Source, year
Patients (n)
Prevalence of DVT (%)
Proportion of proximal DVTs detected by the second CUS % (95% CI)
Three-month thromboembolic risk, % (95% CI)a
Birdwell et al. [22], 1998
405
16
2 (0.8–4.2)
0.6 (0.1–2.1)
Cogo et al. [10], 1998
1702
24
0.9 (0.3–1.2)
0.7 (0.3–1.2)
Bernardi et al. [23], 1998
946
28
5.7 (1.9–12.8)
0.4 (0–0.9)
Wells et al. [24], 1997
593
16
1.8 (0.3–5.2)
0.6 (0.1–1.8)
Perrier et al. [25], 1999
474
24
N.A.*
2.6 (0.2–4.9)
Kraaijenhagen et al. [26], 2002
1756
22
3 (1.9–5.2)
0.7 (0.3–1.6)
Pooled estimate
5876
23
N.A.
0.6 (0.4–0.9)
Clinical Outcomes of Patients Treated with Anticoagulants for Distal DVT
Two registry-based analyses aimed to assess patients’ outcomes after a symptomatic distal DVT and identified 933 and 1885 eligible patients, respectively. As the vast majority of patients included in these French (OPTIMEV) [3] and international (RIETE) [27] registries received therapeutic anticoagulation (97% and 89%, respectively), these studies could not add knowledge on the true natural history of distal DVT. Nevertheless, they revealed interesting findings on some differences between patients treated for distal and proximal DVT. The 3-month VTE rate was similar in distal and proximal DVT patients. However, mortality was significantly higher in patients with proximal DVT vs distal DVT in both studies (8% vs 4.4% in OPTIMEV and 7.5% vs 2.7% in RIETE). In distal DVT patients, mortality was non-VTE related in the majority of cases. Interestingly, distal DVT was found to be more often associated with transient risk factors (such as recent travel, hospitalization, and recent surgery) than proximal DVT.
The long-term outcome after stopping treatment in patients prescribed therapeutic anticoagulation for distal DVT was analyzed in two recent prospective observational studies. The first study consisted of a 3-year follow-up of patients included in the OPTIMEV registry. It showed that after treatment cessation, patients with distal DVT (n = 490) had a lower annual rate of overall VTE recurrence compared to patients with proximal DVT (2.7% vs 5.2%, p = 0.02), but a similar rate of PE (0.9% vs 1%, p = 0.83). Some predictors of recurrence in patients with index distal DVT were identified: age > 50 years, unprovoked event, and multiple distal vein involvement [13]. The second study was a single-center small study (n = 90) assessing 2-year outcomes after stopping therapeutic anticoagulation for distal DVT. Treatment duration was of 30 days and 3 months in patients with provoked and unprovoked distal DVT, respectively. In this study, male sex and the presence of cancer were associated with higher VTE recurrence rates after treatment cessation, whereas location and the provoked character of the index distal DVT were not [28].
Comparison of Patients’ Outcomes Between Treated and Untreated Patients
Variations in study design and target populations are too large to allow a clinically relevant pooled estimate to compare the proportion of patients with distal DVT who extend to proximal DVT between treated and untreated patients. Nevertheless, a systematic review published in 2006 reported an estimated rate of extension of 10% (95% CI, 7–12%) in untreated patients and of 4% (95% CI, 3–6%) in treated patients [2].
A recent systematic review published this year, including prospective cohort studies and some of the most recent randomized studies, reported an overall proximal extension rate varying between 0 and 35%, corresponding to a mean extension rate of 9%. Although the true signification of a mean value in view of the large heterogeneity of studies can be debated, it helps to give a rough idea of the potential range of extension rate. The reported rate of PE ranged from 0 to 5.8% with a mean rate of 1.4%. None of the available studies found that anticoagulant treatment was associated with a reduction in adverse outcomes. In terms of bleeding, the major bleeding rate (excluding an older study which showed a high major bleeding rate of 7%) was of 0–2.1% in patients treated with anticoagulants, whereas no major bleeding was reported in patients who did not receive anticoagulant treatment [21].
