The Clinical Validity of Normal Compression Ultrasonography in Outpatients Suspected of Having Deep Venous Thrombosis

Clinical trials have shown that, because the symptoms and signs of deep venous thrombosis are highly nonspecific, objective testing is required for patients suspected of having the condition [1-9]. Ultrasonography is the most commonly used test in the United States [10-13]; it is highly sensitive and specific for proximal venous thrombosis (thrombosis of the popliteal or more proximal veins) [10-14]. A recent report described a simplified ultrasonography technique in which imaging is limited to the deep veins at the groin and popliteal fossa [14]. These anatomic areas are evaluated by using the single criterion of vein compressibility [14]. This simplified compression ultrasonography technique is highly sensitive and specific for proximal venous thrombosis in outpatients suspected of having deep venous thrombosis [14]. Although imaging with the simplified technique is limited to the groin and popliteal fossa, it is very sensitive because thrombosis isolated to the iliac vein or superficial femoral vein is rare in symptomatic patients [15]. However, thrombosis confined to the deep veins of the calf is not rare, occurring in up to 13% of symptomatic patients [4-6]. Ultrasonography done by using compression, either alone or with color Doppler capacity, does not uniformly visualize the deep veins of the calf and has limited sensitivity (40% to 70%) for thrombosis of the calf veins [10-13, 16]. Therefore, serial testing is required to identify patients who develop extension of thrombosis into the popliteal vein or more proximal veins [6-917, 18], for whom treatment is required [19-21]. A clinical outcome study has shown that it is safe to withhold anticoagulation in symptomatic outpatients in whom the results of simplified compression ultrasonography are normal on initial testing and two repeated tests [17]. More than 500 000 patients are referred for testing each year in the United States [22]; 80% of these patients (400 000) will have a normal result on the first test and will need repeated testing [17]. Cost analysis shows that a single repeated test compared with two repeated tests results in substantial savings-$260 per patient (in 1990 U.S. dollars) [23]. Therefore, more than $100 million could be saved yearly in the United States if the use of two repeated tests were replaced by the use of one repeated test. However, the safety of this approach is uncertain because it has not been evaluated by clinical trials. Of the patients with normal initial ultrasonography results who then have abnormal results on repeated testing, half have abnormal results the day after presentation and half have abnormal results on day 7 [17]. Patients whose results are abnormal the day after presentation may have detectable thrombosis on the initial test if the popliteal vein is imaged beyond the popliteal fossa to its most distal point (that is, to the trifurcation of the calf veins) because compression ultrasonography is sensitive for thrombi that barely extend out of the calf veins into the popliteal vein [24]. Repeated testing could then be limited to a single test done 5 to 7 days after the first test [16, 23]. We performed a prospective cohort study of outpatients suspected of having first-episode deep venous thrombosis. This was done to test the safety of withholding anticoagulation in patients who 1) have normal results on simplified compression ultrasonography that was done at presentation and that completely imaged the popliteal vein to its most distal point and 2) have a normal result on a single repeated test done 5 to 7 days after the first test. We used long-term follow-up to test the validity of this approach because inadequate management of proximal venous thrombosis results in clinically evident venous thromboembolic events that can be measured objectively [19-21]. Methods Patients and Study Protocol The study sample consisted of consecutive outpatients who were suspected of having first-episode deep venous thrombosis and were referred by their physicians to the noninvasive vascular laboratory of University Hospital or Veterans Administration Medical Center in Oklahoma City, Oklahoma, between December 1993 and 31 December 1995. Each patient was seen by a consultant physician who obtained a clinical history, performed a physical examination, and evaluated the patient's eligibility for the study. Eligible patients who gave informed consent were then managed according to the study protocol (Figure 1). Patients were ineligible if compression ultrasonography could not be done because of physical or technical limitations, if the patients were unable to return for repeated testing in 5 to 7 days, if long-term follow-up was not possible because of geographic inaccessibility, if the patients had received therapeutic doses of heparin for more than 24 hours before their referral, or if the patients were pregnant. The institutional review board approved the study