Noninvasive Diagnosis of Deep Venous Thrombosis

  1. Clive Kearon, MB, PhD;
  2. Jim A. Julian;
  3. M Math;
  4. Toni E. Newman, BA; and
  5. Jeffrey S. Ginsberg, MD
  1. for the McMaster Diagnostic Imaging Practice Guidelines Initiative. For members of the McMaster Diagnostic Imaging Practice Guidelines Initiative, Diagnosis of Deep Venous Thrombosis Working Group, see Appendix. Grant Support: Dr. Ginsberg is a Career Investigator of the Heart and Stroke Foundation of Ontario. Ms. Newman is supported by the Cancer Care Ontario Practice Guidelines Initiative. Requests for Reprints: Clive Kearon, MB, PhD, McMaster Medical Unit, Henderson General Hospital, 711 Concession Street, Hamilton, Ontario L8V 1C3, Canada. Current Author Addresses: Dr. Kearon: McMaster Medical Unit, Henderson General Hospital, 711 Concession Street, Hamilton, Ontario L8V 1C3, Canada.
     
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    Abstract

    Purpose: To review noninvasive methods for diagnosis of first and recurrent deep venous thrombosis and provide evidence-based recommendations for the diagnosis of deep venous thrombosis in symptomatic, asymptomatic, and pregnant patients.

    Data Sources: Accuracy (comparison with contrast venography) and management (safety of withholding anticoagulants when results were normal) studies that evaluated tests for diagnosis of deep venous thrombosis were identified from a MEDLINE search, personal files, and bibliographies of reviews and original studies.

    Study Selection: Prospective cohort studies (accuracy and management studies) and randomized comparisons (management studies) that satisfied predefined methodologic criteria were included.

    Data Extraction: Sensitivity, specificity, and positive and negative predictive values were determined for accuracy studies. Rates of venous thromboembolism during long-term follow-up of patients with normal results were determined for management studies.

    Data Synthesis: Data from individual studies were combined under a random-effects model. The accuracy of noninvasive tests was compared, with emphasis on within-study comparisons. Recommendations for diagnosis of deep venous thrombosis were developed by a multidisciplinary group and graded according to the strength of the supporting evidence.

    Venous ultrasonography is the most accurate noninvasive test for the diagnosis of a first symptomatic proximal deep venous thrombosis.However, neither ultrasonography nor impedance plethysmography is accurate in asymptomatic postoperative patients. Venous ultrasonography is less accurate for symptomatic isolated distal (calf) deep venous thrombosis than for proximal deep venous thrombosis, and the clinical utility of venous ultrasonography of the distal veins is uncertain. Withholding anticoagulant therapy in symptomatic patients with suspected deep venous thrombosis who have normal results on serial venous ultrasonography or impedance plethysmography is safe. Diagnosis of recurrent deep venous thrombosis requires evidence of new thrombus formation, such as a new noncompressible venous segment detected by venous ultrasonography, conversion of a normal result on impedance plethysmography to abnormal, or presence of an intraluminal filling defect on venography. Suspected deep venous thrombosis in pregnant patients can usually be managed with serial venous ultrasonography or impedance plethysmography. In symptomatic patients with a suspected first episode of deep venous thrombosis, clinical assessment and d-dimer testing are complementary to testing with venous ultrasonography and impedance plethysmography.

    Conclusions: Patients with suspected deep venous thrombosis can usually be managed with noninvasive testing. However, if the results of this testing are nondiagnostic or are discordant with the clinical assessment, venography should be considered.

    Deep venous thrombosis affects approximately 84 persons per 100 000 each year [1]. For each person with confirmed deep venous thrombosis, the diagnosis is excluded in approximately 3 others. This suggests that more than 1 million patients are investigated for suspected deep venous thrombosis in North America annually. Objective testing for deep venous thrombosis is crucial because clinical assessment alone is unreliable [2-5], because undiagnosed deep venous thrombosis can cause fatal pulmonary embolism [6, 7], and because treatment of deep venous thrombosis is effective [8-10]. However, treatment is expensive and is associated with side effects, and its inappropriate use should be avoided.

    Contrast venography is the gold standard for diagnosis of deep venous thrombosis [11-13] but is not ideal because of its invasive nature, its technical demands, its costs, and the risks associated with contrast media. Many noninvasive tests have therefore been developed for the diagnosis of deep venous thrombosis [10, 14], causing confusion. To identify optimal strategies and generate recommendations [15] for the diagnosis and management of suspected deep venous thrombosis, we performed a critical review of the literature.

    Of the noninvasive methods for diagnosis of deep venous thrombosis, impedance plethysmography [16, 17] and venous ultrasonography (compression ultrasonography with or without Doppler flow assessment) [18-20] have been extensively evaluated and are widely used. Therefore, we concentrated on the roles of impedance plethysmography and venous ultrasonography in the diagnosis of deep venous thrombosis. We also considered clinical assessment, fibrinogen leg scanning [21], and d-dimer blood tests [22, 23] as adjuncts to impedance plethysmography and venous ultrasonography.

