Prevention of Postthrombotic Syndrome

Abstract

General Considerations

Despite conventional anticoagulation therapy (low-molecular-weight heparin [LMWH] for 5 days followed by warfarin), 30%-50% of the patients with deep venous thrombosis (DVT) will develop the postthrombotic syndrome (PTS)¹ which consists of a constellation of symptoms and signs of variable severity. These include limb swelling, pain, heaviness, itching, skin changes, and ulceration.² The most predictive single clinical finding is the presence of a venous ulcer that may occur as early as 3 months.³ The established PTS is a significant cause of chronic incapacity and inability to work with considerable consequences for both the patient and the society.^4–7

Postthrombotic syndrome is the result of venous hypertension produced by reflux in veins with damaged valves and/or persisting outflow obstruction.⁸ Venous hypertension is associated with chronic inflammation affecting not only the venous wall but also the microcirculation producing excessive capillary leakage and impairment of skin nutrition with skin changes and eventual skin ulceration.⁹

Factors associated with the development of PTS consist of iliofemoral DVT,^4,5 chronic iliofemoral vein obstruction,^10,11 increased body mass index,^5,12 recurrent DVT,¹² which often obstructs part of the collateral circulation and subtherapeutic anticoagulant therapy that allows recurrence.¹³ More recently, it has been demonstrated that elevated inflammatory biomarkers such as interleukin 6, intercellular adhesion molecule 1, and C-reactive protein^14,15 are also associated with increased rates of PTS following DVT.

Prevention of PTS

Prevention of primary and secondary DVT

Prevention of DVT should reduce the prevalence of PTS in the general population. There is an interplay between PTS and recurrent DVT. Patients with PTS have a high frequency of recurrent DVT. Recurrent DVT in the same leg results in a higher frequency and severity of PTS. Until recently, PTS was viewed as a late complication. However, recent data show that PTS occurs early and that review of signs and symptoms at 1 month after the onset of DVT is highly predictive of the presence of PTS.⁵ Prevention of recurrence in patients with DVT will lessen the severity and frequency of PTS. The evidence and guidelines for primary prevention have been summarized in sections 3-12 and for secondary prevention in sections 14, 15, 17, and 18. Guidelines aiming to reduce PTS and leg ulcers by 50% in the next 10 years have been published.¹⁶

Graduated elastic compression

Effective elastic compression has been shown to reduce venous hypertension and edema and to minimize damage to the microcirculation.^17,18 Four RCT involving 745 patients demonstrated that in patients with proximal DVT, elastic compression for 2 years reduces the incidence of PTS from 39% to 19% (relative risk [RR] 0.49; 95% confidence interval [CI] 0.38-0.62).^19–22 It appears that treatment with LMWH combined with early ambulation and elastic compression further prevents PTS.^23,24

Early thrombus removal

Thrombectomy was popularized 30 years ago. Early surgical thrombectomy in a small series of patients with iliofemoral DVT was associated with increased iliac vein patency compared to standard anticoagulation therapy alone (67% vs 34%; RR for patency 1.92; 95% CI 1.06-3.51) and decreased incidence of PTS from 93% in the absence of thrombectomy to 58% when thrombectomy was performed (RR 0.63; 95% CI 0.44-0.90).^25,26

Limited data with catheter-directed thrombolysis (CDT) from observational cohort studies and comparative nonrandomized studies appear to demonstrate increased vein patency and reduction in the incidence of PTS compared to conventional anticoagulation^27–30

Two RCTs compared pharmacologic CDT with standard anticoagulation involving a total of 138 patients with iliofemoral DVT.^31,32 At 6 months, the patency rate was 70% in the CDT group and 33% in the standard anticoagulation group (RR 0.48; 95% CI 0.33-0.70). The second study continued to recruit 209 patients and has recently reported on iliofemoral patency and PTS.³³ Iliofemoral patency at 6 months was 64% in the CDT group and 47% in the conventional treatment group (RR for patency 1.42; 95% CI 1.09-1.85). At 24 months, PTS developed in 41% of the patients in the CDT group and 56% of the patients in the standard anticoagulation therapy group (RR 0.74; 95% CI 0.55-1.00; P = .047). Clinically relevant bleeding events occurred in 9% of the patients. More RCTs are needed with PTS as the primary end point to assess efficacy and harm.

Relief of chronic postthrombotic obstruction of iliofemoral segment

Prospective observational studies have raised the hope that percutaneous endovascular venoplasty and stenting to relieve chronic venous obstruction may alleviate the symptoms of PTS.^10,34 The RCTs are needed to demonstrate the efficacy of endovascular venoplasty and stenting for preventing symptoms and ulcer recurrence.

In the largest series published,¹⁰ primary, assisted-primary, and secondary cumulative patency rates at 72 months were 79%, 100%, and 100%, respectively, for nonthrombotic disease and 57%, 80% and 86%, respectively, for thrombotic disease. Severe leg pain (visual analogue scale >5) and leg swelling (grade 3) decreased from 54% to 44%, respectively, prior to stenting to 11% and 18% after stenting. At 5 years, cumulative rates for complete relief of pain and swelling were 62% and 32%, respectively, and ulcer healing occurred in 58%. The mean construction and international validation questionnaire (CIVIQ) scores of quality of life improved significantly in all categories. The RCTs are needed to determine efficacy.

Long-term LMWH

Standard treatment of DVT (initial LMWH for 5 days followed by vitamin K antagonist [VKA]) prevents thrombus extension and embolization but does not directly lyse the thrombus that often results in only partial recanalization. Several studies have compared long-term treatment with LMWH versus standard therapy^35–40 and have demonstrated better recanalization in the long-term LMWH groups. A meta-analysis on 5 studies that reported on total recanalization demonstrated a risk ratio of 0.66 (95% CI 0.57-0.77; P < .0001) in favor of long-term LMWH.⁴¹ In a large multicenter study involving 480 patients, there was a reduction in PTS (RR 0.77; P = .001).⁴² Pooled analysis from 2 studies reporting on subsequent development of leg ulcers^42,43 yielded an 87% risk reduction with LMWH for the incidence of venous ulcers (P = .019).⁴¹

Recommendations

Adherence to the guidelines for the prevention of primary DVT in hospitalized patients is essential. In patients who present with DVT, every effort should be made to reduce the recurrence rates. This can be achieved using adequate intensity and duration of anticoagulation according to the guidelines.

Early thrombus removal using CDT (level of evidence: low) or pharmacomechanical thrombolysis (level of evidence: low) may be used in expert centers in selected patients with iliofemoral DVT. If thrombolysis is contraindicated, surgical thrombectomy could be used in expert centers (level of evidence: low). Angioplasty and stenting of a proximal stenosis along with early thrombus removal may be required (level of evidence: low). However, a method to select appropriate patients for this procedure is not available.

Although conventional anticoagulation (LMWH for 5 days followed by VKA) is based on a high level of evidence in terms of VTE recurrence, prolonged therapy with LMWH in patients with proximal DVT is preferable in terms of PTS prevention (level of evidence: moderate).

In patients with proximal DVT, graduated elastic compression stockings for at least 2 years in addition to appropriate anticoagulation are recommended (level of evidence: high).

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