All these elements highlight the uncertainty about the natural history of distal DVT, its clinical significance, and the need for its treatment and modality and duration of treatment. The increasing occurrence of this medical condition since the implementation in many vascular laboratories of systematic whole-leg compression ultrasound in all patients with suspected DVT has led to considerable efforts over the last 10–15 years to answer the question on the need for its treatment with anticoagulants, without any definitive conclusion but with some important data on the potential necessity to stratify the risk of extension in patients with distal DVT to guide decision on treatment. In view of the uncertainty regarding the necessity to treat distal DVT, the question of the necessity to diagnose distal DVT can be raised. As the diagnostic management of distal DVT varies as widely as its therapeutic management among centers, this issue is discussed first in detail the next section. Then, the most recent studies comparing outcomes between treated and untreated patients will be discussed in a dedicated section.
Venous Ultrasonography for the Diagnosis of DVT
Venous compression ultrasound using B-mode imaging was first reported in 1986 and is currently the main ultrasonographic method used to diagnose DVT [29]. This technique allows a two-dimensional imaging of the lower extremity veins. With the patient in the supine position and a slight external rotation of the leg, deep veins can be visualized starting from the common femoral vein at the inguinal level and then followed down along the femoral vein (formerly called superficial femoral vein although this vein is part of the deep venous system). The popliteal and calf veins are better assessed in sitting position. Normal veins collapse completely under pressure applied by the transducer. When a thrombus is present, compression of the vein is impossible. Inability to compress the vein, also called noncompressibility , is the most reliable criterion for DVT diagnosis [30]. This technique is illustrated in Figs. 24.1 and 24.2.
Fig. 24.1
Schematic representations of compression testing using the ultrasound probe. Adapted from reference [31]. A normal compression test is depicted in (a) and (b). The third schematic image depicts incompressibility of the vein, the most reliable and validated criterion for DVT diagnosis (c) (A artery, V vein, T transducer ultrasound probe)
Fig. 24.2
Ultrasound images of compression testing of a normal vein. Vein seen before compression. (a) Under compression (image on the right side), the vein is not seen any more as it is fully compressed. (b) Adapted from reference [31] (A artery, V vein)
Other criteria for the diagnosis of acute DVT are reported in the literature and are summarized in Table 24.2. Direct thrombus visualization using B-mode imaging has variable accuracy, since visibility of the clot may depend on its age. Fresh thrombus usually appears anechoic and can be missed [32]. Enlargement of the occluded vein is another criterion for acute thrombosis. Doppler studies (color flow imaging or spectral Doppler ) are used to assess venous blood flow. Color flow imaging can assist in the characterization of the thrombus as obstructive or partially obstructive. These diagnostic criteria have not been shown to improve diagnostic accuracy for DVT and should not be used without the noncompressibility criterion to confirm DVT [33]. However, it is important to point out that the examination of the Doppler signal at the level of the common femoral vein can give indirect evidence of iliac and inferior vena cava patency [30].
Table 24.2
Ultrasonographic diagnostic criteria for acute lower limb deep vein thrombosis
Primary diagnostic criterion | Secondary diagnostic criteria |
|---|---|
Vein noncompressibilitya | Echogenic thrombus within the lumen of the veinb |
Vein distention | |
Absence of pulsed wave or color Doppler signal within the vein lumen | |
Loss of venous flow phasic pattern (associated with breathing) and/or response to Valsalva’s maneuver |
Different Protocols of Compression Ultrasound (CUS)
Depending on the extent of lower limb venous system examination, two main types of protocols using compression maneuvers are described in the literature [34]. The proximal CUS (two-point or extended CUS) limits ultrasonographic examination to the proximal deep veins, whereas the whole-leg or complete CUS assesses both proximal and distal deep veins of the leg. These technical distinctions are important to discuss in detail as the applied diagnostic protocol has a direct impact on the rate of diagnosis (± treatment) of distal DVT.
