Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial.
Context Although physicians often recommend elastic stockings to help prevent the post-thrombotic syndrome, few studies have evaluated the stockings' effectiveness. Contribution One hundred eighty patients with proximal deep venous thrombosis (DVT) were randomly assigned to wear or not wear below-knee elastic compression stockings for 2 years. More than 90% of the patients assigned to elastic stockings wore them daily during the 2-year period, but 5 of 90 patients stopped using them because of itching, redness, or discomfort. Twenty-six percent of the patients in the elastic stockings group developed the post-thrombotic syndrome compared with 49% of controls. Implications Below-knee elastic compression stockings reduce post-thrombotic sequelae in patients with proximal DVT. The Editors One of every 3 to 4 patients with symptomatic proximal deep venous thrombosis (DVT) of the lower extremities will develop post-thrombotic sequelae (1-5). The incidence of the post-thrombotic syndrome is highest in elderly patients and after recurrent episodes of ipsilateral thrombosis (1, 3, 4, 6). This syndrome usually appears within 1 year after the index thrombosis (1, 2). Clinical presentation may vary from minor signs, including skin discoloration, venous ectasia, discomfort, and swelling, to severe manifestations, such as chronic pain, intractable edema, or leg ulcer (7, 8). Post-thrombotic sequelae have a substantial negative impact on quality of life (9) and have considerable socioeconomic consequences for both the individual patient and the health care system (10). There is indirect evidence that the incidence of the post-thrombotic syndrome is reduced when anticoagulation for the index episode of DVT is adequate in intensity and duration (1). Graduated elastic compression stockings assist the calf muscle pump and reduce venous hypertension and reflux, thereby reducing edema and improving tissue microcirculation (11-14). However, evidence supporting the effectiveness of elastic stockings comes primarily from the results of a single randomized study conducted in patients with proximal DVT, which assessed the post-thrombotic syndrome by using a nonvalidated scale (2). Use of tailor-made and sized-to-fit elastic stockings decreased the incidence of mild or moderate sequelae from 47% to 20% and decreased the incidence of severe sequelae from 23% to 11% (2). In practice, however, such stockings are difficult to use because they are not widely available and are relatively expensive. The limitations of the available evidence have hindered widespread implementation of compression elastic stockings for prevention of the post-thrombotic syndrome after DVT (15).We performed a randomized study to evaluate the efficacy of off-the-rack elastic compression stockings for prevention of post-thrombotic sequelae in patients with a first episode of acute symptomatic proximal DVT. Methods Study Design and Outcomes Our randomized, controlled trial evaluated the efficacy of below-knee compression elastic stockings, worn for 2 years, in preventing the post-thrombotic syndrome in patients with a first episode of proximal DVT. The main aim of the study was to compare the 5-year cumulative incidence of the post-thrombotic syndrome in patients who were assigned to the elastic stockings group and those who were not. We also assessed risk factors for the development of late sequelae. Patients Consecutive patients referred to the 2nd Division of Internal Medicine of the University of Padua, Padua, Italy, between January 1997 and March 2000 with clinically symptomatic proximal DVT, as confirmed by compression ultrasonography, were considered for the study. One of the trial physicians assessed eligibility criteria. Patients were excluded if they had recurrent ipsilateral DVT, preexisting leg ulcers or signs of chronic venous insufficiency, bilateral thrombosis, a short life expectancy, or a contraindication for use of stockings (for example, advanced-stage peripheral arterial insufficiency). Patients who met the inclusion criteria and had no exclusion criteria received detailed written information about the study hypotheses and procedures and were asked to participate. In detail, they were informed that the value of elastic stockings for prevention of post-thrombotic sequelae was uncertain and that they would be randomly assigned to wear or not wear a supplied elastic stocking during the daytime. Patients had to give written informed consent to participate in the study. The Institutional Review Board of the University of Padua approved the study protocol. Anticoagulant Treatment Patients were treated with unfractionated or low-molecular-weight heparin, followed by at least 3 months of vitamin K antagonist therapy (target international normalized ratio, 2.0 to 3.0). Heparin treatment was discontinued when the international normalized ratio remained above 2.0 for 2 consecutive days and patients had received heparin for at