    Key elements of the natural history of deep venous thrombosis that relate to the clinical setting in which the condition occurs must be appreciated. Deep venous thrombosis usually starts in the calf [3, 7, 21, 24, 25]. When deep venous thrombosis causes symptoms, more than 80% of them involve the popliteal or more proximal veins (proximal deep venous thrombosis) [5, 25-29]. However, in asymptomatic high-risk patients (such as those who have just had orthopedic surgery), only about one third of deep venous thromboses are proximal [29-33]. In patients with isolated calf (hereafter called distal) deep venous thrombosis, about 20% of thromboses subsequently extend into the proximal veins [21, 24], usually within a week of presentation [34-39]. Nonextending distal deep venous thrombosis rarely causes pulmonary embolism, whereas proximal deep venous thrombosis often does [21].

    The implications of these observations are that 1) isolated distal deep venous thrombosis is uncommon in symptomatic patients, 2) isolated nonextending distal deep venous thrombosis is of minor clinical importance, and 3) proximal extension of distal deep venous thrombosis more than a week after presentation is unusual. Thus, management strategies that use serial impedance plethysmography or venous ultrasonography, which detect proximal deep venous thrombosis at presentation and extending distal deep venous thrombosis with repeated testing, have been developed.

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    Methods

    A panel of thromboembolism physicians, radiologists, radiographers, clinical epidemiologists, and emergency medicine physicians was assembled as part of the McMaster Diagnostic Imaging Practice Guidelines Initiative, McMaster University, Hamilton, Ontario, Canada. This group framed questions, generated and circulated initial evidence-based recommendations, and collated and integrated feedback [15, 40, 41].

    We addressed the following question: What are the validated noninvasive approaches for the diagnosis of deep venous thrombosis in patients with 1) a suspected first deep venous thrombosis [symptomatic and asymptomatic patients], 2) suspected recurrent deep venous thrombosis, and 3) suspected deep venous thrombosis during pregnancy?

    Studies evaluating diagnostic strategies for deep venous thrombosis fall into two broad categories: accuracy studies, in which the new test is compared with an accepted criterion standard (such as venography), and management studies, in which long-term clinical follow-up is done to validate the safety of withholding anticoagulation on the basis of negative test results (that is, a very low frequency of subsequent venous thromboembolism). To provide an unbiased evaluation and to be included in this review, studies had to satisfy predefined methodologic requirements [42-48]. For accuracy studies, all patients must have had venography; the new test and venography must have been evaluated independently (that is, in a blinded manner); consecutive patients must have been studied; the study must have been prospective; and at least 50 evaluable patients must have been studied. For management studies, the study must have been prospective; patients must have been enrolled consecutively; all patients who had anticoagulation withheld on the basis of negative results of serial diagnostic tests must have completed follow-up; objective testing (such as venography, venous ultrasonography, or ventilation-perfusion lung scanning) during follow-up must have been used to evaluate suspected venous thromboembolism (deep venous thrombosis or pulmonary embolism); and at least 50 patients must have been studied. Within-study comparisons of diagnostic tests were considered if two or more tests were performed in the same patients (accuracy studies) or if patients were randomly assigned to evaluation with different tests (accuracy or management studies).

    Studies published by January 1997 were identified from a MEDLINE search done by using combinations of the following Medical Subject Headings, text words, and publication types: thrombosis, thrombophlebitis, plethysmography, impedance, ultrasonography, randomized, controlled trials, and cohort studies. The authors' personal files and bibliographies of original papers and reviews [14, 18, 49] were also searched. A few methodologically sound, recently published abstracts were included. Data were primarily abstracted by one of the authors. Data were independently abstracted on a random sample of approximately 10% of included studies [26, 31, 32, 38, 50, 51] by a second author to assess reliability. In this sample, there was exact agreement between the two authors on 44 of 47 categorical and numerical variables shown in Table 1 and Table 4, Table 2 and Table 5, and Table 3, representing a high level of agreement (94%). Subsequently, a third author checked all tables for internal consistency and re-extracted data from original articles to resolve possible discrepancies.

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    Table 1. Accuracy of Impedance Plethysmography for the Diagnosis of a First Deep Venous Thrombosis in Symptomatic and Asymptomatic Patients*
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    Table 4. Table 1. Continued
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    Table 2. Accuracy of Venous Ultrasonography for the Diagnosis of a First Deep Venous Thrombosis in Symptomatic and Asymptomatic Patients*
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    Table 5. Table 2. Continued
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    Table 3. Management Studies Using Serial Impedance Plethysmography or Venous Ultrasonography in Symptomatic Patients with a First Suspected Deep Venous Thrombosis

    This review was undertaken as part of the Health Services Research Initiative of the Department of Radiology, McMaster University, and did not receive industry funding.