Proximal CUS
The so-called two-point proximal CUS is limited to the assessment of compressibility limited to the common femoral and popliteal veins in transverse plane with a linear probe. With the patient in supine position, the common femoral vein is first identified at the level of inguinal ligament by using the laterally situated common femoral artery as a reference point. The popliteal vein is scanned with the patient in seated or lateral decubitus position and the transducer placed posteriorly in the popliteal fossa. The popliteal vein is generally located above the popliteal artery . This protocol was first described by Lensing et al. in 1989 [35]. The rationale to restrict the examination to these two “points” is based on phlebographic studies which showed the extreme rarity of isolated DVT of the femoral vein between these two points [17]. However, CUS protocols are not always identical between studies using serial proximal CUS (see below). For example, Perrier et al. [25] used a two-point examination (as described above), while Wells et al. [10] also imaged the femoral vein along the thigh. Cogo et al., Kraaijenhagen et al., and Bernardi et al. performed a two-point CUS but extended the popliteal imaging to the calf trifurcation [11, 26, 36]. Finally, Birdwell et al. tried to define more precisely to which extent the popliteal area was imaged , by describing that veins were imaged down to 10 cm under the patella [22].
Management studies using repeat proximal CUS performed at 1-week interval (“serial” testing) have been reported to be safe regardless of the exact proximal imaging protocol used (Table 24.1) [22–26, 36]. However, these differences in diagnostic protocols at the popliteal level highlight the limitations in the ability to provide an exact definition of a distal DVT (vs a proximal DVT) which is thus quite variable. The complexity and variations in the anatomy of the popliteal division render this task even more difficult. Nonetheless, DVTs located near the popliteal vein are generally considered as proximal DVTs and, in the abovementioned studies, received anticoagulation as prescribed for all proximal DVTs.
Single Complete (Proximal and Distal) or Whole-Leg CUS
The ultrasonography protocols described above do not take into account distal veins. Consequently, other authors proposed standardized protocols that assessed the whole leg: all proximal veins (common femoral, femoral, and popliteal veins) and calf veins (posterior tibial, peroneal, and calf muscle veins) are examined. This kind of ultrasound examination has been called whole-leg or complete CUS. Of note, most authors agree that examination of anterior tibial veins is not mandatory as isolated anterior tibial vein DVT is exceptionally rare [37]. Whole-leg CUS as a single diagnostic test in ambulatory patients with suspected symptomatic DVT has been validated in six prospective cohort studies (Table 24.3) and one randomized control trial [11, 37–42].
Table 24.3
Performances and safety of a single complete (proximal and distal) compression ultrasonography for diagnosing DVT in management outcome studies
Source, year | Patients (n) | Prevalence of all DVT n (%) | Distribution of DVT level n (%) | Three-month thromboembolic risk % (95% CI)a | |
|---|---|---|---|---|---|
All | Proximal | Distal | Single proximal and distal CUS | ||
Elias et al. [37], 2003 | 623 | 204 (33) | 112 (55) | 92 (45) | 0.5 (0.1–1.8) |
Schellong et al. [38], 2003 | 1646 | 275 (17) | 121 (44) | 154 (56) | 0.3 (0.1–0.8) |
Stevens et al. [39], 2004 | 445 | 61 (14) | 42 (69) | 19 (31) | 0.8 (0.2–2.3) |
Subramaniam et al. [40], 2005 | 526 | 113 (22) | 49 (43) | 64 (57) | 0.2 (0.01–1.3) |
Bernardi et al. [11], 2008 | 1053 | 278 (26) | 213 (76) | 65 (24) | 1.2 (0.5–2.2) |
Sevestre et al. [41], 2009 | 3871 | 1023 (26) | 454 (44) | 569 (56) | 0.6 (0.3–1.2) |
Sevestre et al. [42], 2010 | 1926 | 395 (21) | 155 (39) | 240 (61) | 0.6 (0.1–1.7) |
Pooled estimate | 10,090 | 2349 (23) | 1146 (49) | 1203 (51) | 0.6 (0.3–0.9) |