protocol. Figure 1. Study protocol and outcomes. Objective Testing for Venous Thrombosis at Study Entry Real-time B-mode ultrasonography was performed immediately after the clinical assessment. The simplified compression technique described by Lensing and colleagues [14] was used, with a minor modification as described below. Ultrasonography was performed by using an Acuson 128 scanner (Acuson Corp., Mountain View, California) equipped with a 7.5-MHz linear-array transducer. Both the common femoral and popliteal veins were imaged in gray scale and were assessed for compressibility [14]. The common femoral vein was imaged from the inguinal line to its bifurcation into the superficial femoral vein and profunda femoris. The popliteal vein was imaged from the proximal popliteal fossa to a point 10 cm distal from the mid-patella. This point was chosen to provide a reproducible method with which to approximate the most distal popliteal vein because the calf-vein trifurcation is often difficult to identify by ultrasonography. Vein anatomy in the popliteal fossa, as well as the formation of the popliteal vein itself, greatly varies; the classic trifurcation pattern is found in only a minority of patients [25-27]. Compressibility of the veins was assessed only in the transverse plane [14]. The results were categorized as normal if all imaged venous segments were fully compressible, as abnormal if a noncompressible segment was identified, or as inadequate for interpretation. If the result of initial compression ultrasonography was normal, anticoagulation was withheld and testing was repeated 5 to 7 days later. Anticoagulation was withheld from all patients whose results remained normal on compression ultrasonography (the normal cohort), regardless of their symptoms. If the result of initial or repeated testing was abnormal (the abnormal cohort), venography was done to confirm the extent of thrombosis. The venographic results were categorized as normal, positive for proximal venous thrombosis (thrombosis of the popliteal, femoral, or iliac vein with or without thrombosis of the calf vein), positive for isolated thrombosis of the calf vein, or inadequate for interpretation. The diagnostic criterion for the presence of deep venous thrombosis was an intraluminal filling defect that was constant on all films [28]. If the venogram was abnormal or inadequate for interpretation, anticoagulation was given unless contraindicated. If the venogram was normal, anticoagulation was not given and the abnormal ultrasonography result was considered falsely abnormal. Long-Term Follow-up All patients were instructed to immediately return to our clinic or emergency department if they had symptoms or signs of venous thrombosis or pulmonary embolism. They were also assessed routinely at 3 months either in the clinic or by telephone. At this follow-up assessment, an interval history was taken that addressed general health, specific symptoms (including leg pain, tenderness and swelling, chest pain, dyspnea, hemoptysis, and syncope), hospitalization, and use of anticoagulants. For all patients who died, the cause of death was determined either from autopsy or by independent clinical review. The primary outcome measure was a diagnosis of venous thrombosis or pulmonary embolism during follow-up confirmed by objective testing. The 3-month follow-up period was chosen because inadequate management of proximal venous thrombosis results in a high rate of recurrent venous thromboembolism during the subsequent 3 months [19-21]. All patients in either cohort who returned during 3-month follow-up with clinically suspected deep venous thrombosis underwent objective testing with impedance plethysmography, which was performed serially according to published protocols [7-929, 30]. Serial impedance plethysmography is highly sensitive and specific for proximal venous thrombosis in symptomatic patients [7-9]. Venography was indicated in patients with abnormal results on impedance plethysmography. If venography could not be done or the results of venography were inadequate, deep venous thrombosis was diagnosed if impedance plethysmography yielded abnormal results in the absence of conditions known to produce false-positive results [7-9, 29-31]. Patients suspected of having pulmonary embolism underwent objective testing with lung scanning and, if indicated, pulmonary angiography, according to published protocols and diagnostic criteria [32-34]. Methodologic Issues and Avoidance of Bias Care was taken to avoid bias. Selection bias was avoided by entering consecutive patients into the study. Bias during the initial testing period was avoided by defining criteria for normal and abnormal ultrasonography results a priori; by prohibiting venography or other objective leg testing in patients with normal ultrasonography results; and by withholding anticoagulation from all patients with normal ultrasonography results, regardless of their symptoms. Diagnostic suspicion bias [35] was avoided by objectively testing all patients who re