    We determined sensitivity for proximal deep venous thrombosis, isolated distal deep venous thrombosis, and all deep venous thromboses; specificity for all deep venous thromboses; positive predictive value for proximal deep venous thrombosis and all deep venous thromboses; and negative predictive value for proximal deep venous thrombosis, isolated distal deep venous thrombosis, and all deep venous thromboses [42].

    For management studies, the incidence of venous thromboembolism during 6 months of follow-up was determined for patients in whom anticoagulation and additional diagnostic testing were withheld on the basis of normal results on serial testing. This was often supplemented by venographic determination of the positive predictive value of an abnormal test result at presentation.

    Data from individual studies were combined by using a random-effects model in which each study is considered to be part of a distribution of effects rather than samples from a single effect. Weighted means were calculated by using weights that were the inverse of the combined within-study and between-study variance. Homogeneity of study findings was assessed by using a chi-square statistic to compare equality of study-specific proportions that were derived by using a fixed-effects model weighted according to the inverse of within-study variance. An associated P value of 0.05 or less was taken as statistically significant evidence of heterogeneity [85]. In management studies and in accuracy studies of symptomatic patients, the unit of analysis was usually patients; in accuracy studies of asymptomatic patients, the unit was either patients or limbs.

    Only studies that satisfied all of the methodologic requirements appropriate to their design were included. The strength of the evidence from individual studies was graded as level 1 or 2, depending on sample size. Level 1 evidence was precise (that is, 95% CIs of ± 5% for estimates from accuracy and management studies or statistically significant differences from studies that compared diagnostic tests). Level 2 evidence did not satisfy these requirements.

    On the basis of our level of confidence, which in turn was based on the quality and quantity of the available evidence, recommendations for diagnostic testing were graded from A to C. A grade of A was assigned on the basis of level 1 evidence from management studies that consistently showed the strategy to be safe. A grade of B was assigned on the basis of the following: 1) level 1 evidence from accuracy studies and a) level 1 evidence from management studies that were generally supportive but were inconsistent with each other or b) no or only small [level 2 evidence] management studies; or 2) level 2 evidence from accuracy or management studies that had consistent findings. A grade of C was based on a consensus of expert opinion without level 1 or 2 evidence that justified a grade of A or B.

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    Data Synthesis

    Literature Review

    Accuracy of Impedance Plethysmography and Venous Ultrasonography in Patients with a First Suspected Deep Venous Thrombosis

    Selected sensitivities, specificities, and positive and negative predictive values of impedance plethysmography and venous ultrasonography for a first episode of deep venous thrombosis in symptomatic and asymptomatic patients are shown in Table 1 and 2 and Figure 1. Most indices of accuracy of impedance plethysmography and venous ultrasonography in both symptomatic and asymptomatic patients showed statistically significant evidence of heterogeneity (Table 1 and Table 2). In general, venous ultrasonography was more accurate than impedance plethysmography, and the accuracy of both tests was higher for proximal deep venous thrombosis than for distal deep venous thrombosis and was higher for symptomatic deep venous thrombosis than for asymptomatic deep venous thrombosis (Figure 1).

    Figure 1. Weighted means and 95% CIs were derived from the studies shown in and . All = all instances of deep venous thrombosis; proximal = proximal deep venous thrombosis; distal = isolated distal deep venous thrombosis; symptomatic = symptomatic patients; asymptomatic = asymptomatic postoperative patients at high risk for deep venous thrombosis; PV = predictive value.
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    Figure 1. Weighted means and 95% CIs were derived from the studies shown in and . All = all instances of deep venous thrombosis; proximal = proximal deep venous thrombosis; distal = isolated distal deep venous thrombosis; symptomatic = symptomatic patients; asymptomatic = asymptomatic postoperative patients at high risk for deep venous thrombosis; PV = predictive value. Accuracy of impedance plethysmography and venous ultrasonography for diagnosis of a first episode of deep venous thrombosis in symptomatic and asymptomatic patients.Table 1Table 2

    Management Studies Using Serial Impedance Plethysmography or Venous Ultrasonography in Symptomatic Patients with a First Suspected Deep Venous Thrombosis

    The main findings of individual studies are shown in Table 3. The safety of withholding anticoagulation in patients with normal results on serial venous ultrasonography was consistent across studies (P > 0.2), with a mean frequency of 2.0% (95% CI, 0.0% to 4.9%) for subsequent confirmed venous thromboembolism during 6 months of follow-up. Studies that evaluated the safety of withholding anticoagulation after normal serial impedance plethysmography showed significant heterogeneity (P = 0.03), with a mean frequency of 1.5% (CI, 0.8% to 2.2%) for subsequent confirmed venous thromboembolism during 6 months of follow-up.

    In these studies combined, 4 of 1625 patients (0.25% [CI, 0.07% to 0.63%]) with normal results on initial impedance plethysmography died of pulmonary embolism during serial testing (2 patients) or long-term follow-up (2 patients) [83]. These deaths occurred in a single study that evaluated a new computerized impedance plethysmography machine [83]. One of 1747 patients (0.06% [CI, 0.00% to 0.32%]) with a normal result on initial venous ultrasonography died of pulmonary embolism during serial testing [39]; no patient died during long-term follow-up.