Detailed Comparison and Respective Limitations of Ultrasound Strategies for Suspected DVT
The sensitivity and specificity of CUS for proximal DVT are high (97 and 98%, respectively) [43], and the necessity of treating proximal DVT by anticoagulants is widely accepted [44]. On the other hand, the sensitivity and specificity of CUS for distal DVT are lower [15, 43]. A meta-analysis by Kearon et al. reported sensitivity of 50–75% and specificity of 90–95% [43]. Even if another more recent meta-analysis published in 2005 suggested similar values for ultrasound accuracy for calf thrombosis [45], one must take into account that some studies in the hands of highly skilled ultrasonographers using the best ultrasound machines reported much higher values of sensitivity and specificity at the calf level [37]. The improvement in ultrasound technology and increased experience in the field have led to a quite reliable diagnosis of distal DVT in experienced hands when the most reliable diagnostic criterion is used, i.e., the lack of compressibility of a venous segment. However, despite such technologic improvements, some other limitations are still present at the calf level. For example, the rate of inconclusive diagnostic tests has been reported to be as high as 50% in some series (Table 24.4) [46–49]. This rate might not be true for outpatients in whom calf examination is usually easier but seems to reflect the reality of inpatients, especially after orthopedic surgery or in the intensive care unit setting.
Table 24.4
Rate of indeterminate calf ultrasound examinations
First author | Study type | Frequency of indeterminate examinations %, (n/n) |
|---|---|---|
Rose et al. [46], 1990 | Prospective | 42% (21/50) |
Simons et al. [47], 1995 | Prospective | 29% (16/56) |
Atri et al. [48], 1996 | Prospective | 9.3% (10/108) |
Gottlieb et al. [49], 1999 | Retrospective | 82.7% (8206/249) |
Pooled total | 54.6% (253/453) |
Serial Proximal CUS in Outcome Studies
The limited performances of distal venous examination reported in some studies may explain why many centers use only proximal CUS, i.e., limited to the popliteal and supra-popliteal veins. Since such protocols do not search for distal DVT (that if present could potentially extend to the proximal veins with a significant risk of PE), the standard diagnostic approach consists of performing a second CUS limited to the proximal veins at day 7, the so-called serial proximal CUS strategy. Patients with a proximal DVT on the initial CUS are treated with anticoagulants. When the initial examination is negative, patients are not given anticoagulants, and a second proximal CUS is repeated 1 week later to detect the possible extension of distal DVT. Patients with a second normal CUS are considered as definitely not having a DVT and are not anticoagulated.
Many prospective well-designed outcome studies have shown the safety of proximal CUS integrated in diagnostic strategies (Table 24.1). The six studies used CUS limited to proximal veins [10, 22–26]. Five of these studies used the classic serial proximal CUS, and one used a single proximal CUS included in a strategy associating pretest clinical probability and D-dimer measurement [25].
The pooled estimate of the 3-month thromboembolic risk of these prospective management studies using CUS limited to proximal veins was 0.6% (95% CI, 0.4–0.9%). There was no significant difference in the 3-month thromboembolic risk between these six studies. If one considers each study individually, the 3-month thromboembolic risk in patients with a negative proximal CUS was low: it was lower than 1% in the studies using serial proximal CUS [10, 22–24, 26] (CUS repeated after 1 week in patients with an initially negative CUS) and 2.6% (95% CI, 0.2–4.9%) in the one study that used clinical probability, D-dimer, and a single proximal CUS (Table 24.1) [25]. This compares favorably with the 3-month thromboembolic risk in patients with clinically suspected DVT left untreated after a negative venogram (the gold standard), which was found to be 1.9% (95% CI, 0.4–5.4%) [50].