least 5 days. All patients received initial treatment and began taking vitamin K antagonists while in the hospital. Patients with transient risk factors were scheduled to receive up to 3 months of oral anticoagulant therapy, while patients with idiopathic thrombosis received at least 6 months of treatment. Patients with permanent risk factors, such as active cancer, were treated for the entire study period. The duration of anticoagulant treatment followed international guidelines and was adapted to conform to each patient's preferences and risk profile. The individual quality of oral anticoagulation was considered satisfactory if the international normalized ratio was within or above the therapeutic range in more than 70% of measurements. Study Procedures At hospital discharge, an average of 1 week after admission (range, 5 to 10 days), patients were randomly assigned in blocks of 20 to the elastic stockings group (that is, to wear a below-knee, graded compression stocking on the affected leg) or to the control group. Study group assignment was based on a computer-generated list that was accessible only to a trial nurse, who informed study physicians about treatment allocation after patients had provided informed consent. New Medical Service, Linea Flebologica Flebysan, Rovigo, Italy, supplied the elastic stockings. The stockings, which were flat-knitted, applied 30 to 40 mm Hg of pressure at the ankle; they were made of cotton, latex, and rubberpolyamide and were available in 5 sizes. Patients received 2 stockings, which were replaced by identical stockings every 6 months. The stockings had to be used during the day or longer for a period of 2 years. The elastic stockings used in this study are currently sold in Europe for approximately 35.00 euros ($42 U.S.) each. At baseline, a clinical history was taken detailing risk factors for venous thrombosis: malignant disease, recent trauma or surgery (within 3 months), prolonged immobilization (>7 days) due to medical illnesses, pregnancy or puerperium, ongoing hormonal therapy, and previous contralateral venous thrombosis. In all patients, we searched for a thrombophilic abnormality (that is, antithrombin, protein C or S deficiency, factor V Leiden mutation, prothrombin G20210 gene mutation, and lupus-like anticoagulants) before anticoagulation was started or at least 2 weeks after anticoagulation was completed, according to standard procedures (16). Patients were discharged with a letter for their family physician indicating that they had agreed to participate in a randomized study assessing the value of elastic stockings and specifying treatment allocation. Patients and their family physicians were given a card that listed the telephone numbers of the thrombosis clinic. Follow-up and Assessment of Recurrent Thromboembolism All patients were followed for a maximum of 5 years. The study was to be stopped when the last recruited patient reached 3 years of follow-up. All patients were asked to attend regular examinations at the study center at 3 and 6 months from the index event and every 6 months thereafter. In the interval between scheduled visits, patients were asked to report to the study center if symptoms or signs worsened. Patients who could not attend follow-up examinations at the study center were visited at home. Patients were asked to return to the center if they developed symptoms suggestive of recurrent venous thromboembolism. Recurrent thromboembolic events were diagnosed as described elsewhere (17-19). Date and cause of death were documented for all patients who died during follow-up. Assessment of the Post-Thrombotic Syndrome Patients were instructed not to wear their stockings on the day of assessment and not to reveal their treatment allocation to the assessor. Therefore, each assessment was performed by an investigator who was aware of the side of the index DVT but did not know the treatment allocation or the results of previous measurements. Only the side of the index DVT was considered for development of the post-thrombotic syndrome. The presence and severity of post-thrombotic signs and symptoms were scored by using a standardized scale, the same as that used in our previous investigations (1, 20, 21). The presence of 5 leg symptoms (pain, cramps, heaviness, pruritus, and paresthesia) and 6 objective signs (pretibial edema, induration of the skin, hyperpigmentation, new venous ectasia, and redness and pain during calf compression) was scored. For each item, a score of 0 to 3 was assigned by using the contralateral unaffected leg as the denominator for all evaluations. A lower-limb venous ulcer indicated severe post-thrombotic syndrome regardless of the sum of the remaining signs and symptoms. In the absence of a venous ulcer, patients were classified as having severe post-thrombotic syndrome if they had a score of 15 or more on 2 consecutive visits at least 3 months apart. A total score of 5 to 14 on 2 consecutive visits at least 3 months apart indicated mild post-throm