    Management Studies Using Serial Impedance Plethysmography or Venous Ultrasonography in Asymptomatic Patients with a First Suspected Deep Venous Thrombosis

    Consistent with the poor accuracy of impedance plethysmography in asymptomatic patients (Table 1 , Table 4), surveillance with serial impedance plethysmography is not a safe management approach in asymptomatic patients with a high risk for venous thromboembolism. Three of 716 patients (0.42% [CI, 0.09% to 1.22%]) with major trauma died of pulmonary embolism during serial testing with impedance plethysmography [86]. The safety of surveillance with serial venous ultrasonography in high-risk asymptomatic patients is also uncertain. After neurosurgery, 5 of 349 patients (1.4% [CI, 0.5% to 3.3%]) with normal results on serial proximal venous ultrasonography developed symptomatic venous thromboembolism during an unspecified period of follow-up (including 2 patients who had fatal pulmonary embolism after discharge) [87]. In a second small study [88], none of 52 patients (0% [CI, 0% to 7%]) with pelvic fractures who had normal results on serial venous ultrasonography developed symptomatic venous thromboembolism during 6 weeks of follow-up.

    Comparison of Impedance Plethysmography and Venous Ultrasonography for Detecting a First Deep Venous Thrombosis

    Level 1 evidence from one study [55] found that venous ultrasonography was more accurate than impedance plethysmography for detecting deep venous thrombosis in symptomatic outpatients (sensitivity for proximal deep venous thrombosis, 89% compared with 77%; P = 0.02) (Table 1 , Table 4 [55] and Table 2 and (Table 5) [5]). Level 2 evidence from one study [28] found no difference in accuracy between impedance plethysmography and venous ultrasonography in symptomatic hospitalized patients (sensitivity for proximal deep venous thrombosis, 96% compared with 97%) (Table 1 , Table 4 and Table 2 , Table 5). Venous ultrasonography was more accurate than impedance plethysmography in asymptomatic postoperative patients (positive predictive value for all deep venous thrombosis, 89% compared with 47%; P = 0.02) (Table 1 , Table 4 and Table 2 , Table 5) [33]. Consistent with these within-study comparisons, between-study comparisons support superior accuracy of venous ultrasonography compared with impedance plethysmography (Figure 1).

    Comparison of Impedance Plethysmography and Venous Ultrasonography for Management of a First Suspected Deep Venous Thrombosis

    Level 1 evidence from one study [38] found that serial venous ultrasonography and serial impedance plethysmography were equally safe management approaches in outpatients with a first suspected deep venous thrombosis but that the positive predictive value of an abnormal result on venous ultrasonography was higher (94% compared with 83%; P = 0.02) (Table 3). Between-study comparisons suggest that the safety of management of a first suspected deep venous thrombosis with serial venous ultrasonography and the safety of serial impedance plethysmography are similar (Table 3).

    Combinations of Tests for Diagnosis of a First Deep Venous Thrombosis

    Clinical assessment and impedance plethysmography. A structured clinical assessment of pretest probability has been shown to validly classify outpatients with suspected deep venous thrombosis into high probability (prevalence, 85%), moderate probability (prevalence, 33%), and low probability (prevalence, 5%) categories [5]. Combining clinical assessment of pretest probability with the results of impedance plethysmography improves diagnostic accuracy [89] (level 1 evidence). Whereas the negative predictive value of impedance plethysmography for all deep venous thrombosis was only 55% in patients with a high pretest probability, it was 97% in patients with a low pretest probability. Conversely, whereas the positive predictive value of impedance plethysmography was only 35% in patients with a low pretest probability, it was 92% in patients with a high pretest probability [89].

    Fibrinogen leg scanning and impedance plethysmography. Combining fibrinogen leg scanning with impedance plethysmography increases sensitivity for all deep venous thrombosis in symptomatic patients (about 92% compared with 72% for impedance plethysmography alone) [26, 34, 90] and asymptomatic patients (about 50% compared with 13%) [30, 31, 91] (level 1 evidence). However, the clinical utility of this combination of tests for assessment of a first suspected deep venous thrombosis is doubtful [30, 31, 34]. For this reason, and because of concerns about viral transmission, this approach to the diagnosis of deep venous thrombosis is no longer used.

    d-dimer blood testing and impedance plethysmography. d-dimer is formed when cross-linked fibrin is lysed by plasmin, and elevated levels of d-dimer can be used to detect deep venous thrombosis. Various d-dimer assays are available, and their accuracy differs markedly [22, 23]. Although all d-dimer assays have a low positive predictive value for deep venous thrombosis [22, 23], some have high sensitivity and negative predictive values [22, 92, 93]. One d-dimer assay had a sensitivity of 89% (CI, 77% to 96%) and a negative predictive value of 95% (CI, 90% to 98%) for all deep venous thromboses in symptomatic outpatients (level 1) [93]. The combination of a normal result on impedance plethysmography and a normal result on d-dimer testing had a negative predictive value of 97% (CI, 92% to 99%) for all deep venous thromboses and 99% (CI, 96% to 100%) (level 1 evidence) for proximal deep venous thrombosis [93]. A subsequent management study reported that it was safe to withhold anticoagulants in patients with normal results on d-dimer testing and impedance plethysmography on the day of presentation (negative predictive value, 98.5% [CI, 96% to 100%] for deep venous thrombosis during 3 months of follow-up) (level 1 evidence) [94].

