectomy have been advocated in the initial treatment of DVT, on the assumption that earlier restoration of venous patency reduces the risk of PTS. 1 However:
As noted above, the associations between extent and occlusiveness of DVT and risk of PTS have not been clearly established; 1
The risk of PTS does not appear to be significantly reduced by thrombolysis or thrombectomy, compared with conventional anticoagulant therapy; 1
The adverse effects (bleeding, other surgical complications) and costs of thrombolysis and thrombectomy are greater than those of conventional anticoagulant therapy.
Hence, current UK practice is to limit these treatments in DVT to patients with threatened limb viability (venous gangrene).14,15
Initial anticoagulation with heparins
Current UK practice is to initiate treatment of suspected acute DVT with subcutaneous or intravenous heparin (low-molecular weight [LMW] or unfractionated), and to add an oral anticoagulant (usually warfarin) when the diagnosis is confirmed.14,15 Heparin should be continued until warfarin has an adequate anticoagulant effect (international normalized ratio [INR] of the prothrombin time >2.0 for 2 consecutive days). Continued heparin is preferred to warfarin in pregnancy (warfarin causes fetal malformations and bleeding) and in patients with active cancer (in whom heparin is associated with less bleeding and also a lower risk of recurrence than warfarin).14,15
Subcutaneous LMW heparins have the advantages over unfractionated heparin of once-daily administration, more predictable effect, no need for routine monitoring of clotting times and lower risk of heparin-induced thrombocytopenia. Many UK hospitals now have teams of thrombosis nurses who organize routine DVT management (diagnosis, patient education, antithrombotic therapy, elastic compression stockings and follow-up) on an outpatient basis. However, there is no evidence that LMW heparin treatment is more effective than unfractionated heparin in prevention of PTS. 16
Continued anticoagulation with oral anticoagulants
Current UK practice is to continue anticoagulation with warfarin for at least three months following a first episode of DVT.14,15 The rationale is to minimize the risks of pulmonary embolism (PE), recurrent DVT and PTS (as noted above, recurrent DVT is a risk factor for PTS).1,5,9,11 The target INR is 2.0–3.0,14,15 and patients with suboptimal control of oral anticoagulants have a higher risk of PE, recurrent DVT and PTS. In one study, patients who had an INR <2.0 for more than 50% of the time were twice as likely to develop PTS. 11
New oral anticoagulants are currently under evaluation, in comparison with warfarin, in treatment of DVT, as well as in prophylaxis of DVT, and prophylaxis of stroke in atrial fibrillation. They include direct antithrombins (e.g. dabigatran) and inhibitors of factor Xa (e.g. rivaroxaban). They have a more predictable effect than warfarin; less interaction with foods, alcohol and other drugs; and do not require routine monitoring of clotting times. Whether or not they reduce the risks of recurrent DVT, and of PTS, compared with warfarin remains to be established.
With regard to duration of warfarin, three months is adequate for patients with a low risk of recurrence. These include the following:
Patients in whom DVT is provoked by a major reversible risk factor, e.g. trauma, surgery, medical illness, immobilization, pregnancy or oestrogen treatment. Their risk of recurrence is low (<5%) in the first year, hence does not justify the bleeding risks, inconvenience and costs of continued warfarin;14,15,17,18
Patients in whom DVT is not provoked by such a risk factor (‘spontaneous’ or ‘idiopathic’ DVT), but is confined to the calf veins. Their risk of recurrence is again low, and does not justify continuing warfarin after three months.19–21
Continued anticoagulation with warfarin after three months should be considered in patients with idiopathic proximal DVT (and also in patients with idiopathic PE). Their risk of recurrence is >5% per year. Several randomized trials of different durations and intensities of oral anticoagulation have been performed in such patients. As expected, continued anticoagulation reduces the risks of recurrent DVT and PE, and increases the risk of bleeding. However, the composite outcome of recurrent DVT/PE, major bleeding and death appears to be reduced. 22
Realizing the results of these trials in clinical practice requires that patients with a first episode of idiopathic proximal DVT (or PE) should be similar to patients included in such trials, and also have access to good quality management of anticoagulation. 22 Patients’ perceptions and preferences also vary widely. 22 Hence, decisions on long-term anticoagulation require an individualized approach, considering patient preferences, risk factors for recurrence and risk factors for bleeding22,23 (Table 1).
DVT = deep vein thrombosis; PE = pulmonary embolism; HRT = hormone replacement therapy; PTS = post-thrombotic syndrome; IVC = inferior vena caval
Among clinical risk factors for recurrence, active cancer and pregnancy carry the highest risk and, as previously noted, continued heparin is preferred to warfarin in such patients for the duration. Male sex increases the relative risk by 1.6 (95% CI, 1.2, 2.0). 24 There is a linear increase in risk with body weight. 25 Continued use of oral contraceptives 26 or oral hormone replacement therapy 27 increases the risk. A further idiopathic event 28 or evidence of PTS 29 also increases the risk, as do permanent inferior vena caval (IVC) filters. 30
Residual ultrasonic evidence of DVT after completion of a routine three-month course of oral anticoagulation has been associated with increased risk of recurrence, although results are conflicting.21,31 Routine imaging for residual DVT at this time is not widely performed in the UK.
Among laboratory tests, persistently raised levels of fibrin D-dimer, measured one month after discontinuation of oral anticoagulants, appears to be the most promising candidate to add to clinical risk factors for risk stratification in consideration of risk of recurrence and long-term oral anticoagulation.32,33 It is routinely available in UK hospitals for exclusion of suspected DVT or PE; and raised levels are also associated with PTS. 10 While several other tests for thrombophilias and coagulation activation (genetic or acquired) are under evaluation, none currently appears indicated in routine clinical practice.
While some have proposed to combine clinical and laboratory risk factors for recurrence in risk scores, 29 these require validation. Meanwhile, evaluation of the risks and benefits of continued oral anticoagulation in prevention of recurrent DVT, and of PTS, remains an individualized process, including patient preferences.
Physical activity and use of elastic compression stockings for patients with DVT
Physical activity
Early walking and continued high levels of physical activity appear to reduce the risks of thrombus extension and PTS. 34
Compression stockings
Two randomized controlled trials have shown 50% reduction in the incidence of PTS with compression stockings, used for up to two years.6,35
The ongoing large SOX trial will expand the evidence base on efficacy of compression stockings, and the associated Bio-SOX study is investigating the predictive value of biomarkers for the development of PTS. 36
Conclusion
The management of DVT to reduce the risk of PTS includes routine DVT prophylaxis in hospital patients; optimal management of DVT to prevent recurrence with anticoagulants; early walking, high physical activity and use of elastic compression stockings.
Key points table
Adequate anticoagulation in acute DVT, to prevent recurrent DVT, is important in the prevention of PTS;
Continued warfarin after three months should be routinely considered in patients with an idiopathic proximal DVT, including assessment of risk factors for bleeding, risk factors for recurrence and patient preferences;
Risk factors for recurrence include active cancer, pregnancy, continued use of oral oestrogens, male sex, obesity, second or subsequent idiopathic event, established PTS, permanent IVC filter, residual DVT or high D-dimer after stopping oral anticoagulation, and possibly thrombophilias;
Early walking, continued high physical activity and use of elastic compression stockings for at least two years may also reduce the risk of PTS.