Even if serial proximal CUS is very safe, its main limitation is the need for a second ultrasound examination , which is cumbersome and costly and has a very low yield as it reveals a proximal DVT in only 1–5.7% of patients (Table 24.1).
Single Complete (Proximal and Distal) CUS in Outcome Studies
Seven prospective outcome studies using a single complete (i.e., proximal and distal) CUS have been published (Table 24.3) [11, 37–42]. Patients were treated if CUS showed a proximal or distal DVT and were left untreated if proximal and distal veins were normal, without any further testing. These studies showed that extending the ultrasonographic examination to distal veins without repeating the CUS at 1 week is very safe. Indeed, the pooled estimate of the 3-month thromboembolic risk performed in a systematic review and meta-analysis is 0.6% (95% CI, 0.3–0.9%) [9].
However, despite their diagnostic safety , these studies point to some important problems. First, such an approach is costly and time-consuming as complete CUS is proposed to all patients with suspected DVT. Indeed, in outpatients with clinically suspected DVT, a normal enzyme-linked immunosorbent assay (ELISA) D-dimer test allows to withhold anticoagulation without further testing in about one third of outpatients at a much lesser expense and with a similar safety [25]. Second, the pooled estimate of the 3-month thromboembolic risk of these studies is similar to that computed for studies using a strategy including proximal CUS only (Tables 24.1 and 24.3). This means that detecting calf DVT may actually be deleterious: it does not reduce the 3-month thromboembolic risk, and it entails a risk of unnecessary anticoagulant treatment in patients who would have fared well without anticoagulant treatment. Moreover, because of the limitations in the diagnostic performance of CUS at the calf level, some of the positive findings might even be false positives, rendering the potentially unnecessary exposure to bleeding risk associated with anticoagulation even more unacceptable. To give an idea of the potential extent of this issue , a pooled analysis of the studies performing complete CUS shows that among a total of 10,090 included patients, 1203/2343 (51%) of diagnosed DVT were distal DVT (Table 24.3). This signifies that in half of patients with suspected DVT undergoing complete CUS with a final positive diagnosis of DVT , there is no clear benefit for diagnosing the (distal) DVT.
Serial Proximal vs Single Complete CUS in Suspected DVT
The next logical step was obviously to perform a direct comparison between serial proximal CUS and single complete CUS diagnostic strategies for DVT. This was performed in three studies, with very similar results [11, 12, 51]. Therefore, only the most robust study in terms of methodology will be discussed here [11].
In this prospective randomized multicenter trial, a strategy including serial two-point (femoral and popliteal) proximal CUS associated with D-dimer testing was compared to a single whole-leg CUS strategy in more than 2000 outpatients with a clinical suspicion of DVT (Table 24.5) [11]. In the proximal CUS arm, patients with a normal two-point CUS underwent qualitative D-dimer testing (SimpliRED®, Agen Biomedical, Australia). Patient with negative D-dimer were spared further investigations and not treated with anticoagulants. Only patients with abnormal D-dimer levels underwent the repeat CUS at 1 week. Both strategies reported similar 3-month rate of VTE: 0.9% (95% CI, 0.3–1.8%) for the two-point proximal CUS and D-dimer arm vs 1.2% (95% CI, 0.5–2.2%) for the complete single CUS arm. The safety of both strategies was therefore similar. It should be noted that 23% (65/278) of patients with confirmed DVT in the complete CUS arm were treated with an anticoagulant for a distal DVT , without decreasing the 3-month thromboembolic risk. Authors thus concluded that detecting isolated distal DVT might not be as relevant as previously believed and that the search for distal DVT might even expose patients to the harm of unnecessary anticoagulant treatment. The advantages and disadvantages of using serial proximal CUS vs a single complete CUS are summarized in Table 24.6.
Table 24.5
Main results of the randomized trial comparing serial proximal CUS with a single complete CUS in patients with suspected DVT [11]
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