    Clinical assessment and venous ultrasonographic imaging. Combining clinical assessment with venous ultrasonography improves diagnostic accuracy for deep venous thrombosis, and deep venous thrombosis can be diagnosed or excluded when the two test results agree [5] (level 1 evidence). For example, the combination of low clinical suspicion and a normal result on venous ultrasonography has a negative predictive value of 98% (CI, 95% to 99%) for all deep venous thromboses [5].

    d-dimer testing and venous ultrasonography. The combination of normal results on d-dimer testing and venous ultrasonography probably has a very high negative predictive value in symptomatic patients, but this hypothesis has yet to be formally assessed.

    Diagnosis of Recurrent Deep Venous Thrombosis

    Because residual venous abnormalities are common after treatment of deep venous thrombosis, diagnosis of recurrent deep venous thrombosis requires evidence of new clot formation.

    Venography that outlines all of the deep venous system and does not show an intraluminal filling defect excludes recurrent deep venous thrombosis. Presence of an intraluminal filling defect is diagnostic of acute deep venous thrombosis, whereas nonfilling of venous segments with contrast media, a common finding after deep venous thrombosis, is nondiagnostic [95-98].

    About 60% of abnormal impedance plethysmography results return to normal after 3 months of treatment, and 90% return to normal at 1 year [96, 99]. In symptomatic patients, conversion of impedance plethysmography results from normal to abnormal has a positive predictive value for recurrent deep venous thrombosis of about 80% [95, 96]. Level 2 evidence from one study [96] supports the safety of withholding treatment in patients with suspected recurrent deep venous thrombosis on the basis of normal results on serial impedance plethysmography with no episodes of venous thromboembolism (CI, 0% to 19%) during 6 months of follow-up. Level 1 evidence from one study [95] supports the use of serial impedance plethysmography in combination with leg scanning in this setting with a 1.1% frequency of venous thromboembolism (CI, 0.13% to 3.9%) during 6 months of follow-up.

    Persistent abnormalities on proximal venous ultrasonography are present in about 80% of patients 3 months after and 50% of patients 1 year after proximal deep venous thrombosis [97, 98]. The finding of a new noncompressible segment in the common femoral vein or popliteal vein is considered diagnostic of recurrence, but this finding is uncommon in patients with recurrent deep venous thrombosis [97, 98]. One level 2 study found that a 2-mm increase in the diameter of the common femoral or popliteal vein, measured during compression and compared with results of previous venous ultrasonography, had a sensitivity of 100% (CI, 69% to 100%) and a specificity of 100% (CI, 81% to 100%) for recurrent deep venous thrombosis (one isolated distal deep venous thrombosis was excluded from this analysis) [98]. These findings were only partially supported by two subsequent preliminary reports [100, 101]. For this assessment to be done, a previous venous ultrasonogram is needed for comparison. Other venous ultrasonographic criteria for the diagnosis of recurrent deep venous thrombosis, such as changes in thrombus length (without a new noncompressible common femoral vein or popliteal vein segment), Doppler flow (spectral or color Doppler), or intraluminal appearance, have not been rigorously evaluated.

    On the basis of extrapolations from studies using venous ultrasonography in symptomatic patients with a suspected first deep venous thrombosis and studies using impedance plethysmography in patients with suspected recurrent deep venous thrombosis, serial venous ultrasonography is expected to be a safe management approach in patients with suspected recurrent deep venous thrombosis who have normal results on an initial test (that is, a fully compressible common femoral vein and popliteal vein).

    Diagnosis of Deep Venous Thrombosis during Pregnancy

    The diagnosis of deep venous thrombosis during pregnancy is complicated because nonthrombotic causes of leg pain and swelling are common and because there is a clinical impression that the risk for isolated iliac deep venous thrombosis is increased. In pregnant patients, serial impedance plethysmography is the only diagnostic approach that has been rigorously evaluated, and it seems safe ([37, 51] [level 1 evidence]) (Table 3). Although serial venous ultrasonography is also likely to be safe in this setting, it is probably insensitive to isolated iliac deep venous thrombosis.

    Recommendations for the Diagnosis of Deep Venous Thrombosis

    First Deep Venous Thrombosis in Symptomatic Patients

    Findings that are diagnostic of deep venous thrombosis include the following.

    1. Venous ultrasonography: Noncompressibility of the common femoral vein or popliteal vein (grade A). Noncompressibility that is confined to the superficial femoral vein, the distal portion of the popliteal vein, or the deep veins of the calf is associated with a lower positive predictive value (approximately 80%) [25, 39, 55] and should be evaluated with venography (grade B).

    2. Impedance plethysmography: Abnormal result on impedance plethysmography and a high clinical suspicion of deep venous thrombosis (grade A). An abnormal result on impedance plethysmography combined with a moderate or low clinical suspicion of deep venous thrombosis should be evaluated with venous ultrasonography or venography (grade B).

    3. Venography: Intraluminal filling defect seen in more than one view (grade A). Nonfilling of the deep veins despite repeated injection of contrast, although highly suggestive of deep venous thrombosis (grade C), must be interpreted in light of the clinical presentation and other investigations (such as results of impedance plethysmography or venous ultrasonography).

    Findings that exclude deep venous thrombosis include the following.

    1. Venography: Normal result (grade A).

    2. Venous ultrasonography: Normal results on venous ultrasonography of the common femoral vein and the politeal vein [including the calf vein trifurcation] and 1) low clinical suspicion of deep venous thrombosis [grade A] or 2) a normal result on a d-dimer assay (which has been shown to be sensitive for deep venous thrombosis) (grade C, extrapolated from experience with impedance plethysmography).

    3. Impedance plethysmography: Normal results on impedance plethysmography and a d-dimer assay (grade B).

    Role of Serial Noninvasive Testing in Patients with a Suspected First Deep Venous Thrombosis Who Have Nondiagnostic Results on Initial Tests

    Serial testing with impedance plethysmography or venous ultrasonography to detect deep venous thrombosis extension is recommended for patients with normal results on impedance plethysmography or venous ultrasonography in whom deep venous thrombosis is not excluded on the day of presentation (grade A).

    1. Venous ultrasonography: One or more follow-up tests should be done over 7 days. If the distal popliteal vein and calf vein trifurcation are not included in the examination, two or more follow-up examinations should be performed (grade A). If clinical suspicion of deep venous thrombosis is high, venography should be considered (grade C) [5].

    2. Impedance plethysmography: Two or more follow-up tests should be done over 7 to 14 days (grade A). If clinical suspicion of deep venous thrombosis is high, venous ultrasonography, venography, or both should be considered (grade C). Approaches to diagnosing a first symptomatic deep venous thrombosis by using venous ultrasonography and impedance plethysmography are shown in Figure 2.

    Figure 2. * = Follow-up venous ultrasonography after 7 days is recommended in all pregnant patients. If clinical suspicion of iliac deep venous thrombosis is high (for example, if the entire leg is swollen or if the patient has back pain), venography or impedance plethysmography should be done. † = In pregnant patients, if symptoms and signs of deep venous thrombosis are confined to below the knee or if intraluminal filling defects are found on limited venography (with abdominal shielding), radiologic examination of the iliac veins is not necessary.
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    Figure 2. * = Follow-up venous ultrasonography after 7 days is recommended in all pregnant patients. If clinical suspicion of iliac deep venous thrombosis is high (for example, if the entire leg is swollen or if the patient has back pain), venography or impedance plethysmography should be done. † = In pregnant patients, if symptoms and signs of deep venous thrombosis are confined to below the knee or if intraluminal filling defects are found on limited venography (with abdominal shielding), radiologic examination of the iliac veins is not necessary. Approaches to diagnosing a first symptomatic deep venous thrombosis (DVT) with venous ultrasonography (VU) or impedance plethysmography (IPG).

    Diagnosis of a First Deep Venous Thrombosis in Asymptomatic Patients

    1. Venography: Venography is the only test that is reliable for the diagnosis of deep venous thrombosis in asymptomatic patients (grade A).

    2. Venous ultrasonography: The role of surveillance testing with venous ultrasonography in asymptomatic patients at high risk for deep venous thrombosis is uncertain. If an abnormal result on venous ultrasonography is found in this setting, confirmatory venography is recommended (grade B).

    3. Impedance plethysmography: Surveillance testing with impedance plethysmography is not recommended (grade A).

    Recurrent Deep Venous Thrombosis

    Findings that are diagnostic for recurrent deep venous thrombosis include the following.

    1. Venography: Intraluminal filling defect seen in more than one view (grade A).

    2. Impedance plethysmography: Conversion of a normal result on impedance plethysmography to an abnormal result strongly suggests recurrent deep venous thrombosis (grade A), as does an abnormal result on impedance plethysmography (no previous test available for comparison) 1 year or more after a previous deep venous thrombosis (grade C). Preferably, these findings should be accompanied by additional evidence of deep venous thrombosis (such as an abnormal result on venous ultrasonography) (grade C).

    3. Venous ultrasonography: A new noncompressible common femoral or popliteal vein (grade A). A 4-mm or greater increase in venous diameter during compression compared with a previous result on venous ultrasonography strongly suggests recurrent deep venous thrombosis (grade B).

    Findings that exclude recurrent deep venous thrombosis include the following.

    Venography: Visualization of all of the deep veins without an intraluminal filling defect (grade A).

    Role of Serial Noninvasive Tests in Patients with Suspected Recurrent Deep Venous Thrombosis

    Serial noninvasive testing can be used to manage patients with suspected recurrent deep venous thrombosis if results of impedance plethysmography (grade B) or venous ultrasonography of the proximal veins (grade C) are normal at presentation.

    Management of Patients with Abnormal but Nondiagnostic Results on Tests for Recurrent Deep Venous Thrombosis

    It is difficult to diagnose or exclude recurrent deep venous thrombosis in patients with persistent abnormalities in the proximal veins (that is, abnormal results on impedance plethysmography, noncompressible veins on venous ultrasonography, and nonfilling of deep veins on venography) that are not diagnostic of recurrent thrombosis. Absence of an increase of 1 mm or more in the diameter of the common femoral and the popliteal veins during compression relative to previous results of venous ultrasonography excludes recurrent proximal deep venous thrombosis (grade B). With this finding, repeated testing is recommended after 1 to 3 days and at 1 week (grade C).

    Clinical suspicion and results of d-dimer testing, serial venous ultrasonography, lung scanning, fibrinogen leg scanning, and nuclear magnetic imaging may help differentiate between old and new deep venous thrombosis. Data are inadequate to propose firm guidelines for the use of these tests and interpretation of their results in patients with nondiagnostic venous ultrasonograms, impedance plethysmograms, and venograms. However, if a thorough evaluation does not yield convincing evidence of recurrent deep venous thrombosis, we recommend that anticoagulation be withheld and patients be followed closely (grade C).

    As approach to the diagnosis of recurrent deep venous thrombosis is shown in Figure 3.

    Figure 3. * = If clinical suspicion for deep venous thrombosis is high, venography should be considered. ILFD = intraluminal filling defect; IPG = impedance plethysmography; VU = venous ultrasonography.
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    Figure 3. * = If clinical suspicion for deep venous thrombosis is high, venography should be considered. ILFD = intraluminal filling defect; IPG = impedance plethysmography; VU = venous ultrasonography. Approach to the diagnosis of recurrent deep venous thrombosis (DVT).

    Diagnosis of Deep Venous Thrombosis in Pregnancy

    Suspected deep venous thrombosis during pregnancy can usually be managed with impedance plethysmography (grade B) or venous ultrasonography (grade C), the results of which are interpreted in the same way they are interpreted for nonpregnant patients (Figure 2). If results of impedance plethysmography or venous ultrasonography of the proximal veins are normal and there is high clinical suspicion of isolated distal deep venous thrombosis, limited venography with abdominal shielding should be considered (grade B). If the result of venous ultrasonography is normal and there is high clinical suspicion of iliac deep venous thrombosis, impedance plethysmography or full venography should be done (grade C).

    Qualifying Remarks

    Our objective was to evaluate the evidence supporting the use of noninvasive tests to detect deep venous thrombosis and to develop practical recommendations for the diagnosis of this condition in different clinical situations. We emphasize that these are guidelines rather than rigid protocols; local factors (such as accessibility of impedance plethysmography or venous ultrasonography) or individual patient factors may influence diagnostic approaches. We focused on impedance plethysmography and venous ultrasonography alone or in combination with other tests because these two tests have been most rigorously evaluated. Emerging evidence suggests that the negative predictive value of certain d-dimer tests, particularly when combined with low clinical suspicion, may be sufficient to exclude deep venous thrombosis [92, 93]. Magnetic resonance imaging may also be accurate for the diagnosis of deep venous thrombosis [102, 103] and may be indicated if isolated iliac vein thrombosis is suspected, particularly if contrast venography is contraindicated [102-104].

    We combined the results of individual studies to yield weighted means as a summary statistic. However, we caution against attaching undue emphasis to these estimates [45, 105, 106]. Although all studies included are methodologically rigorous, they are still heterogenous in terms of the populations studied and the specific examination techniques or diagnostic criteria used (for example, for venous ultrasonography); these and other factors [107] influence accuracy estimates.

    Within-study comparisons of venous ultrasonography and impedance plethysmography support the superiority of venous ultrasonography for the diagnosis of deep venous thrombosis [33, 38, 55]. Venous ultrasonography is also advantageous because it may identify alternative causes of leg symptoms (such as Baker cyst or neoplasm) [18, 57, 59, 64, 67]. Nevertheless, serial impedance plethysmography has generally been found to be a safe management strategy [34-38, 51]. A high mortality rate in a management study that used a new computerized impedance plethysmography system [83] and recent reports of low sensitivity of impedance plethysmography for proximal deep venous thrombosis in three accuracy studies [55, 108, 109] (two of which were not eligible for this review despite having a low potential for bias [108, 109]) have undermined confidence in impedance plethysmography. Consequently, we recommend that additional tests (such as venous ultrasonography and venography) be done in patients with a negative result on initial impedance plethysmography in whom clinical suspicion of deep venous thrombosis is high (grade C).

    Incomplete venous compressibility with application of probe pressure at the common femoral vein and mid-popliteal vein is the most accurate venous ultrasonographic imaging diagnostic criterion for deep venous thrombosis [29, 50, 60, 65, 82]. The appearance of intraluminal venous ultrasonography has been reported to have variable accuracy [29, 50, 58, 60, 65], and neither changes in venous diameter during a Valsalva maneuver [29, 58, 59, 72] nor Doppler assessment of blood flow [50, 64, 65, 82] have been found to improve diagnostic accuracy for deep venous thrombosis. Thus, we do not believe that these assessments should influence diagnosis. Venous ultrasonography may be suitable for the diagnosis of isolated distal deep venous thrombosis, but reported experience is limited and reported accuracy is highly variable [57, 63, 67, 70, 110] Table 2 and (Table 5). The additional diagnostic value of Doppler flow assessment, examination of the deep veins between the common femoral vein and the popliteal vein in symptomatic patients, intraluminal appearance on venous ultrasonography, and examination of the calf vein in patients with normal results on proximal venous ultrasonography deserve further evaluation.

    Our recommendations for the diagnosis of deep venous thrombosis in pregnant patients are influenced by the belief that the risk to mother and child from inadequate diagnostic testing is greater than the risk from radiation exposure associated with venography [111]. We and others [10, 14, 49] conclude that noninvasive testing for deep venous thrombosis is not reliable in asymptomatic patients; venography is the only accurate test in this setting. However, the clinical utility of screening for post-operative deep venous thrombosis in asymptomatic persons is uncertain. It was recently shown that predischarge screening for deep venous thrombosis done by using venous ultrasonography and confirmatory venography after arthroplasty does not improve outcomes in patients who have received prophylaxis against venous thromboembolism [112].

    The approach to diagnostic testing that we recommend is consistent with that of other recent reviews [10, 14, 113]. To our knowledge, however, this is the only review that has used a methodologically rigorous format to develop guidelines [15, 40, 114, 115] for the diagnosis of deep venous thrombosis.

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    Conclusions

    The accuracy and utility of noninvasive tests for the diagnosis of deep venous thrombosis vary with the indication for testing (that is, the population studied). Symptomatic patients can usually be managed with noninvasive testing. Venous ultrasonography that assesses compressibility of the proximal veins is the optimum noninvasive method currently available for the diagnosis of deep venous thrombosis. However, if the findings of noninvasive tests are equivocal or are discordant with clinical assessment, venography should be considered. Diagnostic algorithms and criteria are presented for specific patient populations. Our recommendations are based on currently available evidence and will need to be updated as further studies are done. Such studies may focus on specific subgroups of patients, on refinement of diagnostic criteria of venous ultrasonography, or on evaluation of combinations of tests.

    Addendum: Since this article was submitted for publication, two level 1 studies have been published that evaluated venous ultrasonography, alone [116] or in combination with clinical assessment [117], for management of a first suspected deep venous thrombosis. Birdwell and colleagues [116] confirmed that two normal venous ultrasonograms obtained 1 week apart exclude progressive deep venous thrombosis. During 3 months of follow-up, symptomatic venous thromboembolism occurred in 0.6% (CI, 0.1% to 2.1%) of patients. Wells and coworkers [117] confirmed that a single normal venous ultrasonogram excludes progressive deep venous thrombosis if the clinical assessment of pretest probability is low. During 3 months of follow-up, symptomatic venous thromboembolism occurred in 0.3% (CI, 0.0% to 1.7%) of patients. In addition, this study confirmed that two normal venous ultrasonograms obtained 1 week apart exclude progressive deep venous thrombosis (frequency of venous thromboembolism during follow-up, 1.2% [CI, 0.1% to 4.4%]) if the pretest probability is moderate. Wells and coworkers confirmed that the predictive value of venous ultrasonography is reduced (to about 80%) if the results of this test are discordant with the clinical assessment of pretest probability.

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    Appendix

    The following are members of the McMaster Diagnostic Imaging Practice Guidelines Initiative, Diagnosis of Deep Venous Thrombosis Working Group.

    Jeffery S. Ginsberg, MD (Chair), Patrick Brill-Edwards, MD, George Browman, MD, Geoffrey Coates, MB, Kathy Gilles, RT, David Hynes, MD, Jim A. Julian, M.Math, Eric Jurriaans, MB, Clive Kearon, MB, Toni Newman, BA, Dennis Psutka, MD, Margret Sabine, MD, Harald Stolberg, MD, and A. Graham Turpie, MD.

    Mr. Julian: Hamilton Civic Hospitals Research Centre, 711 Concession Street, Hamilton, Ontario L8V 1C3, Canada.

    Ms. Newman and Dr. Ginsberg: McMaster University, HSC 2C9A, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada.

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    1. Ann Intern Med April 15, 1998 vol. 128 no. 8 663-677
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